text
stringlengths 1.9k
1.3M
| url
stringlengths 24
511
|
|---|---|
2014 Farm Bill Provisions and WTOÂ Compliance
Contents
Introduction
WTO Rules Governing Domestic Support
AoA: Rules and Limits on Domestic Support
SCM: International Market Distortions and Adverse Effects
Changes to Farm Support in the 2014 Farm Bill
Federal Budget "Cost" vs. International Trade Distortion "AMS"
CBO Scores Budget Savings for the 2014 Farm Bill
Evaluating U.S. Farm Programs by WTO Rules
Green Box: Decoupled Income Support
Blue Box: Partially Decoupled or Production-Limiting Programs
Amber Box: Market-Distorting Agricultural Support Programs
Price Deficiency Payment Programs
Shallow-Loss Support Programs
U.S. Crop Insurance
Sugar and Dairy Programs
Permanent Disaster Assistance Programs
Non-Product-Specific DM Exemptions
Product-Specific DM Exemptions
Doha Round Implications
Recap of Potential WTO Issues
Figures
Figure 1. Total U.S. Amber Box Outlays Including De Minimis (DM) Exclusions
Figure 2. Ratio of Price Triggers: 2014 Farm Bill vs. 2008 Farm Bill
Figure 3. Reference Prices Are Near or Well Above Average Farm Prices
Tables
Table 1. Current Farm Safety Net Programs, 2014-2018
Table 2. 2014 Farm Bill: Major Safety Net Programs and Key Parameters
Table 3. 2014 Farm Bill Provisions: WTO Compliance Implications
Summary
The enacted 2014 farm bill (Agricultural Act of 2014;
P.L. 113-79
) could result in potential compliance issues for U.S. farm policy with the rules and spending limits for domestic support programs that the United States agreed to as part of the World Trade Organization's (WTO's) Uruguay Round Agreement on Agriculture (AoA). In general, the act's new farm safety net shifts support away from classification under the WTO's green/amber boxes and toward the blue/amber boxes, indicating a potentially more market-distorting U.S. farm policy regime.
The 2014 farm bill eliminates many of the support programs of the 2008 farm bill (
P.L. 110-246
) and replaces them with several new "shallow-loss" programs, addressing relatively small shortfalls in farm revenue—Agricultural Risk Coverage (ARC), Supplemental Coverage Option (SCO), and Stacked Income Protection Plan (STAX)—as well as a revamped counter-cyclical price support program, Price Loss Coverage (PLC), that relies on elevated support prices. Among the safety net programs, only the marketing loan program and the U.S. sugar program were extended unchanged. The sugar program will continue to count for $1.4 billion against the current U.S. limit of $19.1 billion for non-exempt, trade-distorting amber box outlays.
The most notable safety net change is the elimination of the $5-billion-per-year direct payment (DP) program, which was decoupled from producer planting decisions and was notified as a minimally trade-distorting green box outlay. DPs are replaced by programs that are partially coupled (PLC and ARC) or fully coupled (SCO and STAX), meaning that they could potentially have a significant impact on producer planting decisions, depending on market conditions. Fully and partially coupled farm programs influence planting decisions, both by increasing the overall profitability of farming (as low-price signals are muted) and by changing the relative returns to planting alternative crops. Increased profitability tends to increase total planted acreage and output, while changes in relative returns influence the share of acreage planted to each crop, with consequences that could spill over into international markets.
Many of the new programs authorized by the 2014 farm bill have yet to be fully implemented; thus producer participation is uncertain, while potential distortions have yet to be measured and will likely hinge on future market conditions. For example, under a relatively high market price environment, as existed during the 2010-2013 period, U.S. program outlays would be small and would fall within the $19.1 billion U.S. amber box limit. Most studies suggest that, for U.S. program spending to exceed the $19.1 billion limit, a combination of worst-case events would have to occur—for example, low market prices generating large simultaneous outlays across multiple programs, in addition to the $1.4 billion of implicit costs associated with the sugar program. Such a scenario is unlikely, although not impossible, particularly since outlays under several of the programs (including the new dairy program, SCO, STAX, and crop insurance) are not subject to any per-farm subsidy limit. Perhaps more relevant to U.S. agricultural trade is the concern that, because the United States plays such a prominent role in most international markets for agricultural products, any distortion resulting from U.S. policy would be both visible and vulnerable to challenge under WTO rules. Furthermore, projected outlays under the new 2014 farm bill's shallow-loss and counter-cyclical price support programs may make it difficult for the United States to agree to future reductions in allowable caps on domestic support expenditures and related de minimis exclusions, as envisioned in ongoing WTO multilateral trade negotiations.
2014 Farm Bill Provisions and WTOÂ Compliance
Table of Acronyms
ACRONYMFull TermSourceA&OAdministrative and operating2014 farm billAoAAgreement on AgricultureWTOACREAverage Crop Revenue Election program2008 farm billAMSAggregate measure of supportWTOARCAgricultural Risk Coverage program2014 farm billARC-COCrop-specific, county-based ARC program2014 farm billARC-IDFarm-level ARC program2014 farm billBCAPBiomass Crop Assistance Program2014 farm billCBOCongressional Budget Office2014 farm billCCCCommodity Credit Corporation2014 farm billCCPCounter-cyclical payment program2008 farm billDMDe minimis exemptionWTODMPPDairy Margin Protection Plan2014 farm billDPDirect payment program2014 farm billDPDPDairy Product Donation Program2014 farm billDPPSDairy Price Product Support program2008 farm billELAPEmergency Assistance for Livestock, Honey Bees, and Farm-Raised Fish Program2014 farm billFFPFlexible Feedstock Program2014 farm billGSM-102General Sales Manager-102 export credit guarantee program2014 farm billLIPLivestock Indemnity Program2014 farm billLFPLivestock Forage Disaster Program2014 farm billMILCMilk Income Loss Contract program2008 farm billMLPMarketing Loan Program2014 farm billNAPNoninsured Crop Disaster Assistance program2014 farm billOAOlympic average (excludes the high and low data points from the calculation)2014 farm billPLCPrice Loss Coverage program2014 farm billREAPRural Energy for America Program2014 farm billSAFPSeason-Average Farm Price received by producers2014 farm billSCMAgreement on Subsidies and Countervailing MeasuresWTOSCOSupplemental Coverage Option2014 farm billSTAXStacked Income Protection Plan2014 farm billSURESupplemental Revenue Assurance program2008 farm billTRQTariff rate quotaWTOUSDAU.S. Department of Agriculture2014 farm billWTOWorld Trade OrganizationWTO
Introduction
As a signatory member of the World Trade Organization (WTO),
1
the United States has committed to abide by WTO rules and disciplines, including those that govern domestic farm policy. The WTO's general rules concerning subsidy disciplines, trade behavior, and market access concessions apply to all members. In addition, each individual member country also negotiated its own specific policy commitments—spelled out in a document called a Schedule of Concessions (or Country Schedule).
2
Trade plays a critical role in the U.S. agricultural sector. USDA estimates that exports account for about 20% of total U.S. agricultural production.
3
Because the United States plays such an important role in so many agricultural markets, its farm policy is often subject to intense scrutiny, both for compliance with current WTO rules and for its potential to diminish the breadth or impede the success of future multilateral negotiations—in part because a farm bill locks in U.S. policy behavior for an extended period of time, during which the United States would be unable to accept any new restrictions on its domestic support programs.
Current U.S. farm policy is authorized by the 2014 farm bill (the Agricultural Act of 2014;
P.L. 113-79
) for the 2014-2018 crop years.
4
The 2014 farm bill made significant changes to U.S. farm price and income support programs. These changes could have important implications for U.S. commitments to the WTO in terms of compliance with current spending limits and with rules on mitigating program spillover effects and distortions in international markets.
This report assumes knowledge of the U.S. farm safety net programs and their function. It briefly describes the relevant WTO rules governing domestic support programs under the Agreement on Agriculture (AoA) and the Agreement on Subsidies and Countervailing Measures (SCM). The report then reviews the current U.S. farm safety net programs,
5
including changes made under the 2014 farm bill, particularly to Title I price and income support programs, in light of their potential for compliance with the AoA and SCM and their potential to affect the success of the current Doha Round of multilateral trade negotiations.
6
Table 1
provides a list of current farm safety net programs.
Table 2
lists key parameters of the farm support programs referenced in this report.
Table 3
, at the end of the report, briefly reviews each of the individual 2014 farm bill provisions that are relevant to WTO commitments, including a description of their function, average outlays, any changes made under the 2014 farm bill, WTO status, and related potential WTO effects.
Table 1. Current Farm Safety Net Programs, 2014-2018
Price Deficiency Payment Programs Marketing Loan Program (MLP) and associated benefits Price Loss Coverage (PLC)Shallow-Loss Support Programs Agricultural Risk Coverage, County-Level (ARC-CO) Agricultural Risk Coverage, Farm or Individual-Level (ARC-ID) Supplemental Coverage Option (SCO) Stacked Income Protection Plan (STAX) for upland cottonCrop Insurance Premium subsidy for catastrophic (CAT) yield policies Premium subsidy on additional ("buy-up") yield and revenue insurance policies Risk Sharing with private crop insurance companies under the Standard Reinsurance Agreement (SRA) Delivery, administrative, and operating reimbursements to private crop insurance companiesDairy Support Programs Dairy Margin Protection Program (DMPP) Dairy Product Donation Program (DPDP) Tariff Rate Quota (TRQ) protection Dairy Price Support Program under permanent law (temporarily suspended)Sugar Support Programs Marketing Loan for raw sugar from sugar cane and refined sugar from sugar beets Tariff Rate Quota (TRQ) protection Marketing Allotments Feedstock Flexibility Program (FFP)Disaster Assistance Programs Noninsured Crop Disaster Assistance Program (NAP) Livestock Indemnity Program (LIP) Livestock Forage Disaster Program (LFP) Emergency Assistance for Livestock, Honey Bees, and Farm-Raised Fish Program (ELAP) Tree Assistance Program (TAP) Emergency Disaster loansSpecial Cotton Support Programs Temporary Upland Cotton Transition Payments Special program provisions for Upland Cotton—import quotas Special competitiveness program for extra-long staple (ELS) Cotton Economic Adjustment Assistance to Users of Upland Cotton Cotton Storage Payments
Source:Compiled by CRS.
WTO Rules Governing Domestic Support
A domestic farm support program can violate WTO commitments in two principal ways—first, by exceeding amber box spending limits (see box below), and second, by generating market distortions that spill over into the international marketplace and cause significant or measurable adverse effects. For such a violation to be meaningful, another WTO member country must successfully challenge the violation under the WTO dispute settlement process.
7
AoA: Rules and Limits on Domestic Support
The Agreement on Agriculture (AoA) spells out the rules for countries to determine whether their policies for any given year are potentially trade-distorting, calculate the costs of any distortion, and report those costs to the WTO in a public and transparent manner.
8
WTO Classification of Domestic Support ProgramsThe WTO's AoA categorizes and restricts agricultural domestic support programs according to their potential to distort commercial markets. Whenever a program payment influences a producer's behavior, it has the potential to distort markets (i.e., to alter the supply and market price of a commodity) from the equilibrium that would otherwise exist in the absence of the program's influence. Those outlays that have the greatest potential to distort agricultural markets—referred to as amber box subsidies—are subject to spending limits. In contrast, more benign outlays, which cause less market distortion, are exempted from spending limits. The WTO uses a traffic light analogy to group programs. Green b ox programs are minimally or non-trade distorting and are not subject to any spending limits. Blue b ox programs are described as market-distorting but production-limiting. Payments are based on either a fixed area or yield, or a fixed number of livestock, and are made on 85% or less of historical (i.e., base) production. As such, blue box programs are not subject to any payment limits. Amber box programs, the most market-distorting programs, are cumulatively measured by the aggregate measure of support (AMS). Certain amber box outlays may be excluded under the de minimis exemptions (see below). Non-exempted amber box outlays are subject to an annual aggregate spending limit. Prohibited (i.e., r ed b ox ) programs include certain types of export and import subsidies and non-tariff trade barriers that are not explicitly included in a country's WTO schedule or identified in the WTO legal texts. De minimis (DM) exemptions apply to spending that is sufficiently small—relative to either the value of a specific product or total production—to be deemed benign. DM exemptions are limited to 5% of the value of production (either total or product-specific).
The United States is committed, under the AoA, to spend no more than $19.1 billion annually on amber box programs, subject to DM exemptions. Since 1995, when the AoA rules first came into effect and member countries began notifying their outlays on domestic support, the United States has stayed within its amber box limits (
Figure 1
). However, U.S. compliance has hinged on judicious use of the DM exemptions in a number of years (e.g., 1999-2001 and 2005). This has included the notification of crop insurance premium subsidies during the 1995 to 2011 period as non-product-specific support (see the red bars for 1995-2011 in
Figure 1
), which then allowed for these outlays to be exempted under the DM exclusion for non-product-specific spending, as described later in this report.
In its most recent notification (2012), the United States changed its notification status for crop insurance premium subsidies to product-specific support.
9
A total of $11.8 billion in amber box outlays were notified as "product-specific" in 2012, including $7.0 billion of crop insurance subsidies. However, $5.0-billion product-specific amber box outlays were excluded under the DM product-specific exemption (see the yellow bar for 2012 in
Figure 1
), thus reducing U.S. amber box outlays subject to a spending limit to $6.864 billion.
Figure 1. Total U.S. Amber Box Outlays Including De Minimis (DM) ExclusionsSource:WTO, annual notifications of the United States through 2012, the most recent year of notification.Notes:See the text box above for a description of amber box, the spending limit, and the DMexclusions.
SCM: International Market Distortions and Adverse Effects
In addition to potentially exceeding payment limits, a market-distorting program may be challenged under Articles 5(c) and 6.3 of the Agreement on Subsidies and Countervailing Measures (SCM) when the program's effect spills over into international markets—that is, if it can be established that a subsidy causes adverse market effects.
10
The importance of SCM rules has been made salient by the so-called "Brazil cotton case," in which a WTO dispute settlement panel ruled against both the U.S. cotton price and income support programs and the GSM-102
11
export credit guarantee program.
12
As a result of the ruling and the potential for WTO-sanctioned retaliation, the United States made substantial policy changes in the past two farm bills to bring the related programs into WTO compliance. Because the United States is a major producer, consumer, exporter, and/or importer of many agricultural commodities, the SCM is relevant for most major U.S. agricultural products. If a particular U.S. farm program is deemed to result in a market distortion that adversely affects other WTO members—even if it is within agreed-upon AoA spending limits—then that program may be subject to challenge under the WTO dispute settlement procedures (see box below).
SCM Rules on Adverse Effects in International MarketsBased on precedent from past WTO decisions, several criteria are important under SCM rules in establishing whether a subsidy for a particular commodity results in significant market distortions with resultant adverse effects. First, the subsidy must meet the following criteria: the subsidy constitutes a substantial share of farmer returns or of production costs for a commodity; the subsidized commodity is important to world markets (i.e., it represents a significant global share in terms of either production or trade); and a causal relationship exists between the subsidy and adverse effects in the relevant commodity market.Second, the "market distortion" of a program or policy must have measurable market effects on the international trade and/or market price of the affected commodity, as measured by any of the following criteria: the subsidy displaces or impedes the import of a like product into the domestic market; the subsidy displaces or impedes the export of a like product by another WTO member country; the subsidy (via overproduction and resultant export of the surplus or displacement of previous imports) results in significant price suppression, price undercutting, or lost sales in the international market; or the subsidy results in an increase in the world market share of the subsidizing member.
For any farm program that is challenged under the SCM, a WTO dispute settlement panel reviews the relevant trade and market data and makes a determination of whether the program resulted in a significant market distortion
.
Following these guidelines, a subsidy may be found to be actionable or prohibited. WTO
actionable subsidies
(i.e., policies that incentivize overproduction and result in lower market prices or altered trade patterns) must be withdrawn or altered to minimize or eliminate the subsidy's distorting aspect. WTO
prohibited subsidies
(i.e., certain export- and import-substitution subsidies not included in a member's country schedule) must be stopped or withdrawn "without delay," in accordance with an abbreviated timetable announced by the WTO ruling panel. If the violating policies are not withdrawn or altered according to the timetable, then the WTO member bringing the challenge may take appropriate countermeasures.
Perhaps the most easily recognized distortion occurs when a program offers price support or income payments based on (i.e., coupled to) the current level of farm activity—either area planted or volume of output. Such an incentive can encourage greater production or output than the market is prepared to absorb and, as a result, tends to lower market prices. Given the United States' prominent role in international agricultural markets, such potential market distortions, should they emerge, can be quickly transmitted from domestic to global markets.
Since most governing provisions for U.S. farm programs are statutory, new legislation may be required to implement even minor changes to achieve compliance in the event that a WTO challenge successfully finds a program in violation of a WTO rule.
13
So, a key question that policymakers ask of virtually every existing farm program, as well as of new farm proposals, is how it will affect U.S. commitments under the AoA and U.S. compliance with SCM rules. The answer rests not only on cost, but also on each program's design, implementation, and subsequent market effects.
Changes to Farm Support in the 2014 Farm Bill
The Agricultural Act of 2014 reshaped the structure of U.S. commodity support, otherwise known as the farm "safety net." In general, the new suite of farm support programs shifts support away from the green/amber boxes and toward the blue/amber boxes, thus indicating greater potential for market distortion. In particular, the 2014 farm bill:
14
terminated several of the core "farm safety net" programs from the previous 2008 farm bill, including direct payments (DP), the counter-cyclical payment (CCP) program, and the Average Crop Revenue Election (ACRE) and Supplemental Revenue Assurance (SURE) programs;
retained the traditional marketing loan program (MLP)—which triggers payments when market prices drop below support levels (referred to as loan rates)—but with a single adjustment to the loan rate for upland cotton (which is now allowed to float within a formula-determined range of 45¢/lb to 52¢/lb as compared with the previous fixed value of 52¢/lb);
replaced CCP with a similar counter-cyclical payment program called Price Loss Coverage (PLC) using substantially higher reference support prices; 15
added several new shallow-loss programs, including Agricultural Risk Coverage (to replace ACRE) with county-level (ARC-CO) and farm-level (ARC-ID) 16 options, a Supplemental Coverage Option (SCO), and Stacked Income Protection (STAX); and
repealed the previous dairy product price support (DPPS) and Milk Income Loss Contract (MILC) programs and replaced them with a new Dairy Margin Protection Program (DMPP) and Dairy Product Donation Program (DPDP).
Federal Budget "Cost" vs. International Trade Distortion "AMS"
Evaluating the merits of a domestic support program depends on one's perspective. This is because costs to the federal budget usually do not equal costs (or distortions) in the international marketplace. For the federal budget, changes to a farm program are officially evaluated by the Congressional Budget Office (CBO), which produces a "score" of a proposed program change against a baseline of current farm law. The score measures the net change in federal budget outlays from current policy—increases in outlays are viewed as costs; decreases in outlays are viewed as savings. Much of the "savings" associated with the elimination of the 2008 farm bill programs was used to offset the costs of adding new safety net programs.
In contrast, a foreign producer or exporter may have a different perspective and instead may see U.S. farm programs as providing an unfair advantage to U.S. products in international markets. In this context, domestic support programs for agriculture may be evaluated according to the WTO's rules for determining which programs are most likely to distort production and trade and for calculating their annual cost as measured by the AMS.
These different approaches to tabulating costs (CBO versus WTO) may result in different evaluation outcomes for the same program change. For example, direct payments (DPs) of the 2008 farm bill (
P.L. 110-246
) had a federal budget cost of about $5 billion annually, but from a WTO perspective they were fully decoupled
17
and mostly non-market-distorting, and thus did not count toward the U.S. amber box total.
18
Replacing DPs with a "shallow-loss" program coupled to market prices and current yields, with projected annual outlays of $3 billion, would represent a saving of $2 billion from CBO's perspective but would represent an increase of $3 billion in market-distorting amber box from the WTO's perspective. Similarly, the U.S. sugar program is required by statute to operate at "no net cost" to taxpayers,
19
thus resulting in a budget score of zero. However, the implicit price subsidy inherent in the tariff rate quota (TRQ)
20
protection provided to U.S. sugar producers is valued at about $1.4 billion annually by the WTO.
CBO Scores Budget Savings for the 2014 Farm Bill
According to the January 2014 "score" by the CBO, the 2014 farm bill will reduce the federal budget deficit by $16.6 billion over 10 years, compared with the cost of then-current law. While important for U.S. budget purposes, this provides little guidance with respect to farm program compliance with WTO rules, as those budget scores were based on what are now generally perceived as "outdated" price projections.
21
The possibility that farm program costs might be much larger than originally anticipated is due to record corn and soybean harvests in 2014, which sent farm prices plummeting. According to USDA, the 2014/15 season average farm prices for corn and soybeans have declined 46% and 30%, respectively, from 2012/13's record highs, which prevailed during much of the 2014 farm bill debate and which provided the basis for many of the program parameters in the new farm safety net.
22
Table 2. 2014 Farm Bill: Major Safety Net Programs and Key Parameters
ProgramBasis for Program PaymentRequired LossSubsidyYieldAcresPrice Trigger aLimit bPrice Deficiency Payment ProgramsMarketing-Loan Program (MLP)FarmPlantedFixed$125,000None needed100%Price Loss Coverage (PLC)Base c85% * Base dFixed$125,000None needed100%Shallow-Loss ProgramsAgriculture Risk Coverage-County (ARC-CO) eCounty, 5-yr. OA f85% * BaseSAFP, g5-yr. OA$125,00014%-24% of county avg.100%Agriculture Risk Coverage-Individual (ARC-ID) hBase65% * BaseSAFP, 5-yr. OA$125,00014%-24% of farm avg.100%Stacked Income Protection Plan (STAX)CountyPlantedWithin-year market-basedNone10%-(D or 30%) iof county avg.80% of premiumSupplemental Coverage Option (SCO)CountyPlanted jWithin-year market-basedNone14%-D of county avg.65% of premiumDeep-Loss ProgramFederally subsidized Crop InsuranceFarm or CountyPlantedWithin-year market-basedNoneVaries from 10% to 50% k~62% lof premiumHybrid Program mDairy Margin Protection Program (DMPP)Base n(25% to 90%) * BaseMargin oNoneNone neededIndeter-minate pProgram Support Based on Supply ControlsSugar ProgramIndirect support based on import restrictions, marketing allotments, and price supports for refined beet sugar and raw cane sugar. There is no payment limit.
Source:Compiled by CRS.
a.All price triggers are set at the national level.
b.The $125,000 limit per person applies to combined MLP, PLC, and ARC payments for all commodities except peanuts, which have a separate $125,000 limit across the MLP, PLC, and ARC programs.
c.Base yield is the historical yield of a program crop used to calculate the production that is eligible for payments. Producers were offered a one-time option to update base yields to 90% of the average yield for 2008-2012; otherwise they would retain the program yield used under the 2008 farm bill programs.
d.Base acres are the historical planted acres of program crops used to calculate production eligible for payments. Producers were offered a one-time option to update the allocation of program crops across the farm's total base acres; otherwise they would retain the base allocation used under 2008 farm bill programs.
e.ARC-CO may be applied separately for each program crop.
f.The five-year olympic average (OA) excludes the high and low years from the calculation.
g.The five-year OA of the season-average farm price (SAFP). The 2014 farm bill stipulates that the PLC reference price is used in the ARC guarantee for any year where the SAFP is less than the reference price; thus the reference price acts as a floor price for ARC.
h.The farm-level ARC-ID applies to the aggregate of all program crops.
i.Whichever is smaller, 30% or the underlying insurance policy deductible (D), expressed as a percent of the guarantee.
j.Acres covered by ARC-CO, ARC-ID, or STAX are not eligible for SCO.
k.Crop insurance policy coverage varies across crops and regions. Coverage ranges from 50% up to 85% for farm-based insurance and up to 90% for county-based insurance. The required loss is equal to the policy deductible. For example, a policy with coverage of 75% requires a loss of 25% before an indemnity is made.
l.Crop insurance premium subsidy varies by type of policy and coverage level but averages about 62%.
m.The dairy support programs combine features of (1) a price deficiency payment program that substitutes a producer-selected margin level for a target price, (2) both shallow- and deep-loss programs depending on the producer-selected coverage levels and market conditions, and (3) supply controls, since a system of tariff-rate quotas continues to provide price support for various dairy products.
n.The highest milk marketings of the dairy operation during any one of the three calendar years 2011, 2012, or 2013; special adjustments are available for beginning producers with incomplete production history.
o.The margin equals the all-milk price minus the cost of an average feed ration per 100 lb. of milk.
p.The implicit DMPP subsidy is equal to the difference between an unspecified actuarially fair premium and the fixed premium set in statute for DMPP. This value will vary annually by market conditions as well as by both margin and coverage level selected. In addition, U.S. dairy products receive implicit subsidies from a system of TRQs that provide protection from lower-priced foreign imports and from federal purchases of U.S. dairy products under the Dairy Product Donation Program.
Evaluating U.S. Farm Programs by WTO Rules
Prior to the 2014 farm bill,
23
spending under most price and income support programs was notified as amber box: either product-specific in the case of MLP, ACRE, and the dairy and sugar price support programs, or non-product-specific in the case of the CCP, SURE, and crop insurance programs. The non-product-specific amber box spending was then excluded from counting toward the amber box limit by the DM exemption. An exception to this notification pattern was the direct payment (DP) program, which was notified as fully decoupled green box and thus did not count toward the amber box limit.
It is unclear how USDA will classify several of the new farm programs, such as ARC and PLC, which could potentially be notified as either blue box or non-product-specific amber box outlays in accordance with precedence and their similarity to CCP as partially decoupled programs with payments limited to 85% of historical base. Any assessment of the WTO classification and potential market effect of the new domestic support programs authorized under the 2014 farm bill is very preliminary at this time. Many of the new programs have yet to be fully implemented, and an estimate of spending under their first year (i.e., 2014) will have to wait until late 2015 for the relevant marketing year to end.
24
The programs likely will not be notified by USDA until early 2017, when a more "final" estimate of outlays becomes available. With these caveats in mind, the new programs are discussed in light of their potential market distortions, using previous U.S. notifications as a guide, to better understand how the new U.S. farm commodity support programs of the 2014 farm bill might comply with WTO rules.
25
Green Box: Decoupled Income Support
Green box programs are minimally or non-trade-distorting and are not subject to any spending limits. U.S. green box notifications have grown from $46 billion in 1995 to $127.5 billion in 2012. The United States notifies a broad range of domestic support programs as green-box-compliant, including regulatory and market assistance programs, conservation activities, and domestic food programs. The 2014 farm bill consolidated conservation programs, reauthorized and revised nutrition assistance, and extended authority to appropriate funds for many USDA green box programs through FY2018.
The principal U.S. farm price and income support program included in the green box (under Decoupled Income Support) has been direct payments (DPs), with annual notifications averaging nearly $5 billion from 1996 through 2012. Because DP outlays were both fixed (they did not vary with producer behavior or market conditions) and decoupled (they were based on historical—not current—plantings), they did not influence a producer's current behavior and thus were deemed minimally market-distorting. DPs originated with the 1996 farm bill (
P.L. 104-127
) and were repealed by the 2014 farm bill. Also included in the green box are two subsidy components of the crop insurance program—administrative and operating (A&O) expenses and the underwriting of program losses. For 2012, federal outlays on crop insurance A&O expenses were notified as $1.4 billion, while underwriting costs were $0 (compared with $1.6 billion annually for 2008-2011).
26
The 2014 farm bill added an option for expanded coverage up to 65% under the Noninsured Crop Disaster Assistance Program (NAP). NAP payments are notified as green box since they involve crop losses of at least 50% and are reimbursed at just 55% of the market price. The additional coverage option will not change NAP's green box status. NAP payments also have an annual payment limit of $125,000 per person. None of the current suite of farm price and income support programs and shallow-loss crop insurance programs—MLP, PLC, ARC, SCO, STAX, DMPP, and the sugar program—would qualify for the green box, because they are coupled, partially or fully, to current prices and/or plantings, or receive additional TRQ protection from imports (as is the case for U.S. dairy and sugar producers).
Blue Box: Partially Decoupled or Production-Limiting Programs
Blue box programs are market-distorting but production-limiting. Payments are based on either a fixed area or yield, or a fixed number of livestock, and are made on 85% or less of historical (i.e., base) production. As such, blue box programs are not subject to any payment limits. The United States has not notified any of its farm programs as blue box since 1995.
27
As part of the ongoing Doha Round of trade negotiations,
28
it was generally agreed that the partially decoupled U.S. CCP program would be reclassified from amber box to blue box; however, this reclassification never occurred because the Doha Round of negotiations has not been completed and the CCP program was repealed by the 2014 farm bill. It is not clear if the supposed CCP designation as blue box could be resurrected for PLC and ARC outlays.
As mentioned earlier, the PLC and ARC programs are similar to CCP and ACRE, respectively, in program design. Both PLC and the county-level ARC (ARC-CO) are coupled to market prices but fully decoupled from the producer's planting decision. The farm-level ARC option (ARC-ID) is coupled to both market prices and farm-level yields.
Under PLC, a producer receives a payment on 85% of base acres when the national season average farm price (SAFP) is below a statutorily set reference price for an eligible program crop. The producer need not plant a single acre of the program crop to receive a payment; instead, the producer must have made a one-time permanent declaration of a portion of his or her historical base acres to that program crop at sign up. Similarly, under ARC-CO, a producer does not have to actually plant the crop to receive a payment—any payments are made on 85% of historical base acres, not actual planted acres as in the previous ACRE program. In addition, all ARC-CO program payments are triggered at the county level, not the farm level.
29
Hence payments under both PLC and ARC-CO are fully decoupled from planted acreage and farm-level yield, but not from market prices.
30
However, it remains to be seen how such program payments will be notified by the United States.
31
Since the blue box has no spending limit, there would be plenty of room for potential PLC and ARC payments were they to be notified as such. But such a notification would likely draw international rebuke (if not outright challenge) for its regressive nature—backtracking from a general commitment to gradually reform domestic policy in such a way as to reduce distortion-causing domestic support.
Area Considerations vis-a-vis WTO Measures of Market DistortionFor the price-related distortions (discussed more in the next box) to occur, farms have to be able to shift acres to the crops favored by relatively higher support prices. The 2014 farm bill makes PLC and ARC payments on historical base acres, thus reducing the incentive to shift current plantings toward a crop receiving deficiency payments. Exceptions to this are (1) the annual flexibility inherent in a producer's crop choice for generic base and (2) individual crop selection under the ARC-ID program. Additionally, the potential for base updating in the next farm bill incentivizes shifting acres to the crop with a relative support price advantage.Prior to the 2014 farm bill, actual plantings had diverged significantly from base acres for most program crops (see figure). When base acres diverge significantly from planted acres, producers have more incentive to shift acres back toward their base in response to weak market prices and favorable government support prices.Major Program Crops, Million Acres of Base Versus Planted, 2012Source:Adopted from C. Zulauf, N. Paulson, J. Coppess, and G. Schnitkey, "2014 Farm Bill Decisions: Base Acre Reallocation Option," farmdoc daily(4):138, Department of Agriculture and Consumer Economics, University of Illinois, July 24, 2014.The 2014 farm bill gives producers a one-time option of reallocating their base across program crops or retaining their previous historical base allocation of program crops. By allowing all farms to update their base acres to the average acres planted in a recent time period, the program becomes more reflective of current producer behavior and market conditions, thus better matching a farm's current risk setting. Many producer groups had argued for using planted acres, since a farm's risk is tied directly to its planting decisions, and thus making payments on planted acres enhances a program's risk management effectiveness. 32However, recoupling program payments to planted acres also has the potential to distort resource allocations as producers shift their plantings to crops with the highest reference price relative to the current market price. The base and yield updating provisions are also a form of recoupling, since payments are once again coupled to an updated base reflective of current decision-making.
Price Considerations for Market DistortionMarket prices are a key determinant of the use of resources. 33Thus the relationship between market prices and reference prices is essential in understanding how a program may distort producer behavior. 34Farm programs have their strongest potential to affect market outcomes when market prices are near or below support prices. This is because when the national season average farm price (SAFP) for a program crop falls below its support price, it will trigger deficiency payments for participating producers. In this situation, planting incentives can be distorted: a producer would be inclined to prefer planting those commodities with the highest reference price relative to the current market price. The potential distortion is likely amplified when the relatively high reference price floors of PLC and ARC are combined with the expectation of base/yield updating for each new farm bill. A producer will want to maximize his planting of base acres to program crops with the highest relative price support.If producers make planting decisions based on statutory prices rather than market prices, then the support programs are affecting producer behavior, the production outcome, and the market supply and demand balance. Fixed target or reference prices have the greatest potential to create outcomes that differ from the market because they fail to reflect changes in market conditions. The WTO panel hearing on the Brazil-U.S. cotton case was very clear in its pronouncement that price and income support programs should be responsive to market conditions and should minimize influencing producer behavior in order to avoid noncompliance with WTO trade rules. 35PLC and ARC Price GuaranteeSince both PLC and ARC rely on statutorily fixed reference prices to establish a support price floor (ARC-CO uses a moving-average price formula but substitutes in the reference price for those data years where the market price is less than the reference price), both programs could—during extended periods of low prices—distort planting incentives, depress market prices, and generate large payments. For example, based on market conditions as of May 2014, USDA estimates combined PLC and ARC outlays at $10.1 billion in crop year 2015 and $10.9 billion in 2016. 36SCO, STAX, and Crop Insurance Price GuaranteesSCO, STAX, and crop insurance link their price guarantee to current market conditions—but within-year prices, not across-year prices as used by ARC—since they all use the pre-planting-time average of harvest-time futures contracts as the expected price component in their price or revenue guarantee. Futures contract prices are closely linked to current and expected market conditions. In addition, SCO and STAX payments are based on county revenue triggers that limit moral hazard (i.e., risky behavior to increase probability of a payment). Thus, SCO, STAX, and crop insurance avoid the potential distortion associated with using a statutorily fixed price trigger.
Amber Box: Market-Distorting Agricultural Support Programs
Amber box programs, the most market-distorting programs, are cumulatively measured by the aggregate measure of support (AMS). Certain outlays may be excluded from the amber box under the DM exemptions. Non-exempted amber box outlays are subject to an annual aggregate spending limit.
U.S. amber box outlays, as notified through 2011, have included product-specific payments made under the sugar program, DPPS, MILC, MLP, ACRE, and commodity loan interest subsidies, and non-product-specific payments made under CCP, SURE, crop insurance, farm storage facility loans, irrigation and grazing subsidies, the Biomass Crop Assistance Program (BCAP), and the Renewable Energy for America Program (REAP).
37
However, in its 2012 notification, the United States reclassified federal crop insurance premium subsidies as product-specific support. The distinction between product-specific and non-product-specific outlays is important, because non-exempted amber box outlays count directly against the amber box spending limit.
Price-deficiency and shallow-loss programs—which account for most non-exempted U.S. amber box spending—are counter-cyclical in nature, meaning that their outlays tend to be highest during periods when commodity prices are below support levels and lowest during high-commodity-price years. As a result, the extended period of high market prices from 2006 through 2013 has contributed to relatively low non-exempt U.S. amber box notifications in recent years (
Figure 1
). In contrast, crop insurance premium subsidies are positively correlated with market prices as evidenced by the larger DM exemptions during the 2008-2011 period of high commodity prices. Many economists expect that payment outlook to change under the expanded price and income support benefits of the 2014 farm bill, coupled with an outlook for lower market prices.
38
Price Deficiency Payment Programs
A price deficiency payment program makes a payment when the market price is less than the support price.
39
Support prices can be either statutorily fixed or determined by a formula based on market prices. Current U.S. farm programs include two price deficiency payment programs (
Table 2
)—marketing loan program (MLP) and the new PLC program. Neither program prevents market prices from seeking an equilibrium based on supply and demand conditions, but the program payments do support producer incomes when market prices are below the program price triggers.
Marketing Loan Program (MLP)
The traditional nonrecourse MLP was extended under the 2014 farm bill. Under the MLP, USDA supports prices of eligible crops at statutory loan rates via a nine-month nonrecourse loan program. To avoid selling at the harvest-time low price, a producer may elect to place his/her crop under a USDA marketing loan where the crop is valued at the statutory loan rate. If the market price remains below the loan rate after nine months, the producer may forfeit the crop under loan to USDA. Alternatively, the producer may opt for alternate program benefits that are available whenever the posted county price, or a USDA-announced average world price (AWP) for rice or upland cotton, falls below the respective USDA loan rates. All MLP benefits are based on actual production. As a result, MLP outlays are fully coupled to market prices and planted acres. Like the PLC program, MLP does not require any producer premium or fee to participate, nor does it require any loss to receive a payment. However, it does require actual production, since payments are based directly on output.
MLP operates like a price-deficiency payment. It uses statutorily fixed, commodity-specific loan rates to establish a floor price for all production of all qualifying program crops. When market prices fall below the loan rate, producers are eligible for amber box benefits, including loan deficiency payments and marketing loan gains (which pay the difference between the marketing loan rate and the local posted county price or a USDA-announced average world price in the case of rice and cotton).
The MLP for upland cotton was found by the WTO cotton-case panel to be market-distorting whenever the market price fell below the fixed loan rate. The panel recommended setting the loan rates by formula to capture current market conditions. As a result, the 2014 farm bill included an adjustment to the loan rate for upland cotton—it was lowered from $0.52/lb to a formula-based marketing loan rate that moves within a range of $0.52/lb to $0.45/lb. All other program commodities retain their previous statutorily fixed loan rates.
Price Loss Coverage (PLC)
The PLC program uses statutorily fixed reference prices (for each major program crop) for determining whether any deficiency payments should be made and how much those payments should be. The PLC program does not require any producer premium or fee to participate, nor does it require any loss or actual production to receive a payment.
Reference prices established in the 2014 farm bill were essentially agreed to during the farm bill debate in late 2012 and early 2013, when farm prices for most program crops were at or near record highs. As a result, lawmakers set support prices in the 2014 farm bill at levels well above the CCP trigger price (i.e., target prices adjusted for direct payments) of the 2008 farm bill (
Figure 2
). For example, the new reference price for barley ($4.95/bushel) is 107% above the previous price trigger ($2.39/bushel) under the 2008 farm bill. At that time (late 2012 and early 2013), reference prices appeared to provide support at levels below then-current market conditions, as exhibited by the ratio of reference prices to season-average farm prices (SAFPs) for the 2008-2012 period (
Figure 3
). However, if reference prices are compared to average farm prices for a longer historical period (e.g., 2000-2013), they appear to provide support at levels well above market conditions. For example, the rice PLC reference price of $14.00/cwt represented 95% of the average SAFP of $14.74/cwt during 2008-2012, but 131% of the average SAFP during the 2000-2013 period.
Fixed reference prices ignore market conditions and, when set near or above average market levels, have the potential to distort outcomes—especially during sustained periods of low market prices—by creating incentives to produce more than the market can absorb without additional price declines. Thus, the new, higher reference prices leave the United States vulnerable to sustained high product-specific amber box outlays (if notified as such) during extended periods of low market prices.
Figure 2. Ratio of Price Triggers: 2014 Farm Bill vs. 2008 Farm BillSource:Compiled by CRS from program provisions in the 2008 and 2014 farm bills.
Figure 3. Reference Prices Are Near or Well Above Average Farm PricesSource:Season-Average Farm Prices Received (SAFPs) are from USDA, National Agricultural Statistics Service (NASS). Reference prices are from the 2014 farm bill. Average ratios compiled by CRS.Notes:A ratio greater than 100% occurs when the reference price is greater than the average SAFP.
Shallow-Loss Support Programs
Shallow-loss programs are designed as supplements to current crop insurance programs. In other words, benefits are applied on top of federally subsidized crop insurance and are intended to cover part of the insurance contract's deductible (or so-called shallow loss). According to two prominent economists, "The problem with designing programs that cover the risks that crop insurance does not, is that they have the potential to influence farmer's planting decisions."
40
Three general types of shallow-loss programs are included in the 2014 farm bill: the Agricultural Risk Coverage, Supplemental Coverage Option, and Stacked Income Protection Plan programs.
41
Agricultural Risk Coverage (ARC)
The ARC program is an example of a revenue deficiency payment program—ARC makes a payment when the actual per-acre revenue (i.e., market price x per-acre yield) is less than the revenue target or guarantee. The ARC program has two versions—a county-level, crop-specific program (ARC-CO) and a farm-level, whole-farm-based program (ARC-ID).
42
Like PLC and MLP, the ARC programs do not require any producer premium or fee to participate. In addition, ARC-CO does not require any actual farm-level production or loss to receive a payment, while ARC-ID requires production and a whole-farm revenue loss to occur at the farm level.
In contrast to the PLC program, both ARC programs use a five-year Olympic (excludes the high and low years) moving average of national SAFPs to calculate the revenue guarantee. However, an important provision in the calculation of the price component of the revenue guarantee for ARC is that the PLC reference price is substituted for the SAFP for any year when the SAFP is less than the reference price. As a result, the reference price acts as a floor price in the ARC revenue guarantee. Thus, ARC's moving-average price will only partially follow long-term (i.e., year-to-year) market trends—any downward trend will stop at the reference price. The requirement to use the reference price as a price floor artificially supports the five-year SAFP Olympic average during extended periods of low market prices. Thus, like PLC, ARC can distort planting incentives for program crops and generate large payments during extended periods of low prices.
Supplemental Coverage Option (SCO)
SCO supplements an existing crop insurance policy. SCO is available as either a county-wide yield or revenue loss policy. SCO pays an indemnity on county-level losses not to exceed the deductible percentage of the underlying crop insurance policy.
43
Like all crop insurance programs, a producer must pay a premium to participate in SCO; however, the federal government pays 65% of SCO premiums.
Stacked Income Protection Plan (STAX)
Cotton was dealt with separately from the other major program crops in the 2014 farm bill in an attempt to resolve Brazil's long-standing WTO case against the U.S. cotton program.
44
In lieu of the PLC, ARC, and SCO programs, the 2014 farm bill enacted a new cotton program consisting of a stand-alone, county-based revenue insurance policy called the Stacked Income Protection Plan (STAX). Similar to SCO, STAX sets a revenue guarantee based on expected county revenue (but not revenue
or
yield as under SCO). Producers could purchase this policy in addition to their individual crop insurance policy or as a stand-alone policy.
SCO, STAX, Crop Insurance, and Risk-Market DistortionsWTO Compliance of Insurance ProgramsUnder the WTO Agreement on Agriculture (AoA), for an insurance program to be minimally market-distorting (whereby it would be included in the green box and excluded from counting against amber box spending limits), it must be based on whole-farm revenue, any revenue loss must exceed 30% of average gross income for the preceding three-year period (or the preceding five-year Olympic average), and indemnity payments may not compensate for more than 70% of any loss. By this measure, crop insurance fails to meet the green box criteria and has instead been classified as amber box. The new shallow-loss programs also appear to fail to meet green box criteria and their related federal subsidies will likely be notified as amber box outlays. WTO rules are less clear on when a subsidy is product- or non-product-specific.Shallow-Loss Coverage Close to Market AverageBecause shallow-loss payments are, by definition, made on losses that very nearly approach historical average revenues—potentially guaranteeing up to 86% of the historical average (STAX offers a 90% guarantee)—they have potential to be market-distorting. A primary concern for policymakers is that farmers could use a combination of government farm programs—e.g., PLC or ARC deficiency payments and crop insurance programs—to expand production of crops with high potential returns on marginal lands that otherwise would not be cultivated. 45Federal Subsidies Alter Actuarial Soundness of SCO, STAX, and Crop InsuranceAn actuarially sound premium is priced to cover losses over the long run (i.e., expected indemnities), plus a margin to cover A&O expenses and a portion of insurance company profits. By paying for A&O expenses and a share of the underwriting risk, the federal government alters this equation away from equilibrium and in favor of insurance company profits, thus encouraging insurance companies to sell more crop insurance policies. Federal subsidies of an actuarially fair premium further alter the tradeoff so that farm operators may attain significant risk reduction at relatively low cost, while actually increasing expected (i.e., long-run) returns. As a result, a producer buying federally subsidized crop insurance incurs an incentive to expand plantings of the insured crop.
U.S. Crop Insurance
The federal crop insurance program has grown in importance over the years to become the preeminent farm safety net program. In 2014, federal crop insurance policies covered 294 million acres (about 88% of land planted to principal crops) and were available for over 130 different commodities.
46
For coverage beyond the catastrophic level, producers must pay a premium to participate; however, the federal government pays a substantial share of producer premiums. Subsidy rates range from 38% to 80%, depending on the coverage level and the policy selected, but have averaged about 62% since 2010. Federal crop insurance premium subsidies are notified to the WTO as amber box outlays—from 1995 to 2011 they were notified as non-product-specific amber box outlays, but in 2012 USDA notified them as product-specific outlays. Insurance underwriting costs and A&O expenses are also notified to the WTO but as green box outlays.
Crop insurance premiums are a function of both risk of loss and crop value; as such, both premiums and premium subsidies will fluctuate with participation, size of the insured crop, and market conditions. U.S. federal crop insurance premium subsidies have grown substantially in recent years as coverage has expanded to more acres and crops—rising from a low of $119 million in 1997 to $7.5 billion in 2011, according to official U.S. notifications to the WTO. By 2011, crop insurance subsidies were the largest single farm program cost, accounting for 53% of U.S. amber box outlays. In 2012, federal premium subsidies declined slightly to $7 billion. Insurance underwriting costs have varied over the years in relation to weather-related events (from $2.5 billion in 2008 to $0 in 2012), while A&O expenses have averaged about $1.6 billion annually since 2008.
According to CBO, federal outlays for crop insurance are projected to range between from $8.0 billion in 2015 to $9.0 billion in 2025—including roughly $6 billion in annual premium subsidies, $1.3 billion in delivery support (A&O), and $1.2 billion in underwriting support.
47
Sugar and Dairy Programs
The sugar and dairy programs are perennially two of the largest contributors of amber box outlays notified by the United States. Both programs continue to rely on substantial import restrictions—through WTO-compliant TRQ formulas—to support internal market prices at levels that are generally above international market prices. To date, neither program has been challenged under the WTO dispute settlement process, in large part because the U.S. notification of support for both programs was negotiated as part of the final agreement of the Uruguay Round and subsequently included in the U.S. country schedule.
The U.S. sugar price support program was left unchanged by the 2014 farm bill
48
and is expected to continue to account for approximately $1.4 billion in annual amber box outlays, even though the sugar program is considered a "no net cost" program with respect to federal outlays. In contrast, the U.S. dairy program underwent dramatic changes—the Dairy Product Price Support (DPPS) program, the Milk Income Loss Contract (MILC) program, and the Dairy Export Incentive Program were all eliminated.
Notifications for DPPS averaged $4.2 billion annually during the 1995-2011 period (primarily the result of tariff rate quota protection), making it the single largest component of U.S. product-specific amber box notifications, even though federal outlays averaged only $443 million over the same period.
49
MILC program outlays were much smaller, due to their counter-cyclical design and a strict per-farm cap on payments, averaging about $287 million per year during the 1995-2011 period.
50
Repeal of the DPPS and MILC programs frees up substantial space for new program spending under the $19.1-billion U.S. amber box limit.
The repealed dairy programs are replaced with a new insurance-like margin deficiency payment program—the Dairy Margin Protection Program (DMPP)—that makes payments to participating dairy producers when the national milk margin (calculated as the average farm price of milk minus a formula-based average feed ration) falls below $4.00 per hundredweight (cwt), with coverage at higher margin levels up to $8.00/cwt available for purchase.
51
Under this DMPP program design, payments are coupled to current market prices and recent historical farm-level production (i.e., the maximum annual output during 2011-2013), with no payment limit or cap on potential outlays at either the farm or national level.
Some economists have argued that the proposed margin program fails to follow sound insurance principles: (1) premiums do not reflect the anticipated risk environment in milk and feed markets; and (2) the proposed margin insurance program does not use a rating method to update premiums—instead, premiums are fixed for the life of the farm bill.
52
Another factor in determining WTO compliance and the degree of potential market distortion is the share of the premium paid by the federal government.
53
The lower the statutorily fixed premiums are relative to the expected indemnity (i.e., the less actuarially sound) or the higher the share of the premium paid by the federal government, the greater will be the incentive to increase milk production transmitted to producers by the program.
According to one economic analysis, if milk margins fall to levels that activate indemnity payments, then a weakened feedback process between producers and market price signals could (1) prevent normal market adjustment to milk production, prices, and margins (in other words, producers will not get the necessary market signal to cut back on production) and (2) result in persistent oversupply, lower margins, lower farm incomes, and larger federal expenditures than would have occurred under the previous suite of dairy price and income support programs.
54
The same study found that the program design—the provision that producers may purchase coverage on as much as 90% of their recent historical maximum output; and the $8.00/cwt maximum coverage option, which represents 93% of the national average milk margin during the 15-year period preceding DMPP implementation—could result in annual outlays of as much as $5 billion during low-margin periods, as experienced during 2009 and 2012.
55
However, current market analysis suggests that DMPP payments are unlikely to be triggered, due to strong dairy product prices and weak feed prices.
56
In the initial sign-up for DMPP for 2015, over 50% of U.S. dairy farms elected to participate.
57
Of these, 55% elected to purchase coverage at levels above the $4 minimum margin. Since the first year of coverage, 2015, is still ongoing, final market conditions and program costs (and potential market distortions) are still uncertain.
Permanent Disaster Assistance Programs
The 2014 farm bill permanently authorized three disaster programs for livestock—the Livestock Indemnity Program (LIP), the Livestock Forage Disaster Program (LFP), and the Emergency Assistance for Livestock, Honey Bees, and Farm-Raised Fish Program (ELAP)—and one program for fruit trees, the Tree Assistance Program (TAP).
Payments made under LIP, ELAP, LFP, and TAP are notified as product-specific amber box outlays and count toward the amber box limit, unless they qualify for a product-specific DM exemption. In 2011, a total of $314 million in disaster assistance payments were made to livestock—LFP, $264 million; LIP, $42 million; and ELAP, $8 million—and another $4 million under TAP. All payments under the four disaster programs qualified for a product-specific DM exemption. No payments were notified for these programs in 2012.
Payment Limits Under the 2014 Farm BillPer-operator program payment limits represent a potential tool for limiting or reducing total amber box outlays and concomitantly mitigating potential distortions. The 2014 farm bill set a $125,000 per-person cap on the total payments received for all covered commodities under the PLC, ARC, and MLP programs, with the exception of peanuts, which has its own separate $125,000-per-person limit. This represents a tightening of the per-person limit from the 2008 farm bill, where MLP benefits were unlimited. However, the payment limit is doubled by inclusion of the operator's spouse as co-operator.There is no payment limit for the SCO, STAX, and crop insurance programs. NAP payments have an annual limit of $125,000 per person. The three livestock-related disaster assistance programs—LIP, ELAP, and LFP—have a combined limit of $125,000 per person. TAP has its own separate payment limit of $125,000 per person.To qualify for any program benefits, a recipient's total adjusted gross income (AGI) cannot exceed $900,000 (using a three-year average). The effectiveness of program limits remains in dispute as some have argued that they may be avoided by subdividing a farm operation among family members.
De Minimis (DM) Exemptions
DM exemptions are amber box outlays that, when measured as a share of a defined total output measure (total or product-specific), are sufficiently small (i.e., less than 5%) as to be deemed benign. DM exemptions are identified as either product- or non-product-specific.
Non-Product-Specific DM Exemptions
The non-product-specific exemption is the largest and most favorable in terms of its more generous spending limit—5% of the value of total agricultural output, inclusive of all crops and livestock products. Since 1995, U.S. agricultural production has ranged in total value from $184.7 billion in 1999 to a high of $396.6 billion in 2012. As a result, the U.S. non-product-specific
DM
exemption upper limit has ranged from a low of $9.2 billion in 1999 to a high of $19.8 billion in 2012.
During the first 17 years of U.S. notifications of domestic spending to the WTO (i.e., 1995 to 2011), non-product-specific DM
outlays averaged $4.9 billion, including a high of $9.2 billion in 2011—all well within the DM limit. This category of U.S. program outlays saw considerable growth through 2011, driven largely by growth in U.S. crop insurance premium subsidies, which accounted for $7.5 billion of the $9.2 billion in non-product-specific DM
outlays in 2011. This changed in 2012.
Crop Insurance Reclassification: Non-Product- to Product-Specific Support
Through 2011, U.S. crop insurance premium subsidies were notified as non-product-specific amber box outlays. As a result, despite their large size and importance as a share of domestic support outlays, premium subsidies were routinely exempted from counting against the U.S. amber box limit under the relatively high DM threshold for non-product-specific spending. Furthermore, this notification strategy by the United States has never been challenged despite the fact that individual policies are purchased for coverage of a specific commodity—for example, a corn revenue policy or a soybean yield policy.
In its most recent notification (2012), the United States changed its notification status for crop insurance premium subsidies to product-specific amber support. As such, any product-specific support is first evaluated against 5% of the value of that specific commodity. When a product-specific subsidy is in excess of its 5% product-specific DM exemption threshold, then the entire amount of subsidies for that commodity must be counted against the $19.1 billion amber box limit. As a result, instead of exempting the entire $7 billion in premium subsidies in 2012 under the non-product-specific DM exemption, $5 billion were exempted under product-specific DM exemptions. The remaining $2Â billion in product-specific premium subsidies exceeded the individual product DM thresholds (for wheat, cotton, sorghum, canola, dry beans, dry peas, and flaxseed) and thus counted against the aggregate amber box limit of $19.1 billion.
58
For example, in 2011 the United States was able to exclude $7.5 billion of crop insurance premium subsidies and $1.4 billion of SURE payments from counting against its $19.1 billion amber box limit under the non-product-specific DM exemption. In contrast, in its 2012 notification crop insurance premium subsidies were reclassified as product-specific support. As a result, the United States excluded a much-reduced $0.3 billion of potential amber box outlays under the non-product-specific DM exemption. Non-product-specific DM exemptions are likely to remain insubstantial going forward. In contrast, the product-specific DM exemption rose to $5.0 billion in 2012 after averaging under $0.4 billion annually since 1995.
59
Other Non-Product-Specific Support Is Minimal
Apart from crop insurance premium subsidies, other U.S. farm programs that have been notified as non-product-specific DM
outlays in the past have included CCP payments, irrigation and grazing subsidies, payments under the Supplemental Crop Revenue Assurance (SURE) program, and payments made under two bioenergy programs—the Rural Energy for America Program (REAP) and the Biomass Crop Assistance Program (BCAP).
60
Both the SURE and CCP programs no longer exist, while the REAP and BCAP programs are relatively small in terms of potential outlays.
61
Federal irrigation and grazing subsidies have been small (relative to crop insurance subsidies) and unvarying since 2008, at $200 million and $45 million per year, respectively.
Product-Specific DM Exemptions
Product-specific amber box outlays have included payments made under the following programs: the sugar program, DPPS program, MILC, CCP, MLP, ACRE, SURE, crop insurance subsidies, farm storage facility loans, and commodity loan interest subsidies. U.S. product-specific DM
exemptions averaged $361 million annually during 1995-2011, including a low of $29 million in 1999 and a high of $1.6 billion in 2002. Every program commodity, with the exception of dairy and sugar, has claimed product-specific DM
at some point during the past 17 years. In 2012, with the inclusion of crop insurance premiums, product-specific DM exemptions jumped to $5.0 billion, up from $0.5 billion in 2011.
Doha Round Implications
A consideration for U.S. policymakers is the potential for expanded domestic support programs to sidetrack or delay progress in multilateral trade negotiations.
62
From the U.S. perspective, a successful Doha agreement (under the current negotiating text) would significantly lower allowable spending limits for certain types of U.S. domestic support and eliminate export subsidies, while allowing U.S. agricultural products wider access to foreign markets. Key proposals with respect to new or revised disciplines on farm programs under the 2008 Doha Round texts include two objectives.
63
First, spending limits (total and product-specific) for the amber box and the two DM exemptions would be reduced substantially, while a limit would be established on the otherwise unbounded blue box.
The total limit for U.S. amber box spending would be reduced to $7.6 billion (down from the current $19.1 billion limit), while new product-specific limits would be established at the average annual support received during the 1995-2000 period.
DM exemption limits for non-product-specific outlays would be set at $4.85 billion (as compared to the current variable limit based on total U.S. production, which has averaged $16 to $20 billion), and for product-specific outlays at 2.5% of the average annual production value during the 1995-2000 period, thus establishing a historical base at a level substantially below current production values.
Blue box limits would be established for non-product-specific outlays at $4.85 billion, and for product-specific outlays at 110% or 120% of the annual average during the 2002-2007 period.
Second, a global spending limit—referred to as the overall trade-distorting domestic support (OTDS)—encompassing the four categories of the amber box, the two DM exclusions, and the blue box would be established at a level substantially smaller than the sum of their individual limits. Finally, the criteria for exemption status in the green box would be tightened.
Potential program spending under the new suite of domestic support programs authorized by the 2014 farm bill might exceed the tighter spending limits proposed under the Doha Round draft modalities. For example, the proposed limits for amber box outlays of $7.6 billion are well below USDA's May 2014 projections for PLC and ARC outlays of $10.1 billion in crop year 2015 and $10.9 billion in 2016.
64
Recap of Potential WTO Issues
Assessments of the potential effect of the new domestic support programs authorized by the 2014 farm bill (
P.L. 113-79
), and their compliance with WTO restrictions, are very preliminary at this time. Many of the new programs have yet to be fully implemented, producer participation is uncertain, and program outlays hinge on future market conditions. For example, under a relatively high price environment, as existed during the 2010-2013 period, U.S. program outlays would fall within proposed Doha Round limits with no or only modest changes. However, if market prices were to decline substantially below support levels for an extended period, then outlays could escalate and potentially exceed the proposed spending limits.
All of the new farm safety net programs—PLC, ARC, SCO, STAX, and DMPP—might be notified as amber box, although PLC, ARC, and SCO could be notified as non-product-specific amber box. Alternatively, PLC and ARC-CO might be notified as blue box. USDA is responsible for making this determination.
Of all the price and income support programs, MLP benefits alone are fully coupled to producer behavior, while PLC and ARC are paid on a portion of historical plantings and thus are decoupled from producer planting decisions, making them less vulnerable to WTO challenge. However, because both PLC and ARC would make payments when current market prices are low relative to historical market prices, both programs reduce producer risk associated with price variability and thus likely result in greater acreage and production than would occur in their absence. The new shallow-loss programs—SCO and STAX—could prove more problematic. Both programs provide revenue (or potentially yield in the case of STAX) guarantees that are very near to the market averages, in addition to reducing farm-level risk by protecting revenues when market prices are low. Accordingly, they may incentivize greater acreage and production than would occur in their absence.
Most studies suggest that, for U.S. program spending to exceed the $19.1-billion amber-box limit, a combination of worst-case events would have to occur, for example, low market prices generating large simultaneous outlays across multiple programs, in addition to the $1.4 billion of implicit costs associated with the sugar program. Such a scenario is unlikely, although not impossible, particularly since outlays under several of the programs (including the new dairy program, SCO, STAX, and crop insurance) are not subject to any per-farm subsidy limit.
Perhaps more relevant to U.S. agricultural trade is the concern that—because the United States plays such a prominent role in most international markets for agricultural products—any distortion resulting from U.S. policy would be both visible and vulnerable to challenge under WTO rules. Furthermore, projected outlays under the new 2014 farm bill's shallow-loss and counter-cyclical price support programs may make it difficult for the United States to agree to future reductions in allowable caps on domestic support expenditures and related DM
exclusions as envisioned in ongoing WTO multilateral trade negotiations.
Table 3. 2014 Farm Bill Provisions: WTO Compliance Implications
ProgramFunctionAverage Outlays aStatus Under 2014 Farm BillWTO Status bPotential WTO ImplicationsTitle I Price and Income Support: Programs EliminatedDirect Payments (DP)Fixed annual payments based on historical base acres and yields.Notified annual avg. outlays of $5.3 billion during 1995-2011 (WTO).EliminatedGreen boxFully decoupled payments. Since green box outlays are unlimited, DP elimination has no WTO effect.Counter-Cyclical Payment Program (CCP)Payments triggered when annual national average market price or marketing loan rate, (whichever is higher) fell below a statutorily fixed target price (adjusted for DP); payments based on historical base acres and yields.Notified annual avg. outlays of $2.1 billion during 2003-2008; $79 million during 2009-2011(WTO).EliminatedNon-product-specific amber boxCCP was decoupled from yield and acreage, but not from market prices. Elimination represents potential amber box savings; however, outlays were generally excluded under non-product-specific DM exclusion.Average Crop Revenue Election (ACRE)State-level, crop-specific, revenue-based counter-cyclical program that made payments on 85% of planted acres when state revenue for a commodity is less than 90% of a market-based moving average revenue guarantee. Participants give up 20% of DP, and get a 30% reduction in MLP loan rates.Notified annual avg. outlays of $171 million during 2010-2013(WTO).EliminatedProduct-specific amber boxACRE payments were coupled to planted acres. Elimination represents reduction in amber box outlays.Supplemental Revenue Assistance (SURE)Compensated eligible producers for 60% of whole-farm (i.e., all crops grown by each producer) revenue losses relative to guarantee equal to sum across all crops of both (crop insurance guarantee + 15%) and (Noninsured Crop Disaster Assistance Program [NAP] guarantee + 20%). Crop insurance purchase required for eligibility. Expired at end of FY2011, was not reauthorized.Notified annual avg. outlays of $1 billion during 2008-2011(WTO).Not reauthorizedNon-product-specific amber boxSURE expiration represents potential reduction in amber box outlays; however, outlays were generally excluded under non-product-specific DM exclusion.Dairy Export Incentive Program (DEIP)DEIP provided cash bonuses to U.S. dairy exporters when certain international dairy market conditions were met.DEIP had not been used since 2009 (USDA).EliminatedScheduledDEIP specified in U.S. Country Schedule, thus legal under AoA.Dairy Product Price Support Program (DPPSP)Supported milk, butter, and cheese prices at fluid-milk equivalent cprice of $9.90/cwt via (1) USDA purchases and (2) an import TRQ. The implicit subsidy of the TRQ was measured by the difference between the U.S. domestic price support rate of $9.90/cwt and the international reference price of $7.42/cwt multiplied by the annual U.S. milk production.Notified as $4.6 billion in annual amber box costs during 1995-2007; $2.9 billion annually during 2008-2011, although budget outlays were significantly smaller (WTO).EliminatedProduct-specific amber boxElimination of DPPSP reduces amber box outlays by nearly $3 billion.Milk Income Loss Contract (MILC) ProgramSupported milk producer incomes on first 2.985 million lbs. of annual production when Boston Class I price falls below a feed-adjusted $16.95/cwt.Outlays averaged $182 million annually during 2010-2013; $359 million annually during 2003-2009 (USDA).EliminatedProduct-specific amber boxElimination of MILC represents about $200 million in annual amber box savings, thus freeing up space for new amber box program outlays.Title I Price and Income Support: Programs Continued (with Adjustment)Marketing Loan Program (MLP) BenefitsUSDA supports prices of eligible crops at statutory loan rates via nine-month, nonrecourse loan program. The crop is placed under loan and valued at the loan rate; if the market price rises above the loan rate, the producer reclaims the crop and pays off the loan. If the market price remains below the loan rate after nine months, the producer may forfeit the crop under loan or opt for alternate program benefits. Payments are based on actual production.Notified annual avg. outlays of $2.6 billion during 1995-2011; including annual avg. of $8 billion during 1999-2001 when market prices were historically low (WTO).ReauthorizedProduct-specific amber boxBecause payments are coupled to actual production and market prices, MLP outlays count directly against the amber box spending limit of $19.1 billion.Loan CommoditiesEstablishes eligibility for MLP payments; includes all covered commodities plus upland cotton, extra-long staple cotton, wool, mohair, and honey.— dReauthorized— dNo change.Upland Cotton Market Loan Rate AdjustedUSDA supports upland cotton prices via nine-month, nonrecourse loan program at a loan rate of $0.52/lb. Benefits may be triggered when a USDA-announced average world price (AWP) falls below $0.52/lb.MLP benefits for upland cotton totaled $11.5 billion cumulatively during 1995-2013 (USDA).Loan rate changed to floating range of 52¢/lb to 45¢/lbProduct-specific amber boxDuring 1995-2013, the monthly AWP was below the upland cotton market loan rate of 52¢/lb 113 of the 228 months, and below 45¢/lb 82 months; in each of these instances, MLP benefits could have been reduced by using the floating loan rate, thus resulting in lower total amber box outlays.Sugar Price Support ProgramMaintains previous sugar price supports through 2018 crop year—at 18.75¢/lb market loan rate for raw cane sugar; 24.09¢/lb for refined beet sugar—at no budgetary cost to federal government using three tools: flexible marketing allotments that limit the amount sugar processors can sell domestically, sugar import quotas that restrict foreign sugar imports, and the Feedstock Flexibility Program. USDA continues storage payments to processors that forfeit loans.Notified annual avg. outlays of $1.2 billion during 1995-2011 (WTO).ReauthorizedProduct-specific amber boxContinuation of sugar price support program represents about $1.3 billion in annual amber box outlays.Feedstock Flexibility Program (FFP)Requires USDA to purchase excess domestic sugar production (equal to quantity of imports that USDA estimates exceeds U.S. food demand), and to resell such sugar as a biomass feedstock to produce bioenergy, to ensure that sugar price support program provisions (see above) operate at no cost and to avoid loan forfeitures.In 2013, USDA used the FFP to purchase sugar to avoid loan forfeitures, then resold the sugar as biomass at a loss of $173 million (USDA). CBO projects $0 outlays under FFP for 2014-2018 (CBO-BL).ReauthorizedProduct-specific amber boxOutlays may be triggered if market prices fall below price support levels guaranteed by the U.S. sugar price support program; outlays count towards the U.S. amber box.Adjustment to Covered CommoditiesEstablishes eligibility for DP, CCP, and ACRE under 2008 farm bill; PLC, ARC, and SCO under 2014 farm bill. Includes wheat, oats, and barley (including used for haying and grazing); corn, sorghum, long- and medium-grain rice, and pulse crops (dry peas, lentils, small chickpeas, and large chick peas); soybeans and other oilseeds (sunflower seed, rapeseed, canola, safflower, flaxseed, mustard seed, crambe, and sesame seed); and peanuts.— dUpland cotton removed as covered cropProduct-specific amber boxFrom 1995 to 2011, over $17 billion in amber box program payments were made to upland cotton (about $1 billion annually); removal of upland cotton as covered commodity represents amber box savings.Special Program Provisions for Upland Cotton—Import QuotasSpecial import quota imposed on upland cotton when U.S. cotton prices exceed the world market price for four weeks. Limited global import quota is imposed on upland cotton when U.S. prices average 130% of the previous three-year average of U.S. prices.No estimate of the implicit value of these provisions is available.ReauthorizedSpecific import quotas must be listed in Country ScheduleAs long as the cumulative upland cotton import quota (i.e., sum of temporary special import quotas and any other import quotas in effect) remains within the quota limits defined in the U.S. Country Schedule, then it is WTO-compliant.Special Competitiveness Program for ELS CottonProvides payments to domestic users and exporters whenever AWP for the lowest-priced ELS cotton is below prevailing U.S. price for four-week period; and lowest priced ELS cotton is less than 134% of MLP loan rate for ELS cotton.CBO projects avg. annual outlays of $2 million during 2014-2018 (CBO-BL).ReauthorizedProduct-specific amber boxAny increases in outlays are likely to be notified as amber box.Economic Adjustment Assistance to Users of Upland CottonProvides assistance (3¢/lb) to domestic users of upland cotton for uses of all cotton regardless of origin—domestic or foreign.Avg. $80 million annually during 2009-2011 (WTO).ReauthorizedProduct-specific amber boxBecause the payment is nondiscriminatory (i.e., all cotton, domestic or imported, is eligible for the payment), it appears to be SCM-compliant; however, outlays count toward the amber box.Cotton Storage Payments Rate ReductionUnder the cotton storage incentive program, when domestic prices plus accrued interest plus storage costs for cotton being stored under USDA's MLP are above the AWP, then the CCC pays a portion of the storage costs.No payments have been notified to the WTO under the cotton storage program since 2008 (WTO).Reauthorized; the payment rate is reduced by 10%.Product-specific amber boxThe payment reduction lowers potential USDA outlays that outlays count toward the amber box. However, only minimal payments have been made under this program, such that this payment reduction is likely to have little effect.Adjusted Gross Income (AGI) LimitMaximum income that a person can earn and remain eligible for program payments. Under 2008 farm bill: a person is ineligible if income exceeds $500,000 non-farm AGI; $750,000 farm AGI. Under 2014 farm bill: single AGI limit of $900,000 using three-year average.No estimate available.New feature— dDifficult to interpret any WTO effect: lower overall limit, but potentially larger farm and non-farm-specific incomes.Disaster Program Payment LimitCombined payment limit is $125,000 per person for LIP, LFP, and ELAP; separate limit of $125,000 applies to TAP, and 500 acres limit continues.No estimate available.Limit expanded from $100,000Product-specific amber boxThe expanded limit increases potential for product-specific amber box outlays.Title I Price and Income Support: New ProgramsTemporary Upland Cotton Transition PaymentsFor crop year 2014, upland cotton producers receive decoupled payment based on historical base acres equal to 60% of previous upland cotton DP, in compensation for loss of "covered" status while awaiting implementation of STAX in 2015.CBO estimates 2014 outlays of $515 million (to be paid out in 2015) (CBO-BL).New programGreen box*Fully decoupled payments. Such green box outlays are unlimited.Price Loss Coverage (PLC)Payments triggered when SAFP falls below a statutorily fixed reference price for each covered crop; payments based on 85% of base acres and historical yields.CBO estimates no outlays during FY2014-FY2015, then annual avg. outlays of $2.3 billion during FY2016-FY2018 (CBO-BL).New programNon-product-specific amber box*Payments are decoupled from planted acres, but coupled to market prices. Fixed reference price ignores market conditions. Similarities to CCP suggest that PLC outlays are likely to be notified as nonproduct-specific amber box, making it eligible for the nonproduct-specific DM exemption.Agriculture Risk Coverage—County (ARC-CO)County-wide, shallow-loss program for each covered crop. Payments triggered when county revenue falls between 76% and 86% of a county revenue target (equal to product of five-yr. Olympic avg. of county yield times the national SAFP); payment based on 85% of base acres.CBO estimates no outlays during FY2014-FY2015, then annual avg. outlays of $1.2 billion during FY2016-FY2018 (CBO-BL).New programNon-product-specific amber box*Payments are decoupled from planted acres, but coupled to market prices and the PLC reference price (which sets an annual minimum trigger). The moving-average price trigger helps ARC-CO to reflect market conditions when prices are above the PLC reference price, but not when prices are below. Similarities to CCP suggest that ARC outlays are likely to be notified as non-product-specific amber box making it eligible for the non-product-specific DM exemption.Agriculture Risk Coverage—Individual (ARC-ID)Farm-level, shallow-loss whole-farm program (calculated as aggregate for all covered crops). Payments triggered when whole-farm revenue falls between 76% and 86% of a whole-farm revenue target (equal to sum for all crops of product of five-yr. Olympic avg. of yield times the national SAFP); payment based on 65% of base acres.CBO estimates no outlays during FY2014-FY2015, then annual avg. outlays of $632 million during FY2016-FY2018 (CBO-BL).New programNon-product-specific amber box*Payments made on a whole-farm basis; decoupled from planted acres and but coupled to market prices. The moving-average price trigger helps ARC-ID to reflect market conditions when prices are above the PLC reference price, but not when prices are below. ARC-ID outlays are likely to be notified as non-product-specific amber box, making it eligible for non-product-specific DM exemption.Base Acre OptionOne-time choice: retain current base or make a new allocation of base acres across program crops—may not increase base. Former cotton base acres may not be reallocated but become "generic" acres available for any use.— dNew feature— dReallocation to reflect recent market conditions is a partial form of recoupling across farm bill periods of program payments to producer planting choices. Producers will select the base that potentially maximizes their federal program payments.Generic BaseFormer cotton base acres are renamed generic base and added to producer's base acres for potential payments if at least one covered crop is planted on the farm. e— dNew feature— dRecouples fformer cotton base to current program choices and expands the potential base for covered commodity program payments.Base Yield OptionEach producer has a one-time choice: retain existing CCC yields, or update to 90% of 2008-2012 average yields.— dNew feature— dLikely increases the potential historic production base (base acres * historic yield) eligible to receive program payments under PLC and ARC.Restriction on Planting of Fruits and VegetablesLimits planting of fruit and vegetables on base acres to unpaid portion of base—i.e., 15% for farms in PLC or ARC-CO and 35% for farms in ARC-ID. Fruit and vegetable plantings above these limits will reduce payment acreage one-for-one.— dRevision of 2008 farm bill percentages of unpaid base acres.— dProvides flexibility to plant non-program crops on the % of base acres not receiving payments, but with no subsidy for those non-program crops. This restriction prevents producers from fully responding to market conditions; it was successfully challenged under the Brazil cotton case to show that DPs were not fully decoupled, but was not pursued further in terms of requiring any program change.Price and Income Support Payment LimitsDesigned to cap annual program payments to an individual farm operator. Under 2008 farm bill: $40,000 for DP; $65,000 for CCP and ACRE; a separate, additional limit applies for peanuts; limits effectively doubled with spouse; no limit on MLP benefit payments.— dSingle limit of $125,000 for PLC, ARC, and MLB; doubled with spouse; separate limit for peanuts.— dPer-operator program payment limits represent a potential tool for limiting or reducing total amber box outlays, and concomitantly mitigating potential distortions. The effectiveness of program limits remains in dispute as some have argued that they may be avoided by sub-dividing a farm operation among family members.Dairy Margin Protection Program (DMPP)Provides price-deficiency-like protection for operating margin (difference between all-milk price and formula-based avg. feed ration); payments are based on historical production (HP); HP grows annually with growth in national milk production for participants; producers select margin coverage ($4.00/cwt to $8.00/cwt in $0.50 increments) and portion of HP protected (25% to 90%); premiums are statutorily fixed for FY2014-FY2018 with 25% reduction during calendar 2014 and 2015 for small operations. DMPP has no payment limits. gCBO projects avg. annual outlays of $107 million during FY2015-FY2018 (CBO-BL).New programProduct-specific amber box*Outlays are likely to be notified as amber box. However, depending on market conditions, DMPP outlays are expected to be less than previous notifications under DPPSP.Dairy Product Donation Program (DPDP)DPDP requires USDA to procure certain dairy products when the margin falls below $4.00/cwt for two consecutive months; the dairy products are distributed immediately (i.e., not stored) to individuals from low-income groups and are not allowed for resale into commercial markets. DPDP purchases and distribution end after three months or if the U.S. price for certain dairy products is significantly above world dairy product prices.CBO projects avg. annual outlays of $16 million during FY2015-FY2018 (CBO-BL).New programGreen box*DPDP outlays are likely to be notified as green box, where outlays are unlimited.Crop Insurance ProgramsStacked Income Protection (STAX)Upland cotton producers are eligible for a county-level, shallow-loss revenue insurance program. Payments are triggered when county revenue falls between 90% to as low as 70% (but not lower than the coverage level of any underlying insurance policy) of a county revenue target (which equals product of 10-yr. trend-adjusted avg. county yield times expected price used for area-wide crop insurance policies, i.e., pre-planting-time average of harvest-time futures contract prices). Payments are based on insured acres. The program will start in 2015. hPremiums will be subsidized at 80% rate; CBO projects avg. annual outlays of $261 million during FY2016-FY2018 (CBO-BL).New programProduct-specific amber box*Program prices are within-year, market-based such that they will move up and down with year-to-year changes in market conditions; county-wide parameters mitigate moral hazard; indemnity payments are coupled to planted acres. Premium subsidies are likely to be notified as product-specific amber box. Because indemnities cover shallow losses, they could potentially encourage greater program participation and expanded planting on marginal land.Supplemental Coverage Option (SCO)County-level, shallow-loss insurance program for covered commodities enrolled in PLC and insured with a traditional crop insurance policy (either yield or revenue); SCO rides on top of the underlying policy and covers a portion of the deductible; indemnity triggered when county losses greater than 14% and up to the deductible of the underlying insurance policy occur; program to begin for 2016 crop year.Premiums will be subsidized at 65% rate; CBO projects avg. annual outlays of $223 million during FY2016-FY2018 (CBO-BL).New programNon-product-specific amber box*Program prices are within-year, market-based such that they will move up and down with year-to-year changes in market conditions; county-wide parameters mitigate moral hazard; indemnity payments are coupled to planted acres. Premium subsidies are likely to be notified as non-product-specific amber box, thus qualifying for potential exemption under the non-product-specific DM exemption. Because indemnities cover shallow losses, they could potentially encourage greater program participation and expanded planting on marginal land.Crop InsuranceMore than 100 designated crops (livestock margins and pasture) are eligible for farm- or county-level insurance protection on yields or revenue for individual crops on up to 85% of the crop's value, based on trend-adjusted historic average farm yields (90% coverage available using county yields) and within-year market prices. Premiums are based on value of insured crop and risk of loss as determined by market-based price and volatility measures. Premium subsidy varies with coverage level but averages about 62%. eNotified outlays averaged $5.9 billion during 2009-2011 (WTO). CBO projects avg. annual outlays for premium subsidies of $5.5 billion; underwriting costs of $1 billion; and A&O of $1.4 billion during 2014-2018 (CBO-BL).ReauthorizedPremium subsidies: product-specific amber box. Under-writing costs and A&O: green box.Outlays for premium subsidies (like rates) vary with market prices and yields; they are larger during periods of high market prices. Also, high premium subsidy rates detract from the actuarial soundness of the producer-paid premium and encourage greater program participation and expanded planting on marginal land. Notification as product-specific amber box makes it eligible for product-specific DM exemption, thus exemption status likely to vary across crops and market conditions.Peanut Revenue InsuranceBased on common revenue insurance policy currently available for other crops, provides peanut growers with choice of yield, revenue, and revenue with harvest-time exclusion policies; coverage will range from 50% to 85%; premium will be subsidized at rates similar to other crops, i.e., about 62% on average.CBO projects avg. annual outlays of $9 million during 2014-2018 (CBO-FB).New programSame as above.Expanding current amber-box revenue coverage to peanuts will increase likelihood of higher amber box notifications to WTO for crop insurance.Rice Margin CoverageBy the 2015 crop year, FCIC is required to provide margin coverage for rice producers.CBO projects avg. annual increase in outlays of $3 million during 2014-2018 (CBO-FB).New featureProduct-specific amber boxExpanding current amber box revenue coverage will increase likelihood of higher amber box notifications to WTO for crop insurance.Actual Production History (APH) AdjustmentThe farm-level APH is a critical parameter for calculating crop insurance guarantees, premiums, and indemnities; to be implemented starting with the 2016 crop year. APH adjustment allows exclusion of yield data for any year that county yield losses are 50% or greater. eCBO projects avg. annual increase in outlays of $24 million during 2014-2018 (CBO-FB).New featureProduct-specific amber boxElimination of low-yield years raises the potential insurance guarantee, thus increasing (1) government premium subsidies, (2) the likelihood of receiving an indemnity payment, and (3) the potential level of amber box outlays.STAX/SCO/Crop Insurance interactionLimits total indemnity payments across STAX, SCO, and traditional crop insurance: they cannot exceed the total insured value of the crop.— dNew feature— dPrevents double-payment for same loss; potentially limits amber box outlays under these programs.ARC-Crop Insurance InteractionProducers are expected to purchase less crop insurance coverage when participating in ARC.CBO projects avg. annual savings of $48 million during 2014-2018 (CBO-FB).New featureProduct-specific amber boxAnticipated interaction expected to lower both federal crop insurance participation and total federal premium subsidies more than ARC subsidies, with effect of net savings of amber box outlays.Catastrophic Yield Policy (CAT) Premium AdjustmentTo reduce government costs of reimbursement to private insurance companies, the calculated CAT premium is reduced by a formula-based percentage. iCBO projects avg. annual savings of $31million during 2014-2018 (CBO-FB).New featureProduct-specific amber boxThis adjustment in premium calculations would likely lower government premium subsidies notified to WTO as amber box outlays.Enterprise Units for Irrigated and Non-irrigated cropsUnder the 2008 farm bill, all land of a crop in a county was covered under a single enterprise unit. Starting in 2015 crop year, separate enterprise units are available for irrigated and non-irrigated acreages of a crop.CBO projects avg. annual increase in outlays of $38 million during 2014-2018 (CBO-FB).New featureProduct-specific amber boxExpanding current amber-box revenue coverage to irrigated and non-irrigated acreage will increase likelihood of higher amber box notifications to WTO for crop insurance.Crop Insurance Policy Research and DevelopmentAdds certain requirements governing FCIC review of and federal support for development of new crop insurance products.CBO projects avg. annual increase in outlays of $3 million during 2014-2018 (CBO-FB).New featureGreen boxLikely to be notified as green box.Standard Reinsurance Agreement (SRA) and Risk-SharingThe SRA between FCIC and private insurance companies defines A&O expense reimbursements and risk-sharing by government; FCIC may renegotiate the SRA once every five years.No cost projections available on potential change in federal costs.Requires any renegotiated SRA to be budget-neutral.Green boxThis provision may prevent federal government from obtaining a larger share of underwriting gains or a smaller share of underwriting losses. However, green box changes have no WTO effect.Crop Production on Native SodAdditional restrictions are added as penalty for cultivation on native sod—i.e., virgin soils untouched by cultivation or human activity.CBO projects avg. annual savings of $7 million during 2014-2018 (CBO-FB).New featureAmber boxLowers federal subsidies (as penalty) for producers who cultivate on native sod. The projected effect is to gain some savings of potential amber box outlays.Conservation ComplianceAdds the federally funded portion of crop insurance premiums to list of benefits lost if a producer violates conservation compliance restrictions. jNo estimate available.New feature— dPotentially lowers federal subsidies for producers who fail to comply with certain conservation requirements. The projected effect is to limit potential expansion of crop area onto marginal lands.Coverage Level by PracticeBeginning with 2015 crop year, a producer who grows a crop on both dry land and irrigated land may elect a different coverage level for each production practice.CBO projects avg. annual increase in outlays of $5 million during 2014-2018 (CBO-FB).New featureAmber boxExpanding current amber box revenue coverage will increase likelihood of higher amber box notifications to WTO for crop insurance.Beginning Farmer and Rancher ProvisionsBeginning farmers and ranchers are given additional support in the form of lower fees, higher premium subsidies, and adjustments for missing historical data or excluded yields.CBO projects avg. annual increase in outlays of $17 million during 2014-2018 (CBO-FB).New featureNon-product-specific amber boxExpanding current amber box revenue coverage will increase likelihood of higher amber box notifications to WTO for crop insurance.Crop Insurance for Organic CropsBy 2015, FCIC is required to offer price elections that reflect actual retail or wholesale prices of organic (not conventional) crops.CBO projects avg. annual increase in outlays of $1 million during 2014-2018 (CBO-FB).New featureNon-product-specific amber boxBecause organic prices tend to have a market premium, the associated insurance liability, premium, and premium subsidy will all be larger, thus increasing likelihood of higher amber box notifications to WTO for crop insurance.Index-Based Weather InsuranceFCIC is authorized to conduct pilot programs to provide producers of underserved specialty crops and livestock commodities with index-based weather insurance; premium subsidy may not exceed 60%.CBO projects avg. annual increase in outlays of $7 million during 2014-2018 (CBO-FB).New featureNon-product-specific amber boxExpanding current amber box revenue coverage will increase likelihood of higher amber box notifications to WTO for crop insurance.Supplemental Agricultural Disaster Assistance Programs kLivestock Indemnity Program (LIP)LIP provides disaster assistance payments to eligible livestock owners and contract growers at a rate of 75% of market value for livestock deaths in excess of normal mortality caused by adverse weather; LIP has no payments limit.CBO projects avg. annual increase in outlays of $54 million during 2014-2018 (CBO-BL).ReauthorizedProduct-specific amber boxOutlays count against the amber box limit.Livestock Forage Disaster Program (LFP)LFP provides disaster assistance payments to eligible livestock producers who have suffered grazing losses on drought-affected pasture or grazing land, or on rangeland managed by a federal agency due to a qualifying fire; LFP has no payments limit.CBO projects avg. annual increase in outlays of $434 million during 2014-2018 (CBO-BL).ReauthorizedProduct-specific amber boxOutlays count against the amber box limit.Emergency Assistance for Livestock, Honey Bees, and Farm-Raised Fish Program (ELAP)ELAP provides payments to producers of livestock, honey bees, and farm-raised fish as compensation for losses due to disease, adverse weather, and feed or water shortages; total outlays are capped at $20 million per year.CBO projects avg. annual increase in outlays of $18 million during 2015-2019 (CBO-BL).ReauthorizedProduct-specific amber boxOutlays count against the amber box limit.Tree Assistance Program (TAP)TAP makes payments to orchardists/nursery tree growers for losses in excess of 15% to replant trees, bushes, and vines damaged by natural disasters; TAP has no payments limit.CBO projects avg. annual increase in outlays of $10 million during 2014-2018 (CBO-BL).ReauthorizedProduct-specific amber boxOutlays count against the amber box limit.Noninsured Crop Disaster Assistance Program (NAP)NAP is available for crops not currently eligible for traditional crop insurance; payments are triggered for yield loss of at least 50% or prevented plantings on at least 35% of intended area; participants pay a $250 administrative fee; base premiums subsidized at 100% but buy-up coverage available with 94.75% subsidy rate; payments made on planted or intended plantings at 55% of avg. market price; NAP has no payments limit.CBO projects avg. annual increase in outlays of $243 million during 2012-2014 (USDA).Reauthorized, but enhanced with buy-up option from previous max of 50% up to 65%.Green boxGreen box outlays are unlimited, thus additional NAP would have no WTO effect; however, it remains to be seen if "buy-up" coverage is notified as amber box or green box.Emergency Disaster (EM) LoansWhen a county has been declared a disaster area by either the President or the Secretary of Agriculture, producers in that county may become eligible for low-interest emergency disaster (EM) loans for crop or physical loss of at least 30%; funding subject to appropriation.Total EM loans made average less than $100 million per year; no data is available on the actual cost or subsidy portion of the loans made.Reauthorized appropriationsGreen boxGreen box outlays are unlimited.Miscellaneous Provisions (Outside of Title I): Potential Non-Green BoxGSM-102 Export Credit GuaranteesThe federal government guarantees repayment when U.S. banks extend credit to foreign banks to finance import purchases into foreign markets of U.S. agricultural goods.Section 3101(b) of the 2014 farm bill authorizes $5.5 billion annually of CCC funding for the program; however, outlays are not included in U.S. notifications to the WTO.Tenor (i.e., length of term) reduced to 24 months from 36 monthsContains implicit subsidies declared illegal by WTO in 2004 lWhen tenor reduction is added to previous USDA program changes, GSM-102 should no longer be providing an implicit export subsidy. The texts for the ongoing Doha Round negotiations would codify export credit tenor at a maximum of 180 days or approximately six months.Reimbursement Transportation Cost Payment (RTCP) [Sec. 1606]Provides payments to reimburse for higher costs of transporting a commodity or input faced by "geographically disadvantaged farmers" in insular areas, Alaska, and Hawaii; authorized under 2008 farm bill but first implemented in 2010.Notified outlays of $2 million in 2011 (WTO).Reauthorized for FY2014-FY2018 with $15 million in annual appropriations.Non-product-specific amber boxAvailable funding is minimal relative to the amber box limit, and generally excluded under the non-product-specific DM exemption.Biomass Crop Assistance Program (BCAP)Provides financial assistance to establish, produce, and deliver biomass feedstocks under two categories of assistance: (A) establishment and annual payments and (B) matching payments to help eligible material owners with collection, harvest, storage, and transportation (CHST) of eligible material for use in a qualified biomass conversion facility.Notified outlays of $8 million in 2009, $11 million in 2010, and $1.7 million in 2011 (WTO).Reauthorized for FY2014-FY2018 with mandatory annual funding of $38.6 million.Non-product-specific amber boxAvailable funding is minimal relative to the amber box limit, and generally excluded under the non-product-specific DM exemption.Rural Energy for America Program (REAP)Provides financial assistance of grants, guaranteed loans, and combined grants and guaranteed loans for the development and construction of renewable energy systems (RES) and for energy efficiency improvement (EEI) projects; grants for conducting energy audits and for conducting renewable energy development assistance; and grants for conducting RES feasibility studies.Notified outlays of $83 million in 2011 (WTO).Reauthorized for FY2014-FY2018 with mandatory annual funding of $68.2 million.Non-product-specific amber boxAvailable funding is minimal relative to the amber box limit, and generally excluded under the non-product-specific DM exemption.Miscellaneous Provisions (Outside of Title I): Green BoxSupplemental Nutrition Assistance Program (SNAP) and Other USDA-Managed Nutrition ProgramsUSDA nutrition programs assist targeted populations—including children, pregnant or lactating women, and low-income households—to meet nutritional needs.Notified outlays averaged $42 billion per year during 1995-2008. mMore recently, 2009-2011, the annual avg. outlay was $92.3 billion (WTO).Subject to budgetary spending reductions.Green boxGreen box outlays are unlimited.Section 32Section 32 permanently appropriates 30% of annual customs receipts to support the farm sector through a variety of activities. Most funds are used to supplement child nutrition programs and for emergency removal of surplus commodities, disaster relief, or other unanticipated needs.About $8 to $9 billion per year, of which ~$7 billion annually is used for child nutrition programs, with the remainder available for other USDA programs. nAuthorized outside of farm bill.Green boxGreen box outlays are unlimited..Conservation ProgramsUSDA currently administers about 20 programs and subprograms that are available to directly or indirectly assist producers and landowners who wish to practice conservation on agricultural lands.Notified outlays averaged $2.3 billion per year during 1995-2008. More recently, 2009-2011, the annual avg. was $4.6 billion (WTO).Reauthorized subject to consolidation and budgetary spending reductions.Green boxGreen box outlays are unlimited.Specialty Crop ProvisionsIndividual specialty crop and organic producers do not directly benefit from price and income supports as traditional program commodities; instead, most support is indirect in the form of research; pest and disease control; food safety and quality standards; support for local foods and markets; generic market promotion; and nutrition programs favoring fruits and vegetables.No direct specialty crop outlays; instead, support is indirect primarily through green-box-type programs.Mandatory funding expected to average $773 million annually.Green boxGreen box outlays are unlimited.
Source:Compiled by CRS from various sources as cited.
a.Outlay estimates are from four sources: U.S. notifications to the WTO (WTO); USDA program data (USDA); CBO's score of the 2014 farm bill conference agreement of H.R. 2042, the Agricultural Act of 2014, as reported on January 27, 2014 (CBO-FB); and CBO's "April 2014 Baseline for Farm Programs," April 14, 2014 (CBO-BL). Outlays from both CBO sources were made using price projections that are substantially above current market conditions. As such, they likely (1) understate farm program outlays, since they do not include the substantial decline in farm prices that occurred through the spring and summer of 2014, and (2) overstate crop insurance subsidy outlays, since premiums are based on the underlying insured value, which declines with falling prices.
b.Potential WTO classification is based on previous U.S. program notifications or, if a new program, on CRS estimate of most likely notification. An asterisk is used to denote CRS estimates, i.e., * = CRS estimate of likely WTO classification for new U.S. farm programs.
c.The dairy products cheese, butter, and powdered milk are converted to a common unit—the content of fluid milk in the underlying product—to derive the support price in fluid-milk equivalents.
d.Program feature that does not involve specific outlays but may be relevant to payments made under other farm programs.
e.Specifically, for each crop year, generic base acres are attributed to (i.e., temporarily designated as) base acres to a particular covered commodity base in proportion to that covered crop's share of total plantings of all covered commodities in that year. However, if the total number of acres planted to all covered commodities on the farm does not exceed the generic base acres on the farm, only generic acres equal to the amount of acreage actually planted to a covered commodity are eligible for payment.
f.Federal payments made to historical base acres were decoupled from producer behavior by the 1996 farm bill ( P.L. 104-127) which established the Direct Payments (DP) program. DP payments were made independent of producer planting choices. The new "generic base" recouples federal payments to producer crop choices.
g.For details on the DMPP and DPDP programs, see CRS Report R43465, Dairy Provisions in the 2014 Farm Bill (P.L. 113-79) .
h.See CRS Report R43494, Crop Insurance Provisions in the 2014 Farm Bill (P.L. 113-79).
i.For details see CRS Report R43494, Crop Insurance Provisions in the 2014 Farm Bill (P.L. 113-79) .
j.For more information on conservation compliance, see CRS Report R42459, Conservation Compliance and U.S. Farm Policy.
k.For more information, see CRS Report RS21212, Agricultural Disaster Assistance.
l.USDA intended to operate the GSM-102 program in a subsidy-neutral manner with fees and charges covering any costs to USDA; however, in 2004 a WTO panel found that GSM-102 was being operated with an implicit illegal subsidy. USDA responded with several program changes, including a risk-based fee structure to increase user charges so as to ensure that they covered long-run operating costs. In the 2008 farm bill, Congress removed a 1% cap on user fees.
m.A large subset of USDA-managed nutrition programs—most notably, Supplemental Nutrition Program for Women, Infants, and Children (WIC)—are authorized outside of the farm bill; however, these programs are notified together under the general title of "domestic food aid."
n.For more information, see CRS Report RL34081, Farm and Food Support Under USDA's Section 32 Program.
Footnotes
1 .The WTO is a global rules-based, member-driven organization dealing with the rules of trade between nations. As of June 26, 2014, the WTO included 160 members. See CRS Report IF10002, The World Trade Organization at 20. 2 .Any possible exceptions to the WTO's rules, e.g., certain product-specific export subsidies, are identified for individual member countries in their Schedule of Concessions. Each member country's schedule is publicly available at the WTO website at http://www.wto.org/english/tratop_e/schedules_e/goods_schedules_e.htm. 3 .CRS Report R43696, Agricultural Exports and 2014 Farm Bill Programs: Background and Issues . 4 .CRS Report R43076, The 2014 Farm Bill (P.L. 113-79): Summary and Side-by-Side . 5 ."Safety net" broadly describes all price and income support programs and risk management programs available to U.S. agricultural producers. Farm program critics contend that "safety net" is a euphemism for federal subsidies. 6 .For specific farm program details, see CRS Report R43448, Farm Commodity Provisions in the 2014 Farm Bill (P.L. 113-79); CRS Report R43494, Crop Insurance Provisions in the 2014 Farm Bill (P.L. 113-79); and CRS Report RS21212, Agricultural Disaster Assistance. 7 .For a summary of WTO rules see CRS Report IF10192, WTO Disciplines of Domestic Support for Agriculture. For a detailed review of WTO domestic support classification and a description of how U.S. farm programs have been categorized through 2011, see CRS Report RS20840, Agriculture in the WTO: Rules and Limits on Domestic Support. 8 .See CRS Report RL32916, Agriculture in the WTO: Policy Commitments Made Under the Agreement on Agriculture(pdf). 9 .The U.S. change in notification for crop insurance premium subsidies and the subsequent implication for WTO compliance is discussed later in this report in "De Minimis (DM) Exemptions." 10 .See CRS Report RS22522, Potential Challenges to U.S. Farm Subsidies in the WTO: A Brief Overview. 11 .Under the General Sales Manager (GSM) 102 program, the federal government guarantees repayment when U.S. banks extend credit to foreign banks to finance import purchases into foreign markets of U.S. agricultural goods. 12 .See CRS Report R43336, The WTO Brazil-U.S. Cotton Case . 13 .The 2014 farm bill includes a provision, Sec. 1601(d), that effectively serves as a safety trigger for USDA to adjust program outlays in such a way as to avoid breaching the amber box limit. 14 .For specific program details, see CRS Report R43448, Farm Commodity Provisions in the 2014 Farm Bill (P.L. 113-79 ); CRS Report R43494, Crop Insurance Provisions in the 2014 Farm Bill (P.L. 113-79); and CRS Report RS21212, Agricultural Disaster Assistance . 15 .Payments under these programs are counter-cyclical because they tend to rise when prices fall and to fall when prices rise. 16 .Although the acronym ARC-ID signifies "individual," it is more accurately described as a farm-level program because it uses yields from the farm to determine the guaranteed and actual revenues. In contrast, ARC-CO uses the county average yield, rather than the farm-level yield, for determining payments. County-level programs are easier to administrate (since county data is more reliable and more readily available than farm-level data) and discourage producer manipulation of farm-level production data. 17 ."Decoupled" means that program payments are not linked to either planted acres or output. In contrast, "coupled" means that payments are directly linked to plantings or production. 18 .As an aid to understanding how the new safety net of the 2014 farm bill might affect markets, able 2 Table 2groups the principal support programs into four categories: price-deficiency-payment programs, shallow-loss programs, deep-loss programs, and programs based on supply control. 19 .An important aspect of the sugar program is that it operates, to the maximum extent possible, at no budgetary cost to the federal government by avoiding marketing loan forfeitures to USDA's Commodity Credit Corporation (CCC). See the section below entitled "Marketing Loan Program (MLP)" for a description of loan forfeiture. 20 .Under a TRQ, a quota is established below which imports may enter with no or minimal duty, and above which imports are subject to a higher, often prohibitive duty. 21 .CBO cost estimates for the 2014 farm bill, January 28, 2014, available at http://www.cbo.gov/publication/45049. 22 .USDA, World Agricultural Supply and Demand Estimate, World Agricultural Outlook Board, Nov. 10, 2014. 23 .For information on pre-2014 farm bill programs, see CRS Report RL34594, Farm Commodity Programs in the 2008 Farm Bill; CRS Report R40422, A 2008 Farm Bill Program Option: Average Crop Revenue Election (ACRE); CRS Report R40452, A Whole-Farm Crop Disaster Program: Supplemental Revenue Assistance Payments (SURE); and CRS Report RL34207, Crop Insurance and Disaster Assistance in the 2008 Farm Bill . 24 .Annual notifications to the WTO may correspond to each country's relevant crop or marketing year. 25 .See CRS Report RS20840, Agriculture in the WTO: Rules and Limits on Domestic Support. 26 ."U.S. Domestic Support Notification for Marketing Year 2012," G/AG/N/USA/100, WTO, December 8, 2014. 27 .That was the last year that payments were made under the old target-price deficiency payment program linked to acreage set-asides, which was repealed by the 1996 farm bill and replaced by direct payments. 28 .CRS Report RS22927, WTO Doha Round: Implications for U.S. Agriculture . 29 .An exception would be "generic" base acres—i.e., historical cotton base acres that are no longer linked to cotton programs but become eligible for program payments if planted to "covered" program crops. Re-establishing a link between producer crop choices and federal payments, in effect, recouples producer behavior and program payments. 30 .For more information, see CRS Report R43448, Farm Commodity Provisions in the 2014 Farm Bill (P.L. 113-79) . 31 .One prominent economist has already declared them to be "unambiguously amber box" because they are triggered by current-year market prices. See V. H. Smith, The 2014 Agricultural Act: U.S. Farm Policy in the Context of the 1994 Marrakesh Agreement and the Doha Round, Issue Paper No. 52, International Centre for Trade and Sustainable Development (ICTSD), Geneva, Switzerland, June 2014. Two other noted economists, Joseph Glauber, former chief economist of USDA, and Patrick Westhoff, Director, Food and Agriculture Policy Research Institute (FAPRI) at the University of Missouri, contend that both PLC and ARC would likely qualify as non-product-specific amber outlays under current WTO rules, but as blue box outlays under the proposed Doha texts; J. Glauber and P. Westhoff, 50 Shades of Amber: The 2014 Farm Bill and the WTO, paper presented at the Allied Social Science Association annual meeting, January 3-5, 2015, Boston, MA. 32 .Carl Zulauf, "The Base vs. Planted Acre Issue: Perspectives, Trade-Offs, and Questions," CHOICES28(4), 4 thquarter 2013. 33 .Carl Zulauf, "Market Distortion and Farm Program Design: A Case Examination of the Proposed Farm Price Support Programs," farmdoc daily, June 7, 2013. 34 .Carl Zulauf and David Orden, U.S. Farm Policy and Risk Assistance, ICTSD Issue Paper No. 44, September 2012. 35 .CRS Report RL32571, Brazil's WTO Case Against the U.S. Cotton Program. 36 ."Final Rule: Agriculture Risk Coverage and Price Loss Coverage Programs," Federal Register, vol. 79, no. 187, September 26, 2014. 37 .REAP was originally classified as green box; however, in its 2011 notification to the WTO, USDA reclassified REAP payments as non-product-specific amber box spending. The SURE program expired in 2011 and was not reauthorized. CCP, DPPS, MILC, and ACRE were repealed in the 2014 farm bill. 38 .As implied by the Congressional Budget Office's (CBO's) March 2015 Baseline for Farm Programs, released March 9, 2015, at http://www.cbo.gov/sites/default/files/cbofiles/attachments/44202-2015-03-USDA.pdf. 39 .This discussion is drawn from Carl Zulauf, "Market Distortion and Farm Program Design: A Case Examination of the Proposed Farm Price Support Programs," farmd oc d aily, Department of Agriculture and Consumer Economics, University of Illinois Urbana-Champaign, June 7, 2013. 40 .B. Babcock and N. Paulson, Potential Impact of Proposed 2012 Farm Bill Commodity Programs on Developing Countries, Issue Paper No. 45, ICTSD, Geneva, Switzerland, October 2012. 41 .For program details, see CRS Report R43448, Farm Commodity Provisions in the 2014 Farm Bill (P.L. 113-79)and CRS Report R43494, Crop Insurance Provisions in the 2014 Farm Bill (P.L. 113-79) . 42 .Whole-farm means that data for all program crops produced by the farm must be combined into a single calculation. 43 .The insurance guarantee is based on historical county yield data, and the insurance "actual" uses current-year county yield data. National SAFPs, historical and current, are combined with county yield data for revenue calculations. 44 .CRS Report R43336, The WTO Brazil-U.S. Cotton Case. 45 .For example, J. Ifft and T. Kuethe, "The Impacts of Insurance on Agricultural Land Values." farmdoc daily(4):231, Department of Agricultural and Consumer Economics, University of Illinois at Urbana-Champaign, December 3, 2014. 46 .CRS Report R40532, Federal Crop Insurance: Background . 47 .CBO, "CBO's March 2015 Baseline for Farm Programs," March 9, 2015. 48 .CRS Report R42551, Sugar Provisions of the 2014 Farm Bill (P.L. 113-79) . 49 .A modification to the DPPS program in the 2008 farm bill—switching the focus away from supporting the fluid milk price and to directly supporting dairy product prices—had lowered the annual notification to an average of $2.8 billion during 2008-2011. 50 .MILC outlays ranged from a low of $0 in 2001 to a high of $1.8 billion in 2002. 51 .For program details, see CRS Report R43465, Dairy Provisions in the 2014 Farm Bill (P.L. 113-79) . 52 .John Newton and Cam Thraen, "The Dairy Safety Net Debate of 2013 Part I: Questions and Answers," farmdoc daily.com, Department of Agricultural and Consumer Economics, University of Illinois at Urbana-Champaign, December 17, 2013. 53 .The fixed nature of the DMPP premium implies that the federal subsidy share is both indirect and varies with the underlying risk conditions. 54 .C. F. Nicholson and M. W. Stephenson, "Dynamic Market Impacts of the Dairy Margin Protection Program of the Agricultural Act of 2014," Program on Dairy Markets and Policy Working Paper Series, Working Paper No. WP14-03, May 2014. 55 .In contrast, the CBO April 2014 baseline projects DMPP net outlays of about $84 million per year through 2024. 56 .Using CBO April 2014 baseline projections for the price of all-milk compared with the feed ration cost generated using the FAPRI November 2014 price projections, CRS estimates that the annual average margin stays above $8.00 through 2018. Actual margin payments are based on a moving two-month average, not the annual average. 57 ."USDA Provides Additional Data on Dairy Farms Enrolled in Margin Protection Program," news release, January 16, 2015, National Milk Producers Federation, http://www.nmpf.org. 58 .This appears to be a strategy designed to facilitate compliance under a future successful Doha-Round-like agreement. For a related discussion, see CRS Report RS22927, WTO Doha Round: Implications for U.S. Agriculture. 59 .This notification change is visible as the decline in the red bar between 2011 and 2012 in Figure 1and the concomitant increase in the yellow bar for those same years. 60 .REAP was originally classified as green box; however, in its 2011 notification to the WTO, USDA reclassified REAP payments as non-product-specific amber box spending. 61 .Under the 2014 farm bill, mandatory funding of $50 million per year and discretionary funding of $20 million per year were authorized for REAP, while BCAP funding was limited to mandatory funding of $20 million per year for FY2014-FY2018. 62 .For a full discussion of this issue, see CRS Report RS22927, WTO Doha Round: Implications for U.S. Agriculture . 63 .Although not formally approved by the entire WTO membership, the negotiating texts represent agreement among the three countries with the largest domestic support programs—the United States, the European Union, and Japan. 64 ."Final Rule: Agriculture Risk Coverage and Price Loss Coverage Programs," Federal Register, vol. 79, no. 187, September 26, 2014.
| https://www.everycrsreport.com/files/20150422_R43817_99b51455ccf738000770e7b7fb0b164c327be67f.html |
Multiple biliary hamartomas | Changeset | Radiopaedia.org
Multiple biliary hamartomas
Diagnosis certain
Updates to Case Attributes
Status
changed from pending reviewto published (public).
Published At
was set to.
Body was changed:
Multiple biliary hamartomas (MBH) or von Meyenburg complexes are focal collections of duct like structures which are lined by biliary epithelium that set in a fibrous stroma and dilated in different degrees. They are rare benign malformations of the intrahepatic bile ducts. (1,2).
MBH incidence ranging between 0.6% and 2.8%. They are usually asymptomatic and may diagnosed incidentally at liver biopsy, surgery or at autopsy(3).
MBH is reportedly three times more common in females than males.
The prevalence of MBH on imaging is <1% because most of hamartomas measures less than 5 mm and often not detected, however, is ~3% at autopsy. (4).
On ultrasound, biliary hamartomas appear as small well-circumscribed lesions scattered throughout the liver, with hyperechoic, hypoechoic, or mixed echogenicity depending on solid, cystic, or mixed components, respectively. “Comet tail” sign, which is nonspecific sonographic sign for biliary hamartomas may be seen (5).
On CT, biliary hamartomas appear as hypoattenuating multiple lesions which measures less than 1.5 cm with irregular margins more than what seen in simple hepatic cysts. Compared with simple hepatic cysts, biliary hamartomas are more likely to be uniformly numerous, small in size, typically smaller than the hepatic cysts seen in autosomal-dominant polycystic kidney disease (5).
On MRI, biliary hamartomas are hyperintense on T2-weighted imaging and hypointense on T1-weighted imaging. Predominantly cystic lesions show no enhancement after gadolinium (5).
MRCP shows multiple cystic lesions that do not communicate with the biliary tree (5).
Malignant transformation of biliary hamartoma to cholangiocarcinoma is extremely rare. An isolated finding of biliary hamartomas in a healthy patient requires no further diagnostic workup or treatment (5).
Special thanks to Dr.Tamer Elholiby.
-<p>Multiple biliary hamartomas (MBH) or von Meyenburg complexes are focal collections of duct like structures which are lined by biliary epithelium that set in a fibrous stroma and dilated in different degrees. They are rare benign malformations of the intrahepatic bile ducts. (1,2).</p><p> </p><p>MBH incidence ranging between 0.6% and 2.8%. They are usually asymptomatic and may diagnosed incidentally at liver biopsy, surgery or at autopsy(3).</p><p>MBH is reportedly three times more common in females than males.</p><p>The prevalence of MBH on imaging is <1% because most of hamartomas measures less than 5 mm and often not detected, however, is ~3% at autopsy. (4).</p><p> </p><p>On ultrasound, biliary hamartomas appear as small well-circumscribed lesions scattered throughout the liver, with hyperechoic, hypoechoic, or mixed echogenicity depending on solid, cystic, or mixed components, respectively. “Comet tail” sign, which is nonspecific sonographic sign for biliary hamartomas may be seen (5).</p><p>On CT, biliary hamartomas appear as hypoattenuating multiple lesions which measures less than 1.5 cm with irregular margins more than what seen in simple hepatic cysts. Compared with simple hepatic cysts, biliary hamartomas are more likely to be uniformly numerous, small in size, typically smaller than the hepatic cysts seen in autosomal-dominant polycystic kidney disease (5).</p><p>On MRI, biliary hamartomas are hyperintense on T2-weighted imaging and hypointense on T1-weighted imaging. Predominantly cystic lesions show no enhancement after gadolinium (5).</p><p>MRCP shows multiple cystic lesions that do not communicate with the biliary tree (5).</p><p>Malignant transformation of biliary hamartoma to cholangiocarcinoma is extremely rare. An isolated finding of biliary hamartomas in a healthy patient requires no further diagnostic workup or treatment (5).</p><p> </p><p>Special thanks to Dr.Tamer Elholiby.</p>
+<p>Multiple biliary hamartomas (MBH) or von Meyenburg complexes are focal collections of duct like structures which are lined by biliary epithelium that set in a fibrous stroma and dilated in different degrees. They are rare benign malformations of the intrahepatic bile ducts. (1,2).</p><p>MBH incidence ranging between 0.6% and 2.8%. They are usually asymptomatic and may diagnosed incidentally at liver biopsy, surgery or at autopsy(3).</p><p>MBH is reportedly three times more common in females than males.</p><p>The prevalence of MBH on imaging is <1% because most of hamartomas measures less than 5 mm and often not detected, however, is ~3% at autopsy. (4).</p><p>On ultrasound, biliary hamartomas appear as small well-circumscribed lesions scattered throughout the liver, with hyperechoic, hypoechoic, or mixed echogenicity depending on solid, cystic, or mixed components, respectively. “Comet tail” sign, which is nonspecific sonographic sign for biliary hamartomas may be seen (5).</p><p>On CT, biliary hamartomas appear as hypoattenuating multiple lesions which measures less than 1.5 cm with irregular margins more than what seen in simple hepatic cysts. Compared with simple hepatic cysts, biliary hamartomas are more likely to be uniformly numerous, small in size, typically smaller than the hepatic cysts seen in autosomal-dominant polycystic kidney disease (5).</p><p>On MRI, biliary hamartomas are hyperintense on T2-weighted imaging and hypointense on T1-weighted imaging. Predominantly cystic lesions show no enhancement after gadolinium (5).</p><p>MRCP shows multiple cystic lesions that do not communicate with the biliary tree (5).</p><p>Malignant transformation of biliary hamartoma to cholangiocarcinoma is extremely rare. An isolated finding of biliary hamartomas in a healthy patient requires no further diagnostic workup or treatment (5).</p><p>Special thanks to Dr.Tamer Elholiby.</p>
Updates to Study Attributes
Findings was changed:
MRI liver without contrast was performed and showed the liver uniformly studded with innumerable non-communicating cystic lesions, the largest of which was seen measuring around 2 x 2 cm at hepatic segment VII.
The cystic lesions revealed low signal intensity in T1WIs
&
and
very bright signal intensity in T2WIs. Hepatic parenchyma showed a typical 'starry sky' like appearance.
How to use cases
You can use Radiopaedia cases in a variety of ways to help you learn and teach.
Add cases to playlists
Share cases with the diagnosis hidden
Use images in presentations
Use them in multiple choice question
Creating your own cases is easy.
Case creation learning pathway
| https://radiopaedia.org/cases/multiple-biliary-hamartomas-7/changesets/132514/edits?from_revision_history=true&lang=us |
53\u0022\u003ELength\u2013tension relationships of biceps and triceps specify elbow joint angle. Muscle tension is plotted along the \u003Cem\u003Ey\u003C\/em\u003E-axis against elbow joint angle (\u03b8) as opposed to muscle length on the \u003Cem\u003Ex\u003C\/em\u003E-axis. The red line represents the length\u2013tension curve of biceps and the blue line triceps at given muscle activity levels. Gray squares represent levels of muscle tension produced by biceps and triceps at the beginning of two example starting hand positions. Given this level of HFLD-ICMS-evoked biceps and triceps activity, these muscles will produce movement from either starting hand position to a final hand position reflecting the equilibrium point (heavy and light diagonal arrows). The black square represents the point of intersection between length\u2013tension curves; the equilibrium position of the joint (heavy vertical line). Horizontal lines represent corresponding changes in elbow angle associated with movement toward the equilibrium position.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan class=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022fig-data-tables\u0022 class=\u0022group frag-table\u0022\u003E\u003Cdiv class=\u0022fig-data-title-jump clearfix\u0022\u003E\u003Ch3 class=\u0022fig-data-group-title\u0022\u003ETables\u003C\/h3\u003E\u003Cdiv class=\u0022fig-data-jump-links\u0022\u003E\u003Cul class=\u0022fig-data-jump-links-list links inline\u0022\u003E\u003Cli class=\u0022figure first last\u0022\u003E\u003Ca href=\u0022#fig-data-figures\u0022 class=\u0022fig-data-jump-link fig-data-jump-link-figure link-icon\u0022\u003E\u003Cspan class=\u0022icon-caret-up\u0022\u003E\u003C\/span\u003E \u003Cspan class=\u0022title\u0022\u003EFigures\u003C\/span\u003E\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022item-list\u0022\u003E\u003Cul class=\u0022fig-data-list clearfix\u0022 id=\u0022fragments-table\u0022\u003E\u003Cli class=\u0022first last\u0022\u003E\u003Cdiv class=\u0022element-fig-data clearfix table-caption\u0022\u003E\u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 class=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022table-expansion \u0022 id=\u0022T1\u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cul class=\u0022inline table-expansion-links\u0022\u003E\u003Cli class=\u0022view-popup first last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/568524\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables-1123157079\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \u003Cp id=\u0022p-12\u0022\u003EJoint angles achieved with different hand starting positions\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Ctable frame=\u0022hsides\u0022 id=\u0022table-1\u0022 alt=\u0022Table 1.\u0022\u003E\u003Cthead valign=\u0022bottom\u0022 id=\u0022thead-1\u0022 class=\u0022table-vbottom\u0022\u003E\u003Ctr id=\u0022tr-1\u0022\u003E\u003Cth align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022th-1\u0022 class=\u0022table-left\u0022\u003EHand starting positions\u003C\/th\u003E\u003Cth align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022th-2\u0022 class=\u0022table-left\u0022\u003EJoint\u003C\/th\u003E\u003Cth align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022th-3\u0022 class=\u0022table-left\u0022\u003EAngle\u003C\/th\u003E\u003C\/tr\u003E\u003C\/thead\u003E\u003Ctbody valign=\u0022top\u0022 id=\u0022tbody-1\u0022 class=\u0022table-vtop\u0022\u003E\u003Ctr id=\u0022tr-2\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-1\u0022 class=\u0022table-left\u0022\u003EA\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-2\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-3\u0022 class=\u0022table-left\u0022\u003E50\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-3\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-4\u0022 class=\u0022table-left\u0022\u003E115\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-4\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-5\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-6\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-7\u0022 class=\u0022table-left\u0022\u003E105\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-5\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-8\u0022 class=\u0022table-left\u0022\u003EB\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-9\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-10\u0022 class=\u0022table-left\u0022\u003E50\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-6\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-11\u0022 class=\u0022table-left\u0022\u003E125\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-7\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-12\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-13\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-14\u0022 class=\u0022table-left\u0022\u003E115\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-8\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-15\u0022 class=\u0022table-left\u0022\u003EC\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-16\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-17\u0022 class=\u0022table-left\u0022\u003E110\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-9\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-18\u0022 class=\u0022table-left\u0022\u003E125\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-10\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-19\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-20\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-21\u0022 class=\u0022table-left\u0022\u003E135\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-11\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-22\u0022 class=\u0022table-left\u0022\u003ED\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-23\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-24\u0022 class=\u0022table-left\u0022\u003E110\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-12\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-25\u0022 class=\u0022table-left\u0022\u003E115\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-13\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-26\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-27\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-28\u0022 class=\u0022table-left\u0022\u003E120\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-14\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-29\u0022 class=\u0022table-left\u0022\u003E1\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-30\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-31\u0022 class=\u0022table-left\u0022\u003E50\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-15\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-32\u0022 class=\u0022table-left\u0022\u003E120\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-16\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-33\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-34\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-35\u0022 class=\u0022table-left\u0022\u003E70\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-17\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-36\u0022 class=\u0022table-left\u0022\u003E2\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-37\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-38\u0022 class=\u0022table-left\u0022\u003E110\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-18\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-39\u0022 class=\u0022table-left\u0022\u003E120\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-19\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-40\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-41\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-42\u0022 class=\u0022table-left\u0022\u003E70\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-20\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-43\u0022 class=\u0022table-left\u0022\u003E3\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-44\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-45\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-21\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-46\u0022 class=\u0022table-left\u0022\u003E120\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-22\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-47\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-48\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-49\u0022 class=\u0022table-left\u0022\u003E170\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-23\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-50\u0022 class=\u0022table-left\u0022\u003E4\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-51\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-52\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-24\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-53\u0022 class=\u0022table-left\u0022\u003E120\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-25\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-54\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-55\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-56\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-26\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-57\u0022 class=\u0022table-left\u0022\u003E5\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00222\u0022 colspan=\u00221\u0022 id=\u0022td-58\u0022 class=\u0022table-left\u0022\u003EShoulder\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-59\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Horizontal plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-27\u0022\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-60\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003Ctr id=\u0022tr-28\u0022\u003E\u003Ctd rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-61\u0022\u003E\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-62\u0022 class=\u0022table-left\u0022\u003EElbow\u003C\/td\u003E\u003Ctd align=\u0022left\u0022 rowspan=\u00221\u0022 colspan=\u00221\u0022 id=\u0022td-63\u0022 class=\u0022table-left\u0022\u003E90\u00b0 Vertical plane\u003C\/td\u003E\u003C\/tr\u003E\u003C\/tbody\u003E\u003C\/table\u003E\u003Cdiv class=\u0022table-foot\u0022\u003E\u003Cul class=\u0022table-footnotes\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-4\u0022\u003E\u003Cp id=\u0022p-13\u0022\u003EAngles estimated to the nearest 5\u00b0. See \u003Cspan id=\u0022xref-fig-1-10\u0022 class=\u0022xref-fig\u0022\u003EFigure 1\u003C\/span\u003E for identification of starting hand positions.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan class=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.jneurosci.org\/sites\/default\/files\/js\/js_hZg96SP9gBcOluDp2mGc57d8sP8uJ7g8P_JYsCISOgQ.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}
| https://www.jneurosci.org/panels_ajax_tab/jnl_sfneneuro_tab_data/node:380784/1 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Report
Themes
Assistive & Accessible Technology
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Cite
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Type
Journal Paper
Themes
Assistive & Accessible Technology
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Jamie Danemayer,Cathy Holloway,Youngjun Cho, Nadia Berthouze, Aneesha Singh, William Bhot, Ollie Dixon, Marko Grobelnik, John Shawe-Taylor
Paper highlights: Assistive technology (AT) information networks are insular among stakeholder groups, causing unequal access to information. Participants often cited fragmented international marketplaces as a barrier and valued info-sharing across industries. Current searches produce biased results in marketplaces influenced by commercial interests and high-income contexts. Smart features could facilitate searching, update centralised data sources, and disseminate information more inclusively.
International Journal of Human-Computer Studies; 2023
Abstract
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain.
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Type
Journal Paper
Themes
Assistive & Accessible Technology
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Cite
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
Share
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Type
Journal Paper
Themes
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Cite
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledge
on all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
Cite
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
Share
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Cite
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Emma M Smith, Maria Luisa Toro Hernandez, Ikenna D Ebuenyi, Elena V Syurina,Giulia Barbareschi, Krista L Best,Jamie Danemayer,Ben Oldfrey, Nuha Ibrahim,Catherine Holloway, Malcolm MacLachlan
The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
International Journal of Health Policy and Management; 2020
Abstract
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Abstract
Background:The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
Methods:This study was a rapid, international online qualitative survey in the 6 United Nations (UN) languages (English, French, Spanish, Russian, Arabic, Mandarin Chinese) facilitated by extant World Health Organization (WHO) and International Disability Alliance networks. Themes and subthemes of the qualitative responses were identified using Braun and Clarke's 6-phase analysis.
Results:Four primary themes were identified in in the data: Disruption of Services, Insufficient Emergency Preparedness, Limitations in Existing Technology, and Inadequate Policies and Systems. Subthemes were identified within each theme, including subthemes related to developing resilience in AT systems, based on learning from the pandemic.
Conclusion:COVID-19 has disrupted the delivery of AT services, primarily due to infection control measures resulting in lack of provider availability and diminished one-to-one services. This study identified a need for stronger user-centred development of funding policies and infrastructures that are more sustainable and resilient, best practices for remote service delivery, robust and accessible tools and systems, and increased capacity of clients, caregivers, and clinicians to respond to pandemic and other crisis situations.
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Smith EM, Toro Hernandez ML, Ebuenyi ID, Syurina EV, Barbareschi G, Best KL, Danemayer J, Oldfrey B, Ibrahim N, Holloway C, MacLachlan M. Assistive Technology Use and Provision During COVID-19: Results From a Rapid Global Survey. Int J Health Policy Manag. 2022 Jun 1;11(6):747-756. doi: 10.34172/ijhpm.2020.210. PMID: 33201656;
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Share
Assistive Technology (AT), for What?
Type
Journal Paper
Themes
Assistive & Accessible Technology
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Katte, Cynthia Liao, Mathilde Chaudron, Novia Afdhila
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle- income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of a market and sector analysis that was conducted under the UK aid funded AT2030 programme and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle-income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of market analyses conducted under the UK aid funded AT2030 programme in support of ATscale and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs. The paper also explores how market shaping for AT markets could be part of a mission-oriented approach AT policy. A mission-oriented approach can help accelerate progress toward a common objective among stakeholders, at country or global level. While market-shaping activities direct the outcomes of the market toward a specific end goal, such as access to quality, affordable products and services, missions are more comprehensive and include other policy interventions and stakeholder collaborations in order to create a robust and sustainable structure.
Cite
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Kattel, Cynthia Liao, Mathilde Chaudron & Novia Afdhila (2021) Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries, Assistive Technology, 33:sup1, 124-135, DOI: 10.1080/10400435.2021.1991050
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive technology access in longitudinal datasets: a global review
Jamie Danemayer, Sophie Mitra,Cathy Holloway, Shereen Hussein
A person’s access to assistive products such as hearing aids, wheelchairs, and glasses, is an essential part of their ability to age in a healthy way. But, according to the World Health Organization, a staggering 90% of people who need assistive products worldwide, do not have access to them. In many instances access is limited or simply non-existent. This is often due to assistive products being too expensive, demand outweighing supply, not always being suitable to use in different environments, or even the lack of availability of trained providers. In such circumstances, people are more likely to age ‘unhealthily’ if they do not have access to assistive products that are designed to support their day to day functioning and independence.
International Journal of Population Data Science; 2023
Abstract
Assistive technology access in longitudinal datasets: a global review
Functional limitations become more prevalent as populations age, emphasising an increasingly urgent need for assistive technology (AT). Critical to meeting this need trajectory is understanding AT access in older ages. Yet few publications examine this from a longitudinal perspective.
This review aims to identify and collate what data exist globally, seeking all population-based cohorts and repeated cross-sectional surveys through the Maelstrom Research Catalogue (searched May 10, 2022) and the Disability Data Report (published 2022), respectively. Datasets incorporating functional limitations modules and question(s) dedicated to AT, with a wave of data collection since 2009, were included.
Of 81 cohorts and 202 surveys identified, 47 and 62 meet inclusion criteria, respectively. Over 40% of cohorts were drawn from high-income countries which have already experienced significant population ageing. Cohorts often exclude participants based on pre-existing support needs. For surveys, Africa is the most represented region (40%). Globally, 73% of waves were conducted since 2016. 'Use' is the most collected AT access indicator (69% of cohorts and 85% of surveys). Glasses (78%) and hearing aids (77%) are the most represented AT. While gaps in data coverage and representation are significant, collating existing datasets highlights current opportunities for analyses and methods for improving data collection across the sector.
Cite
Assistive technology access in longitudinal datasets: a global review
Danemayer, J., Mitra, S., Holloway, C. and Hussein, S. (2023) “Assistive technology access in longitudinal datasets: a global review”, International Journal of Population Data Science, 8(1). doi: 10.23889/ijpds.v8i1.1901.
Assistive technology access in longitudinal datasets: a global review
Type
Journal Paper
Themes
Assistive & Accessible Technology
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Jamie Danemayer, Dorothy Boggs, Vinicius Delgado Ramos, Emma M. Smith, Ariana Kular, William Bhot, Felipe Ramos Barajas, Sarah Polack,Catherine Holloway
Assistive technology (AT) includes assistive products (APs) and related services that can improve health and well-being, enable increased independence and foster participation for people with functional difficulties, including older adults and people with impairments or chronic health conditions. 1This paper uses the umbrella term ‘functional difficulty’ (FD) to refer to all of these groups. This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
BMJ Global Health; 2021
Abstract
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Introduction:To improve access to assistive products (APs) globally, data must be available to inform evidence based decision-making, policy development and evaluation, and market-shaping interventions.
Methods:This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
Results:Data including 656 AP access indicators were extracted from 207 studies, most of which (n=199, 96%) were cross-sectional, either collecting primary (n=167) or using secondary (n=32) data. There was considerable heterogeneity in assessment approaches used and how AP indicators were reported; over half (n=110) used a combination of clinical and self-reported assessment data. Of 35 studies reporting AP use out of all people with functional difficulty in the corresponding functional domains, the proportions ranged from 4.5% to 47.0% for hearing aids, from 0.9% to 17.6% for mobility devices, and from 0.1% to 86.6% for near and distance glasses. Studies reporting AP need indicators demonstrated >60% unmet need for each of the five APs in most settings.
Conclusion:Variation in definitions of indicators of AP access have likely led to overestimates/underestimates of need and coverage, particularly, where the relationship between functioning difficulty and the need for an AP is complex. This review demonstrates high unmet need for APs globally, due in part to disparate data across this sector, and emphasises the need to standardise AP data collection and reporting strategies to provide a comparable evidence base to improve access to APs.
Cite
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Danemayer J, Boggs D, Delgado Ramos V, et al. Estimating need and coverage for five priority assistive products: a systematic review of global population-based research. BMJ Global Health 2022;7:e007662. doi:10.1136/bmjgh-2021-007662
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Type
Journal Paper
Themes
Assistive & Accessible Technology
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick,Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga,Catherine Holloway
An estimated 1.5 million people undergo limb amputation each year [1]. Low- and middle-income countries (LMICs) are projected to have a rapid increase in people living with an amputation in the coming years due to prevalence of non-communicable dis-ease, trauma and conflict [1–3]. This paper explores the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Disability and Rehabilitation; 2022
Abstract
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
PurposeTo explore the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Materials and methodsThis study employed a qualitative approach to explore the motivations and satisfaction of individuals with lower limb loss engaging with a prosthetic service in Mombasa, Kenya. In-depth interviews were conducted over Microsoft Teams with 10 lower limb prosthesis users and thematic analysis was applied.
ResultsFive key themes emerged: acceptance, self-determination, hope, clinician relationship and perception. These findings demonstrate the importance of hopeful thinking and a supportive community in overcoming physical and stigmatising challenges. The findings further highlight the value of the service provider relationship beyond just prescribing an assistive device.
ConclusionThese results have relevance in developing patient-centred services, assistive devices and personnel training that are responsive, motivating, and cognisant of the service user. This is of particular interest as assistive technology services are newly developed in low resource settings.
Cite
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick, Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga & Catherine Holloway (2022) Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes, Disability and Rehabilitation, DOI:10.1080/09638288.2022.2152875
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Victoria Austin,Catherine Holloway, Ignacia Ossul Vermehren, Abs Dumbuya,Giulia Barbareschiand Julian Walker
The World Health Organisation (WHO) estimates that there are currently one billion people in the world who need access to assistive technology (AT). Yet over 90% currently do not have access to assistive products (AP)—such as wheelchairs, hearing aids, walking sticks and eyeglasses—they need, nor and the systems and services necessary to support their appropriate provision [1]. This shocking deficit is set to double by 2050, with about two billion of us likely to require AT but no anticipated reduction in lack of access. The World Health Organisation defines AT as the “the umbrella term covering the systems and services related to the delivery of assistive products and services”, which are products that “maintain or improve an individual’s functioning and independence, thereby promoting their well-being” [2], and the importance of AT provision is strongly highlighted in the Convention on the Rights of Persons with Disabilities (CRPD) [3]. AT has also been shown to be essential to achieving many of the United Nation’s Sustainable Development Goals (SDG) [4]. Without access to AT, many persons with disabilities are unable to go to school, be active in their communities, earn an income, or play a full role in their families [5]. As a recent study found, “AT can make the impossible possible for people living with a wide range of impairments, but a lack of access to basic AT …excludes individuals and reduces their ability to live full, enjoyable, and independent lives” [6].
International Journal of Environmental Research and Public Health; 2021
Abstract
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
The importance of assistive technology (AT) is gaining recognition, with the World Health Organisation (WHO) set to publish a Global Report in 2022. Yet little is understood about access for the poorest, or the potential of AT to enable this group to participate in the activities of citizenship; both formal and informal. The aim of this qualitative study was to explore AT as mediator of participation in citizenship for persons with disabilities who live in two informal settlements in Freetown, Sierra Leone (SL). The paper presents evidence from 16 participant and 5 stakeholder interviews; 5 focus groups and 4 events; combining this with the findings of a house-to-house AT survey; and two national studies—a country capacity assessment and an informal markets deep-dive. Despite citizenship activities being valued, a lack of AT was consistently reported and hindered participation. Stigma was also found to be a major barrier. AT access for the poorest must be addressed if citizenship participation for persons with disabilities is a genuine global intention and disability justice is to become a reality.
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Austin, V.; Holloway, C.; Ossul Vermehren, I.; Dumbuya, A.; Barbareschi, G.; Walker, J. “Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone. Int. J. Environ. Res. Public Health2021, 18, 5547.https://doi.org/10.3390/ijerph...
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Chapal Khasnabis,Catherine Holloway, Malcolm MacLachlan
We are now in an era of assistive care and assistive living—whereby many people, of all ages, in good health, and those who are more frail, or with cognitive or functional impairments, are using a broad range of technologies to assist and enhance their daily living. Assistive living 1is becoming an important part of population health and rehabilitation, which can help to maximise an individual's abilities, regardless of age or functional capacity. This encouraging shift in ethos has been strengthened by the response to the COVID-19 pandemic, in which a plethora of digital and remote technologies have been used.
The Lancet; 2020
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Additive manufacturing techniques for smart prosthetic liners
B Oldfrey, A Tchorzewska, R Jackson, M Croysdale, R Loureiro,C Holloway, M Miodownik
Elastomeric liners are commonly worn between socket and limb by prosthetic wearers. This is due to their superior skin adhesion, load distribution and their ability to form a seal. Laboratory tests suggest that elastomeric liners allow reduced shear stress on the skin and give a higher cushioning effect on bony prominences, since they are soft in compression, and similar to biological tissues [1]. However, they also increase perspiration reducing hygiene and increasing skin irritations. Prosthetic users in general face a myriad of dermatological problems associated with lower limb prosthesis such as ulcers, cysts, and contact dermatitis, which are exacerbated by the closed environment of a fitted socket where perspiration is trapped and bacteria can proliferate [2].
Medical Engineering & Physics; 2021
Abstract
Additive manufacturing techniques for smart prosthetic liners
Elastomeric liners are commonly worn between the prosthetic socket and the limb. A number of improvements to the state of the art of liner technology are required to address outstanding problems. A liner that conforms to the residuum more accurately, may improve the skin health at the stump-socket interface. Previous work has shown that for effective thermal management of the socket environment, an active heat removal system is required, yet this is not available. Volume tracking of the stump could be used as a diagnostic tool for looking at the changes that occur across the day for all users, which depend on activity level, position, and the interaction forces of the prosthetic socket with the limb. We believe that it would be advantageous to embed these devices into a smart liner, which could be replaced and repaired more easily than the highly costly and labour-intensive custom-made socket. This paper presents the work to develop these capabilities in soft material technology, with: the development of a printable nanocomposite stretch sensor system; a low-cost digital method for casting bespoke prosthetic liners; a liner with an embedded stretch sensor for growth / volume tracking; a model liner with an embedded active cooling system.
Cite
Additive manufacturing techniques for smart prosthetic liners
, Additive manufacturing techniques for smart prosthetic liners, Medical Engineering & Physics, Volume 87, 2021, Pages 45-55, ISSN 1350-4533,https://doi.org/10.1016/j.mede....
Share
Additive manufacturing techniques for smart prosthetic liners
Type
Journal Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Disability Interactions
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Giulia Barbareschi, Mark T. Carew, Elizabeth Aderonke Johnson, Norah Kopi,Catherine Holloway
Stigmatizing attitudes and beliefs towards disability represent one of the most pervasive and complex barriers that limits access to health care, education, employment, civic rights and opportunities for socialization for people with disabilities [1,2,3]. The damaging impact of disability stigma is widely acknowledged and, according to article 8 of the UN Convention on the Rights of Persons with disabilities, developing strategies, campaigns, policies and other initiatives to combat disability stigma and ensure that all people with disabilities are treated with dignity and respect is also a duty of the 182 countries who ratified the treaty [4]. Although the majority of literature focused on understanding disability stigma has been carried out in high-income settings [5,6,7], in the last decade, an increasing number of scholars have conducted studies looking at the negative stereotypes, prejudices and inaccurate beliefs that shape disability stigma in the Global South [3,8,9,10]. Most of these studies have described how these stigmatizing beliefs are often driven by a combination of personal and societal factors, ranging from misconceptions concerning the causes of different impairments (e.g., disability to be seen as a form of curse or punishment); assumptions about the lack of capabilities of people with disabilities; or discriminatory practices that actively endorse separation between people with and without disabilities [3,9,11,12]. Yet, there is a dearth of comparative studies that examine the perspectives of both people with and without disabilities of disability stigma and discrimination, including how the use of assistive technology may shape stigmatizing interactions.
International Journal of Environmental Research and Public Health; 2021
Abstract
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Disability stigma in many low- and middle-income countries represents one of the most pervasive barriers preventing people with disabilities from accessing equal rights and opportunities, including the uptake of available assistive technology (AT). Previous studies have rarely examined how disability stigma may be shaped through factors endemic to social interactions, including how the use of assistive technology itself may precipitate or alleviate disability stigma. Through two strands of work, we address this gap. Via a series of focus groups with Kenyans without disabilities (Study 1) and secondary data analysis of consultations with Kenyans with disabilities and their allies (Study 2), we identify shared and divergent understandings of what shapes disability stigma and discrimination. Specifically, Kenyans with and without disabilities were cognizant of how religious/spiritual interpretations of disability, conceptions of impairments as “different” from the norm, and social stereotypes about (dis)ability shaped the experience of stigma and discrimination. Moreover, both groups highlighted assistive technology as an influential factor that served to identify or “mark” someone as having a disability. However, whereas participants without disabilities saw assistive technology purely as an enabler to overcome stigma, participants with disabilities also noted that, in some cases, use of assistive technologies would attract stigma from others.
Cite
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Barbareschi G, Carew MT, Johnson EA, Kopi N, Holloway C. “When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya. International Journal of Environmental Research and Public Health. 2021; 18(8):4272.https://doi.org/10.3390/ijerph...
Share
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Type
Journal Paper
Themes
Inclusive Design
Culture and Participation
Research Group
Disability Interactions
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi,Ben Oldfrey, Long Xin, Grace N. Magomere, Wyclife A. Wetende, Carol Wanjira, Joyce Olenja,Victoria Austin, andCatherine Holloway
The World Health Organisation estimate that there are approximately a billion people with disabilities who require access to appropriate assistive technology and this number is set to double by 2050 [82]. Assistive technologies (ATs) play a crucial role in the lives of people with disabilities and are necessary to be able to access essential services and participate in family and community life according to one’s aspirations [40, 62, 68, 81]. Although this is not often specifcally mentioned, the large majority of people with disabilities will routinely use more than one assistive device in their everyday lives [25, 26]. For example a person with a visual impairment is likely to use a white cane to navigate from their house to the office where they work and have a screen-reader, or an equivalent accessibility software, on their computer to be able to do their work once in the office [17].
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Living in informality is challenging. It is even harder when you have a mobility impairment. Traditional assistive products such as wheelchairs are essential to enable people to travel. Wheelchairs are considered a Human Right. However, they are difficult to access. On the other hand, mobile phones are becoming ubiquitous and are increasingly seen as an assistive technology. Should therefore a mobile phone be considered a Human Right? To help understand the role of the mobile phone in contrast of a more traditional assistive technology – the wheelchair, we conducted contextual interviews with eight mobility impaired people who live in Kibera, a large informal settlement in Nairobi. Our findings show mobile phones act as an accessibility bridge when physical accessibility becomes too challenging. We explore our findings from two perspective – human infrastructure and interdependence, contributing an understanding of the role supported interactions play in enabling both the wheelchair and the mobile phone to be used. This further demonstrates the critical nature of designing for context and understanding the social fabric that characterizes informal settlements. It is this social fabric which enables the technology to be useable.
Cite
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi, Ben Oldfrey, Long Xin, Grace Nyachomba Magomere, Wycliffe Ambeyi Wetende, Carol Wanjira, Joyce Olenja, Victoria Austin, and Catherine Holloway. 2020. Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal settlement. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 50, 1–13.https://doi.org/10.1145/337362...
Share
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Type
Editorial
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Social Justice
Critical Junctures in Assistive Technology and Disability Inclusion
Dr Maria Kett,Catherine Holloway,Vicki Austin,Dr Maria Kett
It is clear from the events of the last 18 months that while technology has a huge potential for transforming the way we live and work, the entire ecosystem—from manufacturing to the supply chain—is vulnerable to the vagaries of that ecosystem, as well as having the potential to exacerbate new and existing inequalities [1]. Nowhere has this been more apparent than in the lives of people with disabilities, who make up around 15% of the world’s population and already face barriers to accessing education, employment, healthcare and other services [2]. Some of these barriers are a result of unequal access and opportunities. However, there is a growing movement to better understand how assistive technology systems and services can be designed to enable more robust and equitable access for all. As part of this growing movement, the Paralympic Games in Tokyo this autumn saw the launch of a new global campaign to transform the lives of the world’s 1.2 bn persons with disabilities: the ‘WeThe15’ campaign reached more than 4.5 billion people through its marketing and stands ready to be the biggest of its kind in history. Next year, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), AT scale and GDI Hub will publish the first World Report on Access to Assistive Technology, which will include research from the £20 million, UK Aid funded, GDI Hub-led, programme, AT2030. Ahead of that, in this Special Issue, we focus on how some events and situations—as diverse as the coronavirus pandemic and the Paralympics—can act as ‘critical junctures’ that can enable a rethink of the status quo to facilitate and promote change.
Sustainability; 2021
Cite
Critical Junctures in Assistive Technology and Disability Inclusion
Kett, M.; Holloway, C.; Austin, V. Critical Junctures in Assistive Technology and Disability Inclusion. Sustainability2021, 13, 12744.https://doi.org/10.3390/su1322...
Share
Critical Junctures in Assistive Technology and Disability Inclusion
Type
Book
Research Group
Disability Interactions
Disability Interactions Creating Inclusive Innovations
Catherine Holloway,Giulia Barbareschi
; 2021
Abstract
Disability Interactions Creating Inclusive Innovations
Disability interactions (DIX) is a new approach to combining cross-disciplinary methods and theories from Human Computer Interaction (HCI), disability studies, assistive technology, and social development to co-create new technologies, experiences, and ways of working with disabled people. DIX focuses on the interactions people have with their technologies and the interactions which result because of technology use. A central theme of the approach is to tackle complex issues where disability problems are part of a system that does not have a simple solution. Therefore, DIX pushes researchers and practitioners to take a challenge-based approach, which enables both applied and basic research to happen alongside one another. DIX complements other frameworks and approaches that have been developed within HCI research and beyond. Traditional accessibility approaches are likely to focus on specific aspects of technology design and use without considering how features of large-scale assistive technology systems might influence the experiences of people with disabilities. DIX aims to embrace complexity from the start, to better translate the work of accessibility and assistive technology research into the real world. DIX also has a stronger focus on user-centered and participatory approaches across the whole value chain of technology, ensuring we design with the full system of technology in mind (from conceptualization and development to large-scale distribution and access). DIX also helps to acknowledge that solutions and approaches are often non-binary and that technologies and interactions that deliver value to disabled people in one situation can become a hindrance in a different context. Therefore, it offers a more nuanced guide to designing within the disability space, which expands the more traditional problem-solving approaches to designing for accessibility. This book explores why such a novel approach is needed and gives case studies of applications highlighting how different areas of focus—from education to health to work to global development—can benefit from applying a DIX perspective. We conclude with some lessons learned and a look ahead to the next 60 years of DIX.
Share
Disability Interactions Creating Inclusive Innovations
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith,Cathy Holloway
GReAT, but do we care?
If accessible, assistive technology would be life changing for a billion people across the world today – and two billion people in 2050 (WHO,2018). It would make the difference between independence and dependence, inclusion and exclusion, life and death. It holds the potential to improve and transform health, education, livelihood and social participation; fundamental human rights everyone is entitled to. And if we are lucky to grow old, the chances are that we all would use assistive technology by then. But do we care?
Assistive Technology, The Official Journal of RESNA; 2021
Cite
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith & Cathy Holloway (2021) Introduction to the companion papers to the global report on assistive technology, Assistive Technology, 33:sup1, 1-2, DOI:10.1080/10400435.2021.2003658
Share
Introduction to the companion papers to the global report on assistive technology
Type
Journal Paper
Themes
Assistive & Accessible Technology
Climate & Crisis Resilience
Research Group
Disability Interactions
Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer,Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella,Cathy Holloway,and Sarah Polack
An assistive product (AP) is defined as a product used exter-nally to the human body, whose primary purpose is to main-tain or improve an individual’s functioning and independence and thereby promote his or her well-being (WHO, 2016). Global population aging forecasts a rise in the need for solu-tions that support participation and independence, including APs. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Measuring assistive technology supply and demand: A scoping review
The supply of and market demand for assistive products (APs) are complex and influenced by diverse stakeholders. The methods used to collect AP population-level market data are similarly varied. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation. Abstracts resulting from a systematic search were double-screened. Extracted data include WHO world region, publication year, age-groups, AP domain(s), study method, and individual assessment approach.497 records were identified. Vision-related APs comprised 65% (n = 321 studies) of the body of literature; hearing (n = 59), mobility (n = 24), cognitive (n = 2), and studies measuring multiple domains (n = 92) were proportionately underrepresented. To assess individual AP need, 4 unique approaches were identified among 392 abstracts; 45% (n = 177) used self-report and 84% (n = 334) used clinical evaluation. Study methods were categorized among 431 abstracts; Cross-sectional studies (n = 312, 72%) and secondary analyses of cross-sectional data (n = 61, 14%) were most common. Case studies illustrating all methods are provided. Employing approaches and methods in the contexts where they are most well-suited to generate standardized AP indicators will be critical to further develop comparable population-level research informing supply and demand, ultimately expanding sustainable access to APs.
Cite
Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer, Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella, Cathy Holloway & Sarah Polack (2021) Measuring assistive technology supply and demand: A scoping review, Assistive Technology, 33:sup1, S35-S49, DOI: 10.1080/10400435.2021.1957039
Share
Measuring assistive technology supply and demand: A scoping review
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Humanitarian & Disasters
Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero,Maria Kett, Kirstin Lange
This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Meeting AT needs in humanitarian crises: The current state of provision
Humanitarian coordination systems increasingly recognize and aim to respond to the needs of people with disabilities within populations affected by crises, spurred on by the UN Convention on the Rights of Persons with Disabilities (CRPD) which was adopted in 2006. Many agencies state their aim to meet the requirements of the CRPD using a “twin track” approach: ensuring the inclusion of people with disabilities in mainstream provision, alongside targeted support for their needs, which may include the need for Assistive Technology (AT). However, there is very little evidence of AT provision in humanitarian settings, which is a specific and urgent need for many people including the elderly and people with disabilities, and an implicit requirement of Article 11 of the CRPD and World Health Assembly resolution on improving access to assistive technology. There is also little evidence of effective mechanisms for AT provision in humanitarian settings. This is despite high and growing levels of unmet AT need in crises, and despite the legally binding requirement in the CRPD to provide AT for those who need it. AT provision faces unique challenges in humanitarian settings. This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020. We found very few examples in that academic literature of systematic and coordinated AT provision at the acute stage of crisis, and even less in the preparedness and post-acute stages. However, it is difficult to assess whether this is the result of insufficient academic attention or reflects a lack of provision. The small body of academic literature that describes AT provision in humanitarian settings paints a picture of small-scale provision, specialized to single types of impairments, and delivered by predominantly by NGOs. We also conducted a search of the gray literature, using the same inclusion criteria, in two countries: Afghanistan and South Sudan (case studies forthcoming). This gray literature provided supplementary evidence of the types of AT providers and AT provision available in those protracted crises. There are very few examples of how AT services can be scaled up (from a very low baseline) and maintained sustainably within a strengthened health system. The literature also describes more examples of provision of assistive products for mobility over assistive products for other impairments. If the paucity of literature on AT provision in humanitarian settings is a reflection of the scale of provision, this implies a deficiency in humanitarian response when it comes to providing people with AT needs with the essential products and services to which they have a right, and which will enable their access to basic, life-saving assistance. We conclude by providing recommendations for urgent actions that the AT and humanitarian community must take to fill this critical gap in the provision of essential products and services for a potentially marginalized and excluded group.
Cite
Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero, Maria Kett & Kirstin Lange (2021) Meeting AT needs in humanitarian crises: The current state of provision, Assistive Technology, 33:sup1, S3-S16, DOI: 10.1080/10400435.2021.1934612
Share
Meeting AT needs in humanitarian crises: The current state of provision
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Ben Oldfrey,Giulia Barbareschi, Priya Morjaria, Tamara Giltsoff, Jessica Massie, Mark Miodownik andCatherine Holloway
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have.
Sustainability
Abstract
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have. We show the intrinsic links between disability inclusion and the climate crisis, and the particular vulnerability people with disabilities face in its wake. In particular, we discuss how localised circular models of production could be beneficial, facilitating context driven solutions and much needed service elements such as repair and maintenance. Key discussion areas include systems approaches, digital fabrication, repair and reuse, and material recovery. Finally, we look at what needs be done in order to enable these approaches to be implemented. In conclusion, we find that there are distinct parallels between what AT provision models require to improve equitable reliable access, and strategies that could reduce environmental impact and bring economic benefit to local communities. This could allow future AT ecosystems to be key demonstrators of circular models, however further exploration of these ideas is required to make sense of the correct next steps. What is key in all respects, moving forward, is aligning AT provision with sustainability interventions.
Cite
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Oldfrey, B.; Barbareschi, G.; Morjaria, P.; Giltsoff, T.; Massie, J.; Miodownik, M.; Holloway, C. Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World? Sustainability2021, 13, 10867.https://doi.org/10.3390/su1319...
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez,Tigmanshu Bhatnagar,Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi,Giulia Barbareschi,Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan,Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally.
Assistive Technology The Official Journal of RESNA
Abstract
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally. We conducted a scoping review of innovation strategies and processes in peer-reviewed literature databases and complemented this by identifying case studies demonstrating innovation strategies. The review includes WHO world region, publication year, AT type and a sector analysis against the Systems-Market for Assistive and Related Technologies Framework. We analyzed the case studies and interviews using thematic analysis. We included 91 papers out of 3,127 after review along with 72 case studies. Our results showed that product innovations were more prevalent than provision or supply innovations across papers and case studies. Case studies yielded two themes: open innovation (OI); radical and disruptive innovation. Financial instruments which encourage OI are needed and we recommend pursuing OI for AT innovation. Embedding AT within larger societal missions will be key to success governments and investors need to understand what AT is and their translational socioeconomic value.
Cite
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez, Tigmanshu Bhatnagar, Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi, Giulia Barbareschi, Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan, Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha (2021) A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems, Assistive Technology, 33:sup1, 68-86, DOI:10.1080/10400435.2021.1970653
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Type
Journal Paper
Themes
Inclusive Design
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Mikaela Patrick,Iain McKinnon
Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments. Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya.
The Journal of Public Space
Abstract
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
This paper presents some of the findings from a global research study on inclusive infrastructure and city design and will focus on inclusive public spaces. Persons with disabilities can experience multi-dimensional exclusion from urban life, including but not limited to physical, attitudinal and social barriers. Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments.Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya. Research participants and objectives are organised by three stakeholder groups:
People- first-hand experiences of persons with disabilities living in the city and their aspirations for a more inclusive city
Policy- the awareness and understanding of inclusive design among policy-makers
Practice- the awareness and understanding of inclusive design among practitioners including barriers to implementation, opportunities and the relationship with assistive technology
Methods include document reviews, interviews, photo diaries and co-design workshops with participatory and inclusive engagement of persons with disabilities throughout. Findings on public spaces are discussed in three ways:
The types of public spaces valued by participants in each of the four cities.
The barriers and challenges experienced by persons with disabilities in the public realm.
Aspirations for more inclusive public spaces and opportunities for inclusive design
The paper concludes by discussing how the targeted stakeholder groups of people, policy and practice also help represent three essential dimensions of inclusive city design and forming a framework for successful implementation and delivery and supporting targets set out through the UNCRPD and Sustainable Development Goals (SDGs).
Cite
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Patrick, M. and McKinnon, I. (2022) “Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities”, The Journal of Public Space, 7(2), pp. 93–116. doi: 10.32891/jps.v7i2.1500.
Share
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Jessica Noske-Turner, Emma Pullen, Mufunanji Magalasi, Damian Haslett, Jo Tacchi
Communication & Sport
Abstract
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
The purpose of this commentary is to discuss how Paralympic coverage in sub-Saharan Africa can be effectively mobilised to stimulate discursive and structural change around disability. Paralympic coverage has demonstrated its pedagogical power to engage public(s) and challenge stigma toward disability. Yet, the Global picture of Paralympic broadcasting is deeply uneven, with audiences in parts of the Global South afforded limited opportunities to watch the Games. Considering this, the International Paralympic Committee has begun to broadcast Paralympic coverage across sub-Saharan Africa with an explicit aim to challenge stigma toward disability. In this article, we draw on examples from research to argue that ideas from the field of Communication for Social Change (CfSC) can add value towards this aim. We begin by providing a brief overview of CfSC before critically examining one of the field’s key concepts – Communicative (E)ecologies. Following this, we critically reflect on the potential of Paralympic broadcasting as a vehicle for social change and disability rights agendas in sub-Saharan Africa. We argue that thinking with CfSC concepts show the importance of a ‘decentred’ media approach that engages with disability community advocacy groups, localised communication activities and practices, and culturally specific disability narratives.
Cite
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Noske-Turner, J., Pullen, E., Magalasi, M., Haslett, D., & Tacchi, J. (2022). Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change. Communication & Sport, 10(5), 1001–1015.https://doi.org/10.1177/216747...
Share
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Victoria Austin,Kate Mattick, andCathy Holloway
Disability inclusion necessitates proactive efforts to ensure everybody has an independent and equitable opportunity to meaningfully participate in the activities of their choosing [1,2,3]. Furthermore, disability justice is not a minority concern. There are more than a billion disabled people worldwide, and impairment is something which affects most people’s family right now and will impact all of us over our lifetime. The United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enshrines human rights of all disabled people [4], and in 2015 the Sustainable Development Goals (SDG’s) recognised disability inclusion for the first time with the call to ‘leave no-one behind’. Increasingly, governments, non-governmental agencies and businesses alike are seeking to develop and implement policy and practice which enables greater social inclusion for disabled people (In this paper, Disabled People is used in line with the Social Model of Disability in the UK, though please note the UN uses ‘Persons with Disabilities’ as is common in North America) [5]. Eighty percent of the disabled people in the world live in low resource settings in the Global South [3] with a projected growth of this number due to an increase in population age, there is the ever-pressing need to critically evaluate how best to approach disability inclusion to build a societies where we all can flourish. Despite this, we lack case studies of how disability inclusion can be done well—in the literature and in practice. For this reason, we set out to undertake this research using one the most recognised cases of ‘disability inclusion done well’.
Sustainability
Abstract
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
The London 2012 Paralympic Games was called “the most successful Paralympic Games ever” (by the then-President of the IPC), and it saw more athletes from more countries than ever before compete and become global heroes for the first time in a redeveloped part of East London which also hosted “the most accessible Olympic Games ever” that summer. However, the model used to design and deliver disability inclusion for London 2012, and its legacy, has never been explicitly written up. This paper presents new primary evidence from first-hand research from those who were involved; retrospectively framing the London 2012 Disability Inclusion Model such that it might be usable and developed for other global disability challenges. We used an adapted Delphi methodology, through four rounds: beginning with an initial hypothesis and testing through semi-structured interviews with ten key players in the London 2012 disability inclusion approach. Using thematic analysis with consensus building surveys and workshops we came to a settled unanimous agreement on the 12-step London 2012 Disability Inclusion Modelcomprising three parts: (Get ready) community-led mission setting, (Get set) essential building blocksand (Go) enabling a culture of success. The model is presented here, alongside a narrative on its uniqueness and replicability to other major programs, as a public good. We welcome its active use, testing and adaption by others in service of disability innovation for a fairer world.
Cite
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Victoria Austin, Kate Mattick, and Cathy Holloway. 2021. "“This Is the Story of Community Leadership with Political Backing. (PM1)” Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges" Sustainability13, no. 16: 9253.https://doi.org/10.3390/su13169253
Share
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Type
Editorial
Themes
Assistive & Accessible Technology
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi& Tom Shakespeare
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
RESNA
Abstract
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
However, when it comes to assistive technology (AT) research, our focus seems to be primarily geared toward values and activities in the domains of education, employment, transport or health, often framed according to an outcome driven perspective that is heavily influenced by what is seen as useful (often what is measurable), vs what is frivolous (less tangible social or emotional aspects).
This disparity parallels the priorities of the disability rights movement and disability studies research that have helped to shape the research agenda around disability and AT. Often influenced by labor movement politics, or feminism, there appears to have been more concern with public and practical aspects of social life as opposed to the more private and sensitive ones (Shakespeare,2014). The focus on the public utilitarian function of AT becomes even more evident when we consider AT research carried out in the Global South. In this context the success of an intervention is usually assessed using measures of outcome and impact which can be somehow linked to economic improvement (Alkire,2016).
In this editorial, we are not suggesting that enabling people with disabilities to gain a good education, obtain a fulfilling job or be able to vote are not important goals for the APs we develop and research. But are those the only worthwhile goals? Should we not also enquire whether existing and future APs could help people with disabilities to develop meaningful friendships, enjoy fulfilling sex lives with their partners of choice, cook sociable dinners, or engage in their favorite hobbies? Although sporadic publications focus on the role of APs in the context of personal relationships, sexuality, or fun and play for people with disabilities do exist, these are rare, and often framed around utilitarian goals. For example, research around AT and play is largely focused on children and often examined in connection to learning outcomes. Similarly, sex and sexuality are often explored solely in connection to dysfunction, abuse or sexual health (Shakespeare & Richardson,2018).
These unbalanced narratives show how the AT research agenda is dictated by a set of universal priorities that are largely focused on global measurable goals that do not necessarily match the everyday values of people with disabilities. We invite researchers and practitioners to consider ways to find a better balance between public and private aspects of life, and between utilitarian and emotional values. Both approaches have a significant impact on the lives of people with disabilities.
Ultimately, as AT researchers we need to actively engage with people with disabilities to uncover their priorities, understand what different people with disabilities most value in life, and identify how current and future APs might help to make a positive impact on wellbeing. Aspects of life such as friendship, socialization, sexuality, love and play might indeed be more frivolous than practical ones such as education, health, employment and civil rights, but they are inherent to our shared humanity and fundamental to our happiness.
Cite
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi & Tom Shakespeare (2021) A right to the frivolous? Renegotiating a wellbeing agenda for AT research, Assistive Technology, 33:5, 237, DOI:10.1080/10400435.2021.1984112
Share
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Physiological Computing
STEP-UP: Enabling Low-Cost IMU Sensors to Predict the Type of Dementia During Everyday Stair Climbing
Catherine Holloway, William Bhot, Keir X. X. Yong, Ian McCarthy, Tatsuto Suzuki, Amelia Carton, Biao Yang, Robin Serougne, Derrick Boampong, Nick Tyler, Sebastian J. Crutch, Nadia Berthouze andYoungjun Cho
Posterior Cortical Atrophy is a rare but significant form of dementia which affects people's visual ability before their memory. This is often misdiagnosed as an eyesight rather than brain sight problem. This paper aims to address the frequent, initial misdiagnosis of this disease as a vision problem through the use of an intelligent, cost-effective, wearable system, alongside diagnosis of the more typical Alzheimer's Disease.
Frontiers in Computer Science
Abstract
STEP-UP: Enabling Low-Cost IMU Sensors to Predict the Type of Dementia During Everyday Stair Climbing
Posterior Cortical Atrophy is a rare but significant form of dementia which affects people's visual ability before their memory. This is often misdiagnosed as an eyesight rather than brain sight problem. This paper aims to address the frequent, initial misdiagnosis of this disease as a vision problem through the use of an intelligent, cost-effective, wearable system, alongside diagnosis of the more typical Alzheimer's Disease. We propose low-level features constructed from the IMU data gathered from 35 participants, while they performed a stair climbing and descending task in a real-world simulated environment. We demonstrate that with these features the machine learning models predict dementia with 87.02% accuracy. Furthermore, we investigate how system parameters, such as number of sensors, affect the prediction accuracy. This lays the groundwork for a simple clinical test to enable detection of dementia which can be carried out in the wild.
STEP-UP: Enabling Low-Cost IMU Sensors to Predict the Type of Dementia During Everyday Stair Climbing
| https://www.disabilityinnovation.com/publications?page=8&type=report+journal-paper+editorial+book |
Man up, Graeme. Beautiful game is not just for guys behaving badly. - Free Online Library
Free Online Library: Man up, Graeme. Beautiful game is not just for guys behaving badly.(News; Opinion, Columns) by " Sunday Mail (Glasgow, Scotland)" ; News, opinion and commentary General interest
Man up, Graeme. Beautiful game is not just for guys behaving badly.
Citations:
MLA style:"Man up, Graeme. Beautiful game is not just for guys behaving badly.." The Free Library. 2022 MGN Ltd. 04 Jul. 2023 https://www.thefreelibrary.com/Man+up%2c+Graeme.+Beautiful+game+is+not+just+for+guys+behaving+badly.-a0714517379
Chicago style: The Free Library. S.v. Man up, Graeme. Beautiful game is not just for guys behaving badly.." Retrieved Jul 04 2023 from https://www.thefreelibrary.com/Man+up%2c+Graeme.+Beautiful+game+is+not+just+for+guys+behaving+badly.-a0714517379
APA style:Man up, Graeme. Beautiful game is not just for guys behaving badly.. (n.d.) >The Free Library.(2014). Retrieved Jul 04 2023 from https://www.thefreelibrary.com/Man+up%2c+Graeme.+Beautiful+game+is+not+just+for+guys+behaving+badly.-a0714517379
Byline: Jean Johansson
Graeme Souness was a legendary footballer and he's also an excellent pundit but I was surprised by his poor choice of words while commenting on a Chelsea v Tottenham match.
The fiery game featured two managers getting red-carded, fisticuffs and general bad behaviour all summed up by Souness as a "man's game". Eye roll. Haven't we moved on from perpetuating and supporting toxic masculinity and the oldfashioned "boys will be boys" rhetoric?
I would describe the scenes from the end of that game as disgraceful, immature and unprofessional but, hey, that's just me and is probably why I host property programmes, not football shows.
I have had a brief foray into the world of sports - I once auditioned for a big sports broadcaster and was told from a co-presenter I was "easy on the eye" and years later I filmed a pilot for a football preview show where the panel of (all male) experts sat glaring at me like I was an alien from outer space.
Souness has made women g a unwelcome
I'm sure the likes of Kirsty Gallagher, Hayley McQueen and Eilidh Barbour have plenty of stories of sexism and misogyny to recount.
Earlier this year Barbour walked out of a Scottish football event over sexism, tweeting that the event had made her feel "unwelcome".
And that's just it. What Souness said has made a lot of women in the game feel unwelcome.
hat said a lot of in the feel
What's even worse is that he could have easily avoided criticism by simply saying sorry for his careless phrasing but instead he doubled down on his gaffe and lost the respect of a lot of female professional footballers and fans.
I wasn't offended that he called the sport "a man's game" but I cringed at the fact he was sat next to 144-capped
England player Karen Carnay when he said it. Surely he must be able to admit it was the wrong language to use, especially as the England Women's team recently became European champions.
It was the Lionesses who brought football "home", not the men, so they deserve the respect of everyone connected to the game.
Live TV isn't easy. It's fast-moving and high energy and, in a viral world where every word is scrutinised and judged, presenters now have to think very carefully about each sentence they utter. I know the buzz of live studio shows - mistakes will be made but they can just as quickly be corrected.
It was bad timing and a careless choice of words to use but it's not that deep so why let it turn into a huge furore instead of instantly clearing up any misunderstanding?
For Souness to try to clarify later what he said without an apology was beneath him.
The clip went viral and made headlines and incited a wave of misogyny and idiotic responses on social media.
If they'd just stop shouting about "FOOTBALL TURNING WOKE" and listen to women who are also part of the sport, there may be space for constructive conversations around ensuring the message is clear - football is for everyone.
And that's said has
What Souness said
has made a lot of women in the game feel unwelcome.
and
CAPTION(S):
DIGGING A HOLE Graeme Souness
| https://www.thefreelibrary.com/Man+up,+Graeme.+Beautiful+game+is+not+just+for+guys+behaving+badly.-a0714517379 |
Promised Blood: Difference between revisions - Puella Magi Wiki
Promised Blood: Difference between revisions
Revision as of 12:19, 9 June 2021 (view source) Warcraft278 (talk|contribs) ( →Trivia) ← Older edit Latest revision as of 21:51, 23 May 2023 (view source) Karminja (talk|contribs) m ( →Known Members)
(21 intermediate revisions by 8 users not shown)
Line 1: Line 1:
[[File:102601 comment promise.jpg|500px|thumb|right]] [[File:102601 comment promise.jpg|500px|thumb|right]]
'''Promised Blood''' is an organization in [[Kamihama City]] consisting of magical girls from {{nihongo|'''Futatsugi City'''|二木市|Futatsugi-shi}}. They act as one of the game's antagonists in Arc 2 of [[Magia Record]]. '''Promised Blood''' is an organization in [[Kamihama City]] consisting of magical girls from {{nihongo|'''Futatsugi City'''|二木市|Futatsugi-shi}}. They act as one of the game's antagonists in Arc 2 of [[Magia Record]].
*'''Faction name :''' Promised Blood
*''"Girls who took an oath of sisterhood at the end of the conflict over witches"''
*'''Type :''' Violent and egoistic
*'''Goal :''' Putting an end to the conflict by taking the system to the hometown
*'''Atmosphere :''' Cold and tense
*'''Ideology :''' Don't care about the others as long as we are saved
*'''Internal relationship :''' Keeping a proper distance and solemn
*'''Keywords :''' Blood oath, Three sisters and their minions, Murder, Abandoned train depot
==Summary== ==Summary==
They are the remains of three Futasugi magical girl gangs: {{nihongo|'''The Ryuugasaki'''|竜ケ崎|Ryūgasaki}} faction, {{nihongo|'''The Torayamachi'''|虎屋町|Torayamachi}} faction and finally, {{nihongo|'''The Jyanomiya'''|蛇の宮| Jyanomiya}} faction. Because of the [[Wings of Magius]] work, there was a severe drought of Witches in areas outside of Kamihama, which ultimately led to a very bloody civil war in Futatsugi between the three gangs. After lotsof fighting, the leadersof the gangs eventually decided that they needed to unite if they were all going to survive.
They are the remains of three Futasugi magical girl gangs: {{nihongo|'''The Ryuugasaki'''|竜ケ崎|Ryūgasaki}} faction, {{nihongo|'''The Torayamachi'''|虎屋町|Torayamachi}} faction and finally, {{nihongo|'''The Janomiya'''|蛇の宮| Janomiya}} faction. Because of the [[Wings of Magius]] 'swork, there was a severe drought of Witches in areas outside of Kamihama, which ultimately led to a very bloody civil war in Futatsugi between the three gangs. After monthsof fighting and dozens of deaths, they learned thatthe Magius had caused their Witch drought and united on the basisof vengeance. Their goal in Arc 2 is to steal Kamihama’s Automatic Purification System as revenge forthe Magius stealing their witches and causing so many deaths.
They soon learned about Kamihama's Witch surplus and Doppel system, and are currently tryingto invadethe citywith the goal of eliminating its native magical girls and taking the territory and Doppel barrier for themselves. Yuna, in particular, blames Kamihama for the Futatsugi gang war and has become so angry that it has resulted in a change in her appearance. As of Arc 2 Chapter 7, {{spoiler|they finally put an endto the conflictwith the Union. }}
==Organization== ==Organization==
===Leaders=== ===Leaders===
The original leaders of the three factions of Futatsugi City. They united as one group and serve as the leaders of Promised Blood: The original leaders of the three factions of Futatsugi City. They united as one group and serve as the leaders of Promised Blood:
*[[Yuna Kureha]] (former leader of the Torayamachi faction) *[[Yuna Kureha]] ( also known as “the Fang”;former leader of the Torayamachi faction)
*[[Ao Kasane]] (former leader of the Jyanomiyafaction; Temporary Undercoverin the Ryuugasaki faction during the Futatsugi civil war) *[[Ao Kasane]] ( also known as “the Venom”;former leader of the Janomiyafaction; temporarily undercoverin the Ryuugasaki faction during the Blood Tragedy; {{spoiler|defects to Neo-Magius in Arc 2 Chapter 8}})
*[[Juri Oba]] (former leader of the Ryuugasaki faction) *[[Juri Oba]] ( also known as “the Flame”;former leader of the Ryuugasaki faction)
[[Hikaru Kirari]], while not a leader, acts as a direct subordinate of the three. [[Hikaru Kirari]], while not a leader, acts as a direct subordinate of the three.
Line 20: Line 30:
Several Magical Girls have been sent in to infiltrate and investigate Kamihama, in an aim to learn more about the purification system that's in place: Several Magical Girls have been sent in to infiltrate and investigate Kamihama, in an aim to learn more about the purification system that's in place:
*[[Ranka Chizu]] (former member of the Ryuugasaki faction) *[[Ranka Chizu]] (former member of the Ryuugasaki faction)
*[[Sakuya Suzuka]] (former member of the Torayamachi faction) *[[Sakuya Suzuka]] (former member of the Torayamachi faction ; {{spoiler|deceased}})
===Known Members=== ===Known Members===
Other known members of Promised Blood that operate in other capacities. Other known members of Promised Blood that operate in other capacities.
*[[ UlalaYume]] ( Associate, outsider from other city) *[[ UraraYume]] ( undercover member of [[Folklore of Zero]] {{spoiler|who leaves in Arc 2 Chapter 8 following Promised Blood’s disbandment}})
*[[Hikaru Kirari]] (also known as 'The Horse'; Temporary Undercoverin the Jyanomiyafaction during the Futatsugi civil war) *[[Hikaru Kirari]] (also known as “the Horse”; Torayamachi member temporarily undercoverin the Janomiyafaction during the Blood Tragedy)
===Futatsugi City Magical Girls=== ===Futatsugi City Magical Girls===
Line 67: Line 77:
File:青F.png File:青F.png
</gallery> </gallery>
== Gallery ==
<gallery>
File:102802 pb tactics1.jpg
File:102802 pb tactics2.jpg
File:102802 pb tactics3.jpg
File:102802 pb tactics4.jpg
File:102802 pb tactics4.jpg
File:102802 pb triumph.jpg
File:102804 yuna history.jpg
File:103202 promisedblood.jpg
File:103202 promisedblood leader out.jpg
</gallery>
== Trivia == == Trivia ==
* The names of the former factions refer to animals. In particular, ''Ryuu''gasaki and ''Tora''yamachi refer to the duality between dragon and tiger, respectively, while '' Jya''nomiya refers to a snake. It should be noted that Ryuugasaki and Torayamachi in particular were bound in a rivalry. * The names of the former factions refer to animals. In particular, ''Ryuu''gasaki and ''Tora''yamachi refer to the duality between dragon and tiger, respectively, while '' Ja''nomiya refers to a snake. It should be noted that Ryuugasaki and Torayamachi in particular were bound in a rivalry.
*Yuna, Juri and Ao forming a sisterhood is likely referencing the [https://en.wikipedia.org/wiki/Oath_of_the_Peach_Garden Oath of the Peach Garden] in the historical novel about Three Kingdoms in China. *Yuna, Juri and Ao forming a sisterhood is likely referencing the [https://en.wikipedia.org/wiki/Oath_of_the_Peach_Garden Oath of the Peach Garden] in the historical novel about Three Kingdoms in China.
**In the Oath of the Peach Garden, Liu Bei, Guan Yu and Zhang Fei became sworn brothers although they are not related by blood. **In the Oath of the Peach Garden, Liu Bei, Guan Yu and Zhang Fei became sworn brothers although they are not related by blood.
Line 74: Line 98:
***This is basically what Yuna, Juri and Ao did at the end of [[Magia Record Story Crimson Resolve|Crimson Resolve]], hence the name: Promised Blood. But in their case, they cut their wrists instead of their fingers. ***This is basically what Yuna, Juri and Ao did at the end of [[Magia Record Story Crimson Resolve|Crimson Resolve]], hence the name: Promised Blood. But in their case, they cut their wrists instead of their fingers.
* In the middle part of their logo, there is a spiked club, or a ''Kanabo'', which is [[Yuna Kureha| Yuna]]'s weapon. * In the middle part of their logo, there is a spiked club, or a ''Kanabo'', which is [[Yuna Kureha| Yuna]]'s weapon.
* The Promised Blood were a structured and hierarchical group with the three sisters - [[Yuna Kureha|First-born Sister(長女, ''Chōjo'')]], [[Juri Oba|Second-born Sister(次女, ''Jijo'')]] , [[Ao Kasane|Third-born Sister(三女, ''Sanjo'')]] (boss, regarded as a surrogate Big Sister) at the top and Younger Sister(妹, ''imouto'') (gang members, regarded as a surrogate Younger Sister) at the bottom. This hierarchy resembles a structure similar to the family – like a Yakuza's hierarchy structure(oyabun-kobun relationship) that similarto the family. * The Promised Blood were a structured and hierarchical group with the three sisters - [[Yuna Kureha|First-born Sister(長女, ''Chōjo'')]], [[Juri Oba|Second-born Sister(次女, ''Jijo'')]] , [[Ao Kasane|Third-born Sister(三女, ''Sanjo'')]] (boss, regarded as a surrogate Big Sister) at the top and Younger Sister(妹, ''imouto'') ( subordinategang members, regarded as a surrogate Younger Sister) at the bottom. This hierarchy resembles a structure similar to the family – like a Yakuza's hierarchy structure(oyabun-kobun relationship) .
* During the battle between Torayamachi and Ryuugasaki on Monzenbashi Bridge, each faction is shownto have 18 members (plus 2 in Ryuugasaki and 1 in Torayamachi who did not participate in the battle). As 11 more girls died beforethe formation of Promised Blood, it can be assumed Promised Blood has about 28 members (not including Ulala).
[[Category:Organizations]] [[Category:Organizations]]
Promised Blood
is an organization in
Kamihama City
consisting of magical girls from
Futatsugi City
( 二木市 , Futatsugi-shi)
. They act as one of the game's antagonists in Arc 2 of
Magia Record
.
Faction name :Promised Blood
"Girls who took an oath of sisterhood at the end of the conflict over witches"
Type :Violent and egoistic
Goal :Putting an end to the conflict by taking the system to the hometown
Atmosphere :Cold and tense
Ideology :Don't care about the others as long as we are saved
Internal relationship :Keeping a proper distance and solemn
Keywords :Blood oath, Three sisters and their minions, Murder, Abandoned train depot
Contents
1 Summary
2 Organization
2.1 Leaders
2.2 Infiltration
2.3 Known Members
2.4 Futatsugi City Magical Girls
2.4.1 Executive Soldiers
2.4.2 General Soldiers
2.4.3 Nameless Soldiers
3 Gallery
4 Trivia
Summary
They are the remains of three Futasugi magical girl gangs:
The Ryuugasaki
( 竜ケ崎 , Ryūgasaki)
faction,
The Torayamachi
( 虎屋町 , Torayamachi)
faction and finally,
The Janomiya
( 蛇の宮 , Janomiya)
faction. Because of the
Wings of Magius
's work, there was a severe drought of Witches in areas outside of Kamihama, which ultimately led to a very bloody civil war in Futatsugi between the three gangs. After months of fighting and dozens of deaths, they learned that the Magius had caused their Witch drought and united on the basis of vengeance. Their goal in Arc 2 is to steal Kamihama’s Automatic Purification System as revenge for the Magius stealing their witches and causing so many deaths.
As of Arc 2 Chapter 7,
they finally put an end to the conflict with the Union.
Organization
Leaders
The original leaders of the three factions of Futatsugi City. They united as one group and serve as the leaders of Promised Blood:
Yuna Kureha(also known as “the Fang”; former leader of the Torayamachi faction)
Ao Kasane(also known as “the Venom”; former leader of the Janomiya faction; temporarily undercover in the Ryuugasaki faction during the Blood Tragedy; defects to Neo-Magius in Arc 2 Chapter 8)
Juri Oba(also known as “the Flame”; former leader of the Ryuugasaki faction)
Hikaru Kirari
, while not a leader, acts as a direct subordinate of the three.
Infiltration
Several Magical Girls have been sent in to infiltrate and investigate Kamihama, in an aim to learn more about the purification system that's in place:
Ranka Chizu(former member of the Ryuugasaki faction)
Sakuya Suzuka(former member of the Torayamachi faction; deceased)
Known Members
Other known members of Promised Blood that operate in other capacities.
Urara Yume(undercover member of Folklore of Zero who leaves in Arc 2 Chapter 8 following Promised Blood’s disbandment)
Hikaru Kirari(also known as “the Horse”; Torayamachi member temporarily undercover in the Janomiya faction during the Blood Tragedy)
Futatsugi City Magical Girls
The lowest ranking members of the group. Nameless magical girls only identified by rank, they are the ones wearing hoodies or vests and a face mask sometimes adorned with spray-painted fangs.
Executive Soldiers
General Soldiers
Nameless Soldiers
Gallery
Trivia
The names of the former factions refer to animals. In particular, Ryuugasaki and Torayamachi refer to the duality between dragon and tiger, respectively, while Janomiya refers to a snake. It should be noted that Ryuugasaki and Torayamachi in particular were bound in a rivalry.
Yuna, Juri and Ao forming a sisterhood is likely referencing the
Oath of the Peach Garden
in the historical novel about Three Kingdoms in China.
In the Oath of the Peach Garden, Liu Bei, Guan Yu and Zhang Fei became sworn brothers although they are not related by blood.
This ceremony later evolved over time in the mafia world, as during the similar ceremony, the participants cut their fingers, let blood flowed out and mixed into their drink, then drink them together, as if their blood has blended together to make them siblings.
This is basically what Yuna, Juri and Ao did at the end ofCrimson Resolve, hence the name: Promised Blood. But in their case, they cut their wrists instead of their fingers.
In the middle part of their logo, there is a spiked club, or a Kanabo, which isYuna's weapon.
The Promised Blood were a structured and hierarchical group with the three sisters -First-born Sister(長女, Chōjo ),Second-born Sister(次女, Jijo ),Third-born Sister(三女, Sanjo ) (boss, regarded as a surrogate Big Sister) at the top and Younger Sister(妹, imouto) (subordinate gang members, regarded as a surrogate Younger Sister) at the bottom. This hierarchy resembles a structure similar to the family – like a Yakuza's hierarchy structure(oyabun-kobun relationship).
During the battle between Torayamachi and Ryuugasaki on Monzenbashi Bridge, each faction is shown to have 18 members (plus 2 in Ryuugasaki and 1 in Torayamachi who did not participate in the battle). As 11 more girls died before the formation of Promised Blood, it can be assumed Promised Blood has about 28 members (not including Ulala).
Category
:
Organizations
| https://wiki.puella-magi.net/w/index.php?diff=136876&oldid=108333 |
Azole resistance in Aspergillus fumigatus isolates from lung transplant recipients with cystic fibrosis: preliminary results - Aspergillus and Aspergillosis
Azole resistance in Aspergillus fumigatus isolates from
lung transplant recipients with cystic fibrosis: preliminary
results
Ref ID: 19378
Author:
F. Choukri,2 F. Morio,3 R. Guillemain,4 V. Boussaud,4 C. Amrein,4E.M. Billaud,5 P.Le Pape,3 J. Guillot,6 F. Botterel2 andE. Dannaoui1
Author address:
1Mycology, AP-HP, H^opital Europ!een Georges Pompidou andUMR BIPAR, Dynamyc, Paris, France; 2Mycology, APHP,H^opital Henri Mondor, and UMR BIPAR, Dynamyc, Cr!eteil,France; 3Parasitologie-Mycologie, Institut de Biologie, CHU deNantes and EA115
Full conference title:
6th Trends in Medical Mycology 2013
Date: 11 October 2014
Abstract:
Objectives Azole resistance in Aspergillus fumigatus is an emergingproblem. The mechanism of resistance is mostly related to mutationsin the CYP51A gene encoding 14-alpha-demethylase, the target ofazoles drugs.Azole resistance can be probably acquired through two distinctways that are long term azole treatment or inhalation of de novoazole resistant isolates from our environment. Importantly, both sce-nario can be distinguished as their underlying mechanisms differ, thelatter involving not only mutations in the CYP51A gene but also atandem repeat in its promoter region.The aim of the study was to screen for azole resistance a collectionof A. fumigatus isolates recovered from cystic fibrosis lung-transplantrecipients (CF-LTx) over a 12-year period (2001-2012) at a singlecenter. The molecular mechanisms leading to azole resistance werealso investigated.Methods The screening was performed by subculturing each isolateon RPMI agar plates supplemented with itraconazole (4 mg/L) andvoriconazole (1 mg/L). In vitro resistance was confirmed by the EU-CAST reference method. EUCAST clinical breakpoints were used tocategorize the isolates. For each azole resistant isolate, the wholeCYP51A gene and its promoter were sequenced and compared withthat of a wild type isolate (GenBank acc. number AF338659).Results We present here preliminary results for three patients(Table) with A. fumigatus azole resistant isolates.Most of the isolates displayed azole cross-resistance. TR34/L98Hwas the most prevalent mutation being recovered from 5 out of the8 isolates (in patients 1 and 2). At least for patient 1, our data sup-port the acquisition of the azole resistant isolate through environ-mental exposure as this patient had not been given azole therapybefore recovering the first azole-resistant isolate. Other amino acidsubstitutions (codons 54 and 216) have been previously reported inpatients receiving long term therapy suggesting that both mutationsare probably the result of selective pressure in the patient itself.Conclusions This preliminary study confirmed the occurrence ofazole resistance (with distinct molecular mechanisms) in A. fumigatusisolates recovered from cystic fibrosis lung transplant patients. These findings highlight again the need for systematic antifungal suscepti-bility testing of Aspergillus spp. recovered in this patient population.
Abstract Number: p018
Conference Year: 2013
Link to conference website: NULL
New link: NULL
Conference: Select conference AAA 1st (2004) AAA 2nd (2006) AAA 3rd (2008) AAA 4th (2010) AAA 5th (2012) AAA 6th (2014) AAA 7th (2016) AAA 8th (2018) AAA 9th (2020) AAAAI 2000 (56th) AAAAI 2001 (57th) AAAAI 2002 (58th) AAAAI 2003 (59th) AAAAI 2004 (60th) AAAAI 2005 (61st) AAAAI 2006 (62nd) AAAAI 2007 (63rd) AAAAI 2008 (64th) AAAAI 2009 (65th) AAAAI 2010 (66th) AAAAI 2011 (67th) AAAAI 2012 (68th) AAAAI 2013 (69th) AAAAI 2014 (70th) AAAAI 2015 (71st) AAAAI 2016 (72nd) AAAAI 2017 (73rd) AAAAI 2019 AAAAI/WAO 2018 AAAM 2022 (10th) AAPS 2013 ALA-ATA All Russian CMMCM XI All Russian CMMCM XII All Russian CMMCM XIIV All Russian CMMCM XIV All Russian CMMCM XIX All Russian CMMCM XV All Russian CMMCM XVI All Russian CMMCM XVII All Russian CMMCM XVIII AMC 2013 AS, 2013 ASCPT 2013 ASCPT 2014 ASH 37th (1996) ASH 38th (1997) ASH 39th (1998) ASH 40th (1999) ASH 41st (2000) ASH 43rd (2001) ASH 44th (2002) ASH 45th (2003) ASH 46th (2004) ASH 47th (2005) ASH 48th (2006) ASH 49th (2007) ASH 50th (2008) ASH 51st (2009) ASH 52nd (2010) ASH 53rd (2011) ASH 54th (2012) ASH 55th (2013) ASH 56th (2014) ASH 57th (2015) ASH 58th (2016) ASH 59th (2017) ASH 60th (2018) ASH 61st (2019) ASM 100th (2000) ASM 101st (2001) ASM 102nd (2002) ASM 110th (2010) ASM 111th (2011) ASM 112th (2012) ASM 113th (2013) ASM 114th (2014) ASM 115th (2015) ASM 71st (1971) ASM 95th (1995) ASM 96th (1996) ASM 98th (1998) ASM 99th (1999) ASM microbe 1st (2016) ASM Microbe 2nd (2017) ASM/ESCMID (2019) Asperfest 10 (2013) Asperfest 11 (2014) Asperfest 12 (2015) Asperfest 13 (2016) Asperfest 14 (2017) Asperfest 15 (2018) Asperfest 6 (2009) Asperfest 7 (2010) Asperfest 8 (2011) Asperfest 9 (2012) ATS 2007 ATS 2008 ATS 2009 ATS 2010 ATS 2011 ATS 2012 ATS 2018 BIA 2013 BIA 2017 BIA 2018 BTS WM 2016 BTS WM 2018 BTS WM 2019 BTSWM 2010 CIPI 4th Coccidioidomycosis EAACI 2016 EAACI 2017 EAACI 2018 EAACI 2019 EAACI 2020 EBMT 2004 EBMT 35th (2009) EBMT 36th (2010) EBMT 37th (2011) EBMT 38th (2012) EBMT 39th (2013) EBMT 40th (2014) EBMT 41st (2015) EBMT 42nd (2016) EBMT 43rd (2017) EBMT 44th (2018) EBMT 45th (2019) ECC 3rd (2000) ECCMID 11th (2001) ECCMID 12th (2002) ECCMID 13th (2003) ECCMID 14th (2004) ECCMID 15th (2005) ECCMID 16th (2006) ECCMID 17th (2007) ECCMID 18th (2008) ECCMID 19th (2009) ECCMID 20th (2010) ECCMID 21st, ICC 27th (2011) ECCMID 22nd (2012) ECCMID 23rd (2013) ECCMID 24th (2014) ECCMID 25th (2015) ECCMID 26th (2016) ECCMID 27th (2017) ECCMID 29th (2019) ECCMID 30th (2020) ECCMID 9th (1999) ECFG 10th (2010) ECFG 11th (2012) ECFG 13th (2016) ECFG 14th (2018) ECFG 3rd (1996) ECFG 7th (2004) ECFG 8th (2006) ECFG 9th (2008) ECMM 2nd (1995) ECMM 5th (1999) ECMM 6th (2000) ERS 15th (2005) ERS 16th (2006) ERS 17th (2007) ERS 18th (2008) ERS 19th (2009) ERS 20th (2010) ERS 21st (2011) ERS 22nd (2012) ERS 26th (2016) ERS 27th (2017) ERS 28th (2018) ERS 29th (2019) ESOT 2013 European Federation of Biotechnology 7th (1995) FFI 12th (2002) FFI 13th (2003) FFI 14th (2004) FFI 15th (2005) FIS (2007) FIS 2017 FIS 2018 FIS 2019 FIS/HIS 2016 Focus on Fungal Infection 11 (2001) Focus on Fungal Infection 18 (2008) Focus on Fungal Infection 19 (2009) Focus on Fungal Infection 3 (1993) Focus on Fungal Infection 5 (1995) Focus on Fungal Infection 6 (1996) Focus on Fungal Infection 7 (1997) Fungal Genetics Conference 20th (1999) Fungal Genetics Conference 21st (2000) Fungal Genetics Conference 22nd (2001) Fungal Genetics Conference 23rd (2002) Fungal Genetics Conference 24th (2003) Fungal Genetics Conference 25th (2004) Fungal Genetics Conference 26th (2005) Fungal Genetics Conference 27th (2013) Fungal Genetics Conference 30th (2019) Fungal Update 2019 GCCMID 2018 ICAAC 33rd ICAAC 34th ICAAC 35th ICAAC 36th ICAAC 37th ICAAC 38th ICAAC 39th ICAAC 40th ICAAC 41st ICAAC 42nd ICAAC 43rd ICAAC 44th ICAAC 45th ICAAC 46th ICAAC 47th ICAAC 48th ICAAC 48th/IDSA 46th ICAAC 49th ICAAC 50th ICAAC 51st ICAAC 52nd (2012) ICAAC 53rd (2013) ICAAC 54th (2014) ICAAC 55th (2015) ICAAC, 53rd (2013) ICC 18th ICC 19th ICC 20th ICC 21st ICC 22nd ICC 24 th ICC 25th ICCC 9th ICMC Karachi (1st) ICMM 2011 ID Week 2018 ID week 2019 IDSA 33rd IDSA 34th IDSA 35th IDSA 36th IDSA 37th IDSA 38th IDSA 39th IDSA 40th IDSA 44th IDWeek 2012 IDWeek 2013 IDWeek 2014 IDWeek 2015 IDWeek 2016 IDWeek 2017 Infectious Diseases Society of America 41st Infectious Diseases Society of America 42nd Infectious Diseases Society of America 43rd International Fungal / Plant Cell Wall Meeting 1st Irish SGM ISEB 4th ISHAM 11th (1991) ISHAM 12th (1994) ISHAM 13th (1997) ISHAM 14th (2000) ISHAM 15th (2003) ISHAM 16th (2006) ISHAM 17th (2009) ISHAM 18th (2012) ISHAM 19th (2015) ISHAM 20th (2018) ISIIH 12th ISIIH 13th ISIIH 15th ISIIH 16th ISIIH, 14th LRD 5th MS 2013 MS 2014 MS 2015 MS 2016 MS 2017 MS 2018 MS 2019 RICAI 24th (2004) RICAI 25th (2005) RICAI 26th (2006) RICAI 27th (2007) RICAI 28th (2008) RICAI 29th (2009) RICAI 30th (2010) RICAI 31st (2011) RICAI 32nd (2012) RICAI 33rd (2013) RICAI 34th (2014) RICAI 35th (2015) SFRC (2007) SFRC (2009) SFRC (2010) SFRC (2011) SGM 156th (2005) SGM 157th (2005) SGM 158th (2006) SGM 160th (2007) SGM 161st (2007) SGM 163rd (2008) SGM 164th (2009) SGM 166th (2010) SGM 167th (2010) SGM 2012 SGM 2013 SIHAM SPE The genus Aspergillus TIFI 3rd TIFI 5th TIFI 6th TIMM (2019) TIMM 2nd (2010) TIMM 3rd (2011) TIMM 4th (2012) TIMM 5th (2013) TIMM 6th (2014) TIMM 7th (2015) TIMM 8th (2017) UK GNM, 1st WPCCID 6th
Title
Author
Year
Number
Poster
Novel qPCR demonstrates azole-resistant TR34/L98H and TR46/Y121F/T289A Aspergillus fumigatus, in air sporesamplings around Danish agricultural fields
v
Rasmus Krøger Hare *1, Thies Marten Heick 2, Lise Jørgensen 2, Maiken C. Arendrup 1;3;4
6173
n/a
Gliotoxin, a new candidate against methicillin-resistant Staphylococcus aureus showing synergistic effect with classical antimicrobial drugs in Caenorhabditis elegans infection model
v
Patricia Esteban *1, Sergio Redrado 2, Laura Comas 2, Cristina Seral 3, Julián Pardo Jimeno 1;4;5, Maykel Arias 2, Eva María Gálvez 2
6144
n/a
Diagnostic value of the IMMY Aspergillus LFA on bronchoalveolar lavage fluid of intensive care patients
v
Albert Dunbar 1, Toine Mercier *2, Vincent Veldhuizen 1, Bart Rijnders 1
6119
n/a
Presence and distribution of fungal species and dermatophytes in nail and skin samples
v
Lilla Marki 1, Andreas Brachner 2, Bernhard Ronacher 2, Helena Enroth *1
6065
n/a
Basophil activation test use for identification of fungal sensitisation in severe asthma patients
v
Yana Kozlova 1, Ekaterina Frolova 2, Aleksandra Uchevatkina 2, Larisa Filippova 2, Oleg Aak 2, Galina Solovjeva 2, Valeriy Kuznetsov 1,Natalya Vasilyeva 2, Nikolai Klimko *1
6056
n/a
Optimisation of culture protocol for the recovery of fungal pathogens from expectorated sputum of cystic fibrosis patients
v
Warda Memon *1, Relinda Abellera 1, Sean X. Zhang 1;2, Remedios Marayan 1
5763
n/a
A leak in compliance with ventilation system maintenance instructions resulted in an aspergillosis outbreak
v
Gulcin Dizman, Gokhan Metan, Dolunay Gülmez, Zeynep Bastug, Ömer Dizdar, Sevtap Arikan-Akdagli, Serhat Unal
5603
n/a
Antifungal susceptibility patterns among clinical isolates of Aspergillus fumigatus from paediatric cystic fibrosis patients in Greece: a laboratory-based study with focus on azole resistance
v
Maria Siopi *1, Angeliki Stathi 2, Helen Kirikou 2, Levantia Zachariadou 2, Spyros Pournaras 1, Joseph Meletiadis 1;3
5558
n/a
Prevalence of azole resistance in clinical Aspergillus fumigatus isolates in Greece
v
Maria Siopi *1, Olga Rivero-Menendez 2, Athanasios Chatzimoschou 3, Aristea Velegraki 4;5, Ana Alastruey-Izquierdo 2, Emmanuel Roilides 3, Georgia Vrioni 4, Spyros Pournaras 1, Joseph Meletiadis 1;6
5520
n/a
Interest of immunoblotting with Aspergillus fumigatus western blot IgE assay for the differential diagnosis of IgE sensitisation and allergic broncho pulmonary aspergillosis
v
Raphaël Piarroux *1, Stéphane Ranque 2, Joana Vitte 2
5493
n/a
24
25
| https://www.aspergillus.org.uk/conference_abstracts/azole-resistance-in-aspergillus-fumigatus-isolates-fromlung-transplant-recipients-with-cystic-fibrosis-preliminaryresults/?wpv_paged=25&wpv_view_count=62516-TCPID26785 |
Pharmaceuticals | Free Full-Text | Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects
Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.
Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects
by Hyewon Chung 1 , Jong-Min Kim 2 , Jin-Woo Park 2,3 , Jihyeon Noh 2 , Kyoung-Ah Kim 2 and Ji-Young Park 2,*
Author to whom correspondence should be addressed.
Pharmaceuticals 2023 , 16 (3), 364; https://doi.org/10.3390/ph16030364
Received: 16 January 2023 / Revised: 17 February 2023 / Accepted: 23 February 2023 / Published: 27 February 2023
(This article belongs to the Special Issue Anticoagulants and Antiplatelet Drugs )
Abstract
Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.
Keywords:
dabigatran
;
simvastatin
;
interaction
;
pharmacokinetics
1. Introduction
Dabigatran, one of the novel oral anticoagulants, is a direct thrombin inhibitor [ 1 ]. It is used for the prevention and treatment of deep venous thrombosis and pulmonary embolism as well as for reducing risks of stroke and systemic embolism in patients with non-valvular atrial fibrillation [ 2 ]. Dabigatran etexilate is administered to patients as a prodrug since dabigatran is not orally available [ 3 ]. Its absolute bioavailability has been reported to be 7% [ 4 ]. After absorption, it undergoes two sequential metabolisms to form dabigatran and its glucuronide form, which are active metabolites pharmacologically. Carboxyesterase (CES1) is involved in the disposition of dabigatran etexilate [ 5 ]. It is rapidly absorbed and metabolized to dabigatran reaching maximum concentration (C max ) at about 1.25–1.5 h after a single dose administration in healthy subjects [ 6 ]. Dabigatran is further metabolized to dabigatran acylglucuronide by uridine 5-diphospho (UDP)-glucuronosyltransferase (UGT) in the liver. Glucuronidation of the carboxylate moiety is the major human metabolic pathway of dabigatran and UGT2B15 is the major isoform involved in its glucuronidation [ 7 ]. Plasma protein binding of dabigatran is 35%, and 85% of the intravenous dabigatran is excreted via urine [ 4 ].
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that can lower cholesterol and reduce cardiovascular complications or mortality [ 8 ]. Statins can also be co-prescribed for patients taking dabigatran. Patients with atrial fibrillation with asymptomatic atherosclerosis should be treated with a statin and an oral anticoagulant [ 9 ]. Two studies including more than 90,000 patients using direct oral anticoagulant have reported a concomitant use of atorvastatin in 31.5% and 27.6% of patients [ 10 , 11 ].
Statins have a direct antithrombotic effect. They might interact with other antithrombotic drugs pharmacodynamically. It is known that co-prescription of a statin and warfarin can increase the risk of bleeding in patients [ 12 , 13 ]. Similarly, a case-control study has reported an association between major hemorrhage after use of dabigatran and co-administration with simvastatin [ 14 ]. However, reports are controversial since another clinical study has shown that the use of statin can reduce the risk of bleeding complication in patients taking dabigatran [ 15 ].
Simvastatin is a lactone form of prodrug for simvastatin acid, the active substance [ 16 ]. Time to reach C max (T max ) is about 1.8 h and 4.2 h for simvastatin and simvastatin acid, respectively [ 17 ]. It is extensively bound to plasma proteins and is primarily metabolized by CYP3A4 and excreted via bile [ 18 ]. It has a relatively short elimination half-life of about 2.8 h and 4.4 h for simvastatin and simvastatin acid, respectively [ 17 ]. Both dabigatran etexilate and simvastatin are substrates of P-glycoprotein (P-gp). Their competitive activities for P-gp might affect pharmacokinetics of dabigatran followed by bleeding complications. A clinical study has shown that co-administration of verapamil, a known P-gp inhibitor, with dabigatran etexilate can increase systemic exposure of dabigatran by 179%, indicating that dabigatran is a substrate of P-gp [ 19 ].
In addition to P-gp, there is also a possibility of simvastatin affecting pharmacokinetics of dabigatran via CES1 metabolism. Simvastatin shows inhibitory effects on imidapril hydrolase activities by recombinant CES1A1 and human liver microsomes [ 20 ]. Another in vitro study has reported that simvastatin can inhibit CES1-mediated hydrolysis of clopidogrel [ 21 ]. Therefore, simvastatin might inhibit the metabolism of dabigatran etexilate into dabigatran, leading to reduction of dabigatran levels and reduced anticoagulant effects.
Based on the wide use of statin and its potential concomitant use with dabigatran, pharmacokinetic interaction studies between atorvastatin and dabigatran in healthy volunteers have been conducted. No influence of atorvastatin on pharmacokinetics or pharmacodynamics of dabigatran has been reported [
22
]. However, no clinical studies evaluating pharmacokinetic interactions between dabigatran and simvastatin, which share metabolizing enzyme and drug transporter with each other, have been reported yet. Therefore, the objective of this study was to explore the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran in healthy subjects.
2. Results
2.1. Subjects
A total of 12 subjects were enrolled for this study. All 12 subjects were administered with dabigatran etexilate alone followed by 7 days of simvastatin administration where dabigatran etexilate was co-administered at the seventh day of simvastatin administration. No subject was dropped out and all 12 subjects completed the study. All subjects were males and their mean age, height, weight, and body mass index (BMI) were 25.8 years, 174 cm, 71.6 kg, and 23.6 kg/m 2 , respectively. With the exception of one subject experiencing mild pharyngitis, which resolved, there were no adverse events or clinically significant changes in vital signs, clinical laboratory tests, or electrocardiogram.
2.2. Effects of Simvastatin on Dabigatran Pharmacokinetics
Plasma concentrations of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were assessed before and after treatment with simvastatin. Average concentration profile of dabigatran etexilate was similar regardless of administration of simvastatin. However, those of dabigatran and dabigatran acylglucuronide tended to be higher after simvastatin co-administration compared to those without simvastatin co-administration (
Figure 1
). Pharmacokinetic characteristics of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide did not exhibit any statistically significant difference between administration of dabigatran alone and co-administration with simvastatin (
Table 1
). When co-administrated with simvastatin, C
max
values for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 138%, 124%, and 163% of values when dabigatran was administrated alone, respectively. Similarly, area under the time–concentration curve from 0 h to the last measurable concentration (AUC
last
) values of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide after co-administration with simvastatin were 147%, 121%, and 157% of values when they were administered alone, respectively. The mean AUC
last
ratio of dabigatran acylglucuronide to dabigatran was 3.03 when dabigatran was administered alone. The ratio was higher (3.65) after co-administration with simvastatin (
p
= 0.0025).
Figure 1. Mean plasma concentration profiles of ( A ) dabigatran etexilate, ( B ) dabigatran, and ( C ) dabigatran acylglucuronide after administration of 150 mg dabigatran etexilate with or without simvastatin.
Table 1. Pharmacokinetic parameters of dabigatran etexilate, dabigatran, and dabigatran glucuronide before and after co-administration of simvastatin.
2.3. Effects of Simvastatin on Dabigatran Anticoagulant Effects
Baseline thrombin generation and coagulation assays measured before dabigatran administration were not different according to simvastatin administration (
Table 2
). Mean activated partial prothrombin time (aPTT), prothrombin time (PT), diluted PT (dPT), and thrombin time (TT) rose after the administration of dabigatran etexilate to reach their highest mean value at 2–4 h. Coagulation profiles were comparable between administration of dabigatran alone and co-administration with simvastatin (
Figure 2
). Area under the effect curve (AUEC) and maximum response (R
max
) values of pharmacodynamic parameters were not significantly different according to simvastatin co-administration except for AUEC of PT (
Table 3
). Thrombin generation assay (TGA) also showed similar profiles in terms of peak thrombin concentration (C
max
), endogenous thrombin potential (AUC), lag time, and T
max
(
Figure 3
).
Figure 2. Coagulation assay profiles after administration of dabigatran etexilate alone and co-administration with simvastatin (activated partial prothrombin time (aPTT, ( A )), prothrombin time (PT (s), ( B )), prothrombin time (PT (INR), ( C )), diluted PT (dPT, ( D )), thrombin time ( E ), and fibrinogen ( F )).
Figure 3. Thrombin generation assay profiles after administration of dabigatran alone and co-administration with simvastatin (( A ) Peak thrombin concentration (C max ), ( B ) endogenous thrombin potential (AUC), ( C ) lag time, and ( D ) time to C max (T max )).
Table 2. Baseline thrombin generation and coagulation assays measured before dabigatran etexilate administration.
Table 3. Pharmacodynamic parameters of dabigatran before and after co-administration of simvastatin.
3. Discussion
In this study, we first explored the possibility of drug interaction by determining the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran in humans. The Canadian Drug Safety and Effectiveness Research Network team reported that the use of simvastatin or lovastatin is associated with a higher risk of major hemorrhage than other statins in patients taking dabigatran etexilate who require statin therapy [
14
]. It has been hypothesized that inhibition of intestinal P-gp by simvastatin increases dabigatran levels in blood, leading to potentiated anticoagulant effects of dabigatran since dabigatran is a substrate of P-gp. However, results of the present study did not show significant effects of simvastatin on dabigatran blood levels or anticoagulant effects.
AUC
last
values of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide after simvastatin co-administration increased 47%, 21%, and 57% compared to those after dabigatran administered alone, respectively. When the single dose pharmacokinetics of dabigatran etexilate is compared between healthy subjects and patients with renal impairment, the increase in exposure was 1.5 times in mild renal impairment patients [
2
]. Nevertheless, dose adjustment for these patients is not recommended. Therefore, pharmacokinetic changes observed in this study can be considered not clinically significant. Furthermore, anticoagulant effects including thrombin generation, PT, aPTT, dPT, and TT after dabigatran dosing were identical based on plasma concentration profiles over the time. Considering that dabigatran is a direct thrombin inhibitor, its anticoagulant effect would have moved the same way as blood dabigatran levels over the time [
6
]. Although AUEC of PT was statistically increased after simvastatin co-administration, it is difficult to establish clinical significance given that the R
max
was similar. Furthermore, other coagulation tests such as aPTT and TT, which are reported to be more sensitive tests for dabigatran than PT, remained unchanged after the co-administration [
23
,
24
].
We could not fully understand the reason(s) why simvastatin clinically interacted with dabigatran etexilate and thereby increased the risk of bleeding in patients taking dabigatran in previous publications. Our findings suggest that pharmacokinetic interaction between dabigatran and simvastatin is not a key factor that increases the bleeding risk. As our study failed to show significant effects of simvastatin on pharmacokinetics and pharmacodynamics of dabigatran, it can be assumed that simvastatin itself has an anticoagulant effect in addition to dabigatran. Anticoagulant properties of statins reported in experimental and clinical studies involve decreased tissue factor expression that results in reduced thrombin generation and attenuation of pro-coagulant reactions as well as enhanced endothelial thrombomodulin expression [
25
]. However, when we assessed anticoagulant effects of simvastatin without dabigatran, there was no significant difference observed in thrombin generation or coagulation assays between before and after once daily administration of simvastatin for 7 days.
Simvastatin is a known inhibitor of P-gp transport [ 26 , 27 ]. It is also a substrate for P-gp [ 28 ]. Given that dabigatran etexilate is the substrate for P-gp, findings presented in this study suggest that P-gp might not be the main factor that causes clinical drug interaction between simvastatin and dabigatran, which causes hemorrhage in patients taking the two drugs concomitantly. A previous study has shown that verapamil, a potent inhibitor of P-gp, can elevate systemic exposure of total dabigatran (dabigatran + dabigatran acylglucuronide) by 54% compared to dabigatran alone [ 19 ]. In the case of fexofenadine, a substrate of P-gp, verapamil elevated systemic exposure of fexofenadine more than two-fold (261% for S-fexofenadine and 234% for R-fexofenadine) [ 29 ]. It implies that dabigatran might be a weak substrate of P-gp and that interaction with simvastatin plays a minor role in pharmacokinetic variability of dabigatran through P-gp transport.
Interestingly, average dabigatran acylglucuronide levels tended to be increased more than dabigatran levels after simvastatin treatment in this study. As mentioned above, dabigatran etexilate is a substrate of P-gp. It is mainly converted to its active metabolite, dabigatran, by CES1. Dabigatran is further metabolized to dabigatran acylglucuronide by UGT in the liver. Assuming that simvastatin acts as an inhibitor for P-gp-mediated transport or CES1 metabolism of dabigatran etexilate, systemic exposure of dabigatran and its acylglucuronide might have increased simultaneously. However, geometric mean ratios (GMRs) of pharmacokinetic parameters for dabigatran acylglucuronide was higher than those for dabigatran. Accordingly, mean AUC ratio of dabigatran acylglucuronide to dabigatran was significantly higher after co-administration with simvastatin. This implies that simvastatin might enhance metabolism of dabigatran to its acylglucuronide form. It has been reported that simvastatin acid undergoes glucuronidation in human microsomes and forms its lactone form [
30
]. In addition, efficacy of simvastatin has been found to be associated with single nucleotide polymorphisms in UGT1A1 [
31
]. However, there is no confirmatory evidence of whether simvastatin can induce UGT.
Our study has some limitations that should be acknowledged. First, we assessed the pharmacokinetics and anticoagulant effects of dabigatran in healthy subjects after a single dose of dabigatran, even though dabigatran is used for a long-term period. However, the objective of the present study was to assess the possibility of drug interaction between dabigatran and simvastatin. A single dose of dabigatran was justified based on linear pharmacokinetic characteristics with dose-proportional increases in pharmacokinetic parameters of dabigatran [
6
]. We first hypothesized that simvastatin was a perpetrator that could influence dabigatran pharmacokinetics. Therefore, simvastatin treatment was carried out for 7 days considering its long-term clinical use and to assess whether it exhibited anticoagulant effects itself. Second, a relatively small sample size showed a poor statistical power, which was inevitable for a complete pharmacokinetic study design with various anticoagulant assays. To exclude inter-subject variability and carry-over effect of simvastatin, single sequence crossover study design was adopted. The sample size was determined based on 15.18% of intra-subject variability in pharmacokinetic parameters of dabigatran assuming drop-out rate of 15% [
32
].
4. Materials and Methods
4.1. Subjects
All subjects provided signed informed consent prior to the screening procedure, which included vital signs, clinical laboratory tests, electrocardiogram, physical examination, and medical history. Healthy male subjects aged 19 to 50 with BMI of 18.5 to 29.9 kg/m
2
were enrolled. Subjects who had clinically significant renal, gastrointestinal, hepatic, cardiovascular, respiratory, hematological, endocrinal, neurological, psychological, dermatological, or immune related medical condition or history were excluded. Other major exclusion criteria were: history of hypersensitivity to simvastatin or dabigatran, creatinine clearance less than 60 mL/min, aspartate aminotransferase or alanine aminotransferase exceeding two times of upper normal limit, and status of active bleeding or increased risk of bleeding, use of other anticoagulants or drugs known to have interaction with dabigatran or simvastatin prior to 2 weeks of study, participating in other clinical trials within 90 days of the study.
4.2. Study Design
An open-label, two-period, single sequence clinical study was conducted. After an overnight fast and drinking 200 mL of water one hour before drug administration, eligible subjects were administered with a capsule of dabigatran etexilate 150 mg (Pradaxa
®
) on the first day of the study. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained using EDTA tubes and citrate tubes, respectively. The samples were analyzed at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h post-dose of dabigatran etexilate. Subjects remained at fasting stage until 4 h after the administration. From the second day of this study, subjects took simvastatin 40 mg (Zocor
®
) with 200 mL of water once daily for seven days at a fasting state. To ensure compliance, subjects visited the study site for every drug administration. On the last day of simvastatin administration, subjects were administered with dabigatran etexilate 150 mg one hour after simvastatin administration. Blood samples were obtained at the same time point scheduled as the first day of the study. Adverse events were collected during the entire study period. This study was conducted in accordance with the Declaration of Helsinki, good clinical practice, and local regulation. The study was approved by the Institutional Review Board at Korea University Guro Hospital (2018GR0336, date of approval: 11 October 2018) and registered at ClinicalTrials.gov (NCT03728101).
4.3. Determination of Dabigatran Etexilate, Dabigatran, and Dabigatran Acylglucuronide
Separate plasma samples were kept frozen below −70 ℃ until analysis. Plasma concentrations of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were quantified using a high-performance liquid chromatography (Nanospace series SI-2, Shiseido Co., Ltd., Tokyo, Japan) coupled with tandem mass spectrometry (API4000, AB SCIEX LLC, Framingham, MA, USA) method [
33
]. The method was validated in terms of selectivity, linearity, precision, accuracy, recovery, matrix effect, and stability prior to the analysis. In brief, 100 μL of plasma samples were deproteinized using 400 μL of acetonitrile and centrifuged at 13,000×
g
for 20 min. Dabigatran-d3 was used as an internal standard. The supernatants were evaporated and then dissolved in a 300 μL mobile phase consisting of acetonitrile and 10 mM ammonium formate (215:85,
v
/
v
). These samples were injected onto an Atlantis HILIC Silica™ column (2.1 mm × 150 mm, 3 μm, Waters, Milford, MA, USA) at a flow rate of 0.3 mL/min. The mass spectrometer equipped with an electrospray ionization source was operated in a positive ion mode. Selected ion pairs of
m
/
z
629.464→290.100 for dabigatran etexilate,
m
/
z
472.300→289.100 for dabigatran,
m
/
z
648.382→289.100 for dabigatran acylglucuronide were detected. Calibration curves were linear over ranges of 0.2–500 ng/mL, 1–1000 ng/mL, and 1–1000 ng/mL for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide, respectively. The accuracies of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 95.84–109.44%, 99.4–103.42%, and 98.37–104.42%, respectively, while precisions of those were 3.84–9.79%, 1.07–8.76%, and 2.56–4.51%, respectively.
4.4. Anticoagulant Assay
Anticoagulant assays of aPTT, PT, dPT, TT, and fibrinogen were measured using STA
®
Compact Max (Stago, Asnieres, France) according to the manufacturer’s instructions. Briefly, 100 μL of plasma sample and STA
®
thrombin were mixed in a cuvette to measure TT. To measure PT, 100 μL of STA
®
Neoplastine
®
CI reagent was added to a cuvette with 50 μL of plasma. To measure aPTT, 50 μL of plasma sample was placed in a cuvette in the presence of STA
®
-PTT (50 μL) and 50 μL of 0.025 M CaCl
2
. For fibrinogen, 7.5 μL of plasma which was automatically diluted with Owren-Koller buffer was placed into a cuvette and then 50 μL of STA
®
-LIQID FIB was added.
TGA was performed using a Technothrombin
®
TGA kit (Technoclone, Vienna, Austria) on a fully automated, computer-controlled microplate reader (Flexstation 3; Molecular Devices, San Jose, CA, USA) with a 360 nm excitation wavelength and 460 nm emission wavelength [
34
]. In brief, 30 μL of plasma samples were mixed with 25 μL of 400 μmol/L fluorogenic substrate (Z-Gly-Gly-Arg-AMC; Bachem, Bubendorf, Switzerland). The assay was initiated by dispensing 10 μL of 5 pmol/L recombinant human tissue factor lipidated with synthetic phospholipids and 10 μL of 15 mmol/L CaCl
2
. TGA results are expressed as C
max
, AUC, T
max
, and lag time.
4.5. Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic parameters of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were derived from noncompartmental analysis using Phoenix Winnonlin
®
version 8.3 (Certara, Princeton, NJ, USA). Observed values from individual time-concentration profiles were used for C
max
and T
max
. Area under the time-concentration curve (AUC) was calculated using linear-up log-down trapezoidal rule. The AUC from 0 h to infinity (AUC
inf
) was calculated as follows: AUC
inf
= AUC + C
t
/k
e
, where C
t
was the last plasma concentration and k
e
was the elimination rate constant. The terminal elimination half-life (t
1/2
) was calculated as the natural logarithm of 2 divided by k
e
. Mean residence time (MRT) was calculated as area under the moment curve from time of dosing to the last measurable concentration divided by AUC
last
.
For pharmacodynamic assessment, Phoenix Winnonlin
®
version 8.3 (Pharsight, Mountain View, CA, USA) was used to calculate AUEC with the linear trapezoidal method and R
max
was directly determined from individual profiles.
4.6. Statistical Analysis
All statistical analyses were performed using SAS ® version 9.4 (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were used to summarize demographic, pharmacokinetic, and pharmacodynamic data. A linear mixed effects model was used to compare C max , AUC last , and AUC inf between two treatment periods. GMRs and their 90% confidence interval (CI) were derived from the model by applying the exponential function to the difference of least squares means between the two periods. Parameters before and after co-administration with simvastatin were compared using paired t -test, where p -values less than 0.05 were considered statistically significant.
5. Conclusions
In conclusion, results of the present study provide evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate in humans.
Author Contributions
Conceptualization, H.C. and J.-Y.P.; methodology, H.C., J.-M.K., J.-W.P. and J.N.; formal analysis, H.C. and J.-Y.P.; investigation, H.C., J.-M.K. and J.-W.P.; resources, H.C., K.-A.K. and J.-Y.P.; data curation, H.C.; writing—original draft preparation, H.C.; writing—review and editing, J.-M.K., J.-W.P., J.N., K.-A.K. and J.-Y.P.; project administration, H.C. and K.-A.K.; funding acquisition, H.C. All authors have read and agreed to the published version of the manuscript.
Funding
This study was supported by Korea University Guro Hospital ‘KOREA RESEARCH-DRIVEN HOSPITALS’ Grant (O1801461).
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki. It was approved by the Institutional Review Board of Korea University Guro Hospital (2018GR0336 and date of approval: 11 October 2018).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data presented in this study are available from the corresponding author upon reasonable request. The data are not publicly available due to the privacy issue of subjects.
Conflicts of Interest
The authors declare no conflict of interest.
References
Wienen, W.; Stassen, J.M.; Priepke, H.; Ries, U.J.; Hauel, N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb. Haemost. 2007 , 98 , 155–162. [ Google Scholar ]
PRADAXA® Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022512s041lbl.pdf (accessed on 13 September 2022).
Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin. Pharmacokinet. 2008 , 47 , 285–295. [ Google Scholar ] [ CrossRef ]
Blech, S.; Ebner, T.; Ludwig-Schwellinger, E.; Stangier, J.; Roth, W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab. Dispos. Biol. Fate Chem. 2008 , 36 , 386–399. [ Google Scholar ] [ CrossRef ][ Green Version ]
Laizure, S.C.; Parker, R.B.; Herring, V.L.; Hu, Z.Y. Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab. Dispos. Biol. Fate Chem. 2014 , 42 , 201–206. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Stangier, J.; Rathgen, K.; Stahle, H.; Gansser, D.; Roth, W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br. J. Clin. Pharmacol. 2007 , 64 , 292–303. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Ebner, T.; Wagner, K.; Wienen, W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: In vitro formation, stability, and pharmacological activity. Drug Metab. Dispos. Biol. Fate Chem. 2010 , 38 , 1567–1575. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005 , 366 , 1267–1278. [ Google Scholar ] [ CrossRef ]
Steffel, J.; Collins, R.; Antz, M.; Cornu, P.; Desteghe, L.; Haeusler, K.G.; Oldgren, J.; Reinecke, H.; Roldan-Schilling, V.; Rowell, N.; et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Eur. Eur. Pacing Arrhythm. Card. Electrophysiol. J. Work. Groups Card. Pacing Arrhythm. Card. Cell. Electrophysiol. Eur. Soc. Cardiol. 2021 , 23 , 1612–1676. [ Google Scholar ] [ CrossRef ]
Chang, S.H.; Chou, I.J.; Yeh, Y.H.; Chiou, M.J.; Wen, M.S.; Kuo, C.T.; See, L.C.; Kuo, C.F. Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA 2017 , 318 , 1250–1259. [ Google Scholar ] [ CrossRef ]
Harskamp, R.E.; Himmelreich, J.C.L.; Wong, G.W.M.; Teichert, M. Prescription patterns of direct oral anticoagulants and concomitant use of interacting medications in the Netherlands. Neth. Heart J. Mon. J. Neth. Soc. Cardiol. Neth. Heart Found. 2021 , 29 , 451–459. [ Google Scholar ] [ CrossRef ]
Douketis, J.D.; Melo, M.; Bell, C.M.; Mamdani, M.M. Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin? Am. J. Med. 2007 , 120 , 369.e9–369.e14. [ Google Scholar ] [ CrossRef ]
Schelleman, H.; Bilker, W.B.; Brensinger, C.M.; Wan, F.; Yang, Y.X.; Hennessy, S. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am. J. Med. 2010 , 123 , 151–157. [ Google Scholar ] [ CrossRef ][ Green Version ]
Antoniou, T.; Macdonald, E.M.; Yao, Z.; Hollands, S.; Gomes, T.; Tadrous, M.; Mamdani, M.M.; Juurlink, D.N.; Canadian Drug, S. Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation. CMAJ Can. Med. Assoc. J. = J. l’Association Med. Can. 2017 , 189 , E4–E10. [ Google Scholar ] [ CrossRef ][ Green Version ]
Ho, B.L.; Lin, Y.J.; Lin, S.F.; Chou, P.S.; Chen, C.F.; Lin, R.T.; Hu, H.H.; Chao, A.C. Statins and the risk of bleeding in patients taking dabigatran. Acta Neurol. Scand. 2019 , 139 , 455–461. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mauro, V.F. Clinical pharmacokinetics and practical applications of simvastatin. Clin. Pharmacokinet. 1993 , 24 , 195–202. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Najib, N.M.; Idkaidek, N.; Adel, A.; Admour, I.; Astigarraga, R.E.; Nucci, G.D.; Alam, S.M.; Dham, R. Pharmacokinetics and bioequivalence evaluation of two simvastatin 40 mg tablets (Simvast and Zocor) in healthy human volunteers. Biopharm. Drug Dispos. 2003 , 24 , 183–189. [ Google Scholar ] [ CrossRef ]
Schachter, M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundam. Clin. Pharmacol. 2005 , 19 , 117–125. [ Google Scholar ] [ CrossRef ]
Hartter, S.; Sennewald, R.; Nehmiz, G.; Reilly, P. Oral bioavailability of dabigatran etexilate (Pradaxa((R))) after co-medication with verapamil in healthy subjects. Br. J. Clin. Pharmacol. 2013 , 75 , 1053–1062. [ Google Scholar ] [ CrossRef ][ Green Version ]
Fukami, T.; Takahashi, S.; Nakagawa, N.; Maruichi, T.; Nakajima, M.; Yokoi, T. In vitro evaluation of inhibitory effects of antidiabetic and antihyperlipidemic drugs on human carboxylesterase activities. Drug Metab. Dispos. Biol. Fate Chem. 2010 , 38 , 2173–2178. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Wang, X.; Zhu, H.J.; Markowitz, J.S. Carboxylesterase 1-mediated drug-drug interactions between clopidogrel and simvastatin. Biol. Pharm. Bull. 2015 , 38 , 292–297. [ Google Scholar ] [ CrossRef ][ Green Version ]
Stangier, J.; Rathgen, K.; Stahle, H.; Reseski, K.; Kornicke, T.; Roth, W. Coadministration of dabigatran etexilate and atorvastatin: Assessment of potential impact on pharmacokinetics and pharmacodynamics. Am. J. Cardiovasc. Drugs Drugs Devices Other Interv. 2009 , 9 , 59–68. [ Google Scholar ] [ CrossRef ]
Van Ryn, J.; Stangier, J.; Haertter, S.; Liesenfeld, K.H.; Wienen, W.; Feuring, M.; Clemens, A. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb. Haemost. 2010 , 103 , 1116–1127. [ Google Scholar ] [ CrossRef ]
Dager, W.E.; Gosselin, R.C.; Kitchen, S.; Dwyre, D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: A multicenter, in vitro study. Ann. Pharmacother. 2012 , 46 , 1627–1636. [ Google Scholar ] [ CrossRef ]
Undas, A.; Brummel-Ziedins, K.E.; Mann, K.G. Anticoagulant effects of statins and their clinical implications. Thromb. Haemost. 2014 , 111 , 392–400. [ Google Scholar ] [ CrossRef ]
Bogman, K.; Peyer, A.K.; Torok, M.; Kusters, E.; Drewe, J. HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br. J. Pharmacol. 2001 , 132 , 1183–1192. [ Google Scholar ] [ CrossRef ][ Green Version ]
Wang, E.; Casciano, C.N.; Clement, R.P.; Johnson, W.W. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm. Res. 2001 , 18 , 800–806. [ Google Scholar ] [ CrossRef ]
Hochman, J.H.; Pudvah, N.; Qiu, J.; Yamazaki, M.; Tang, C.; Lin, J.H.; Prueksaritanont, T. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm. Res. 2004 , 21 , 1686–1691. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sakugawa, T.; Miura, M.; Hokama, N.; Suzuki, T.; Tateishi, T.; Uno, T. Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil. Br. J. Clin. Pharmacol. 2009 , 67 , 535–540. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Prueksaritanont, T.; Subramanian, R.; Fang, X.; Ma, B.; Qiu, Y.; Lin, J.H.; Pearson, P.G.; Baillie, T.A. Glucuronidation of statins in animals and humans: A novel mechanism of statin lactonization. Drug Metab. Dispos. Biol. Fate Chem. 2002 , 30 , 505–512. [ Google Scholar ] [ CrossRef ][ Green Version ]
Iwuchukwu, O.F.; Feng, Q.; Wei, W.Q.; Jiang, L.; Jiang, M.; Xu, H.; Denny, J.C.; Wilke, R.A.; Krauss, R.M.; Roden, D.M.; et al. Genetic variation in the UGT1A locus is associated with simvastatin efficacy in a clinical practice setting. Pharmacogenomics 2014 , 15 , 1739–1747. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Stangier, J.; Stahle, H.; Rathgen, K.; Fuhr, R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin. Pharmacokinet. 2008 , 47 , 47–59. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Park, I.H.; Park, J.W.; Chung, H.; Kim, J.M.; Lee, S.; Kim, K.A.; Park, J.Y. Development and validation of LC-MS/MS method for simultaneous determination of dabigatran etexilate and its active metabolites in human plasma, and its application in a pharmacokinetic study. J. Pharm. Biomed. Anal. 2021 , 203 , 114220. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kim, J.M.; Noh, J.; Park, J.W.; Chung, H.; Kim, K.A.; Park, S.B.; Lee, J.S.; Park, J.Y. Dabigatran Acylglucuronide, the Major Metabolite of Dabigatran, Shows a Weaker Anticoagulant Effect than Dabigatran. Pharmaceutics 2022 , 14 , 257. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Figure 1. Mean plasma concentration profiles of ( A ) dabigatran etexilate, ( B ) dabigatran, and ( C ) dabigatran acylglucuronide after administration of 150 mg dabigatran etexilate with or without simvastatin.
Figure 2. Coagulation assay profiles after administration of dabigatran etexilate alone and co-administration with simvastatin (activated partial prothrombin time (aPTT, ( A )), prothrombin time (PT (s), ( B )), prothrombin time (PT (INR), ( C )), diluted PT (dPT, ( D )), thrombin time ( E ), and fibrinogen ( F )).
Figure 3. Thrombin generation assay profiles after administration of dabigatran alone and co-administration with simvastatin (( A ) Peak thrombin concentration (C max ), ( B ) endogenous thrombin potential (AUC), ( C ) lag time, and ( D ) time to C max (T max )).
Table 1. Pharmacokinetic parameters of dabigatran etexilate, dabigatran, and dabigatran glucuronide before and after co-administration of simvastatin.
Parameter Dabigatran Alone Dabigatran Co-Administered with Simvastatin GMR (90% CI) p -Value Dabigatran etexilate AUC inf (h∙ng/mL) 33.7 (26.0) 36.4 (18.5) 1.60 (0.89–2.88) 0.3847 AUC last (h∙ng/mL) 26.1 (23.6) 27.3 (16.4) 1.47 (0.87–2.48) 0.8242 CL/F (L/h) 12,208.4 (16,447.7) 5235.1 (2729.4) - C max (ng/mL) 24.5 (19.2) 25.1 (13.8) 1.38 (0.81–2.35) 0.9139 t 1/2 (h) 3.4 (5.8) 6.4 (13.6) - MRT (h) 1.9 (2.4) 2.2 (1.8) - T max (h) 1 (0.5–1.5) 1 (0.5–2) - Dabigatran AUC inf (h∙ng/mL) 663.9 (377.5) 740.2 (342.0) 1.19 (0.71–2.00) 0.6033 AUC last (h∙ng/mL) 617.1 (357.4) 688.2 (318.9) 1.21 (0.71–2.08) 0.6079 CL/F (L/h) 362.3 (331.8) 275.8 (197.4) - C max (ng/mL) 87.0 (51.4) 98.6 (47.5) 1.24 (0.72–2.12) 0.5601 t 1/2 (h) 6.1 (0.9) 6.2 (0.6) - MRT (h) 7.1 (0.9) 7.5 (0.7) - T max (h) 2 (1–4) 3 (1.5–4) - Dabigatran acylglucuronide AUC inf (h∙ng/mL) 1576.5 (1154.0) 2376.8 (2096.8) 1.56 (0.94–2.59) 0.2903 AUC last (h∙ng/mL) 1480.1 (1090.5) 2227.5 (1994.6) 1.57 (0.93–2.66) 0.3042 CL/F (L/h) 176.8 (161.8) 97.1 (56.1) - C max (ng/mL) 266.8 (187.1) 392.0 (290.2) 1.63 (0.94–2.80) 0.2885 t 1/2 (h) 6.4 (1.9) 6.0 (1.8) - MRT (h) 6.8 (0.9) 7.1 (0.8) - T max (h) 2 (1.5–4) 2.5 (1–4) - AUC last ratio of dabigatran acylglucuronide to dabigatran 3.03 (2.42) 3.65 (2.54) 1.30 (1.15–1.46) 0.0025
Data are presented as mean (standard deviation) except for T max which is presented as median (min–max). GMR: geometric mean ratio, CI: confidence interval, AUC inf : area under the time-concentration curve from 0 h to infinity, AUC last : area under the time-concentration curve from 0 h to the last measurable concentration, CL/F: apparent clearance, C max : maximum concentration, t 1/2 : terminal elimination half-life, MRT: mean residence time, T max : time to reach C max.
Table 2. Baseline thrombin generation and coagulation assays measured before dabigatran etexilate administration.
Dabigatran Alone Dabigatran with Simvastatin p -Value Thrombin Generation Assay C max (nM) 241.3 (43.0) 233.6 (46.7) 0.5629 AUC (nM∙min) 3937.1 (537.4) 4073.1 (642.2) 0.3383 lag time (min) 3.5 (0.5) 3.5 (0.5) 0.3388 T max (min) 7.6 (1.2) 7.3 (0.8) 0.2072 Coagulation Assay aPTT (s) 40.6 (3.3) 40.4 (3.3) 0.6502 PT (s) 13.8 (0.4) 13.7 (0.6) 0.2068 PT (INR) 1.1 (0.0) 1.0 (0.1) 0.1718 dPT (s) 43.2 (1.7) 43.2 (1.8) 0.9726 TT (s) 16.5 (1.2) 16.2 (0.9) 0.4361 Fibrinogen (mg/dL) 250.3 (63.9) 259.3 (39.4) 0.5432
Data are presented as mean (standard deviation). C max : Peak thrombin concentration, AUC: endogenous thrombin potential, T max : time to C max , aPTT: activated partial prothrombin time, PT: prothrombin time, dPT: dilute PT, TT: thrombin time.
Table 3. Pharmacodynamic parameters of dabigatran before and after co-administration of simvastatin.
Parameter Dabigatran Alone Dabigatran with Simvastatin p -Value Thrombin Generation C max AUEC (nM∙h) 5755.0 (1129.2) 5734.0 (993.9) 0.9369 R max (nM) 180.2 (48.8) 177.8 (35.8) 0.8684 AUC AUEC (nM∙min∙h) 84,994.8 (14,977.1) 79,286.4 (10,676.3) 0.0746 R max (nM∙min) 2423.6 (734.9) 2231.7 (326.0) 0.2944 Lag time AUEC (min∙h) 131.7 (20.8) 128.5 (20.1) 0.6835 R max (min) 7.8 (1.7) 8.0 (1.5) 0.7206 T max AUEC (min∙h) 214.8 (21.9) 207.0 (22.0) 0.2667 R max (min) 11.0 (1.6) 11.3 (1.7) 0.6767 Coagulation assay aPTT AUEC (s∙h) 1203.1 (153.1) 1235.7 (131.7) 0.4873 R max (s) 69.5 (13.8) 71.7 (12.2) 0.6408 PT (sec) AUEC (s∙h) 344.9 (14.3) 353.8 (12.3) 0.0331 R max (s) 16.6 (1.4) 17.2 (1.4) 0.3048 PT (INR) AUEC 26.9 (1.4) 27.7 (1.2) 0.0474 R max 1.3 (0.1) 1.4 (0.1) 0.3038 dPT (1:256) AUEC (s∙h) 1404.8 (184.7) 1482.9 (144.9) 0.2977 R max (s) 87.5 (19.2) 92.5 (15.3) 0.5068 TT AUEC (s∙h) 1690.1 (535.9) 1976.2 (643.8) 0.3393 R max (s) 169.2 (74.0) 180.7 (50.4) 0.6841 Fibrinogen AUEC (h∙mg/dL) 6249.8 (1133.1) 6040.9 (758.3) 0.4101 R max (mg/dL) 288.0 (55.9) 309.3 (96.0) 0.4907
Data are presented as mean (standard deviation). C max : peak thrombin concentration, AUC: endogenous thrombin potential, T max : time to C max , aPTT:,activated partial prothrombin time, PT: prothrombin time, dPT: dilute PT, TT: thrombin time, AUEC: area under the effect curve, R max : maximum response.
MDPI and ACS Style
Chung, H.; Kim, J.-M.; Park, J.-W.; Noh, J.; Kim, K.-A.; Park, J.-Y. Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects. Pharmaceuticals 2023, 16, 364.
https://doi.org/10.3390/ph16030364
AMA Style
Chung H, Kim J-M, Park J-W, Noh J, Kim K-A, Park J-Y. Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects. Pharmaceuticals. 2023; 16(3):364.
https://doi.org/10.3390/ph16030364
Chicago/Turabian Style
Chung, Hyewon, Jong-Min Kim, Jin-Woo Park, Jihyeon Noh, Kyoung-Ah Kim, and Ji-Young Park. 2023. "Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects" Pharmaceuticals16, no. 3: 364.
https://doi.org/10.3390/ph16030364
Article Metrics
Chung, H.; Kim, J.-M.; Park, J.-W.; Noh, J.; Kim, K.-A.; Park, J.-Y. Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects. Pharmaceuticals 2023, 16, 364.
https://doi.org/10.3390/ph16030364
| https://www.mdpi.com/1424-8247/16/3/364/htm |
Viruses | Free Full-Text | Interpreting Viral Deep Sequencing Data with GLUE
Using deep sequencing technologies such as Illumina& rsquo;s platform, it is possible to obtain reads from the viral RNA population revealing the viral genome diversity within a single host. A range of software tools and pipelines can transform raw deep sequencing reads into Sequence Alignment Mapping (SAM) files. We propose that interpretation tools should process these SAM files, directly translating individual reads to amino acids in order to extract statistics of interest such as the proportion of different amino acid residues at specific sites. This preserves per-read linkage between nucleotide variants at different positions within a codon location. The samReporter is a subsystem of the GLUE software toolkit which follows this direct read translation approach in its processing of SAM files. We test samReporter on a deep sequencing dataset obtained from a cohort of 241 UK HCV patients for whom prior treatment with direct-acting antivirals has failed; deep sequencing and resistance testing have been suggested to be of clinical use in this context. We compared the polymorphism interpretation results of the samReporter against an approach that does not preserve per-read linkage. We found that the samReporter was able to properly interpret the sequence data at resistance-associated locations in nine patients where the alternative approach was equivocal. In three cases, the samReporter confirmed that resistance or an atypical substitution was present at NS5A position 30. In three further cases, it confirmed that the sofosbuvir-resistant NS5B substitution S282T was absent. This suggests the direct read translation approach implemented is of value for interpreting viral deep sequencing data.
Column Width:
Background:
Interpreting Viral Deep Sequencing Data with GLUE
by
Joshua B. Singer 1,* ,
Emma C. Thomson 1 ,
Joseph Hughes 1 ,
Elihu Aranday-Cortes 1 ,
John McLauchlan 1 ,
Ana da Silva Filipe 1 ,
Lily Tong 1 ,
Carmen F. Manso 2 ,
Robert J. Gifford 1 ,
David L. Robertson 1 ,
Eleanor Barnes 3 ,
M. Azim Ansari 3 ,
Jean L. Mbisa 2 ,
David F. Bibby 2 ,
Daniel Bradshaw 2 and
David Smith 3
1
MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK
2
Virus Reference Department, National Infection Service, Public Health England, Colindale, London NW9 5EQ, UK
3
Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK
*
Author to whom correspondence should be addressed.
Viruses 2019 , 11 (4), 323; https://doi.org/10.3390/v11040323
Received: 28 February 2019 / Revised: 13 March 2019 / Accepted: 14 March 2019 / Published: 3 April 2019
(This article belongs to the Special Issue Virus Bioinformatics )
Abstract
:
Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads from the viral RNA population revealing the viral genome diversity within a single host. A range of software tools and pipelines can transform raw deep sequencing reads into Sequence Alignment Mapping (SAM) files. We propose that interpretation tools should process these SAM files, directly translating individual reads to amino acids in order to extract statistics of interest such as the proportion of different amino acid residues at specific sites. This preserves per-read linkage between nucleotide variants at different positions within a codon location. The samReporter is a subsystem of the GLUE software toolkit which follows this direct read translation approach in its processing of SAM files. We test samReporter on a deep sequencing dataset obtained from a cohort of 241 UK HCV patients for whom prior treatment with direct-acting antivirals has failed; deep sequencing and resistance testing have been suggested to be of clinical use in this context. We compared the polymorphism interpretation results of the samReporter against an approach that does not preserve per-read linkage. We found that the samReporter was able to properly interpret the sequence data at resistance-associated locations in nine patients where the alternative approach was equivocal. In three cases, the samReporter confirmed that resistance or an atypical substitution was present at NS5A position 30. In three further cases, it confirmed that the sofosbuvir-resistant NS5B substitution S282T was absent. This suggests the direct read translation approach implemented is of value for interpreting viral deep sequencing data.
Keywords:
deep sequencing
;
virus genomics
;
hepatitis C virus
;
variant calling
;
sequence interpretation
;
drug resistance
;
bioinformatics
1. Introduction
For some virus species, their highly error-prone replication mechanism produces a population of related genomic variants of the virus within a single infected host individual [
1
]. Sequencing systems such as Illumina’s platform produce short, relatively accurate nucleotide sections of viral genome, often generating thousands of reads for a given genomic location from a single sample [
2
]. Such deep sequencing technologies therefore offer methods for understanding the nature of viral intra-host diversity. Whole genome and deep sequencing of virus genomes has been widely applied in basic virology research but has also found applications in clinical contexts such as the detection of drug resistance [
3
].
Various bioinformatics stages must be applied in the interpretation of viral deep sequencing data. Reads unrelated to the virus genome are removed and low-quality reads removed or trimmed. Following this, we must then construct an alignment: how the reads are arranged relative to each other within the virus genome, accounting for sequence homology. Reference-based alignment or mapping methods such as Bowtie 2 [ 4 ], BWA [ 5 ], MOSAIK [ 6 ], Stampy [ 7 ] or Tanoti [ 8 ] use one or more reference sequences to guide the alignment of reads. In contrast, de novo assembly approaches such as SPAdes [ 9 ] and VICUNA [ 10 ] use associations derived purely from the read data itself to propose large genome fragments, avoiding the biases arising from the choice of reference sequence. A drawback of de novo methods is that they may not accurately capture the full genomic structure or diversity, thus, for well-known viruses with high levels of genomic diversity, combinations of de novo assembly and reference-based alignment methods, such as shiver [ 11 ], are often used. One aspect common to almost all recent methods in this area is that they output their results in the form of a sequence alignment mapping (SAM) file. The SAM format [ 12 ] integrates nucleotide, read quality and alignment data in a single file. It was standardised at an early point in the adoption of deep sequencing, allowing diverse methods to be compared with each other and integrated into processing pipelines for a broad set of applications.
A range of variant-calling methods have been developed to analyse genomic heterogeneity within deep sequencing data. Error rates in short read technologies such as Illumina are low but it can be challenging to distinguish errors from real single nucleotide variants (SNVs) occurring at frequencies comparable to the error rate. Therefore, variant-calling methods such as LoFreq [ 13 ] and V-Phaser [ 14 , 15 ] apply statistical techniques to the aligned read data to identify probable SNVs occurring even at very low frequency in the presence of sequencing errors. The focus on low frequency SNVs is critical in applications such as cancer genomics where somatic deviations from the consensus are both rare and of high consequence [ 16 ]. However, virus bioinformatics has distinct priorities from fields focused on eukaryote or bacterial organisms with higher replication fidelity [ 17 ]. Since viruses typically have a low replication fidelity, there is a higher level of diversity within an infected host and the viral population can be expected to contain many variants.
For reasons of clarity within the research community, virus genome locations can be defined in terms of a standard virus strain with a well-established “master reference” genome. In hepatitis C virus (HCV) for example, codons within viral proteins are numbered relative to the H77 strain [
18
]. Polymorphisms at these standardised locations are reported with phenotypic associations established experimentally or in clinical trials. The advent of deep sequencing data prompts questions such as: What are the relative proportions of different amino acid residues at a given genome location? What proportion of reads support the presence of a certain sequence motif? What proportion of reads indicate a deletion? However, it is challenging to answer these questions within deep sequencing data, since read alignments do not in general use the reference coordinate space, and a mapping between the two spaces must be established and applied.
The genomes of the virus population may contain multiple nucleotide base variants at different positions within a single codon location. Both Verbist et al. [
19
] and Döring et al. [
20
] pointed out that linkage between nucleotide positions is lost when variants are called as SNVs. This linkage must be retained within datasets in order to accurately predict the amino acid residues arising from protein translation. Suppose for example we observe significant levels of both adenine (A) and thymine (T) at the first position of a particular codon location. At the second position, we observe cytosine (C) and guanine (G). With cytosine at the third position, what amino acids are the genomes in the virus population coding for? Without retaining linkage, these observations are consistent with a mix of Threonine (codon ACC) and Cysteine (TGC), or alternatively with purely Serine (AGC/TCC), or with any combination of these amino acids. By retaining linkage, we can accurately select between these interpretations. Haplotype reconstruction methods aim to determine linkage by associating sub-populations of reads as haplotypes. Schirmer et al. [
21
] found that this was exceptionally unreliable for viral deep sequencing data. However, full haplotype reconstruction may not be necessary for practical applications where the variants of interest are linked within the span of a single read or read pair.
We present a subsystem of the GLUE software package [
22
] called samReporter, focused on the analysis of aligned deep sequencing viral genome data. It directly processes the SAM file format produced by most methods, and can also process the more compact Binary Alignment Map (BAM) format. The samReporter can be instantiated within an existing GLUE project containing reference sequences and alignments for a given virus. This allows the software to establish a reading frame for coding region reads within a SAM file, and map between the read alignment coordinate space and standardised genome locations. In turn, this facilitates the scanning of reads directly for different classes of sequence pattern such as codons, amino acid residues, indels and motifs. This approach of scanning reads directly has the advantage of retaining linkage and we can report how often combinations of variations appear together on the same viral RNA, certainly within a codon location but also further, at least as far as paired-end read data allows.
We demonstrate the benefits of applying the GLUE samReporter to hepatitis C virus (HCV) deep sequencing data. HCV is a positive-sense single-stranded RNA virus of the family Flaviviridae. Its genome of about 9000 bases codes for a single polyprotein that produces 10 mature viral proteins. HCV affects over 100 million people worldwide and can cause liver disease and cirrhosis. The infection can be treated with a range of direct-acting antiviral (DAA) drugs which inhibit three of the mature proteins: NS3, NS5A and NS5B. Such therapies produce a sustained virological response (SVR) in the vast majority of patients, clearing the virus in around 95% of cases [
23
]. Notwithstanding this therapeutic success, HCV is proving difficult to treat in certain categories of patients, including “retreatment” patients: those for whom prior DAA treatment has failed. It has been shown both in vitro and in vivo that certain resistance-associated substitutions (RASs) in the viral genome confer resistance to DAA drugs [
24
].
Vermehren et al. suggested that retreatment patients have RASs in multiple drug target genes and that therefore “genomic resistance testing may be useful to select the optimal combination and treatment duration” for subsequent rounds of drug therapy [
23
]. Recent guidance suggests that, if deep sequencing is used, observing a RAS in 15% of the virus population may be clinically relevant [
25
]. Tools aimed at HCV resistance testing such as geno2pheno[ngs-freq] [
20
] suggest frequencies of 2%, 10% and 15%. Thus, while HCV RAS testing can benefit from deep sequencing methods, moderately-low rather than ultra-low frequencies are of most interest. RAS testing for retreatment patients therefore provides a good case study for a deep sequencing data interpretation system.
2. Results
We analysed viral genome diversity within a group of 241 HCV retreatment patients sampled within the United Kingdom. A range of genotypes were represented: Gt1
n
= 115, Gt2
n
= 5, Gt3
n
= 104, Gt4
n
= 14 and Gt6
n
= 3. The five most frequent subtypes: were 1a
n
= 98, 1b
n
= 13, 3a
n
= 95, 3b
n
= 6 and 4r
n
= 6. Fourteen other subtypes were represented each by three or fewer patients. In three cases, a subtype could not be assigned.
The samReporter scans aligned reads directly, retaining linkage within reads with the intention of more accurate detection of specific variants. To test the benefits of this approach, we also contrived an alternative method that attempts to capture within-host diversity without retaining linkage.
Besides the four concrete bases A, C, G and T/U, IUPAC notation for nucleic acids, used in the FASTA sequence file format, contains 11 ambiguity codes, covering all possible combinations of more than one base [
26
]. For example, code S can represent a combination of C and G. Any method which calls SNVs can encode these variants within a FASTA file. This aspect of the encoding is used to capture minor nucleotide variants. Web-based HCV drug resistance interpretation systems such as HCV-GLUE [
27
] and geno2pheno[hcv] [
28
] do attempt to interpret ambiguity codes if they appear in the input data. We produced FASTA files with ambiguity codes for each sample using the samReporter
nucleotide-consensus
command, which produces one IUPAC code for each nucleotide position in the SAM reference coordinate space. Read bases with a Phred quality score of less than 25 were excluded. A “concrete” base (A, C, G or T) was encoded at a given position if it appeared both in at least five individual reads and in 5% of the quality-filtered reads at that location. IUPAC ambiguity codes are then used if multiple concrete bases are to be encoded. We found that FASTA files for all but two samples contained at least one ambiguity code. On average, files contained ambiguity codes which represent two bases at 1.02% of nucleotide positions (std. dev.
1.3
%
) and codes which represent three bases at 0.0161% of nucleotide positions (std. dev.
0.0475
%
).
A triplet of concrete bases, i.e., a codon, specifies a single amino acid. If ambiguity codes occur within nucleotide data for a given codon location, multiple distinct codons are present in the underlying data at that location; the precise composition is unknown. For a given ambiguous triplet (possibly containing ambiguity codes), there is set of “possible” amino acids comprising any residues coded by one or more of the possible codons. For example, for the ambiguous triplet YTM, the set of possible amino acids is Leucine (L) and Phenylalanine (F) because the set of codons and their corresponding amino acids are CTA (L), CTC (L), TTA (L) and TTC (F). Additionally, there is a (possibly empty) subset of “definite” amino acid residues, i.e., those that must be coded by at least some of the underlying codons, whatever the composition, under reasonable assumptions. For the ambiguous triplet YTM, every combination of codons which produces the ambiguity codes contains at least some codons for Leucine (L); this is the single definite amino acid. In general, if there is a single ambiguity code encoding two bases within the triplet, there will be one or two definite amino acids, and these will also be the only possible amino acids.
The FASTA files were analysed for “ambiguous” codon locations where the definite and possible amino acid sets were different. This typically occurs when there are two ambiguity codes within a triplet. Such locations present a challenge for drug resistance interpretation systems based on FASTA file inputs. Whereas amino acid residues in the definite set can be inferred to be present in the virus population, the status of amino acids in the possible set but not the definite set cannot be established clearly from FASTA data. We excluded from the analysis degenerate locations i.e., those where the possible set, excluding stops, contained more than five amino acids or where the read depth for the whole codon location was less than 10.
In total, 435 ambiguous locations were found in patients, within all ten viral proteins: Core n = 62, E1 n = 24, E2 n = 205, p7 n = 5, NS2 n = 14, NS3 n = 30, NS4A n = 1, NS4B n = 9, NS5A n = 38 and NS5B n = 47. The full set of ambiguous locations is given in the Supplementary Materials . Scaling by the length of each region, this implies that the E2 and Core proteins had a higher rate of ambiguous locations. The drug target proteins NS3, NS5A and NS5B have rates in the lower part of the range.
The current version of HCV-GLUE [
27
] documents 44 locations associated in the literature with resistance to six DAA drugs in current use: 18 in NS3, 15 in NS5A and 11 in NS5B. These are listed in the
Supplementary Materials
. Within the FASTA data, we found 10 ambiguous resistance-associated locations in nine patients, six in NS5A and four in NS5B. We resolved these locations using the GLUE samReporter, calculating the frequencies of codons and amino acids by directly analysing reads. Codons were excluded if any Phred base quality was below 25. Amino acid residues were deemed to be present if 5% or more of filtered read codons at the location coded for the residue. The 10 locations are shown in
Table 1
. HCV-GLUE classifies an amino acid as typical at a location for a given subtype if 10% or more of the GenBank sequences of that subtype contain the residue, these are also shown in the table. In all cases except one (R25, NS5B position 159) the definite residues set (not shown) was empty.
In the cases shown in
Table 1
, samReporter was able to eliminate many possible residues. Whereas the possible set contained up to four residues, samReporter confirmed that only one or two were actually present at the 5% level. Two resistance locations occur three times each and merit a discussion. For NS5A position 30, in subtype 1a the typical residue is Glutamine (Q). In sample R67, samReporter found Tyrosine (Y) at around 74%, which has not been documented as a RAS but is atypical for the subtype. In samples HCV300 and R164 (subtype 3a) the typical residue is Alanine (A); samReporter found Lysine (K), a well-documented RAS, at levels of 92% and 82% respectively. Thus, in these three cases samReporter confirmed the presence of a RAS or atypical substitution. Substitutions at NS5B position 282 have been strongly associated with resistance to sofosbuvir, particularly the substitution of the typical Serine (S) with Threonine (T). In contrast with NS5A position 30, samReporter was able to eliminate this resistant residue and the other possible atypical residue Cysteine (C); in these three ambiguous cases, only Serine is present, but is actually coded by significantly distinct codons in each case. For sample HCV294, the codons were TCT at 54%, AGT at 25% and AGC at 20%, for sample R25, AGC at 85% and TCC at 15%, and, for sample R36, TCC at 92% and AGC at 7%. The effect of the presence of these diverse codons is to create ambiguity at the nucleotide level. One possible explanation for the codon diversity is that Threonine codons became frequent in the viral population during sofosbuvir treatment, and that following the end of the treatment course the descendants of these virions reverted to Serine, but now coded using diverse alternative codons.
The HCV296 sample is typical in the sense that the size of the BAM file (24.6 MB) was closest to the mean for this dataset, it contains ≈282,000 paired-end reads with an average depth across the HCV polyprotein of ≈3700. To evaluate performance, we ran some samReporter commands on this file using a 2014 MacBook Pro with a 2.5 GHz Intel Core i7 processor and 16 GB of RAM. The samReporter was configured to use up to four CPU cores. The
amino-acid
command was run to translate reads for the whole polyprotein, producing amino acid residue frequencies at each codon location, without any read filters. Using the auto-align feature with a known target reference sequence, this command took 7.5 s. Using the max-likelihood-placer feature, the command took 29.2 s, with most of the extra time spent in the RAxML-EPA step. See
Section 3.2
for details of the samReporter design.
3. Materials and Methods
3.1. Sequencing Data
Deep whole genome HCV sequencing data was derived from blood samples collected from 241 patients resident in the United Kingdom, who had not achieved virological clearance after previous courses of antiviral therapy. Sequencing was performed using target enrichment on Illumina sequencers at three different institutes: the MRC-University of Glasgow Centre for Virus Research (
n
= 56), the University of Oxford Nuffield Department of Medicine (
n
= 25) and the Virus Reference Department at Public Health England (PHE) (
n
= 160).
The Glasgow library preparation protocol was as follows. RNA was isolated from 200
μ
L of plasma using the RNAdvance Blood extraction kit (Beckman Coulter, Brea, CA, United States) and collected in 27
μ
L of water. Following conversion of RNA to double-stranded DNA, libraries were prepared for Illumina sequencing using the KAPA DNA LTP Library Preparation Kit (Roche, Basel, Switzerland), and NEBNext Multiplex Oligos for Illumina (New England Biolabs, Ipswich, MA, United States). Libraries were quantified using Qubit dsDNA HS Assay Kit (Invitrogen, Carlsbad, CA, United States) and size distribution assessed using Agilent TapeStation with D1K High Sensitivity Kit (Agilent, Santa Clara, CA, United States); libraries were normalised according to viral load and mass. A 500 ng aliquot of the pooled library was enriched using SeqCap EZ Developer Probes (Roche), following the manufacturer’s protocol. Following a 14 cycle post-enrichment PCR, the cleaned pool was sequenced with 151-base paired-end reads on a NextSeq cartridge (Illumina, San Diego, CA, United States).
The Oxford libraries were prepared for Illumina sequencing using the NEBNext Ultra Directional RNA Library Prep Kit (New England Biolabs) with 8
μ
L of RNA extracted from plasma using NUCLISENS easyMAG (bioMérieux, Marcy-l’Étoile, France) and previously published modifications of the manufacturer’s guidelines (v2.0) [
29
]: omission of heat fragmentation, omission of Actinomycin D at first-strand reverse transcription, library amplification for 15 PCR cycles using custom indexed primers [
30
], and post-PCR clean-up with 0.85x volume Ampure XP (Beckman Coulter). Libraries were quantified using Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen) and size distribution analysed using Agilent TapeStation D1K High Sensitivity kit. A 500 ng aliquot of the pooled libraries (96 plex) was enriched using the xGen Lockdown protocol (Rapid Protocol for DNA Probe Hybridization and Target Capture Using an Illumina TruSeq or Ion Torrent Library v1.0, Integrated DNA Technologies, Coralville, IA, United States) with equimolar-pooled 120 nt DNA oligonucleotide probes (Integrated DNA Technologies) followed by a 12-cycle on-bead post-enrichment PCR. The cleaned post-enrichment ve-Seq library was quantified by qPCR with the KAPA SYBR FAST qPCR Kit (Roche) and sequenced with 150b paired-end reads on a single run of the Illumina MiSeq.
The PHE library preparation protocol is the laboratory component of a pipeline aimed at clinical use; a manuscript describing the full pipeline is in preparation. RNA was extracted from 350
μ
L of plasma using the NUCLISENS easyMAG system (bioMérieux). Total eluates were subjected to Turbo DNAse treatment (Thermo Fisher, Waltham, MA, United States) followed by library preparation using KAPA RNA HyperPrep kit (Roche). Libraries were pooled based upon DNA concentration and HCV quantity, assessed using the Quant-iT kit on the Glomax platform (Promega, Madison, WI, United States) and the Qiagen QuantiTect kit with primers and probes from Davalieva et al. [
31
]. Pools were enriched by hybridisation to a biotinylated probe set (Integrated DNA Technologies, described by Bonsall et al. [
32
]) followed by further PCR cycles depending upon HCV quantity. The two pools were pooled, again by concentration and HCV quantity. The final pool was quantified using the KAPA SYBR FASTA qPCR kit (Roche) on a PRISM 7500 (Applied BioSystems, Foster City, CA, United States) before being sequenced on a MiSeq using Reagent kit v2 (Illumina).
The Illumina read data were processed into SAM files using different bioinformatics pipelines at the different institutions. At Glasgow, reads were trimmed and filtered using TrimGalore [ 33 ] with quality threshold 30 and minimum read length 75. The most appropriate HCV reference sequence was identified via a k -mer-based approach, using k -mers unique to each genotype [ 34 ]. SAM files were generated by mapping against the best-matching HCV reference using Tanoti [ 8 ]. At Oxford, de-multiplexed sequence read-pairs were trimmed of low-quality bases using QUASR v7.01 [ 35 ] and adapter sequences with CutAdapt version 1.7.1 [ 36 ] and subsequently discarded if either read had fewer than 50 bases in its remaining sequence or if both reads matched the human reference sequence using Bowtie version 2.2.4 [ 4 ]. Remaining reads were mapped using BWA mem [ 5 ] and Stampy [ 7 ] against a database of reference sequences, both to choose an appropriate reference and to select those reads which formed a majority population for de novo assembly using VICUNA [ 10 ] and finishing with V-FAT [ 37 ]. The reads were then mapped back to this assembly using MOSAIK [ 6 ]. At PHE, human reads were filtered out from trimmed FASTQ files using SMALT [ 38 ], remaining reads were then assembled using VICUNA de novo assembly [ 10 ]. Contigs were matched to HCV reference genomes using BLAST [ 39 ] and gaps filled using LASTZ [ 40 ] to generate a draft assembly. Reads were then mapped to the draft assembly with BWA [ 5 ].
The deep sequencing data used in this study has been deposited in the NCBI Sequence Read Archive ( http://www.ncbi.nlm.nih.gov/sra ), under BioProject accession number PRJNA527067 and experiment accession numbers SRX5528430 to SRX5528670.
3.2. GLUE samReporter Design
The GLUE samReporter aims to provide a convenient tool for interpreting viral deep sequencing data. As part of the wider GLUE system [ 22 ], it can be used interactively in the command line interpreter or within bioinformatics scripts. Instantiated within a GLUE project for a specific category of viruses such as HCV-GLUE, it can take advantage of certain data objects within that project.
When interpreting viral deep sequencing data, one obstacle is mapping the SAM file coordinate space to a standard codon numbering system. Within the HCV-GLUE project the H77 strain (RefSeq accession NC_004102) is defined as the “master” reference sequence object. The precursor polyprotein and the 10 mature proteins are defined as coding features and their locations are specified on the H77 sequence. A wider set of reference sequence objects is also defined within HCV-GLUE; there are currently over 200 of these, based on the ICTV HCV resource [
41
]. HCV-GLUE then specifies an unconstrained “master” alignment object containing all these reference sequences, which is used to map their locations to those on the H77 sequence. HCV-GLUE also contains a reference phylogeny of the same set of sequences, computed using RAxML [
42
].
SAM files for HCV typically map each read to a single coordinate space. To interpret individual reads the samReporter must infer sequence homology (i.e., pairwise alignment) between this SAM file coordinate space and one of the reference sequences defined within GLUE—the “target” reference. The simplest method, to specify that the SAM file coordinate space is identical to that of a specific target reference sequence, is appropriate if one of the project’s reference sequences was used for the SAM file coordinate space. A more flexible “auto-align" method allows GLUE to generate a codon-aware pairwise alignment between the consensus of the SAM file and a selected target reference, using techniques based on BLAST+ [
39
]. This is appropriate if the SAM virus strain is closely related to the target reference, but importantly, it allows the method producing the SAM file, which may have a de novo element, to construct a coordinate space appropriate for the viral reads. The final and most general and robust method is “max-likelihood-placer”. This allows GLUE to select the target reference itself, by feeding the consensus of the SAM file into the first two stages of the GLUE genotyping pipeline. This consists of incorporating it into the master alignment using MAFFT [
43
], placing it in the reference phylogeny using RAxML-EPA [
42
] and selecting as the target the reference sequence with the lowest patristic distance from the SAM consensus. The auto-align method is then used to generate the homology. The master alignment will also typically act as the “linking” alignment, providing a mapping between the target reference and the master reference. The result of this process is then a chain of pairwise homology relationships, as shown in
Figure 1
, from each individual read to the SAM file coordinate space, to the target reference sequence and finally, via the linking alignment, to the master reference sequence.
The samReporter offers a range of GLUE commands for interpreting SAM files (
Table 2
). These each accept similar arguments for specifying the coordinate homology and genome region. The “variation scan” command scans each read for the presence or absence of sequence patterns defined by GLUE
Variation
objects [
22
]. If paired-end read data are supplied, the reads in each pair are processed together.
Variation
objects can encapsulate insertions, deletions, regular expressions and combinations at the nucleotide or amino acid level. In HCV drug resistance this capability may become important. For example, the Magellan-1 trial of the drug pibrentasvir found that the combination of a Methionine at NS5A position 28 with the deletion of the residue at NS5A position 32 was associated with resistance to the drug for HCV subtype 1b [
44
]. It remains to be seen whether such deletions and combinations occurring as minority variants are clinically relevant but if so, the samReporter offers a means of detecting these.
The commands also allow simple, optional filtering based on Phred base qualities, MAPQ mapping quality and depth. In command outputs, codon numbering is based on the system proposed by Kuiken et al. [
18
]; nucleotide coordinates both within the SAM file and the mapped location on the master reference are also given. Individual input files may be processed more quickly using parallelisation of command operations across multiple processors. Finally, for paired-end read data, regions where paired reads overlap are not counted twice in command outputs. As part of the GLUE engine, the SAM reporter is implemented in Java, using the Htsjdk library [
45
] to interpret the SAM format.
The samReporter is delivered as part of the GLUE software package. This study used GLUE version 1.1.33, HCV-GLUE project version 0.1.51 with PHE-HCV-DRUG-RESISTANCE extension version 0.1.21. GLUE is licensed under the open source GNU Affero General Public License version 3.0. and may be installed on Mac OSX, Windows or Linux systems. Documentation specific to the samReporter may be found at:
http://tools.glue.cvr.ac.uk/#/deepSequencingData
. Documentation for other aspects of GLUE and links to the source code repository can be found on other pages within the same web site.
4. Discussion
The results show that, within virus genomes of HCV retreatment patients, linkage between nucleotide variants within a codon location is not a purely theoretical issue. In a small number of cases among UK retreatment patients, such linkage did occur at sites critical for drug resistance. Approaches that do not preserve linkage, such as those encoding variants as ambiguity codes, cannot correctly resolve these cases. How would such a system deal with amino acid residues in the possible set but not in the definite set? If the system is configured not to report such residues, the result is false negative detection of a substitution at NS5A position 30 in three patients, obscuring A30K RAS in two cases. Conversely, if the system reports these residues, the result is false positive detection of the NS5B RAS S282T in three other patients. As far as we are aware, the current study is novel in terms of quantifying the effect of such linkage on resistance detection in real HCV patient data.
The current HCV-GLUE database [
27
] documents many RASs that combine substitutions at locations within the span of a typical Illumina read. The samReporter can report the presence or absence of these on any read (or read pair for paired-end data) that covers the relevant locations. Future work might consider whether detection of these “combination” RASs at a minority level are of clinical relevance. It would also be of interest to incorporate existing low frequency variant-calling mechanisms from the literature into GLUE. The samReporter and GLUE generally are intended to be useful in both research and clinical contexts. However, even once a SAM file has been generated from a sample, the samReporter only represents one part of the process in terms of drug resistance analysis. The HCV-GLUE system is currently being developed to provide a comprehensive drug resistance report, using samReporter to interpret a SAM file.
Other software, for example the VirVarSeq system [
19
], calls variants at the codon level but is focused on very low frequency variants. DiversiTools [
46
] provides frequencies of amino acids on a per read basis but does not link to a standardised coordinate system as is available in the GLUE framework. The geno2pheno[ngs-freq] system [
20
] directly interprets drug resistance in deep sequencing data. Users must transform their data into a table of nucleotide or codon frequencies and a web-based system then performs interpretation on this table, using a user-defined frequency threshold. In comparison with samReporter, this design facilitates fast transfer over a network since the frequency table is much more compact than a typical SAM or BAM file. However, some information is necessarily lost in the processing, for example the codon frequency table cannot encode linkage beyond a codon location which would be required for example to detect combination RASs.
While the current study applied samReporter to HCV, it can also be used to analyse deep sequencing data for other viruses. In many simple cases, the prerequisites would simply be a nucleotide alignment of alternative target reference sequences and a master reference sequence with coding region annotations. In more complex cases, for example where virus genomes contain ambisense genomes or RNA editing, GLUE and samReporter would need to take account of this. The GLUE samReporter shows that a simple, pragmatic software design can conveniently answer some common questions concerning within-host variation in viral deep sequencing data.
Supplementary Materials
The following are available online at https://www.mdpi.com/1999-4915/11/4/323/s1 . The complete set of “ambiguous” codon locations that were found is supplied in a tab-delimited supplementary data file unclearCodonLocations.txt . Resistance associated locations are supplied in a tab-delimited supplementary data file resistanceAssociatedLocations.txt .
Author Contributions
Conceptualisation, J.B.S., E.C.T., J.L.M., J.H., J.M., E.B., D.L.R. and R.J.G.; methodology, J.B.S., J.H., D.S., D.F.B. and M.A.A.; software, formal analysis, and validation, JBS; data curation, E.A.-C., E.C.T., D.B., D.S., D.F.B. and M.A.A.; resources, A.d.S.F., L.T., C.F.M., D.F.B., E.A.C. and M.A.A.; writing—original draft preparation, J.B.S.; writing—review and editing, J.H., E.C.T., J.L.M., R.J.G., E.B., D.L.R. and J.M.; and supervision, R.J.G., D.L.R., E.C.T., J.M., E.B. and J.L.M.
Funding
This work was funded by the Medical Research Council (MRC) of the United Kingdom, award number MC_UU_12014/12. JBS was also part funded by a MRC Confidence in Concept award to the University of Glasgow, MC_PC_16045. ECT was funded by the Wellcome Trust (102789/Z/13/Z). EB is funded by the MRC, the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.
Acknowledgments
The authors would like to thank the participants and clinicians at NHS sites who contributed samples, and Will Irving and Emma Hudson for their contributions, particularly for sample collection and project management.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
BAM Binary alignment mapping DAA Direct-acting Antiviral DNA Deoxyribonucleic Acid ICTV International Committee for the Taxonomy of Viruses HCV Hepatitis C virus RAS Resistance-associated Substitution RNA Ribonucleic Acid SAM Sequence alignment mapping SNV Single nucleotide variant SVR Sustained virological response
References
Holmes, E.C. The Evolution and Emergence of RNA Viruses ; Oxford University Press: Oxford, UK, 2009. [ Google Scholar ]
Goodwin, S.; McPherson, J.D.; McCombie, W.R. Coming of age: Ten years of next-generation sequencing technologies. Nat. Rev. Genet. 2016 , 17 , 333–351. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Houldcroft, C.J.; Beale, M.A.; Breuer, J. Clinical and biological insights from viral genome sequencing. Nat. Rev. Microbiol. 2017 , 15 , 183–192. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Langmead, B.; Salzberg, S.L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 2012 , 9 , 357–359. [ Google Scholar ] [ CrossRef ]
Li, H.; Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 2009 , 25 , 1754–1760. [ Google Scholar ] [ CrossRef ]
Lee, W.P.; Stromberg, M.P.; Ward, A.; Stewart, C.; Garrison, E.P.; Marth, G.T. MOSAIK: A Hash-Based Algorithm for Accurate Next-Generation Sequencing Short-Read Mapping. PLoS ONE 2014 , 9 , e90581. [ Google Scholar ] [ CrossRef ]
Lunter, G.; Goodson, M. Stampy: A statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 2011 , 21 , 936–939. [ Google Scholar ] [ CrossRef ]
Tanoti: A BLAST-Guided Reference-Based Short Read Aligner. Available online: http://www.bioinformatics.cvr.ac.uk/tanoti.php (accessed on 24 February 2019).
Bankevich, A.; Nurk, S.; Antipov, D.; Gurevich, A.A.; Dvorkin, M.; Kulikov, A.S.; Lesin, V.M.; Nikolenko, S.I.; Pham, S.; Prjibelski, A.D.; et al. SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing. J. Comput. Biol. 2012 , 19 , 455–477. [ Google Scholar ] [ CrossRef ]
Yang, X.; Charlebois, P.; Gnerre, S.; Coole, M.G.; Lennon, N.J.; Levin, J.Z.; Qu, J.; Ryan, E.M.; Zody, M.C.; Henn, M.R. De novo assembly of highly diverse viral populations. BMC Genom. 2012 , 13 , 475. [ Google Scholar ] [ CrossRef ]
Wymant, C.; Fraser, C.; Hall, M.; Golubchik, T.; Bannert, N.; Fellay, J.; Fransen, K.; Porter, K.; Gourlay, A.; Grabowski, M.K.; et al. Easy and accurate reconstruction of whole HIV genomes from short-read sequence data with shiver. Virus Evol. 2018 , 4 , vey007. [ Google Scholar ] [ CrossRef ]
Li, H.; Wysoker, A.; Handsaker, B.; Marth, G.; Abecasis, G.; Ruan, J.; Homer, N.; Durbin, R.; Fennell, T. The 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009 , 25 , 2078–2079. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wilm, A.; Aw, P.P.K.; Bertrand, D.; Yeo, G.H.T.; Ong, S.H.; Wong, C.H.; Khor, C.C.; Petric, R.; Hibberd, M.L.; Nagarajan, N. LoFreq: A sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 2012 , 40 , 11189–11201. [ Google Scholar ] [ CrossRef ]
Macalalad, A.R.; Zody, M.C.; Charlebois, P.; Lennon, N.J.; Newman, R.M.; Malboeuf, C.M.; Ryan, E.M.; Boutwell, C.L.; Power, K.A.; Brackney, D.E.; et al. Highly Sensitive and Specific Detection of Rare Variants in Mixed Viral Populations from Massively Parallel Sequence Data. PLoS Comput. Biol. 2012 , 8 , e1002417. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Yang, X.; Patrick, C.; Macalalad, A.; Henn, M.R.; Zody, M.C. V-Phaser 2: Variant inference for viral populations. BMC Genom. 2013 , 14 , 674. [ Google Scholar ] [ CrossRef ]
Sandmann, S.; de Graaf, A.O.; Karimi, M.; van der Reijden, B.A.; Hellström-Lindberg, E.; Jansen, J.H.; Dugas, M. Evaluating Variant Calling Tools for Non-Matched Next-Generation Sequencing Data. Sci. Rep. 2017 , 7 , 43169. [ Google Scholar ] [ CrossRef ]
Ibrahim, B.; McMahon, D.P.; Hufsky, F.; Beer, M.; Deng, L.; Mercier, P.L.; Palmarini, M.; Thiel, V.; Marz, M. A new era of virus bioinformatics. Virus Res. 2018 , 251 , 86–90. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kuiken, C.; Combet, C.; Bukh, J.; Shin-I, T.; Deleage, G.; Mizokami, M.; Richardson, R.; Sablon, E.; Yusim, K.; Pawlotsky, J.M.; et al. A comprehensive system for consistent numbering of HCV sequences, proteins and epitopes. Hepatology 2006 , 44 , 1355–1361. [ Google Scholar ] [ CrossRef ]
Verbist, B.M.; Aerssens, J.; Reumers, J.; Thys, K.; Van der Borght, K.; Clement, L.; Thas, O.; Talloen, W.; Wetzels, Y. VirVarSeq: A low-frequency virus variant detection pipeline for Illumina sequencing using adaptive base-calling accuracy filtering. Bioinformatics 2014 , 31 , 94–101. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Döring, M.; Büch, J.; Friedrich, G.; Pironti, A.; Kalaghatgi, P.; Knops, E.; Heger, E.; Obermeier, M.; Däumer, M.; Thielen, A.; et al. geno2pheno[ngs-freq]: a genotypic interpretation system for identifying viral drug resistance using next-generation sequencing data. Nucleic Acids Res. 2018 , 46 , W271–W277. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Schirmer, M.; Sloan, W.T.; Quince, C. Benchmarking of viral haplotype reconstruction programmes: An overview of the capacities and limitations of currently available programmes. Brief. Bioinform. 2012 , 15 , 431–442. [ Google Scholar ] [ CrossRef ]
Singer, J.B.; Thomson, E.C.; McLauchlan, J.; Hughes, J.; Gifford, R.J. GLUE: A flexible software system for virus sequence data. BMC Bioinform. 2018 , 19 , 532. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Vermehren, J.; Park, J.S.; Jacobson, I.M.; Zeuzem, S. Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection. J. Hepatol. 2018 , 69 , 1178–1187. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sorbo, M.C.; Cento, V.; Maio, V.C.D.; Howe, A.Y.; Garcia, F.; Perno, C.F.; Ceccherini-Silberstein, F. Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. Drug Resist. Updates 2018 , 37 , 17–39. [ Google Scholar ] [ CrossRef ] [ PubMed ]
European Association for the Study of the Liver. Recommendations on Treatment of Hepatitis C 2016. J. Hepatol. 2017 , 66 , 153–194. [ Google Scholar ] [ CrossRef ] [ PubMed ]
IUPAC-IUB Commission on Biochemical Nomenclature (CBN). Abbreviations and symbols for nucleic acids, polynucleotides and their constituents. Recommendations 1970. Biochem. J. 1970 , 120 , 449–454. [ Google Scholar ] [ CrossRef ]
HCV-GLUE: A Sequence Data Resource for Hepatitis C Virus. Available online: http://hcv.glue.cvr.ac.uk (accessed on 24 February 2019).
Kalaghatgi, P.; Sikorski, A.M.; Knops, E.; Rupp, D.; Sierra, S.; Heger, E.; Neumann-Fraune, M.; Beggel, B.; Walker, A.; Timm, J.; et al. Geno2pheno[HCV]—A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents. PLoS ONE 2016 , 11 , e0155869. [ Google Scholar ] [ CrossRef ]
Batty, E.M.; Wong, T.H.N.; Trebes, A.; Argoud, K.; Attar, M.; Buck, D.; Ip, C.L.C.; Golubchik, T.; Cule, M.; Bowden, R.; et al. A Modified RNA-Seq Approach for Whole Genome Sequencing of RNA Viruses from Faecal and Blood Samples. PLoS ONE 2013 , 8 , e66129. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lamble, S.; Batty, E.; Attar, M.; Buck, D.; Bowden, R.; Lunter, G.; Crook, D.; El-Fahmawi, B.; Piazza, P. Improved workflows for high throughput library preparation using the transposome-based Nextera system. BMC Biotechnol. 2013 , 13 , 104. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Davalieva, K.; Kiprijanovska, S.; Plaseska-Karanfilska, D. Fast, reliable and low cost user-developed protocol for detection, quantification and genotyping of hepatitis C virus. J. Virol. Methods 2014 , 196 , 104–112. [ Google Scholar ] [ CrossRef ]
Bonsall, D.; Ansari, M.; Ip, C.; Trebes, A.; Brown, A.; Klenerman, P.; Buck, D.; STOP-HCV Consortium; Piazza, P.; Barnes, E.; Bowden, R. ve-SEQ: Robust, unbiased enrichment for streamlined detection and whole-genome sequencing of HCV and other highly diverse pathogens [version 1; referees: 2 approved, 1 approved with reservations]. F1000Research 2015 , 4 , 1062. [ Google Scholar ] [ CrossRef ] [ PubMed ]
TrimGalore: A Wrapper around Cutadapt and FastQC to Consistently Apply Adapter and Quality Trimming to FastQ Files, with Extra Functionality for RRBS Data. Available online: https://github.com/FelixKrueger/TrimGalore (accessed on 24 February 2019).
Sreenu, V.B.; (MRC-University of Glasgow Centre for Virus Research, Glasgow, UK). Personal Communication, 2019.
Gaidatzis, D.; Lerch, A.; Hahne, F.; Stadler, M.B. QuasR: Quantification and annotation of short reads in R. Bioinformatics 2014 , 31 , 1130–1132. [ Google Scholar ] [ CrossRef ]
Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011 , 17 , 10–12. [ Google Scholar ] [ CrossRef ]
V-FAT: A Post-Assembly Pipeline for the Finishing and Annotation of Viral Genomes. Available online: https://www.broadinstitute.org/viral-genomics/v-fat (accessed on 24 February 2019).
SMALT: A Mapper for DNA Sequencing Reads. Available online: https://www.sanger.ac.uk/science/tools/smalt-0 (accessed on 24 February 2019).
Camacho, C.; Coulouris, G.; Avagyan, V.; Ma, N.; Papadopoulos, J.; Bealer, K.; Madden, T.L. BLAST+: Architecture and applications. BMC Bioinform. 2009 , 10 , 421. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Harris, R.S. Improved Pairwise Alignment of Genomic DNA. Ph.D. Thesis, Pennsylvania State University, State College, PA, USA, 2007. [ Google Scholar ]
Smith, D.B.; Bukh, J.; Kuiken, C.; Muerhoff, A.S.; Rice, C.M.; Stapleton, J.T.; Simmonds, P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource. Hepatology 2014 , 59 , 318–327. [ Google Scholar ] [ CrossRef ]
Stamatakis, A. RAxML version 8: A tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 2014 , 30 , 1312–1313. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Katoh, K.; Standley, D.M. MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability. Mol. Biol. Evol. 2013 , 30 , 772–780. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Poordad, F.; Pol, S.; Asatryan, A.; Buti, M.; Shaw, D.; Hézode, C.; Felizarta, F.; Reindollar, R.W.; Gordon, S.C.; Pianko, S.; et al. Glecaprevir/Pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology 2018 , 67 , 1253–1260. [ Google Scholar ] [ CrossRef ] [ PubMed ]
A Java API for High-Throughput Sequencing Data (HTS) Formats. Available online: http://samtools.github.io/htsjdk/ (accessed on 24 February 2019).
DiversiTools: Tool for Analysing Viral Diversity from HTS. Available online: http://josephhughes.github.io/DiversiTools/ (accessed on 24 February 2019).
Figure 1. The chain of pairwise homology relationships between reads and the master reference sequence (H77 for HCV), established during the operation of GLUE samReporter.
Figure 1. The chain of pairwise homology relationships between reads and the master reference sequence (H77 for HCV), established during the operation of GLUE samReporter.
Table 1. Ambiguous resistance-associated locations resolved using GLUE samReporter.
Table 1. Ambiguous resistance-associated locations resolved using GLUE samReporter.
Sequencing Sample Subtype Virus Codon Ambiguous Typical Possible Confirmed Facility ID Protein Location Triplet Residue (s) Residues Set Residues Set Glasgow HCV294 3b NS5B 282 WSY S CST S Glasgow HCV300 3a NS5A 30 RMG A AEKT AK PHE R127 1a NS5A 24 RSG K AGRT GT PHE R164 3a NS5A 30 RMG A AEKT AK PHE R25 4r NS5B 159 YTM L FL L PHE R25 4r NS5B 282 WSC S CST S PHE R36 4r NS5B 282 WSC S CST S PHE R67 1a NS5A 30 YAW Q HQY QY PHE R91 1a NS5A 28 RYG M AMTV MV Oxford 7444 3a NS5A 62 SYA ST ALPV AL
Table 2. GLUE samReporter commands.
Table 2. GLUE samReporter commands.
| https://www.mdpi.com/1999-4915/11/4/323/html |
Legal Document: In the Marriage of Melissa Kay Gonion and Richard Peter Gonion | Trellis.Law
Access this legal document in In the Marriage of Melissa Kay Gonion and Richard Peter Gonion on Trellis.Law. Review the document, case details, and relevant case updates to stay informed on this notable legal proceeding.
Track Case Changes
On June 15, 2012 a
Findings, Order, Judgment and Decree-Dissolution
was filed
involving a dispute between
and
for Dissolution with Child
in the District Court of Ramsey County.
Preview
Filed im Second Judicis Distict Court
491972013 1:17:18 PM
Ramsey County Famity, MN
STATE OF MINNESOTA DISTRICT COURT
COUNTY OF RAMSEY SECOND JUDICIAL DISTRICT
a FAMILY COURT DIVISION
In Re the Matter of;
Melissa Kay Gonion,
Frnpines OF Fact, CONCLUSIONS OF
Petitioner, Law, ORDER FOR JUDGMENT AND
STIPULATED JUDGMENT AND DECREE
Respondent. Court File No. 62-FA-12-1782
This proceeding for dissolution of marriage came before the Honorable William H. Leary Ml, Judge
of District Court on January 30, 2013 for a scheduled prehearing conference at the Ramsey County Juvenile
Justice Center, City of Saint Paul, County of Ramsey. The parties and their attorneys were personally
present before the court. Patti Adams Schinzing represents Petitioner in this proceeding. Mary Catherine
Lauhead represents Respondent in this proceeding.
Prior to any trial in this matter, the parties negotiated a resolution of all issues, the terms of which
have been incorporated into this final Stipulated Findings of Fact, Conclusions of Law, Order for Judgment
and Judgment and Decree. The agreements of the parties were read into the record at the January 30, 2013
prehearing conference, with each party signifying their agreement to the provisions of the settlement upon
the record.
The parties acknowledged and stated their understanding that the agreements of their final
Stipulation as made of record with the court was permanent in nature and would be incorporated into the
Court’s administrative approval of Findings of Fact, Conclusions of Law, Order for Judgment and
Stipulated Judgment and Decree, pursuant to Minn. Stat, § 518.13, Subd. 5.Fited in Second Judicial District Court
4019/2093 1:17:15 PM
Ramsey County Farvily, MN
FINDINGS OF FACT
L
The true and correct name of the Petitioner is Melissa Kay Gonion, Petitioner has been previously
known by her maiden name of Melissa Kay Parenteau. She was born on March 20, 1971 and is forty-two
(42) years of age. Petitioner resides at 3675 Highland Avenue, Apartment B31, White Bear Lake,
Minnesota 55110, The social security number of the Petitioner is set forth in the Confidential Information
Form, which has been filed with the court pursuant to Minn. Gen. R. Prac, 313.01.
Patty Adams Schinzing, Attomey 1D. No. 256481, of ADAMS SCHINZING, P.A., Ivy League Place,
475 North Cleveland Avenue, Suite 222, Saint Paul, Minnesota, 55104, represents Petitioner in this
proceeding.
i.
‘The true and correct name of the Respondent is Richard Peter Gonion. He has also been known as
Richard Peter Kiritschenko. He was born on March 17, 1969 and is presently forty-four (44) years of age.
Respondent resides at the fumily residence, 3485 Centerville Road, Vadnais Heights, Minnesota 55127.
The social security number of Respondent is listed on the Confidential Information Form.
Mary Catherine Lauhead, Attorney ID No. 61086, of LAW Orrices oF MARY CATHERINE LAUHEAD,
3985 Clover Avenue, Saint Paul, Minnesota 55127-7015, represents Respondent in this proceeding.
u.
‘The parties were married to cach other on October 14, 1994 in the City of Maplewood, Ramscy
County, State of Minnesota, and ever since have been and now are husband and wife, Respondent moved
out of the family residence on May 1, 2012. Thereafter, Petitioner moved out of the family residence on
September 4, 2012 to her rental residence, and Respondent took possession of the marital residence.
Court File No. 62-FA-12-1782 ‘Gonion Judgment aad Decree Page 2Filed in Second Judicial District Court
4/99/2013 1.17.15 PM
Ramsey County Famity, MN
Iv.
For more than one hundred and cighty (180) days immediately preceding the commencement of this
proceeding for dissolution of marriage herein, both parties have resided within the County of Ramsey, State
of Minnesota.
Vv.
‘Neither party is in the military service of the United States, Consequently, neither party is entitled
to any protection under the Service Members Civil Relief Act, formerly known as the Soldiers’ and Sailors’
Civil Relief Act of 1940, as amended.
VI.
No separate proceeding for dissolution of marriage or legal separation of the parties has been
commenced by the Respondent nor is any such proceeding pending in any court in the State of
Minnesota or elsewhere,
vi.
‘The parties filed bankruptcy on February 2, 2010 with the Chapter 7 discharge entered on May 4,
2010. There has been no prior domestic abuse proceeding between the parties.
Val.
The Petition and Answer and Counter Petition herein has been filed in good faith for the purpose
of obtaining a dissolution of the marriage relationship of the parties, based upon the irretrievable
breakdown of the marital relationship within the meaning of Minn. Stat. § 518.06, as amended.
Ix.
The parties have two minor children, namely:
Nicholaus Anthony Gonion, born on April 26, 1996, presently sixteen (16) years of age; and
Alexis Rose Gonion, born on September 17, 1999, presently thirteen (13) years of age.
Court File No. 62-FA-12-1782 Gonion Judgment and Decree Page 3Filed in Second Judicial District Court
41/2013 1:17-15 PM
Ramsey County Family, MN
The social security numbers of the minor children have been filed as confidential information,
consistent with the requirements of Minn. R Gen. Prac. 313.01.
Petitioner is not pregnant,
Petitioner has a non-joint adult son who is not subject to this proceeding.
x.
This Court has jurisdiction over the custody status of the minor children born to the marriage within
the parameters of Minn. Stat. §$18D, known as the Uniform Child Custody Jurisdiction and Enforcement
Act and the Parental Kidnapping and Prevention Act, us amended by the Visitation Rights Enforcement
Act, codified as 28 U.S.C. § 1738 A (2000),
XL.
The parties have agreed to an award of joint legal custody and joint physical custody of the minor
children. Petitioner shall be granted primary residence of Alexis Rose Gonion, subject to Respondent's
right to reasonable parenting time, Respondent shall be granted primary residence of Nicholaus Anthony
Gonion, subject to Petitioner’s right to reasonable parenting time.
XI
Petitioner has been employed on a part-time basis at Apple Academy located in Hugo, Minnesota
as an aide for the past six years. Petitioner's present hourly rate is $9.55 and is now working approximately
80 bours per biweekly pay period.
Respondent is self-employed as the owner of White Bear Asphalt and Sealcoat. His business is
run out of his home office in the family residence. The parties were audited by the IRS in 2009 and
2010.
xi.
The partics have stipulated that Petitioner's reasonable monthly living expenses as set out in her
Court File No, 62-FA-12-1782 Gonion Judgment and Decree Page 4Fhed in Second Judicat District Court
4/19/2093 1:17:15 PM
Ramey County Famiy, MN
Parenting Financial Disclosure Statement of November 16, 2012 are reasonable at $2,264.00 for herself
and Alexis. ,
‘The parties have stipulated that Respondent's reasonable monthly living expenses as set out in
his Parenting Financial Disclosure Statement of November 20, 2012 are reasonable at $4,779.11 for
himself and Nicholaus,
XIV.
For purposes of child support the parties have agreed to use a three-year base on income for
Purposes of the child support obligation, using the last three years of the tax retums (2010, 2011 and 2012).
This tee yeur average recognizes that Petitioner's income has moved from part-time to full-time
employment and recognizes the reductions in Respondent's income due to the downtum in the economy.
‘The parties’ respective incomes over the prior three years were as follows:
Court File No, 62-FA-12-1782 Gonion Judgment and Decree Page 5Filed in Second Judicial District Coun
4/19/2013 1:17:16 PM
Ramsey County Famity, MIN
hates} ——j} ————
|
a ——
Subtotal On Parental Income: $
Petitioner Respondent
Three Year Totals On Parental Income: $ 46,187.00 $ 121,651.00
Three Year Average On Parental Income $ 15,396.00 $ 40,550.00
Consequently, for purposes of child support, the Petitioner's three year average income is
$15,396.00 or $1,283.00 monthly income and Respondent's three year average is $ 40,550.00 or $3,379
monthly income.
xv.
‘The combined monthly parental incomes for determining child support is $ 4,662.00 Pursuant to
Minn. Stat. § $184.35, the combined basic support obligation for two children is $ 1,200.00. Based upon
the combined parental incomes for determining child support (PICS), the Respondent's share of the PICS is
72% and the Petitioner's share of the PICS is 28%. ‘The parties have used a mid-range for parenting time
for the child residing with the other parent (10 to 45.1 %) for the parenting time adjustment, Both of the
children receive MinnCare established as # benefit through the residential parent — Petitioner for Alexis and
Respondent for Nicholaus. Petitioner pays $50.00 each month as the cost of the MinnCare medical
coverage for Alexis. The cost of the medical premium for Alexis paid by Petitioner is $50.00. Respondent
pays $70.00 each month as the cost of the MinnCare medical coverage for Nicholaus
Court File No. 62-FA-12-1782 Gonion Judgment and Decree Page 6Fited in Second Judicial Disinct Court
4(1W203 1.17.15 PM
Ramsey County Farmwly, MN
In calculating the respective child support obligations of the parties, the Sefkow' formula for split
custody, as modified for income shares, would be as follows:
Support for each parent as Parent A was calculated, with Parent B assumed to have
custody of both children.
‘As each parent has one child in residence, with the parties having the same amount of
time of both children in cach parental residence, the parenting time for both children is
equally shared.
Offset the parental support obligations of each parent in the calculation,
Pursuant to Minn, Stat §518A.35 the Minnesota Child Support Guidelines, Respondent's child
support obligation payable to the Petitioner would be $ 396.00 per month. (Split Custody Calculation
and worksheets attached)
XVI.
The parties have agreed to an upward deviation from the statutory guidelines of Minn. Stat. §
518A.35 on the child support obligation payable by the Respondent for the duration of the split custody
arrangement specified above such that Respondent would pay $ 700.00 each month as his total support
~ obligation (basic child support, medical support, etc.) to Petitioner.
The child support obligation shall be subject to a biennial cost-of-living adjustment under Minn.
Stat, § 5184.75, Subd. I, and other statutory requirements for all child support orders.
‘As each party receives public benefits through the State of Minnesota for the medical coverage for
cach child The issue of support has been submitted for approval by the Ramscy County Attomey, as
required by Minnesota law.
XVil.
‘The dependent unreimbursed and deductible expenses of the minor children are allocated
‘ ‘Seficow v. Sefhow, 427 N,W.2d 203 (Mina, 1988)
Court File No. 62-FA-12-1782 ‘Gonion Judgment and Decree Page 7Filed in Secona Judicial District Coun
4119/2013 1:17:15 PM
Ramsey County Famity, MN
between the parties such that Petitioner will bear 28 % of the expense and Respondent will bear 72 % of
the medical and dental premium expense and the unreimbursed and deductible expenses of the minor
children per the PICS percentages.
There are no work-related childcare expenses for either of the children.
XVI
Each party is able-bodied and not in need of spousal maintenance, whether past, present or
future. The parties have waived any claim to spousal maintenance. By waiving their right to receive
maintenance, the parties intend to divest the court from having any jurisdiction whatsoever to award
lemporary or permanent spousal maintenance to either of the parties now or in the future.
XIX.
‘The parties own in joint tenancy real property commonly known as 3485 Centerville Road, Vadnais
Heights, Ramsey County, Minnesota $5127, and legally described as:
‘That part of the North % of the Northeast % of Section 32, Township 30, Range 22, lying
West of the old center line of Centerville Road and lying East of the West 564 feet of afore
described fraction of Section 32, and lying South of a line described as follows: Beginning
at a point distant 564 feet East of the West line of said fraction and 145 feet North of the
South line of said fraction; thence running East parallel to said South line, 310.3 feet, thence
deflecting 35° 20° to the right and Southeasterly 70 feet more or less to an intersection with
said center line, and lying North of a line described as follows: Beginning at a point distant
564 feet East of said West line and 49.52 feet North of said South line thence running East
paralle! to said South line 216 fect, thence deflecting 32° 07° to the right and Southeasterly
to an intersection with said center line. Also the North 84.48 feet of the South 134 feet of
the East 231 feet of the West 564 feet of the North 4 of the Northeast % of Section 32,
Township 30, Range 22.
‘The parties bought this property on December 3, 1999 for approximately $156,000.00, The real
Property is encumbered by a first mortgage in favor of Bank of America, with an approximate balance
owing of $251,460.00. Respondent hus been making attempts to bring the mortgage payments current
and is currently only behind on the March 2013 payment. The Ramsey County 2013 Estimated Market
Court File No, 62-FA=12-1782 Goaion Judgment and Decree Page 3Filed in Second Judicial District Court
4/10/2013 1.17.15 PM
Ramsey County Family, MN
Value is $209,900.00. The parties stipulated to award the residence to the Respondent at a zero balance,
subject to its outstanding mortgage, free and clear of any clair thereon by Petitioner,
XX.
‘The parties are the owners of the usual assortment of houschold goods and furnishings and other
items of personal property, which have been substantially divided between the parties in a fair and
equitable manner.
The parties own the following vehicles:
1. 2000 Ford Expedition. This automobile is unencumbered and customarily driven by
2s 2006 Mercury Mariner, subject to a Joan held by Harris Bank with an outstanding
balance of approximately $4,967.00 as of July 2012 and customarily driven by
Respondent for personal and business use.
XXI.
Respondent’s business, White Bear Asphalt and Sealcoating, owns various pieces of equipment
used in the course of day-to-day business operations. The parties have agreed to award Respondent all the
equipment associated with his business operation, and that the allocation of these assets is fuir and
equitable when the property division and other financial agreements herein are reviewed in their entirety.
XXII.
‘The parties have various individual checking, savings and bank accounts. The parties have agreed
that each would be awarded all right, title and interest in and to existing bank accounts as titled in the
name of each party.
XXOL
‘The parties have various individual and marital indebtedness. The parties have allocated the marital
debt such that the Respondent shall be responsible upon the balances owed to the IRS and State of
Court File No. 62-FA-12-1782 Gonion Judgment and Decree Page 9Filed in Second Judicial District Court
492013 1.1715 PM
Ramsey County Famity. MN
Minnesota (approximately $17,000.00) after application of tax refunds or credits as available to either party
through tax year 2012, In reaching this agreement, the parties do intend to file separate tax returns for
2012, expressly based upon the expectation that the taxing authorities will grab any refund attributable to
the state and federal tax filing of each party for application to the outstanding tax liabilities and penalties
accrued on prior joint returns,
It is appropriate that each party be responsible for any indebtedness undisclosed herein or incurred
in their own name since the commencement of this proceeding.
XXIV.
‘The parties do not have any retirement accounts.
XXV.
Each party has incurred attorney fees and costs in connection with this proceeding. The parties
agreed that each should be responsible upon their respective attomey fees and costs associated with this
proceeding.
XXVL
‘The parties stipulated to the discharge of the attorneys of record sixty-one (61) days following
entry of this Judgment and Decree. It is appropriate that further pleadings of a post-decree nature be
directly served upon cach party to ensure proper notice under the Minnesota Rules of Civil Procedure.
XXVIL
At the prehearing conference of January 30, 2013, the parties entered on the record a recitation of
their agreements to be incorporated into the Judgment and Decree herein. ‘The agreements of the perties as
made of record with the court are a full, complete and final settlement and satisfaction of any and all claims
of any kind, nature and description to which cither party may be entitled or may claim to be entitled, now or
in the future, against the other, and except as is expressly provided herein to the contrary, each is released
Court File No. 62-FA+12-1782 Gonion Judgment and Decree Page 10Filed in Second Judicit Distinct Court
4/99/2013 1:17:95 PM
Ramsey County Family, MN
from any and all further liability of any kind, nature or description whatsoever to the other.
From the foregoing, the Court hereby enters the following:
CONCLUSIONS OF LAW
1. Dissolution: The bonds of matrimony existing between the parties are dissolved,
2. Military Service: Neither party is entitled to eny protection under the Service Members
Civil Relief Act, as amended.
3. Uniform Child Custody Jurisdiction and Enforcement Act: Minnesota is the proper
jurisdiction within the contemplation of the Uniform Child Custody Jurisdiction and Enforcement Act
and the Parental Kidnapping and Prevention Act, as amended by the Visitation Enforcement Act,
codified as 28 U.S.C. SS 1738 A (2000) to enter an order regarding the custody, care and contro! of the
minor children.
4. Spousal Maintenance: Each party has waived and foregone any right to receive
spousal maintenance (alimony) peyable from the other party, now and forever, This is a permanent and
irrevocable waiver, with the court divested of any jurisdiction over any future claim of entitlement to the
receipt of spousal maintenance.
5. Custody, The parties are awarded joint legal and joint physical custody of the minor
children, namely:
Nicholaus Anthony Gonion, born on April 26, 1996, presently sixteen (16) years of age; and
Alexis Rose Gonion, born on September 17, 1999, presently thirteen (13) years of age.
Petitioner is awarded primary residence of Alexis Rose Gonion, subject to Respondent’s right to
reasonable parenting time, Respondent is awarded primary residence of Nicholaus Anthony Gonion,
subject to Petitioner's right to reasonable parenting time.
Court File No. 62-FA-12-1782 Gonioe Judgment and Decree Page 11Filed in Secong Judicial Otstrict Court
4/98/2013 1.17.15 PM
Ramsey Courity Family. MN
6. Parental Access Schedule. As a minimum, the parental access schedule should be as
follows. However, duc to the ages and active personal schedules of the parties’ minor children, neither
parent shall force any child to exactly follow the below Parental Access Schedule if the child does not
wish to on an occasional basis.
a) Alternating weekends, commencing on Friday after school through Monday
moming with retum of the children to school, or their residence by 10:00 a.m. on
Mondays, if academic release days. Alternating weekends will be structured such that the
children are together each weekend.
b) One weeknight overnight, with both children in the residence of a parent.
c) Both parents are entitled to attend school, sports and extracurricular activities in
which the children may be involved.
d) The parties shall alienate holidays and academic release days as follows:
Holid: Odd Years Even Years
New Year's Eve/New Year's Day, including Petitioner
weekend closest to holiday through return to school.”
“Martin Luther King D Petitioner
“Spring Break, but not to include Easter weekend as -——>—
defined below *
Easter Sunday, from 9:00 a.m. to 3:00 p.m. Responder
“Easter Sunday from 3:00 pm.to9:00pm. Petitioner
* New Year holiday is defined by reference to Deceenber 31.
- If a parent wishes to take a trip away from home, then s/he may take the entire spring break, with an even-odd
allocation between the partics with Petitioner in odd years and Respondent in even years.
Court File No. 62-FA-12-(782 ‘Gonion Judgment and Decree Page 12Filed in Second Judicial Diswict Court
4/19/2013 1:17.15 PM
Ramsey County Family, MN
“Thanksgiving Day from 9:00 am, to 5:00 pm. [Respondent | Respondent ~
giving Day from 3:00 p.m. to 9:00 p.m Petitioner
“Christmas Academic Break
Christmas Eve from 10:00 a.m on December 24 with
return on Christmas Day at 10:00 a.m.
Christmas Day, from 10:00 a.m. through 10:00 a.m.
on December 26
New Year’s Eve/New Year's Day, including
weekend closest to holiday through return to school.
e) Each of the parties is awarded two weeks of vacation time with the minor children
on an annual basis with no parenting time to the other party during that time. The parties
may elect to take a full fourteen days or they may break the vacation time into segments,
to include their scheduled weekend, During periods of vacation time, the other party
shal] not have parenting time.
f) Holiday time is in addition to and not a substitute for regularly scheduled
parenting time and takes precedence over all other parenting or vacation times, The
parents shall not schedule vacation time during the other parent's holiday time.
2) During any exercise of parental access, the “on-duty” parent shall ensure that the
‘Court File No, 62-FA-12-1782 Gonion Judgment and Decree Page 13Fated in Second Judicial District Court
4/78/2013 1.17.15 PM
Ramsey County Family, MN
children complete homework and school projects.
7, Cancellation of Scheduled Parenting Time:
a) If either party cancels their parenting time for any reason, they forfeit that
particular time unless the parties can agree to exchange times,
b) If cither parent cancels parenting time for the other parent for any reason, that
parent must provide the other parent with compensatory time within one month.
8. Resolution of Conflict, Any claim or controversy arising under this document involving
custody, child support, or any other issue which cannot be resolved by the parties through direct
communication without mediation, shall be promptly submitted to mediation.
a) Definition of Mediation. Mediation is a voluntary process entered into by the
parties. In this process, the parties continue direct communication but with the assistance
of @ neutral person who is the mediator, which mediator has no authority to require any
concession or agreements. A good faith effort shall be made to resolve any claim or
controversy arising between the parties.
b) Duties and Responsibilities of Mediator. The mediator shal] have the duty and
responsibility to assist the parties in resolving all issues submitted for mediation.
) Duties of Parties. Both parties shall cooperate and operate in good faith to resolve
the matter(s) in dispute with the assistance of the mediator. Any agreements reached in
mediation shall be immediately put in writing, The enforceability of writen agreements
reached through mediation shall be derivative of the Judgment and Decree herein, shall
be absolutely binding upon both parties, and shall have the force and effect of an Order of
the Court. The parties shall adhere to any written agreement reached through mediation
until modified by subsequent mediation or by further Order of the Court.
d) Payment of Costs, Both parties shall share the mediator's fees and disbursements
equally unless they mutually agree otherwise. The mediator shall provide the parties with
{hisher) fee and disbursement schedule in advance of mediation.
e) Confidentiality and Privilege, Within the limits of the law, the mediator will
accord confidentiality and privilege to all communications with the parties.
f) Restrictions. The mediator shall not participate as a witness, collateral contact or
atomey in a custody or parenting time study or inquiry involving either party. Further,
neither party may ever call the mediator as a witness to testify in any proceeding
Court File No. 62-FA-12-1782 Gonion Judgment ard Decree Page |4Fed im Second Judicel Distinct Court
4/19/2093 1:17:16 PM
Ramsey County Farnty, MN
involving their children or the subject matter of the mediation.
Cae
h) — Applicability of Dispute Settiement Procedures. The above procedure shall apply
to any claims or controversies regarding custody, child support, maintenance, or any other
issue.
i) Exhaustion of Remedies. The above procedure shall be followed before cither
party may apply to the Court for relief.
9. Access to Information. Pursuant (0 Minn. Stat. § 518.17, Subd, 3, notice is hereby
given to the parties:
a) Each party has the right of access to, and to receive copies of, school, medical,
dental, religious training, and other important records and information about the minor
children.
b) Each party has the right of access to information regarding health or dental
insurance available to the minor children,
c) Each party shall keep the other party informed as to the name and address of the
school of atiendance of the minor children, Each party has the right to be informed by
school officials about the children’s welfare, educational progress and status, and to
attend school and parent/teacher conferences. The school is not required to hold a
separate conference for each party.
d) In the case of an accident or serious illness of the minor children, each party shall
notify the other party of the accident or illness, and the name of the health care provider
and the place of treatment.
e) Each party has the right to reasonable access and telephone contact with the minor
children.
10. Changes of Residency. Neither party shall remove the minor children of the parties
from the State of Minnesota for the purpose of changing their place of residence without the written
consent of the other party or until further Order of the Court.
Neither party shall enroll the children in a different school within the White Bear Lake school
district without the written consent of the other party or until further Order of the Court, If either party
Court File No. 62-FA-12-1782 Gonion Judgment and Decree Page 15Filed in Second Judiciat Destrict Court
419192093 1:17:15 PM
Ramsey County Famity, MN
desires to relocate to another state or change the children’s school district, the question of the custody
shall be reviewed and custody shall be re-determined, if appropriate, pursuant to the best interests of the
minor children,
ll. Concealment of Minor Children, This document is subject to the provision of Minn.
Stat. $609.26 referred to in Appendix A, attached hereto and incorporated herein by reference.
12. Child Support:
8) — Support:
1), Commencing February 1, 2013, the Respondent shall pay to Petitioner the
sum of $700 on a monthly basis for his support obligation, basic, medical and PICS
percentages on medical expenses.
2) Both parties recognize that this support obligation is an upward deviation
from the statutory child support guidelines of Minn. Stat. §518A.35 and is expressly
limited to the duration of the split custody arrangement where one of the two minor
children lives with one parent.
3) Child support obligations are subject to cost-of-living increases, with the
first such increase to occur two years subsequent to entry of the Judgment and
Decree herein, all as defined in attached Appendix A.
4) Child support shall be recalculated upon the emancipation of the oldest child
of the parties.
b) —_ Health and Dental Coverage Upon the Minor Children.
1) At this time, the parties shal! continue the enrollment of the children in
MinnCare for so long as they respectively remain eligible for such coverage.
2) Pach party shall provide to the other insurance cards, all information relative
to the available coverage, the costs thereof for that portion of the premium charged
for the minor children as their dependents, network availability for coverage.
3) ‘The parties shall utilize medical and other providers identified as approved
providers by the existing medical network.
4) NOTICE IS HEREBY PROVIDED that a party who fails to maintain court-
ordered coverage upon minor children is liable for the uninsured medical and dental
expenses, unless a court order provides otherwise
Court File No, 62-FA-12-1782 Gonloe Judgmest and Decree Page 16Filed in Second Judicial District Court
49192093 1:17:15 PM
Ramsey County Family, MN
1) Unreimbursed/uninsured medical and dental expenses of the minor children
include but are not be limited to prescriptions, co-pays, deductibles, routine dental
check-ups, orthodontia, mental health or optical expenses (including corrective
lenses) of the amounts not covered by insurance,
2) Petitioner is responsible for 28 % of the minor children’s unreimbursed and
uninsured medical and dental expenses,
3) Respondent is responsible for 72% of the costs of the uninsured and
unreimbursed medical and dental expenses of the minor children.
4) ‘The parties shall regularly exchange written accountings of any uninsured
health care expenses of the minor children. If a party pays for any deductible or
non-covered expense, he/she shall submit a copy of the receipt and all underlying
insurance processing forms to the other party who shall reimburse her/him within
thirty (30) days of the net amount owed, following submission of documentation
as to the expense incurred. Such information shall have documentation of
insurance reimbursements or reductions, if any. Any insurance reimbursement or
reduction shall be offset against the total owed in the calculation of the parties’
Tespective shares,
5) If the obligor party does not reimburse the obligee party within thirty (30)
days, said expense will be collected as child support arrears, upon reporting of the
delinquencies to the child support agency.
6) The parties must exchange all medical and dental reimbursement claims
for the minor children as incurred,
7) NOTICE IS HEREBY PROVIDED TO THE PARTIES that a party
seeking reimbursement for uninsured or unreimbursed medical and dental
expenses must request reimbursement no later than two years from the date the
expenses were incurred, pursuant to Minn. Stat. §518A.41, Subd. 17(b).
13. Duration of Child Support Obligation: Child support continues until the occurrence of
the first of the following events;
a) The last child covered by the order reaches the age of eighteen, or, age twenty, if
still in secondary school;
b) ‘The last child covered by the order becomes emancipated or dies; or
Court File No. 62-PA-12-1782 Gonion Judgment and Decree Page 17Fited im Second Judical Comt
4699/2013 1.17:15 PIA
Ramsey County Farrily, MN
c) Purther order of the court.
14. NonMerger of Support Arrearages: Any support arrearages as owed pursuant to the
Temporary Order for Relief of August 24, 2012, do not merge with the entry of the Judgment and Decree.
15. Automatic Income Withholding Respondent's support obligation shall be paid through
income withholding. A copy of this order shall be provided to Ramsey County Support & Collections for
the implementation for the Title 4D application submitted by Petitioner.
Until income withholding takes effect, Respondent shall send all payments to the Minnesota Child
Support Payment Center;
Minnesota Child Support Payment Center
P.O. Box 64326
Saint Paul, Minnesota 551694-0326
16. Appendix A: Appendix A with its statutory requirements is attached hereto and
incorporated herein in its entirety by reference.
17. Life Insurance Policies: Each party is awarded all right, title and interest in and to their
respective existing life insurance policies, with any cash value as contained therein.
18. Use of Minor Children as Income Tax Exemptions:
a) Petitioner shall be entitled to claim Alexis Rose Gonion, born on September 17,
1999, as a dependency exemption on her state and federal income tax returns during each
year of the child's minority, commencing with tax year 2013.
b) Respondent shall be entitled to claim Nicholaus Anthony Gonion, born on April
26, 1996, as a dependency exemption on his state and federal income tax retums during
each year of the child’s minority, commencing with tax year 2013.
c) Once a child is no longer a minor, the parent who has the primary residence with
the minor child shall have the remaining minor child as a dependency exemption for
federal and state income tax purposes,
d) Upon request from the other party, each party will execute whatever tax forms and
documents necessary to effectuate this provision.
Court File No. 62-FA-12-1782 Gonfon Judgement and Decree Page 18Filed in Second Judicial District Court
192013 1:17:15 PM
Ramsey County Famty, MN
19. Tax Returns of the Parties: The parties shall file separate tax returns for 2012. All tax
refunds as received by either party for the 2012 tax year, or attributable to prior tax years in which the
parties filed joint returns, shall be applied towards the outstanding state and federal tax liabilities as
owed by the parties’ prior tax returns.
For 2012, the partics shall submit the question of an allocation of the children as tax dependents
and status on filing to the tax accountant, Melvin Rozeboom, who shall prepare the separate tax returns
so as to maximize the refunds as might be available through the structuring of exemptions and
deductions for application of the tax refunds as received by either of them towards the outstanding tax
liabilities owed upon prior joint tax returns. Respondent shall be solely responsible for the fees for Mr.
Rozeboom's tax preparation of the parties’ 2012 separate tax returns.
20. Homestead Real Estate: Respondent is awarded all right, title, interest, and equity in
and to the homestead of the parties located at, 3485 Centerville Road, Vadnais Heights, Minnesota 55127,
and legally described as:
‘That part of the North ‘4 of the Northeast 4 of Section 32, Township 30, Range 22, lying
West of the old center line of Centerville Road and lying East of the West 564 feet of afore
described fraction of Section 32, and lying South of a line described as follows: Beginning
at a point distant 564 fect East of the West line of said fraction and 145 feet North of the
South line of said fraction; thence running East parallel to said South line, 310,3 feet, thence
deflecting 35° 20° to the right and Southeasterly 70 feet more or less to an intersection with
said center line, and lying North of a line described as follows: Begianing at a point distant
564 feet East of said West line and 49,52 feet North of said South line thence running East
parallel to said South line 216 feet, thence deflecting 32° 07" to the right and Southeasterly
to an intersection with said center line. Also the North 84.48 feet of the South 134 feet of
the East 231 feet of the West 564 fect of the North % of the Northeast 4 of Section 32,
Township 30, Range 22.
Subject to restrictions, reservations, and easements of record, if any.
a) The Respondent shall continue to pay upon ongoing residential obligations, notes,
insurance, encumbrances, liens, taxes and assessments, and the first mortgage due and
owing upon said homestead.
Court File No, 62-FA-12-1782 Gonion Judgment and Decree Page 19Filed in Second Judicial Otstrict Court
4102013 1:17.15 PM
Ramsey County Family, MN
b) In the event that Respondent is already or becomes delinquent upon the assigned
mortgage obligations upon which the parties are jointly responsible, then notice of such
delinquency shall be promptly provided to the Petitioner. If the Respondent has not cured
Fd en tilda Gi days ot « peed ctena perenne See Se peopety thet) be
i sale,
c) Respondent shall make all reasonable efforts to refinance the existing
encumbrances upon the marital residence as soon as possible but no later than June 2018
$0 as to remove Petitioner from the underlying liability thereon.
d) Immediately upon entry of the Judgment and Decree, Petitioner shall execute and
deliver a Quit Claim Deed to Respondent conveying her interest in the property to
Respondent in the implementation of the property awards specified above. In the event
that Petitioner fails to execute said Quit Claim Deed, a certified copy of the Judgment and
Decree herein or a separate Summary Real Estate Disposition Judgment shall act as such
conveyance. In such event, if Torrens property, the Registrar of Titles in and for the
involved County shall be directed to cancel the existing Torrens certificate as to said real
estate and issue a new certificate.
e) In the event there is any technical error or omission made in describing the legal
ttle or description to the real property referenced herein, the parties shall execute and
deliver to cach other any and all documents necessary to correct such error or omission.
) Counsel has advised the parties about the income tax laws respecting capital gain
tax including the exclusion available under the current Internal Revenue Code. Each
party shall be solely responsible for any capital gains upon the real estate awarded to
him/her. The parties shall be equally responsible for any capital gains attributable to the
sale of the Blue Green timeshare.
2), Personal Property, Household Goods, Furnishings, Etc.; Each party is awarded the
personal property, household goods and furnishings currently in her own and his own respective
possession and/or as agreed upon by the parties.
22. Automobiles:
8) Petitioner is awarded all right, title, interest and equity, free and clear of any claim
on the part of Respondent, in and to the 2000 Ford Expedition currently in Petitioner's
possession, Respondent shall, upon execution of the Stipulation herein, or sooner if he
desires, execute all necessary documents to effect transfer of the title.
b) Respondent is awarded all right, title, interest and equity, free and clear of any
claim on the part of Petitioner, in and to the 2006 Mercury Mariner, subject to any
Court File No. 62-FA-12-1782 Gonion Judgment and Decree Page 20Filed in Second Judicial istrict Court
411972013 1:17:15 PM
Ramsey County Family, MN
encumbrance, currently in Respondent's possession.
c) Each party shall execute all necessary documents to effect transfer of the title of
the vehicles as awarded to cach party.
23, Respondent’s Business: Respondent is awarded all right, title and interest to his business,
White Bear Asphalt and Sealcoating, and all related business equipment, subject to any liabilities, free and
clear of any right, claim or interest of the Petitioner.
24, Bank Accounts; Each party is awarded all right, title, interest and equity in and to the
checking accounts, savings accounts, other investment or banking accounts or stocks as held in theit
respective names, free and clear from any right, claim or interest therein by the other party.
25. Debt: To the extent of this Court's jurisdiction over the parties, the liability of the
Respondent and Petitioner for debts incurred during the marriage, under Minnesota law, terminated as of
the date of commencement of this proceeding, Any bill, debt or other obligation incurred by either party
after the aforesaid date is the obligation only and solely of the party incurring the same. The responsibility,
of the parties for debts is controlled by Minnesota Statutes and case law, including Minnesota Statute
Chapter 519 and the debt instrument, as they may apply.
a) Respondent is solely responsible upon the balance of the IRS and State of
Minnesota tax debt, following the application of 2012 tax refunds or any refunds
attributable to prior joint tax returns filed by the parties towards the existing tax liabilities
attributable to prior joint tax returns filed by the parties.
1) _ Respondent shall establish a payment plan with the state and federal tax
authorities upon the outstanding joint tax liabilities of the parties attributable to,
Prior tax years,
2) In the event that Petitioner has collection efforts directed at her by the state,
or federal tax authorities, whether through wage garnishment or levy upon
financial accounts or recapture of future tax refunds or rebates, then she shall
provide notice to the Respondent of the amounts claimed. Should a taxing
authority be successful in collecting from the Petitioner upon past joint tax!
liabilities, then Respondent shall immediately begin monthly reimbursement to)
Petitioner of the garnished or levied or recaptured amount(s) equal to 1/12th of the
Court File No. 62-FA-12-1782 Goniion Jedgment and Decree Page 21Filed in Second Judicial District Court
4/19/2013 1:97:15 PM
Ramsey County Family, MN
full amount claimed until full satisfaction of the liability collected from Petitioner,
b) Except as otherwise set forth herein, each party is responsible for all debts and
obligations incurred of contracted for by a party, regardless of whether said debts could
be characterized as individual or joint.
26. Attorney Fees: Each party is responsible for his/her attorney fees incurred in this
dissolution of marriage proceeding,
27, Execution And Exchange Of Documents: To implement the terms and provisions
contained herein, each of the pertics shall make, execute and deliver to the other party instruments of
conveyance, assignment and other documents as may be required, In the event cither party fails to do so,
the Judgment and Decree shall operate as said conveyance.
28. Acknowledgment Of Agreements: At the prehcaring conference of January 30, 2013,
the parties made the following acknowledgements on the record:
a) The partics agreed and acknowledged that they had sufficient time to discuss the
circumstances of their marital relationship and the dissolution of that relationship with
their attorneys.
b) The parties agreed they had been advised_by their attorneys as to investigative
discovery and appraisal procedures available to them to determine the nature, extent and
value of their property, and that being fully informed of their right to inquire, they limited
c) The parties acknowledged they were fully advised of their legal rights and the
terms as sct out in the agreements read into the record at the prehearing conference of
January 30, 2013 and that they fully understood the meaning and intent of their
Agreements as incorporated into the Judgment and Decree, including but not limited to its
final and binding effect.
d) The parties acknowledged that their stipulation was the result of prolonged
negotiation and settlement, with the parties’ positions compromised to achieve
agreement. Both parties have stated their understanding they have waived their respective
tight to trial on any contested issues by entering into their stipulation.
e) ‘The parties have agreed the terms set forth in their agreements as read into the
record at the January 30, 2013 prehearing conference were fair and equitable, equitable
under the circumstances,
Court File No, 62-FA-12-1782 Gonion Judgment and Decree Page 22Filed in Second Judicial District Court
4/19/2013 1:17:16 PM
Ramsey County Family, MN
29. Full Disclosure And Reliance: Each party has represented that the extent, nature and
amount of all property, income and indebtedness have been disclosed to each other. In the event
additional income or property of value is determined to exist as of the date hereof, such assets or income
may be subject to future court proceedings pursuant to Rule 60 of Minnesota Rules of Civil Procedure,
and the party failing to disclose the assets or income shal] be responsible for reasonable ettorney fees and
costs as may be ordered by the Court in such proceeding.
30. Full Release; Subject to the foregoing and full compliance therewith, each party is and
shall be, in all respects, manners and things, released and fully discharged from any liability, claims or
obligations of any kind or character of the other party, whether arising out of the marriage relationship or
otherwise. The Judgment and Decree incorporating the terms of the parties’ Marital Termination
Agreement and Stipulation is deemed to constitute a full, final and complete property settlement between
the parties. Each party hereto is released from and has waived forever any claim in and to the propery
of the other,
31. Termination of Attorney of Record Representation: Sixty-one days following the
notive of filing and service of the Judgment and Decree by mail as provided hereafter, Mary Catherine
Lauhead and Patti Schinzing, shall be discharged as the attorneys of record for each of the parties,
Service of any further pleadings in this proceeding shall be directly served upon cach of the parties in
accordance with the Rules of Minnesota Civil Procedure,
32. Service by Mail: Either attorney shall serve the Judgment and Decree herein by mailing
a copy of the Judgment and Decree to the other attorney and providing to the Court an affidavit of such
sevice for attachment to the original Judgment and Decree, as good and proper service for all purposes.
Each attorney is responsible to ensure proper service of the Judgment and Decree herein upon her client.
Court File No. 62-FA-12-1782 Gonioe Judgment and Decree Page 23Filed in Second Judiciat Distinct Court
4162013 1:17:15 PM
Ramsey County Family, MN
33. Immediate Entry of Judgment and Decree by Clerk: The Court orders the immediate
enitry of the Judgment and Decree by the Clerk of Court simultaneous with the signature of the Court
hereafter. The automatic stay of entry of the judgment specified in Rule 125 of the General Rule of
Practice for the District Courts is waived.
LET THIS JUDGMENT AND DECREE BE ENTERED
ACCORDINGLY ON THIS DATE.
I bereby oertify that the above Conclusions of Law constitute the Judgment and Decree of this Court.
Dated: Ye A 2013 TAMA L. HAL.
ENTRY OF JUDGMENT NOT STAYED. District Court Administrator
Approved For Submission To The Court For Entry:
Dated: March 29, 2013 Dated: April_3 , 2013
Attomey for Petitioner Nenad for Respondent
Ivy League Place 3985 Clover Avenue
475 N, Cleveland Avenue, Suite 221 Saint Paul, MN 55127-7015
St. Paul, MN 55104
651-699-8711 651-426-0870
E-mail Address: [email protected] E-mail Address: [email protected]
Support As Structured Approved by Statutory Authority duugment
Dad: Apit__, 23 eee.
fay 2, A. ntry Date HERE |D
Ramsey Qounty Attomey A /QO4SSE
6S). 266 - 3067 Panly Gout
By Deputy, Sd ane
Court File No, 62-PA-12-1782 Gonion Judgment and Decree Page 24Fed in Second Judicial Drsinict Court
4/10/2013 1:17:15 PM
Raney County Family, MN
(UalidSupportuuidelines Worksheet
Child Support Guidelines Worksheet
Parent A: Melissa IV-D Case Number: Number of Joint Children: 2
Parent B: Rick Court Fite Number: 62-F 4-12-1782 Date: 3/29/2013
[Parent A|Parent &| Combined]
Income ‘a Monthly income Received isize3__[sss7vo [—
1b. Chiki(ren)'s Social Securty/Vetorans’
dactstomestonsteenegemy [| i |
7c. Potential Income a
‘a. Spousal Maintenance Orders Obiguted to = Pf |
te. $hbt Supper Orie) Otdgsiod be
restric ee
ieee een [$1263 [s3sx79 [— |
Adjustments 2a, Number of Noni Cie) Be
Home (Maximum number allowed Is 2)
2b, Deduction for Nonjoint Chad(ren) In the
=e Poe
5 Sorortal nacme ft Deteartelen Chie
Spoons) ae |
4. Percentage Share otCombined PICS [28% [72% |— |
5. Combined Basic Support Obligation j— 88200 |
6. Pro Rata Basic Support Obligation ise fT
Basic Child Support 7. Basic Support Obligation After
EgoweAgemen ericae | [||
Child Care Obligation 8 Child Care Support Obligation for Jomt
Sag AF i ETS |
Medical Support Ga. Monihty Cost of Health Care Coverage for
Bseey Ss eo
80, Pro Rata Share of Health Care Coverage
x 7 rary |
Coverage “Ge. Contibution to Health Care Coverage _|sa__| (=|
Available ed. Monbly Cost of Dental Coverage for Joint a" * Es |
Child(ren)
Se. Pro Rata Share of Dental Coverage Costs |80_——|$0_ ||
St. Contribution to Dental Coverage fT
oe
‘No Appropriate 10. Medical Support Obligation for Public
aera ._ tre |
Unineured/Unreimbursed 11. Share of Uninsured and/or Unreinbursed pre
= Pee
12, Net Chad Support Obligation see [|
Benefits 13. ‘6 Social ’
wt tau | | i |
Computing a Final 14. Total Child Support Obligation se saves J—
hitp://childsupportcalculator dhs, state mn_us/ChildSupportGuidelines.aspx?Printable Versio...
Page | of 2
3/29/2013Fited in Second Judicial District Court
4119/2013 1.1715 PM
Ramsey County Family, MN
(ChuldSupportuidelines Worksheet Page 2 of 2
22a, Presumptive Minimum Order for 1 or 2
Joint Chikiren
Olscisimer: The chic support quidsiines worksheet, instructions, and calcutator are far information and
educational use only and are not s guarantee of the ernount of child that wil be ordered. The results
obtained are only 83 accurate ss (he information used. The actual Support order may be affected by other
factors. The Court hes the final authority to determine the amount of the child support order. If this worksheet
http://childsupportcalculator,dhs.state.mn,us/ChildSupportGuidelines.aspx?Printable Versio... 3/29/2013Filed in Second Judicial District Court
4/19/2019 1:17:15 PM
Ramsey County Family, MN
(Lanasupporiuuicelines Worksheet Page | of 2
Child Support Guidelines Worksheet
Parent A: Rick IV-D Case Numbor: Number of Joint Children: 2
Parent 8: Melissa Court File Number: 62-FA-12-1782 Date: 3/29/2013
[Parent A] Parent & [Combined]
Income 1a, Monthly Income Received isss79_ {sizes [—-
‘1b. Child{ren)'s Social Securityeterans”
Benefits Derived From s Pareate Engibity
‘4c. Potential income jo je
smear FE
Paid for Nonjoint Chikd(ran)
1f. Monthly Gross income (1at1b+to-1d-t) [$3379 [$1283 |— _—‘|
Adjustments 2a, Number of Nonjolnt Child(r
Case Info
Judge
Leary, William H., III
Track Judge’s New Case
Case No.
(Subscribe to View)
Document Filed Date
April 19, 2013
Case Filing Date
June 15, 2012
County
Category
Dissolution with Child
Parties
Order for Child Support Index # 10
Attorney
Taken Under Advisement Index # 9
Attorney
Findings, Order, Judgment and Decree-Dissolution
Attorney
Review Hearing
Attorney
Order-Other
Attorney
Pre-trial
Attorney
ICMC Order - Opted Out of Early Neutral Evaluation
Attorney
Initial Case Conference
Attorney
Stipulation and Order
Attorney
Order Granting In Forma Pauperis
Attorney
Support order
Attorney
Judgment
Attorney
Dissolution Granted - Judgment
Attorney
Features
Smart Search
Verdicts
Judge Analytics
Motions & Issues
State Coverage
Company
Home
About
Contact us
Pricing
Resources
Blog
Support & FAQ
Credit System FAQ
Top 20 counties
Los Angeles County, California
Philadelphia County, Pennsylvania
Harris County, Texas
Allegheny County, Pennsylvania
Cook County, Illinois
Palm Beach County, Florida
Sacramento County, California
San Bernardino County, California
Miami-Dade County, Florida
Broward County, Florida
New York County, New York
Montgomery County, Ohio
Orange County, Florida
San Diego County, California
Pinellas County, Florida
King County, Washington
Hillsborough County, Florida
Orange County, California
Alameda, Florida
Montgomery County, Pennsylvania | https://trellis.law/doc/124279203/findings-order-judgment-decree-dissolution |
IJERPH | Free Full-Text | The Role of Environmental Factors on Health Conditions, General Health and Quality of Life in Persons with Spinal Cord Injuries in South Africa
Objective: The objective was to describe the individual items of the environmental factors and to investigate the relationship between the environmental factors to health conditions, general health and quality of life in people with SCI in South Africa. Methods: Two hundred persons with SCI participated in a cross-sectional survey design. This study formed part of the International Spinal Cord Injury (InSCI) Community Survey. Four major domains, environmental factors, health conditions, general health and quality of life of the survey questionnaire responses, were used for the analysis. Regression models were used to determine the association between the independent variable, which consisted of the specific environmental factors items, and the dependent variables comprising health conditions, general health and quality of life. Results: The commonly reported environmental barriers were public access, lack of short- and long-distance transport and finances. Environmental factors such as public access (p < 0.001), short- (p < 0.001) and long-distance transport (p = 0.001), and friends’ (p = 0.003) and colleagues’ (p < 0.001) attitudes and communication (p = 0.042) were significantly associated with the presence of secondary health conditions. Finances (p = 0.026), family attitudes (p = 0.037) and communication (p = 0.039) had a significant association with worsened mental health. Services (p = 0.022) and communication (p = 0.042) were also significantly associated with decreased general health. Conclusion: The results provide insight into modifiable environmental factors policymakers need to consider or adapt to improve the lives of people with SCI in South Africa with respect to health (secondary health conditions), as well as general and mental health.
The Role of Environmental Factors on Health Conditions, General Health and Quality of Life in Persons with Spinal Cord Injuries in South Africa
Lucian Bezuidenhout 1,2,*,† ,
Anthea Rhoda 1,† ,
David Moulaee Conradsson 2,3,4 ,
Joyce Mothabeng 5 and
Conran Joseph 3
Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, 17177 Stockholm, Sweden
3
Department of Health and Rehabilitation Sciences, Division of Physiotherapy, Stellenbosch University, Cape Town 7602, South Africa
4
Medical Unit Occupational Therapy & Physiotherapy, Theme Women’s Health and Allied Health Professional, Karolinska University Hospital, 17176 Stockholm, Sweden
5
Department of Physiotherapy, University of Pretoria, Pretoria 0028, South Africa
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work and share first authorship.
Int. J. Environ. Res. Public Health 2023 , 20 (9), 5709; https://doi.org/10.3390/ijerph20095709
Received: 13 March 2023 / Revised: 26 April 2023 / Accepted: 28 April 2023 / Published: 3 May 2023
(This article belongs to the Special Issue Socio-Environmental Health and Risk Perception )
Abstract
Objective: The objective was to describe the individual items of the environmental factors and to investigate the relationship between the environmental factors to health conditions, general health and quality of life in people with SCI in South Africa. Methods: Two hundred persons with SCI participated in a cross-sectional survey design. This study formed part of the International Spinal Cord Injury (InSCI) Community Survey. Four major domains, environmental factors, health conditions, general health and quality of life of the survey questionnaire responses, were used for the analysis. Regression models were used to determine the association between the independent variable, which consisted of the specific environmental factors items, and the dependent variables comprising health conditions, general health and quality of life. Results: The commonly reported environmental barriers were public access, lack of short- and long-distance transport and finances. Environmental factors such as public access (
p
< 0.001), short- (
p
< 0.001) and long-distance transport (
p
= 0.001), and friends’ (
p
= 0.003) and colleagues’ (
p
< 0.001) attitudes and communication (
p
= 0.042) were significantly associated with the presence of secondary health conditions. Finances (
p
= 0.026), family attitudes (
p
= 0.037) and communication (
p
= 0.039) had a significant association with worsened mental health. Services (
p
= 0.022) and communication (
p
= 0.042) were also significantly associated with decreased general health. Conclusion: The results provide insight into modifiable environmental factors policymakers need to consider or adapt to improve the lives of people with SCI in South Africa with respect to health (secondary health conditions), as well as general and mental health.
Keywords:
environmental factors
;
general health
;
health conditions
;
quality of life
;
spinal cord injury
;
South Africa
1. Introduction
Spinal cord injury (SCI) is one of the most serious and disabling types of traumatic or non-traumatic injury, which usually affects all aspects of the individual’s life including physiological, psychological and social functions [ 1 , 2 ]. Individuals with SCI face a number of major health conditions, secondary health conditions (e.g., sleep problems, bowel dysfunction and pressure sores), mental health conditions (i.e., depression and happiness) and pain issues, which often have a negative impact on life quality, functioning and emotional well-being, which often leads to preventable premature death [ 3 , 4 ]. People living with SCI also experience activity limitations and participation restrictions in everyday life due to the increased physical demands of living with the SCI [ 3 , 5 ]. For example, results from a British cohort that included 85 persons with SCI, who were injured for more than 20 years, showed that participants had lower physical independence, occupation and social integration, which resulted in decreased participation [ 6 ]. Increasing participation for individuals with SCI is important since it can lead to improving mental and physical well-being [ 7 ]. The experience of living with a disability is often shaped by environmental factors rather than the presence of living with the disability [ 8 ]. This is especially true in low-resource settings such as South Africa, where healthcare is restricted due to a lack of resources, raising various barriers (social and environmental) resulting in challenged reintegration into society for individuals with SCI [ 9 ].
In South Africa, data on SCI are rare due to a lack of a national registry and coordinated care systems [ 10 ]. However, a study by Joseph et al. [ 10 ] provided the first population estimates of the incidence of traumatic spinal cord injury (TSCI), reporting a staggering rate of 75.6 per million person, a figure that is almost the highest globally [ 10 ]. A study conducted by Madasa et al. [ 11 ] in South Africa revealed that the mortality rate associated with SCI was 24% over a period of four years [ 11 ], which highlights the significance of SCI as a public health issue in South Africa. The average age of SCI in South Africa is also documented to be lower compared with developed countries [ 12 ], which poses a unique challenge to society and health systems. The younger age of SCI often corresponds to the time of early career development and establishment, and combined with environmental barriers (i.e., transport and inaccessible workplaces) limiting participation, it could further complicate the reintegration of people with SCI into the general society. The South African healthcare system is divided into private and public systems, and access to healthcare services is largely determined by patients’ financial standings. Moreover, the public healthcare system in South Africa has often been documented to have insufficient financial resources, resulting in sub-optimally coordinated and resourced rehabilitation services for individuals with disability [ 13 ]. The inadequate rehabilitation services are further elevated by the continuous longstanding nature of SCI rehabilitation considering initial institutional care and discharge back home and into society. However, in situations where specialized rehabilitation units for persons with SCI are available in the public sector, patients have reported that the rehabilitation staff at these centers possess the required expertise [ 14 ].
Individuals with SCI may experience physical conditions that can be a direct or indirect result of SCI, such as secondary health conditions (e.g., pain and pressure sores), loss of muscle power and functional limitation (e.g., wheelchair transferring and toileting), which could negatively impact participation in activities (e.g., work, family and social) [
15
]. The effects of these conditions can extend beyond the person with the SCI and affect the family members as well. Family members may have to take on additional financial and caregiving responsibilities that could lead to relationship and lifestyle changes. These changes can have a negative impact on the health and well-being of both the person with SCI and their family members.
The International Classification of Functioning, Disability and Health (ICF) has been introduced as a conceptualized framework for the role personal and environmental factors have in the construction of the disability [ 16 ]. The ICF classifies environmental factors comprising physical, social and attitudinal domains in recognition of the environment’s important role in the everyday functioning of the individual with disabilities [ 17 ]. In recent years, an increasing number of studies have focused on understanding participation (i.e., community, physical and social) and factors influencing participation in people with disabilities (e.g., SCI) [ 3 , 8 , 18 , 19 , 20 ].
Environmental factors that vary with physical, social, attitudinal and cultural issues have been documented to be one of the more emphatic factors influencing participation [ 1 ], especially in low-resource settings (i.e., South Africa) [ 21 ]. Environmental factors negatively impacting people with disabilities often appear as multiple factors simultaneously rather than isolated factors that ultimately have a compounded effect on participation [ 22 ]. For example, Cawood et al. [ 23 ] determined the environmental barriers and facilitators to participation in 53 people with disabilities (e.g., stroke) in South Africa. They found multiple factors such as the use of technology in daily living, communication, access to transportation, self-perceived mobility and access to buildings to be environmental barriers to participation [ 23 ]. In a comparable context, Maart et al. [ 24 ] reported similar findings with the addition of educational, climate and labor services as environmental barriers to participation [ 24 ]. In a study that relates environmental factors influencing participation in people with SCI in Morocco, Hajjioui et al. [ 21 ] showed that individuals with SCI who perceived environmental factors such as lack of public access, financial strain and restricted access to public transportation, public and private places to be barriers also reported more secondary conditions, higher pain intensity, lower mental and general health and quality of life (QoL) [ 21 ].
Identifying factors that will overcome physical, social and attitudinal barriers could alleviate the burden on the healthcare system. Moreover, environmental factors negatively affecting people with SCI health conditions, general health and QoL in socio-economically challenged countries such as South Africa are not well described and therefore could lack integrated policy guides and rehabilitation interventions. Therefore, this study aims to describe the individual items of the environmental factors and to investigate the association between environmental barriers with outcomes including health conditions, general health and QoL.
2. Materials and Methods
2.1. Study Design and Participants
Data were collected using a cross-sectional survey. Two hundred participants, aged ≥18 years and with a confirmed primary diagnosis of either traumatic or non-traumatic SCI, were recruited from private and public healthcare registries in the Western Cape and Gauteng provinces of South Africa. The exclusion criteria were individuals who had a severe cognitive impairment, were hospitalized at the time of data collection, had lower motor neuron paralysis and had inability to give written consent and follow instructions. These exclusion criteria were chosen based on the participant’s understanding of the nature of the study and to increase the generalizability and validity of the study, which could be affected by those hospitalized and with lower neuron paralysis. Participants participated in the International Spinal Cord Injury (InSCI) community survey, of which the primary results of the worldwide data have been published [ 25 , 26 ]. The survey was conducted between January 2017 and May 2019. The InSCI project design, content and protocol are detailed elsewhere [ 25 , 26 , 27 ]. The South Africa section of the InSCI project was approved by the Biomedical Research Ethics Committee of the University of Western Cape (BMI16/13/24), and all study participants gave written consent prior to participation.
2.2. Data Collection
All participants with SCI were invited to one interview session (either in person or by telephone), which consisted of 125 questions from the INSCI community survey. Six participants who conducted the survey over the telephone did the interview over two sessions. The interviews were conducted by two research assistants who were trained in the administration of the questionnaire, specifically, what each item elicits and their response options. The survey instrument was available in the local languages, which were English, Afrikaans and isi-Xhosa (
Supplementary File S1
), the most widely spoken languages in the provinces that participated. The sociodemographic data included gender, age, disability pension and education level. Years of education before and after SCI were measured in accordance with the International Standard Classification of Education. The SCI characteristics included age and years since injury, etiology, impairment level (paraplegia or tetraplegia) and severity (motor complete or motor incomplete SCI). Four major domains, namely, environmental factors, health conditions, general health and quality of life, of the survey questionnaire responses were used as specific items for the analysis.
2.2.1. Independent Variable (Environmental Factors)
Environmental factors, which consisted of features associated with the support and relationships from others (e.g., family, friends and colleagues), social attitudes (e.g., negative attitude toward people with disability), public services (e.g., availability of short- and long-distance transportation) and policies, were measured as a sum score using the Notwill Environmental Factors Inventory short form (NEFI-SF) [ 27 , 28 ]. The response scores were 1 = not applicable, 2 = no influence, 3 = made my life a little harder and 4 = made my life a lot harder. For simplicity, we reinterpreted the scores by generating the responses of “not applicable” and “no influence” = 0 and 1 = “made my life a little harder” and 2 = “made my life a lot harder” in accordance with Hajjioui et al. [ 21 ]. The score range for the environmental factors was 0–28, with a higher score indicating more barriers.
2.2.2. Dependent Variables (Health Conditions, General Health and Quality of Life)
(1) Health conditions related to SCI comprise secondary health conditions, pain intensity and mental health. Secondary health conditions were measured using the modified SCI–Secondary Health Conditions scale [ 29 ] and the self-administered comorbidity questionnaire [ 30 ]. The response to each item was 1 = no problem to 5 = extreme problem, and we built a sum score over the 14 items ranging from 14 to 70, with a higher score indicating more secondary health problems [ 21 ]. Pain intensity was measured using a single item from the Brief Pain Inventory (BPI) with a scale of 0 = no pain to 10 = pain [ 31 ]. Mental health (i.e., depression and happiness) was measured using a sub-domain of the short-form health survey (SF-36), and we built a sum score over the five items (5–25), where the response scale for each item was 1 = all of the time to 5 = none of the time in accordance with Ware et al. [ 32 ].
(2) General health was assessed using a single item from the SF-36, where participants were asked to rate their health from 1 = poor to 5 = excellent [ 32 ].
(3) Quality of life was measured using a single item from the World Health Organization Quality of Life assessment (WHOQoL-BREF), where participants were asked to rate their QoL from 1 = very poor to 5 = very good [ 33 ].
2.3. Data Analysis
Statistical analyses were carried out using IBM SPSS v.26 software (IBM Corporation, Chicago, IL, USA). Sociodemographic data and SCI characteristics were presented descriptively as numbers (percentages) and mean values (standard deviations). Multiple linear regression models, adjusted for age, the severity of the injury and sex, were used to determine the association between environmental barriers with secondary health conditions, pain intensity and mental health. Multiple logistic regression models, adjusted for age, the severity of the injury and sex, were used to determine the association between environmental barriers with general health and quality of life. p -value < 0.05 was seen as significant.
3. Results
3.1. Participant Characteristics
Table 1 presents the socio-demographic and SCI-related information of the two hundred persons (44 from private and 156 from public registries) with traumatic and non-traumatic SCI. Most SCI participants were male (75%), employed before SCI (61%) and single at the time of the survey (78%), and around half had complete SCI injuries. The average age at SCI onset was 28 (SD: 11) years, with most of the participants also reporting to have experienced an SCI of a traumatic nature, with the prominent causes related to assault and road accidents.
Table 1. Demographics of participants with spinal cord injury [ 12 ].
3.2. Description of Environmental Factors
Figure 1 shows the frequency of the different responses (as percentages) for each of the individual items/questions about the environmental factors. The majority of the individuals responded “not applicable or no influence” on most of the individual environmental factors ( Figure 1 ). The commonly reported barriers perceived to make “life a little bit or a lot harder” were public access, lack of short- and long-distance transport and finances ( Figure 1 ).
Figure 1. Environmental factors response rate, in percentage.
3.3. Environmental Factors Associated with Health Conditions, General Health and Quality of Life
Table 2 and Table 3 show the relationship between the environmental factors sum score and individual items with health conditions (e.g., secondary health condition, pain intensity and mental health), general health and QoL, which were significantly associated. The environmental factors sum score was significantly associated with secondary health conditions (B = 0.55, p < 0.001), pain intensity (B = 0.16, p = 0.030), mental health (B = − 0.21, p = 0.005) and general health (OR = 0.93, p = 0.016). There was no significant association between the environmental sum score and quality of life ( Table 3 ). On an individual item level, environmental factors such as public access (B = 0.30, p < 0.001), short (B = 0.33, p < 0.001) and long transport (B = 0.25, p = 0.001) and friends’ (B = 0.22, p = 0.003) and colleagues’ (B=0.27, p < 0.001) attitudes and communication (B = 0.15, p = 0.042) were significantly associated with the presence of secondary health conditions. Individuals who reported finances (B = −0.22, p = 0.026), family attitudes (B = −0.16, p = 0.037) and communication (B = −0.16, p = 0.039) also had a significant association with worsened mental health ( Table 2 ). Environmental factors such as services (OR = 6.06, p = 0.022) and communication (OR = 3.30, p = 0.042) were also significantly associated with decreased general health ( Table 3 ). There was no significant association between environmental factors with pain intensity and quality of life. The relationship between all the other environmental factors with health conditions, general health and quality of life are shown in the supplementary material (Tables S1 and S2) .
Table 2. Linear regression model showing the association between environmental factors and health conditions (secondary health conditions, pain intensity and mental health) adjusted for age, sex and severity of SCI.
Table 3. Logistic regression model showing the association between environmental factors and general health and quality of life adjusted for age, sex and severity of SCI.
4. Discussion
The purpose of this study was to describe the individual items of the environmental factors and to investigate the association between environmental factors with health conditions, general health and quality of life in people with SCI in South Africa. The most commonly reported environmental barriers for people with SCI in South Africa were the lack of short- and long-distance transport and finances. Secondary health conditions had the most significant associations with individual items of the environmental factors, followed by mental and general health.
The impact of a lack of finances on the functioning and quality of life of people living with SCI, specifically in low-resource settings, is evident. Similar to Hajjioui et al. [
21
], this study found a lack of finances to be associated with a decrease in mental health conditions (feelings of isolation and depression). A low return to work rate could be a major contributing factor to the financial challenges experienced by individuals post-SCI. In this study, 61% of respondents reported being employed prior to the SCI, while only 25% reported being employed post-SCI. Not having a job impacts the financial independence of individuals, which is further exacerbated by the requirements of living with a condition such as an SCI, which often necessitates additional resources and places additional challenges on individuals and their families. It is worth noting that the South African government does provide disability grants (ZAR 1980 per month) to assist individuals with SCI; however, this is often not enough to sustain financial well-being. It has also been reported that the psychological well-being of people with SCI is not directly associated with their injuries [
34
] but rather formed by daily interaction with their family members and society as a whole [
35
]. Our results are in line with this, with a decrease in mental health being associated with family attitudes (
p
= 0.026), which individuals reported to make life a lot harder. Providing specifically developed effective communication to individuals with SCI and their family members could play an important role in managing SCI and be a complementary cost-effective rehabilitation service that could promote mental well-being.
Similarly to what was found in this study, the provision of access (public and transport) for people living with disabilities is limited in low-resource settings such as South Africa [ 8 , 19 ]. Individuals with SCI often require specialized transport or adapted vehicles to assist with mobility. This is further amplified by the lack of public rehabilitation centers around South Africa, which results in individuals with SCI often traveling for long distances to attend checkups or appointments for medication using borrowed or hired cars due to the lack of wheelchair-accessible public transport [ 8 ]. Although the government in South Africa has tried to improve access to specialized short- and long-distance transport for people with disabilities via a system called “dial a ride”, this is often not ideal as it is not freely available, it needs to be booked well in advance, and reliability of the service is sub-optimal [ 36 ]. This lack of availability of appropriate short- and long-distance transport negatively impacts the participation (e.g., societal) and access of these individuals, which could lead to psychological stress and ultimately worsened secondary conditions [ 21 ].
South Africa has a large number of social inequalities, with environmental factors (e.g., lack of public transport) and physical public access (i.e., wheelchair ramps) limiting participation for people with disability, especially for those living in rural areas, in the labor market and health-related services, which further enhances the social inequalities [
37
]. The lack of easily accessible short- and long-distance public transport for people with SCI is also elevated by the lack of knowledge and positive attitudes of public transport operators (i.e., taxi and bus operators) of commuting these individuals in the public sector; therefore, government policies should provide strategies to promote awareness and integration of easy-to-access transport in the public sector for people with disabilities. It is worth noting that such modification of the transport systems and physical environments in low-resource settings such as South Africa is not always possible, and it often depends on legislation changes and financial investments. In addition to these strategies, community-driven approaches founded on social responsibility and accountability should be evoked and supported, rather than a national policy.
The social support network of people with SCI is smaller than the general population [ 7 ], with some studies showing that support and positive attitudes toward people with disabilities positively impact their health. Individuals with SCI who do not have a good social support network could adapt their social connections by joining support groups (e.g., online or in person) or participating in SCI-related activities (e.g., adaptive sports or volunteer work), which could result in social interactions and building new relationships [ 38 ]. In one of the first studies exploring environmental factors influencing the prevention of secondary health conditions in people with SCI in South Africa, Pilusa et al. [ 8 ] found that social support from family, caregivers and peers aided in the prevention of secondary health conditions [ 8 ]. Our results are in line with this, with the individuals with SCI who reported that the attitudes of their friends ( p = 0.003) and colleagues ( p < 0.001) that “made my life a lot harder” were significantly associated with worsened secondary health conditions. This could be attributed to these individuals moving less to engage socially, which ultimately leads to worsened secondary conditions. Another study by Hosseinigolafshani et al. [ 39 ] found that the disability attitude of colleagues, especially in the first years after the SCI event, plays a key role in the formation of their self-belief in their abilities [ 39 ]. The general attitudes toward individuals with SCI can be attributed to the lack of public education on the ability of individuals with SCI or general disability in low-resource settings such as South Africa. Therefore, frameworks should be developed to better enhance the public and labor markets’ awareness/perception of people with disabilities (i.e., SCI), and greater accountability measures should be enforced on institutions and systems that exclude people with disabilities.
The impact of environmental factors such as services (i.e., wheelchair training and occupational therapy) and communications (i.e., disability management frameworks) plays an important role in social reintegration and could improve health outcomes in people with SCI. Our results showed that environmental factors such as services (
p
= 0.022) and communications (
p
= 0.042), which individuals with SCI reported “made life a little or a lot harder”, were significantly associated with worsened general health. Providing specialized rehabilitation services (e.g., wheelchair training, promoting functional independence, problem-solving skills and access to assistive devices) in acute and post-acute rehabilitation phases could play an important role in overcoming environmental barriers and improving community reintegration. Although the South African government has developed policies to increase accessibility and equality for individuals with a disability, challenges regarding the accessibility of the environment, transport and lack of recreational facilities continue to persist, with no SCI-specific legislation in place.
Our results also differ from previous studies, which showed that quality of life and pain intensity are associated with environmental factors [ 19 , 21 ]. The difference could be attributed to the sample size, SCI characteristics and socioeconomic status of individuals included in various studies. The study had some limitations, including a relatively small sample size and only having data from two of the nine provinces of South Africa; therefore, the results might not be generalizable to the entire SCI population in South Africa. The data from the INSCI survey were self-reported from a cross-sectional study, which could result in responder bias. The majority of the participants were male (75%); however, this is consistent with other studies on people with SCI [ 8 , 19 , 21 ]. One of the shortcomings of this study is that certain SCI characteristics such as the level of impairment (i.e., tetraplegic vs. paraplegic), the severity of impairment (complete vs. incomplete) and socioeconomic status (e.g., employment status post-SCI) might influence several outcomes associated with environmental barriers, health conditions, general health and quality of life. Therefore, future work should entail performing multivariate analysis taking into consideration the roles of these different factors on environmental barriers, health conditions, general health and quality of life. Future work should also entail a better distribution (i.e., representative of all nine provinces) of the sample size and include more females with SCI. In addition, more concerted efforts to evaluate and monitor the implementation of policies to support the breakdown of environmental factors to positively impact health conditions, general health and quality of life are needed.
5. Conclusions
This is the first study to show modifiable environmental barriers such as public access, transport (short and long distances) and attitudes (family, friends and colleagues) to be significant barriers impacting health conditions and the mental and general health of people with SCI in South Africa. The nature of the environmental factors impacting health transacts various layers of society, which calls for approaches and interventions to be installed from the top (policy) to the bottom (inherent patient factors and family).
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijerph20095709/s1 , File S1: International Spinal Cord Injury Survey (InSCI) in Xhosa and Afrikaans languages; Table S1: Linear Regression model showing the association between Environmental factors with Health conditions (Secondary health conditions, Pain Intensity and Mental Health) adjusted for age, sex and severity of SCI. Table S2: Logistic Regression model showing the association between Environmental factors with General Health and QoL adjusted for age, sex and severity of SCI.
Conceptualization, L.B., A.R., J.M., D.M.C. and C.J.; methodology, L.B., A.R., D.M.C. and C.J.; validation, L.B. and C.J.; formal analysis, L.B. and A.R.; investigation, L.B., A.R., D.M.C., J.M. and C.J.; writing—original draft preparation, L.B., A.R. and C.J.; writing—review and editing, L.B., A.R., D.M.C., J.M. and C.J.; project administration, A.R., J.M. and C.J.; funding acquisition, C.J. and A.R. All authors have read and agreed to the published version of the manuscript.
The authors would like to thank all the SCI participants for their valuable time and efforts.
Conflicts of Interest
The authors report no conflict of interest.
References
Unalan, H.; Gencosmanoglu, B.; Akgun, K.; Karamehmetoglu, S.; Tuna, H.; Ones, K.; Rahimpenah, A.; Uzun, E.; Tuzun, F. Quality of life of primary caregivers of spinal cord injury survivors living in the community: Controlled study with short form-36 questionnaire. Spinal Cord. 2001 , 39 , 318–322. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hess, D.W.; Ripley, D.L.; McKinley, W.O.; Tewksbury, M. Predictors for return to work after spinal cord injury: A 3-year multicenter analysis. Arch. Phys. Med. Rehabil. 2000 , 81 , 359–363. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chang, F.H.; Liu, C.H.; Hung, H.P. An in-depth understanding of the impact of the environment on participation among people with spinal cord injury. Disabil. Rehabil. 2018 , 40 , 2192–2199. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Strom, V.; Manum, G.; Arora, M.; Joseph, C.; Kyriakides, A.; Le Fort, M.; Osterthun, R.; Perrouin-Verbe, B.; Postma, K.; Middleton, J. Physical Health Conditions in Persons with Spinal Cord Injury Across 21 Countries Worldwide. J. Rehabil. Med. 2022 , 54 , jrm00302. [ Google Scholar ] [ CrossRef ]
Charlifue, S.; Jha, A.; Lammertse, D. Aging with spinal cord injury. Phys. Med. Rehabil. Clin. N. Am. 2010 , 21 , 383–402. [ Google Scholar ] [ CrossRef ]
Savic, G.; Frankel, H.L.; Jamous, M.A.; Soni, B.M.; Charlifue, S. Participation restriction and assistance needs in people with spinal cord injuries of more than 40 year duration. Spinal Cord. Ser. Cases 2018 , 4 , 28. [ Google Scholar ] [ CrossRef ]
Halvorsen, A.; Pape, K.; Post, M.W.M.; Biering-Sorensen, F.; Mikalsen, S.; Hansen, A.N.; Steinsbekk, A. Participation and quality of life in persons living with spinal cord injury in Norway. J. Rehabil. Med. 2021 , 53 , jrm00217. [ Google Scholar ] [ CrossRef ]
Pilusa, S.; Myezwa, H.; Potterton, J. Environmental factors influencing the prevention of secondary health conditions among people with spinal cord injury, South Africa. PLoS ONE 2021 , 16 , e0252280. [ Google Scholar ] [ CrossRef ]
Tsai, I.H.; Graves, D.E.; Chan, W.; Darkoh, C.; Lee, M.S.; Pompeii, L.A. Environmental barriers and social participation in individuals with spinal cord injury. Rehabil. Psychol. 2017 , 62 , 36–44. [ Google Scholar ] [ CrossRef ]
Joseph, C.; Scriba, E.; Wilson, V.; Mothabeng, J.; Theron, F. People with Spinal Cord Injury in Republic of South Africa. Am. J. Phys. Med. Rehabil. 2017 , 96 , S109–S111. [ Google Scholar ] [ CrossRef ]
Madasa, V.; Boggenpoel, B.; Phillips, J.; Joseph, C. Mortality and secondary complications four years after traumatic spinal cord injury in Cape Town, South Africa. Spinal Cord. Ser. Cases 2020 , 6 , 84. [ Google Scholar ] [ CrossRef ]
Bezuidenhout, L.; Rhoda, A.; Moulaee Conradsson, D.; Theron, F.; Joseph, C. Factors influencing employment among people with spinal cord injury in South Africa. Disabil. Rehabil. 2022 , 29 , 1–7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Maphumulo, W.T.; Bhengu, B.R. Challenges of quality improvement in the healthcare of South Africa post-apartheid: A critical review. Curationis 2019 , 42 , e1–e9. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Badenhorst, M.; Verhagen, E.; Lambert, M.; van Mechelen, W.; Brown, J. Accessing healthcare as a person with a rugby-related spinal cord injury in South Africa: The injured player’s perspective. Physiother. Theory Pract. 2022 , 38 , 1639–1655. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Pilusa, S.I.; Myezwa, H.; Potterton, J. Experiences of secondary health conditions amongst people with spinal cord injury in South Africa: A qualitative study. S Afr. J. Physiother. 2021 , 77 , 1530. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Schneidert, M.; Hurst, R.; Miller, J.; Ustun, B. The role of environment in the International Classification of Functioning, Disability and Health (ICF). Disabil. Rehabil. 2003 , 25 , 588–595. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Giraldo-Rodriguez, L.; Mino-Leon, D.; Murillo-Gonzalez, J.C.; Agudelo-Botero, M. Factors associated with environmental barriers of people with disabilities in Mexico. Rev. Saude Publica 2019 , 53 , 27. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Guilcher, S.J.; Casciaro, T.; Lemieux-Charles, L.; Craven, C.; McColl, M.A.; Jaglal, S.B. Social networks and secondary health conditions: The critical secondary team for individuals with spinal cord injury. J. Spinal Cord. Med. 2012 , 35 , 330–342. [ Google Scholar ] [ CrossRef ]
Reinhardt, J.D.; Middleton, J.; Bokel, A.; Kovindha, A.; Kyriakides, A.; Hajjioui, A.; Kouda, K.; Kujawa, J. Environmental Barriers Experienced by People With Spinal Cord Injury Across 22 Countries: Results From a Cross-Sectional Survey. Arch. Phys. Med. Rehabil. 2020 , 101 , 2144–2156. [ Google Scholar ] [ CrossRef ]
Whiteneck, G.; Meade, M.A.; Dijkers, M.; Tate, D.G.; Bushnik, T.; Forchheimer, M.B. Environmental factors and their role in participation and life satisfaction after spinal cord injury. Arch. Phys. Med. Rehabil. 2004 , 85 , 1793–1803. [ Google Scholar ] [ CrossRef ]
Hajjioui, A.; Fourtassi, M.; Tachfouti, N.; Laaroussi, Z.; Boulman, S.; Boujraf, S.; Fekete, C. People with spinal cord injury in Morocco: Results from the very first systematic data collection. Disabil. Rehabil. 2021 , 44 , 1–12. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Visagie, S.; Eide, A.H.; Dyrstad, K.; Mannan, H.; Swartz, L.; Schneider, M.; Mji, G.; Munthali, A.; Khogali, M.; van Rooy, G.; et al. Factors related to environmental barriers experienced by persons with and without disabilities in diverse African settings. PLoS ONE 2017 , 12 , e0186342. [ Google Scholar ] [ CrossRef ]
Cawood, J.; Visagie, S. Environmental factors influencing participation of stroke survivors in a Western Cape setting. Afr. J. Disabil. 2015 , 4 , 198. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Maart, S.; Eide, A.H.; Jelsma, J.; Loeb, M.; Ka Toni, M. Environmental barriers experienced by urban and rural disabled people in South Africa. Disabil. Soc. 2007 , 22 , 357–369. [ Google Scholar ] [ CrossRef ]
Post, M.W.; Reinhardt, J.D.; Avellanet, M.; Escorpizo, R.; Engkasan, J.P.; Schwegler, U.; Leiulfsrud, A.S. Employment Among People With Spinal Cord Injury in 22 Countries Across the World: Results From the International Spinal Cord Injury Community Survey. Arch. Phys. Med. Rehabil. 2020 , 101 , 2157–2166. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Gross-Hemmi, M.H.; Post, M.W.; Ehrmann, C.; Fekete, C.; Hasnan, N.; Middleton, J.W.; Reinhardt, J.D.; Strom, V.; Stucki, G.; International Spinal Cord Injury Community Survey, G. Study Protocol of the International Spinal Cord Injury (InSCI) Community Survey. Am. J. Phys. Med. Rehabil. 2017 , 96 , S23–S34. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Fekete, C.; Post, M.W.; Bickenbach, J.; Middleton, J.; Prodinger, B.; Selb, M.; Stucki, G.; International Spinal Cord Injury Community Survey, g. A Structured Approach to Capture the Lived Experience of Spinal Cord Injury: Data Model and Questionnaire of the International Spinal Cord Injury Community Survey. Am. J. Phys. Med. Rehabil. 2017 , 96 , S5–S16. [ Google Scholar ] [ CrossRef ]
Ballert, C.S.; Post, M.W.; Brinkhof, M.W.; Reinhardt, J.D.; Swi, S.C.I.S.G. Psychometric properties of the Nottwil Environmental Factors Inventory Short Form. Arch. Phys. Med. Rehabil. 2015 , 96 , 233–240. [ Google Scholar ] [ CrossRef ]
Kalpakjian, C.Z.; Scelza, W.M.; Forchheimer, M.B.; Toussaint, L.L. Preliminary reliability and validity of a Spinal Cord Injury Secondary Conditions Scale. J. Spinal Cord. Med. 2007 , 30 , 131–139. [ Google Scholar ] [ CrossRef ]
Sangha, O.; Stucki, G.; Liang, M.H.; Fossel, A.H.; Katz, J.N. The Self-Administered Comorbidity Questionnaire: A new method to assess comorbidity for clinical and health services research. Arthritis Rheum. 2003 , 49 , 156–163. [ Google Scholar ] [ CrossRef ]
Hand, B.N.; Velozo, C.A.; Krause, J.S. Measuring the interference of pain on daily life in persons with spinal cord injury: A Rasch-validated subset of items from the Brief Pain Inventory interference scale. Aust. Occup. Ther. J. 2018 , 65 , 405–411. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ware, J.E., Jr.; Sherbourne, C.D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 1992 , 30 , 473–483. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Study protocol for the World Health Organization project to develop a Quality of Life assessment instrument (WHOQOL). Qual. Life Res. 1993 , 2 , 153–159. [ CrossRef ]
deRoon-Cassini, T.A.; de St Aubin, E.; Valvano, A.; Hastings, J.; Horn, P. Psychological well-being after spinal cord injury: Perception of loss and meaning making. Rehabil. Psychol. 2009 , 54 , 306–314. [ Google Scholar ] [ CrossRef ]
Al-Owesie, R.M.; Moussa, N.M.; Robert, A.A. Anxiety and depression among traumatic spinal cord injured patients. Neurosciences 2012 , 17 , 145–150. [ Google Scholar ]
Disability Info South Africa. Transport Services and Vehicle Hire. Available online: http://disabilityinfosa.co.za/mobility-impairments/transport-services-vehicle-hire/#Government_Subsidized_Transport (accessed on 15 December 2022).
Vergunst, R.; Swartz, L.; Hem, K.G.; Eide, A.H.; Mannan, H.; MacLachlan, M.; Mji, G.; Braathen, S.H.; Schneider, M. Access to health care for persons with disabilities in rural South Africa. BMC Health Serv. Res. 2017 , 17 , 741. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Joseph, C.; Wahman, K.; Phillips, J.; Nilsson Wikmar, L. Client Perspectives on Reclaiming Participation After a Traumatic Spinal Cord Injury in South Africa. Phys. Ther. 2016 , 96 , 1372–1380. [ Google Scholar ] [ CrossRef ]
Hosseinigolafshani, Z.; Abedi, H.; Ahmadi, F. What are the people’s attitudes toward spinal cord injury victims (from common to elite). Iran. J. Nurs. Midwifery Res. 2014 , 19 , 266–272. [ Google Scholar ]
Figure 1. Environmental factors response rate, in percentage.
Table 1. Demographics of participants with spinal cord injury [ 12 ].
Characteristics ( n = 200) Male sex, n (%) 150 (75) Age at SCI onset (years), mean (SD) a 28 (11) Age ≤ 50 years, n (%) a 176 (93) Age > 50 years, n (%) a 13 (7) Marital status, n (%) b Single 155 (78) Married/cohabiting 44 (22) Employment status before SCI, n (%) Working 121 (61) Not working 79 (39) Employment status after SCI, n (%) Working 49 (25) Not working 151 (75) Level of impairment, n (%) * Paraplegic 119 (61) Tetraplegic 77 (39) Severity of impairment, n (%) * Complete 102 (52) Incomplete 94 (48) Level of education, n (%) Primary 17 (8.5) Secondary 164 (82) Short tertiary 10 (5) Further education 9 (4.5) Environmental factors, mean (SD) b 9.4 (5.6) Health conditions b Secondary conditions 27.7 (8.4) Pain intensity 3.1 (2.6) Mental health 15.6 (2.2) General health, mean (SD) 2.8 (1.0) Quality of life, mean (SD) 3.5 (0.9)
a = not equal to 200 ( n = 189), b = not equal to 200 ( n = 199), * = not equal to 200 ( n = 196).
Table 2. Linear regression model showing the association between environmental factors and health conditions (secondary health conditions, pain intensity and mental health) adjusted for age, sex and severity of SCI.
Secondary Health Conditions Pain Intensity Mental Health B (95% CI) p -Value B (95% CI) p -Value B (95% CI) p -Value Environmental factors sum score 0.55 (0.61–0.95) <0.001 0.16 (0.01–0.13) 0.03 −0.21 (−0.13–−0.02) 0.005 Environmental factors individual items Public access No Influence/not applicable Reference Reference Reference Made my life a little harder 0.08 (−1.31–4.11) 0.310 −0.02 (−0.76–0.98) 0.808 −0.10 (−1.16–0.33) 0.273 Made my life a lot harder 0.30 (2.94–9.57) <0.001 0.05 (−0.74–1.40) 0.547 −0.08 (−1.33–0.48) 0.358 Short transport No Influence/not applicable Reference Reference Reference Made my life a little harder 0.08 (−1.18–3.85) 0.297 0.03 (−0.64–1.00) 0.667 −0.07 (−1.03–0.37) 0.353 Made my life a lot harder 0.33 (4.24–11.00) <0.001 0.08 (−0.54–1.66) 0.317 −0.12 (−1.67–0.20) 0.124 Long transport No Influence/not applicable Reference Reference Reference Made my life a little harder 0.14 (−0.66–4.75) 0.138 −0.02 (−0.99–0.73) 0.771 0.01 (−0.71–0.77) 0.934 Made my life a lot harder 0.25 (1.96–7.89) <0.001 −0.08 (−1.41–0.47) 0.326 0.04 (−0.59–1.03) 0.593 Finances No Influence/not applicable Reference Reference Reference Made my life a little harder 0.01 (−3.08–3.48) 0.904 −0.13 (−1.69–0.33) 0.187 −0.08 (−1.21–0.51) 0.422 Made my life a lot harder 0.08 (−1.76–4.52) 0.388 −0.12 (−1.58–0.36) 0.217 −0.22 (−1.76–0.11) 0.026 Family attitudes No Influence/not applicable Reference Reference Reference Made my life a little harder 0.02 (−2.27–2.93) 0.805 0.00 (−0.83–0.79) 0.955 −0.03 (−0.81–0.56) 0.714 Made my life a lot harder 0.12 (−0.98–8.80) 0.116 0.04 (−1.11–1.93) 0.598 −0.16 (−2.66–−0.09) 0.037 Friends’ attitudes No Influence/not applicable Reference Reference Reference Made my life a little harder 0.00 (−2.57–2.65) 0.974 0.02 (−0.75–0.91) 0.844 −0.11 (−1.20–0.20) 0.161 Made my life a lot harder 0.22 (2.49–12.07) 0.003 0.03 (−1.26–1.78) 0.738 −0.14 (−2.49–0.08) 0.065 Colleagues’ attitudes No Influence/not applicable Reference Reference Reference Made my life a little harder 0.16 (0.46–6.01) 0.023 0.03 (−0.71–1.08) 0.682 −0.12 (−1.38–0.14) 0.112 Made my life a lot harder 0.27 (4.47–14.18) <0.001 0.08 (−0.76–2.38) 0.308 −0.10 (−2.28–0.39) 0.162 Communication No Influence/not applicable Reference Reference Reference Made my life a little harder −0.03 (−3.34–2.14) 0.667 −0.12 (−1.54–0.17) 0.113 −0.16 (−1.49–−0.04) 0.039 Made my life a lot harder 0.15 (0.14–7.28) 0.042 −0.02 (−1.24–1.00) 0.827 −0.02 (−1.07–0.82) 0.791
Table 3. Logistic regression model showing the association between environmental factors and general health and quality of life adjusted for age, sex and severity of SCI.
General Health Quality of Life OR (95% CI) p -Value OR (95% CI) p -Value Environmental factors sum score 0.93 (0.88–0.99) 0.016 0.93 (0.87–1.01) 0.066 Environmental factors individual items Services No Influence/not applicable Reference Reference Made my life a little harder 1.23 (0.63–2.40) 0.541 0.99 (0.33–2.95) 0.985 Made my life a lot harder 6.06 (1.29–28.38) 0.022 2.32 (0.63–8.47) 0.204 Communication No Influence/not applicable Reference Reference Made my life a little harder 0.97 (0.48–1.96) 0.940 0.59 (0.18–1.90) 0.373 Made my life a lot harder 3.30 (1.05–10.41) 0.042 0.23 (0.03–1.82) 0.163
| https://www.mdpi.com/1660-4601/20/9/5709 |
UNIPROT:P26440 - FACTA Search
Analyses were done on a human type-IV cyclic AMP (cAMP) phosphodiesterase (hPDE- IVA -h6.1) expressed in an engineered strain of Saccharomyces cerevisiae. This strain (YMS6) expressed soluble PDE activity, together with an insoluble activity which was not released by re-homogenization, treatment with high-ionic-strength solutions or with the detergent Triton X-100. Pellet and soluble PDE activities were typical of type-IV PDE . They were cAMP-specific, insensitive to the addition of either cGMP (1 microM) or Ca2+/calmodulin, and inhibited by rolipram. Thermostability studies showed both activities to decay as single exponentials, indicating the presence of homogeneous PDE protein species in each fraction. Pellet PDE activity was more thermostable than the soluble enzyme. Mg2+ and Mn2+ dose-dependently increased PDE activity and reversed the inactivating effect of EDTA.h6.1 was engineered to express a C-terminal five-histidine motif (h6.1his5). This allowed purification of the PDE to apparent homogeneity in a simple two-step process involving a rolipram affinity column and a Ni2(+)-chelate column. A single monomeric protein of subunit molecular mass approximately 73 kDa and native molecular mass approximately 74 kDa resulted after a approximately 53000-fold purification. This exhibited a Km for cAMP of 8 microM, a true Vmax. of 0.8 mumol of cAMP hydrolysed/min per mg of PDE protein, a kcat. of 3702 s-1, and a value of the specificity constant kcat/Km of 4.6 x 10(8) M-1.s-1, the last implying a diffusion controlled reaction. Rolipram (Ki 0.4 soluble; 0.7 microM pellet) and 3-isobutyl-1-methylxanthine (Ki 15 soluble; 19 microM pellet) served as simple competitive inhibitors for both soluble and pellet forms of h6.1, respectively.
...
PMID:Purification, characterization and analysis of rolipram inhibition of a human type-IVA cyclic AMP-specific phosphodiesterase expressed in yeast. 752 9
1. We have investigated the inhibitory potency of RP 73401, a novel, highly selective and potent inhibitor of cyclic AMP-specific phosphodiesterase ( PDE IV), against partially-purified PDE isoenzymes from smooth muscle and the particulate PDE IV from guinea-pig eosinophils. The inhibitory effects of RP 73401 on the generation of superoxide (.O2-), major basic protein (MBP) and eosinophil cationic protein (ECP) from guinea-pig eosinophils have also been studied. 2. RP 73401 potently inhibited partially-purified cyclic AMP-specific phosphodiesterase ( PDE IV) from pig aortic smooth muscle (IC50 = 1.2 nM); it was similarly potent against the particulate PDE IV from guinea-pig peritoneal eosinophils (IC50 = 0.7 nM). It displayed at least a 19000 fold selectivity for PDE IV compared to its potencies against other PDE isoenzymes. Rolipram was approximately 2600 fold less potent than RP 73401 against pig aortic smooth muscle PDE IV (IC50 = 3162 nM) and about 250 times less potent against eosinophil PDE IV (IC50 = 186 nM). 3. Solubilization of the eosinophil particulate PDE IV increased the potency of rolipram 10 fold but did not markedly affect the potency of RP 73401. A similar (10 fold) increase in the PDE IV inhibitory potency of rolipram, but not RP 73401, was observed when eosinophil membranes were exposed to vanadate/glutathione complex (V/GSH). 4. Reverse transcription polymerase chain reaction (RT-PCR), using primer pairs designed against specific sequences in four distinct rat PDE IV subtype cDNA clones ( PDE IVA -D), showed only mRNA for PDE IVD in guinea-pig eosinophils. PDE IVD was also the predominant subtype expressed in pig aortic smooth muscle cells. 5. RP 73401 (Kiapp = 0.4 nM) was 4 fold more potent than (+/-)-rolipram (Kiapp = 1.7 nM) in displacing[3H]-(+/-)-rolipram from guinea-pig brain membranes.6. In intact eosinophils, RP 73401 potentiated isoprenaline-induced cyclic AMP accumulation(EC50 = 79 nM). RP 73401 also inhibited leukotriene B4-induced generation of *02- (IC50 = 25 nM), and the release of major basic protein (ICo = 115 nM) and eosinophil cationic protein (IC50 = 7 nM). Rolipram was 3-14 times less potent than RP 73401.7. Thus RP 73401 is a very potent and selective PDE IV inhibitor which suppresses eosinophil function suggesting that it may be a useful agent for the treatment of inflammatory diseases such as asthma. The greatly different inhibitory potencies of rolipram against PDE IV from smooth muscle and eosinophils(in contrast to the invariable effects of RP 73401) are unlikely to be attributable to diverse PDE IV subtypes but suggest distinct interactions of the two inhibitors with the enzyme.
...
PMID:Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. 764 82
We have isolated from a human T-cell Jurkat cDNA library a novel human cDNA (2EL) that is closely related to the human type-IV PDE splice variant family 'A' (PDE-IVA) cDNA characterized previously by us [Sullivan, Egerton, Shakur, Marquardsen and Houslay (1994) Cell. Signalling 6, 793-812]; (h6.1, PDE-IVA/h6.1; HSPDE4A7). ( PDE stands for cyclic nucleotide phosphodiesterase). The novel cDNA 2EL (PDE-IVA/2EL; HSPDE4A8) contains two regions of unique sequence not found in PDE - IVA /h6.1. These are a distinct 5'-end and a 34 bp insert which occurs within a domain thought to encode the type-IV PDE catalytic site and which can be expected to result in premature truncation of any expressed protein. HSPDE4A8 appeared to be catalytically inactive. Isolation and characterization of a human genomic cosmid clone revealed that 2EL and h6.1 represent alternative splice variants of the human PDE - IVA gene. Using a unique sequence found at the 5'-end of the 2EL cDNA, a probe was generated which was used to screen the DNA of human-hamster hybrids. This located the human gene for PDE - IVA to human chromosome 19. Through both the analysis of genomic DNAs from a human-hamster somatic cell hybrid panel and also using fluorescent in situ hybridization, it was shown that the human PDE - IVA gene is located on human chromosome 19, between p13.2 [corrected] and q12. This region on chromosome 19 has been shown to be related to genetic diseases such as the autosomal dominant cerebrovascular disease CADASIL, susceptibility to late-onset Alzheimer's disease and changes seen in benign pituitary and thyroid adenomas.
...
PMID:Molecular cloning of a novel splice variant of human type IVA (PDE-IVA) cyclic AMP phosphodiesterase and localization of the gene to the p13.2-q12 region of human chromosome 19 [corrected]. 777 58
A cyclic AMP specific phosphodiesterase (type IV) was purified 450,000-fold from human peripheral blood mononuclear cells through a sequence of chromatographic steps involving anion exchange, affinity chromatography on a matrix coupled to a derivative of the type IV inhibitor rolipram, and gel filtration. The enzyme showed apparent molecular masses of 70 kDa on gel filtration and 35 kDa on denaturing or native PAGE, indicating a possible dimerization or cleavage under certain conditions. The isoelectric point was 4.6. Kinetic parameters were Km = 2.2 microM, Ki = 1.2 microM (rolipram) and vmax = 80 mumol/min per mg protein. The most probable N-terminal sequence was determined as SLTNTNIPRF, 80% identical to part of the deduced amino acid sequence from cDNA sequences of PDE IVA and PDE IVD.
...
PMID:Isolation, biochemical characterization and N-terminal sequence of rolipram-sensitive cAMP phosphodiesterase from human mononuclear leukocytes. 792 11
We have isolated cDNA clones from human frontal cortex cDNA libraries that encode a unique subtype of the low-Km, cAMP-specific phosphodiesterases (PDEs IV). The 564-amino acid sequence of the protein (human brain PDE IV (hPDE IVB)) shows significant homology to a PDE IV subtype expressed in human monocytes (hPDE IVA ), particularly within the approximately 300-amino acid PDE IV catalytic domain. The degree of protein sequence identity is much greater between hPDE IVB and a homolog derived from rat brain (92% over 562 amino acids) than between hPDE IVB and hPDE IVA (76% over 538 amino acids), suggesting a greater subtype-specific versus species-specific conservation of protein sequence. Analysis of the distribution of hPDE IVB mRNA expression revealed a restricted pattern, with an approximately 4-kilobase mRNA detected in brain, heart, lung, and skeletal muscle and not in placenta, liver, kidney, or pancreas. An additional approximately 5-kilobase hPDE IVB-related mRNA species was detected in brain tissue. Recombinant hPDE IVB displayed all of the expected kinetic characteristics for a PDE IV, including sensitivity to the isozyme-selective inhibitor rolipram (Ki = 0.085 microM). Scatchard analysis of (R)-[3H]rolipram binding data suggested the presence of two noninteracting high affinity rolipram-binding sites (Kd = 0.4 and 6 nM) or a negatively cooperative interaction among multiple binding sites.
...
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=UNIPROT%3AP26440%7C111111%7C0%7C0%7C207770%7C0%7C10 |
K.S.Muthu v. M/s. The Air Deccan | District Consumer Disputes Redressal Commission | Judgment | Law | CaseMine
Get free access to the complete judgment in K.S.Muthu v. M/s. The Air Deccan on CaseMine.
1. The averments in the complaint in brief are as follows: The complainant is residing at Vishalakshipuram, 3rd Street, Madurai. The complainant was working as a Deputy Manager (Legal) in Tamil Nadu State Transport Corporation, Karaikudi and a man of reputation.
2. The complainant booked Air ticket for himself, wife and son in Air Deccan Airways for a travel on 25.05.2006 from New Delhi to Chennai by paying ticket fare of Rs.11,922/- and as a continuation trip from Chennai to Madurai he booked Air ticket for them in the same Airways by paying Rs.6,660/-. ..1..
3. On 25.05.2006 morning the complainant confirmed the ticket through phone at New Delhi for flight No.DN719DLLMAA which was scheduled to depart from New Delhi at 12.40 hours and the opposite party reconfirmed the ticket at 09.20 hours in phone No.00981-8177008.
4. After getting confirmation from the Airline, the complainant along with his family members vacated the room in which they were staying and came to Delhi Airport at about 10.30 hours to check in.
5. To the shock and surprise of the complainant the representative of Air Deccan Airways Ms.Shalini informed the complainant that flight was cancelled. However she refused to inform or assign any reason for the cancellation of flight. The complainant also requested her to arrange alternative flight but she also refused to arrange alternative flight to the complainant. Therefore the complainant and his family members were stranded at New Delhi Airport and finally they met one Ms.Sharu the Manager of opposite party Airline at New Delhi Airport. She also refused to arrange any alternative flight but stated that she can accommodate the complainant and his family members only after two days in another flight of opposite party. As the complainant could not stay for further two days at New Delhi he requested her to refund the fare. The representative of opposite party refunded Rs.11,992/- collected for a travel from New Delhi to Chennai. However the opposite party refused to refund the total fare for the ticket from Chennai to Madurai but refunded only 50% of the fare
i.e. Rs.3,330/-.
6. The cancellation of flight without informing in advance amounts to deficiency in service. The failure to arrange the alternative flight also amounts to deficiency in service.
7. The complainant could not come down to Chennai from New Delhi on 25.05.2006 as he could not arrange ticket on the same day. Anyway the complainant managed to get air ticket through Spice Jet which left New Delhi on 26.05.2006 at 16.10 hours. The complainant has paid Rs.16,872/- for a travel through Spice Jet from New Delhi to Chennai. He was also forced to stay in hotel at New Delhi for two days ..2.. since check out time at the hotel was 09.00 hours. He also spent Rs.2,000/- towards Transport charges from airport to hotel and hotel to Airport.
8. The complainant and his family members reached Chennai airport on 26.05.2006 at 20.30 hours and reached Karaikudi only on 27.05.2006 through bus. Due to continuous journey he could not attend his office for two days which resulted in irreparable loss and hardship.
9. The complainant sent a legal notice to the opposite party on 27.03.2008 demanding compensation and the excess expenditure incurred by him. The opposite party though received notice neither sent any reply nor paid the compensation.
10. Therefore the complainant has filed this complaint before this forum seeking remedy. This Honble forum may be pleased to direct the opposite party to pay sum of Rs.3,330/- towards the deduction made in the air ticket fare amount from Chennai to Madurai and to pay Rs.4,950/- towards extra expenditure incurred in getting ticket an another ticket, and also to pay a sum of Rs.3,850/- towards expense incurred in extended stay and conveyance charges and to pay compensation of Rs.2,00,000/- towards mental agony, pain and suffering and also cost of Rs.5,000/-
11. The written version filed by the opposite party are brief as follows: The Air Deccan is not legal entity and cannot be sued. The Air Deccan was a brand name for Scheduled Air Transport Services (Passenger) (Commercial Airline Business) of Deccan Aviation Limited under Companies Act. Therefore the complaint against the Air Deccan limited is not maintainable. The Deccan Aviation Ltd had been merged with King Fisher Airline limited.
12. The complainant has been filed belatedly. The complainant also failed to provide any reason for such a delayed complaint. The Airlines can cancel the flight in some circumstances with or without notice. It is true that flight No. DN719DLLMAA had been cancelled on 25.05.2006 but the reasons and specific details for cancellation of flight are not retrievable since these details are more than three years old. The ticket charges of Rs.11,922/- for a travel from New Delhi to Chennai was refunded without any deduction. However, the flight from Chennai to Madurai was not cancelled by ..3.. opposite party. As the complainant himself requested for cancellation of ticket from Chennai to Madurai and it was processed immediately and Rs.3,330/- had been refunded on 25.05.2006 at 10.55 hours as per rules.
13. Since the opposite party Airways refunded the entire fare of ticket from New Delhi to Chennai, there was deficiency in service. The said flight might have been cancelled for certain circumstances or reasons which were beyond the control of opposite party. As the opposite party has refunded the entire ticket fare as per rules, there is no deficiency in the service and the complaint is liable to be dismissed.
14. The complainant side filed proof affidavit and Ex.A1 to Ex.A9 were marked on the side of the complainant. The opposite party filed proof affidavit and Ex.B1 to Ex.B3 were marked on the side of the opposite party. Several chances were given to the opposite party side to advance oral arguments even after the opposite party has not advanced his oral argument so far. Hence this forum suo-moto closed the opposite party stage of oral arguments. Written argument of complainant side filed and heard.
15. Points for consideration
1. Whether there is deficiency in service on the part of opposite party?
2. Whether the complainant is entitled to get relief as prayed for? 16.Point 1: It is not dispute that complainant booked confirmed ticket for himself and his family members well in advance for a travel on 25.05.2006 from New Delhi to Chennai and as a continuation trip from Chennai to Madurai in Air Deccan airways. Subsequently the Air Deccan Aviation Limited has been changed to King Fisher Airways Limited now the opposite party in this case.
17. The said flight No.DN719DLLMAA was scheduled to depart from New Delhi on 25.05.2006 at 12.40 hours. The complainant has clearly stated that he along with his family members came to Delhi Airport at about 10.30 hours on 25.05.2006 and after that only he was informed that the said flight was cancelled.
18. The opposite party also admitted that no prior information/intimation was given before the cancellation of flight. The cancellation of flight was confirmed by the fact that opposite party has refunded the full fare of Rs.11,922/- for a travel from Delhi to ..4.. Chennai on the date of journey i.e 25.05.2006 and refunded the half of the amount of Rs.3,330/- for a travel from Chennai to Madurai. Therefore the cancellation of flight on that particular date was not all disputed by the opposite party.
19. Sometimes, it may happen that the Airlines would be constrained to cancel the flight due to certain circumstances which were beyond the control of the Airlines. For that, the Airline should give cogent and proper reason for such a cancellation. But in this case, the opposite party had not provided cogent reason for such a cancellation. The opposite party stated in the written version in para 6 as follows: In the present case also, the Flight No.DN-719 came to be cancelled by the opposite party on 25.05.2006; however the specific details of the same are not retrievable by the opposite party in as much as these details are more than 3 years old. Such a bald statement could not be accepted as reason for cancellation. The opposite party side was unable to state the cogent reason for such cancellation.
20. The cancellation of flight all of a sudden without any cogent reason amounts to unfair trade practice and deficiency in the service. Similarly cancellation of flight without notice also constitute deficiency in the service.
21. The Honble Chandigarh State Commission in a decision reported inII (2009) CPJ 176held as follows:Consumer Protection Act, 1986 Sections 2(1) (g), 2(1) (r), 14(1) (d)Airlines flights cancelled midway Deficiency in service alleged contention, flight cancelled due to technical snag, not acceptable in absence of evidence in support Flight cancelled as there were not sufficient passengers for Srinagar Deficiency in service proved Compensation granted by Forum enhanced considering status of complainant, mental harassment caused to him and family members- Cancellation of flight midway without any cogent reason amounts, unfair trade practice Payment of enhanced compensation along with refund of Rs.1,640/- paid for cancellation of train ticket with interest directed. In that case the Honble Chandigarh State Commission has clearly held the cancellation of flight without any cogent reason amounts to unfair trade practice. ..5..
22. In this case also no cogent reason was provided for the cancellation of flight. Hence the cancellation of flight without cogent reason definitely amount to unfair trade practice.
23. The Honble West Bengal State Commission in a decision reported in2012 (1) CPR 134held as follows: Cancellation of flight without notice constitutes deficiency in service In that case it is clearly held that cancellation of flight without notice construed deficiency in the service.
24. In this case also no prior information was given before cancellation and therefore there is deficiency in the service of opposite party. Thus it has been proved that there was unfair trade practice and deficiency in the service of Air Deccan Airways now King Fisher Airline Ltd the opposite party. 25.Point 2: In the previous point it is decided that there was unfair trade practice and deficiency in the service of the opposite party. The opposite party Airlines (Previously Air Deccan Limited) refunded the ticket fare of Rs.11,922/- for a travel from Delhi to Chennai but the airlines refunded only half of the ticket fare of Rs.3,330/- in PNR. DA04702187 stating that there was no cancellation of flight Chennai to Madurai the ticket fare in PNR. No.DA04702187. Due to the cancellation of flight from New Delhi to Chennai the onward journey of complainant from Chennai to Madurai was made to be cancelled.
26. The cancellation of ticket for a flight from Chennai to Madurai has been occasioned due to the cancellation of flight from New Delhi to Chennai. The said tickets were cancelled by the complainant only due to the cancellation of flight from New Delhi to Chennai. Therefore the opposite party should have returned Rs.6,660/- for cancellation of flight from Chennai to Madurai. Therefore the complainant is entitled to get a sum of Rs.3,330/- from opposite party towards deduction made in the fare amount. The complainant has clearly stated and proved that he incurred expenditure of Rs.4,950/- for getting ticket in another flight therefore the complainant is also entitled to get refund of Rs.4,950/- towards extra expenditure incurred in ..6.. getting another ticket in another flight. The complainant is also incurred an expenditure of Rs.3,850/- towards expenses incurred due to extended stay and conveyance charges therefore the complainant is entitled to get Rs.3,850/- towards expenses incurred for extended stay and conveyance charges.
27. The complainant was working as a Deputy Manager in Tamil Nadu State Transport Corporation, Karaikudi and he was a Chief Personnel of Legal department. The complainant is a respectable person and a man of status. The complainant suffered mental agony and physical harassment due to the said cancellation of flight. Considering the status of the complainant and the mental agony and physical harassment caused to him and his family members, this forum feels that the complainant should be awarded a compensation of Rs.30,000/- for the mental agony and physical harassment. The complainant is also entitled to get cost of Rs.3,000/- from the opposite party.
28. Finally the complaint is allowed as follows:
(i) The opposite party is directed to refund Rs.3,330/- towards deduction made in the fare amount for a travel from Chennai to Madurai.
(ii) The opposite party is directed to pay Rs.4,950/- towards the extra expenditure incurred in getting tickets in another flight.
(iii) The opposite party is directed to pay Rs.3,850/- towards expenses incurred due to the extended stay and conveyance charges.
(iv) The opposite party is also directed to pay compensation of Rs.30,000/- to the complainant towards mental agony and physical harassment etc.
(v) The opposite party is directed to pay cost of Rs.3,000/- to the complainant. The above order shall be complied within six weeks from the date of receipt of copy of this order. Dictated to the Steno-typist and typed by him corrected and pronounced by us on this the 13th day of DECEMBER 2018. (M.MARAIKAMALAI) (S.RAJAREEGA) (V.BALASUNDARAKUMAR) MEMBER I MEMBER-II PRESIDENT ..7.. Documents filed by the complainantEx.A1 25.05.2006 Refund Receipt of Air Deccan (PNR.No.DAO4701916) Xerox Ex.A2 25.05.2006 Refund Receipt of Air Deccan (PNR.No.DAO4702187) Xerox Ex.A3 26.05.2006 BillReceipt of Rs.500/- issued by C.P.Tour and Travels, New Delhi for dropping complainant and his family members to Airport OriginalEx.A4 26.05.2006Spice Jet Boarding pass of complainants son OriginalEx.A5 26.05.2006Spice Jet Boarding pass of complainant OriginalEx.A6 26.05.2006Spice Jet Boarding pass of complainants wife OriginalEx.A7 25.05.2006Spice Jet issued the online booking flight reference to the complainant XeroxEx.A7 27.03.2008Complainant counsel sent legal notice to the opposite party to the opposite party (Postal receipt original attached) XeroxEx.A8 27.03.2008Acknowledgment card Original Documents filed by the opposite party Ex.B1 05.09.2008 Certificate of incorporation consequent upon of change of name issued by Government of India- Ministry of Corporate Affairs, Registrar of Companies, Karnataka Xerox Ex.B2 Terms and conditions of Air Deccan Flight XeroxEx.B3 25.05.2006Transaction details of refund Xerox (M.MARAIKAMALAI) (S.RAJAREEGA) (V.BALASUNDARAKUMAR) MEMBER I MEMBER-II PRESIDENT ..8..
| https://www.casemine.com/judgement/in/5c717e0d4a9326759e3a592a/amp |
Surgery at 13; Now 26 - National Scoliosis Foundation Forums
Adolescents who have been diagnosed but not yet treated
Surgery at 13; Now 26
Surgery at 13; Now 26
Hey guys,
So I have a few questions and was hoping some of you could help! So I am 13 years out of my surgery and have some questions. I don't know if this is the right forum to put it on but here goes nothing. I had surgery a while ago and now I am looking to my future. I do not have much pain right now.
I am very scared as to what my life is going to look like when I am 70, 80 years old. Is there any way I am going to be able to walk? Or live without pain?Everything that I had read has been of people having pain and ending up disabled. This is something I want to avoid at all costs. I am a very active person. I love doing anything outdoors and want to continue to do this.
Please help with some positive outcomes. Please and Thank You.
Tags: None
Originally posted by Camilynns
View Post
Hey guys,
So I have a few questions and was hoping some of you could help! So I am 13 years out of my surgery and have some questions. I don't know if this is the right forum to put it on but here goes nothing. I had surgery a while ago and now I am looking to my future. I do not have much pain right now.
I am very scared as to what my life is going to look like when I am 70, 80 years old. Is there any way I am going to be able to walk? Or live without pain?Everything that I had read has been of people having pain and ending up disabled. This is something I want to avoid at all costs. I am a very active person. I love doing anything outdoors and want to continue to do this.
Please help with some positive outcomes. Please and Thank You.
Hi and welcome.
Where did you get the idea you might not be able to walk at any point or that you will have pain and be disabled? Did a chiropractor tell you that? Ignore chiros. Just deal with experienced surgeons.
Sharon, mother of identical twin girls with scoliosis
No island of sanity.
Question:What do you call alternative medicine that works?
Answer:Medicine
"We are all African."
No, no, no.....Camilynns, you shouldn’t think that way! Never expect or assume the worst. Worrying about things like this are not worth it. Knowing and worrying are two different things. Override the negatives with positives.
Life is about having fun.....I have always loved life and always did everything I wanted to do... with twin 70 degree curves or with a T2-pelvic fusion along with 2 herniated cervical discs. I don’t worry about fusing my neck, I worry about how much fun I can have as soon as I can. I hope this makes sense.....
Do you remember what levels they fused?
Welcome to the forum...Ask any questions you like.
Ed
49 yr old male, now 63, the new 64...
Pre surgery curves T70,L70
ALIF/PSA T2-Pelvis 01/29/08, 01/31/08 7" pelvic anchors BMP
Dr Brett Menmuir St Marys Hospital Reno,Nevada
Bending and twisting pics after full fusion
http://www.scoliosis.org/forum/showt...on.&highlight=
My x-rays
http://www.scoliosis.org/forum/attac...2&d=1228779214
http://www.scoliosis.org/forum/attac...3&d=1228779258
No, no, no.....Camilynns, you shouldn’t think that way! Never expect or assume the worst. Worrying about things like this are not worth it. Knowing and worrying are two different things. Override the negatives with positives.
Life is about having fun.....I have always loved life and always did everything I wanted to do... with twin 70 degree curves or with a T2-pelvic fusion along with 2 herniated cervical discs. I don’t worry about fusing my neck, I worry about how much fun I can have as soon as I can. I hope this makes sense.....
Do you remember what levels they fused?
Welcome to the forum...Ask any questions you like.
Ed
I have all levels fused from C1 to pelvis. Scar from the tip of my back all the way down to pelvis. I have just read so many stories and it scares me so much. Thank You I cant ever really talk to anyone about this.
What does twin 70 degree curves mean? And when did you have surgery and how old are you? I have just never heard a story like mine.
Hi and welcome.
Where did you get the idea you might not be able to walk at any point or that you will have pain and be disabled? Did a chiropractor tell you that? Ignore chiros. Just deal with experienced surgeons.
I have just read so many scary stories and want to live a full body abled life :/
I have just read so many scary stories and want to live a full body abled life :/
Where did you read these stories?
Are you fused from the top of your neck to your pelvis or the top of your back (T1) to your pelvis?
If you have a solid fusion, does your surgeon expect anything to change? I don't see how it could. People with full fusions are the few people who will escape degenerative disc disease with is inevitable if you live long enough. So you might have LESS pain than non-scoliotic people, about 85% of whom have back pain so bad at some point in their life that they are driven to a doctor. So not having scoliosis or a fusion is no guarantee of having no pain in the out years.
Sharon, mother of identical twin girls with scoliosis
No island of sanity.
Question:What do you call alternative medicine that works?
Answer:Medicine
"We are all African."
Where did you read these stories?
Are you fused from the top of your neck to your pelvis or the top of your back (T1) to your pelvis?
If you have a solid fusion, does your surgeon expect anything to change? I don't see how it could. People with full fusions are the few people who will escape degenerative disc disease with is inevitable if you live long enough. So you might have LESS pain than non-scoliotic people, about 85% of whom have back pain so bad at some point in their life that they are driven to a doctor. So not having scoliosis or a fusion is no guarantee of having no pain in the out years.
I am fused from the top of my back. so T1 I guess, I have tried to get information from my doctors but it has been so long ago I do not even know how to find it. But no I don't think anything is expected to change I have just read random stories online. But I was so young, I dont remember half of what my doctor told me. I already have not been able to do things I want in life like skydiving, rugby, and others bc of this I just dont want to end up having chronic pain bc of this. The scoliosis was not genetic supposedly but my youngest sister also had to go through with this. I also think about if I want kids one day how this is going to affect me.
I had a 70 degree thoracic curve and a 70 degree lumbar curve. A perfect S curve.
I had my surgeries in January 2008 when I was 49. I’m now 55 and feel like I’m 39. You realize that I DO get around 5 years at age 39 don’t you? (smiley face) Many full fusion scoli’s coming out of the woodwork these days because of these forums. I was diagnosed 40 years ago. Its good to see you posting.
You can talk to any of us here, this is a scoliosis forum. SOS is a great scoliosis forum also, I post there as “Rod Stewart” since Jose Cuervo was taken. You can also PM any of us if you want to chat in private.
Did you have this very impressive surgery done at age 13? Where was it done? and who did it? Would love to see your x-rays.
We do have the advantage of not having to worry about our discs failing in our fusions. We will never have to deal with this anymore.
Ed
49 yr old male, now 63, the new 64...
Pre surgery curves T70,L70
ALIF/PSA T2-Pelvis 01/29/08, 01/31/08 7" pelvic anchors BMP
Dr Brett Menmuir St Marys Hospital Reno,Nevada
Bending and twisting pics after full fusion
http://www.scoliosis.org/forum/showt...on.&highlight=
My x-rays
http://www.scoliosis.org/forum/attac...2&d=1228779214
http://www.scoliosis.org/forum/attac...3&d=1228779258
I had a 70 degree thoracic curve and a 70 degree lumbar curve. A perfect S curve.
I had my surgeries in January 2008 when I was 49. I’m now 55 and feel like I’m 39. You realize that I DO get around 5 years at age 39 don’t you? (smiley face) Many full fusion scoli’s coming out of the woodwork these days because of these forums. I was diagnosed 40 years ago. Its good to see you posting.
You can talk to any of us here, this is a scoliosis forum. SOS is a great scoliosis forum also, I post there as “Rod Stewart” since Jose Cuervo was taken. You can also PM any of us if you want to chat in private.
Did you have this very impressive surgery done at age 13? Where was it done? and who did it? Would love to see your x-rays.
We do have the advantage of not having to worry about our discs failing in our fusions. We will never have to deal with this anymore.
Ed
Well I didn't know they existed but I called my mom freaking out about a year ago and she cannot really do anything to help, except try and tell me everything is going to be okay. But I was very similar I think mine was at 76 degrees and reduced to below 30 I think. I didnt know really what to post on but did on this one bc I had the surgery when I was an adolescent.
It was done in St Louis in Shriners hospital by Dr. Bird his name was. Do you think I will be able to walk my whole life? I am trying to track down my xray. Hopefully within the next week I can get them.
Records from Shriners
I'd bet you can get your medical records from Shriners. Call the main number and ask for Medical Records. I was able to get my records from Philadelphia Shriners and I was a patient there in the 70s. I believe they mailed me a release form to sign and send back and there was a nominal fee, a few dollars. I didn't receive the actual X Rays but I did get copies of the office visit notes with the doctor's measurements and plan etc. Helped me to fill in the blanks.
Welcome to the forum.
Resilience
treated w Milwaukee Brace FT for 3 yrs
currently 46 with 35 LL and 40 RT curves
8 yr old diagnosed w Scoli 8/10 with 27 LL and 27 RT
11/10 TLSO Full Time
4/11 22 LL and 24 RT on waiting list for VBS at Shriners Phila
12/11 curves still in the 20s but now has some rib cage changes from the brace
VBS 4/25/12 with Dr. Samdani. Pre Op: 29 RT and 25 LL Post Op: 17 RT and 9 LL
10/13: 15 RT and 10 LL
Do you think I will be able to walk my whole life?
When is the last time you saw a surgeon? I understand there is no real reason unless you have pain so it may be a long time.
But you are clearly concerned about this issue of walking. I have never seen a testimonial with a successful full fusion suddenly developing problems like that. If you had unfused vertebra at the bottom, yes, you might expect problems down the road But no unfused vertebrae? Unless you are in a car accident or something like that, I am not clear on why you expect anything to change from now. Can you point us to the scary stories you read? I am guessing they are on a chiro site. Chiros have no expertise in dealing with scoliosis.
I think you should consider doing yourself a favor and booking a consult with a surgeon about this. Get a new x-ray and ask the surgeon if there is any reason whatsoever to suspect you will have trouble walking at any point. I think that would put your mind at ease.
Good luck.
I'd bet you can get your medical records from Shriners. Call the main number and ask for Medical Records. I was able to get my records from Philadelphia Shriners and I was a patient there in the 70s. I believe they mailed me a release form to sign and send back and there was a nominal fee, a few dollars. I didn't receive the actual X Rays but I did get copies of the office visit notes with the doctor's measurements and plan etc. Helped me to fill in the blanks.
Welcome to the forum.
That was my plan. It just has not been priority bc I have so much else on my mind. Thank you. Did you have surgery when you were young? How are you doing now?
When is the last time you saw a surgeon? I understand there is no real reason unless you have pain so it may be a long time.
But you are clearly concerned about this issue of walking. I have never seen a testimonial with a successful full fusion suddenly developing problems like that. If you had unfused vertebra at the bottom, yes, you might expect problems down the road But no unfused vertebrae? Unless you are in a car accident or something like that, I am not clear on why you expect anything to change from now. Can you point us to the scary stories you read? I am guessing they are on a chiro site. Chiros have no expertise in dealing with scoliosis.
I think you should consider doing yourself a favor and booking a consult with a surgeon about this. Get a new x-ray and ask the surgeon if there is any reason whatsoever to suspect you will have trouble walking at any point. I think that would put your mind at ease.
Good luck.
I haven't seen one since I was 14. I read it a few years back and haven't looked back since. I did not realize the difference b/t full fusion and the other surgerys and maybe thats what I was looking at. I am not sure if I had unfused vertebrate at all. I don't know why I would think I think things are going to change.
I think your right, I need to. I am just a college student and don't have that great of insurance Thank You.
Are you sure you are fused from T1 to S1?
It's easy to get the impression that they are reluctant to fuse a young person to S1. And maybe especially so since your fusion starts at T1.
Do you know what kind of scoliosis you had? Was it idiopathic or congenital? Were you first diagnosed younger than 10?
Sharon, mother of identical twin girls with scoliosis
No island of sanity.
Question:What do you call alternative medicine that works?
Answer:Medicine
"We are all African."
That was my plan. It just has not been priority bc I have so much else on my mind. Thank you. Did you have surgery when you were young? How are you doing now?
I have never had surgery, just bracing. My curves ended at about 27 degrees each when my Shriner's records ended at age 20. As you can see from my signature they have increased a bit over the past 28 years. I do have pain from time to time but have learned how to handle it. I am very active: I bike, hike, swim and do pilates.
Knowledge is power. Good for you for looking into this for yourself.
Resilience
treated w Milwaukee Brace FT for 3 yrs
currently 46 with 35 LL and 40 RT curves
8 yr old diagnosed w Scoli 8/10 with 27 LL and 27 RT
11/10 TLSO Full Time
4/11 22 LL and 24 RT on waiting list for VBS at Shriners Phila
12/11 curves still in the 20s but now has some rib cage changes from the brace
VBS 4/25/12 with Dr. Samdani. Pre Op: 29 RT and 25 LL Post Op: 17 RT and 9 LL
10/13: 15 RT and 10 LL
| https://www.scoliosis.org/forum/forum/adolescent-and-teen-patients-under-18/waiting-watching/13717-?pda=1&s=9f10e751c85f5eb849000654486aba56 |
Connecticut Ry. & Lighting Co. v. New Britain Redevelopment Commission - Connecticut - Case Law - VLEX 893788086
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]
Connecticut Ry. & Lighting Co. v. New Britain Redevelopment Commission
<table><tbody><tr><td> Court</td><td> Supreme Court of Connecticut</td></tr><tr><td> Writing for the Court</td><td> RYAN</td></tr><tr><td> Citation</td><td> 287 A.2d 362,161 Conn. 234</td></tr><tr><td> Parties</td><td> CONNECTICUT RAILWAY AND LIGHTING COMPANY et al. v. NEW BRITAIN REDEVELOPMENT COMMISSION.</td></tr><tr><td> Decision Date</td><td> 01 June 1971</td></tr></tbody></table>
Page 362
287 A.2d 362
161 Conn. 234
CONNECTICUT RAILWAY AND LIGHTING COMPANY et al.
v.
NEW BRITAIN REDEVELOPMENT COMMISSION.
Supreme Court of Connecticut.
June 1, 1971.
[161 Conn. 235]
Page 363
Walter F. Torrance, Jr., Waterbury, with whom, on the brief, was Kenneth J. Pocius, Waterbury, for appellants (plaintiffs).
Archie Hovanesian, Jr., New Britain, with whom was Steven E. Perakos, New Britain, for appellee (defendant).
Before [161 Conn. 234] HOUSE, THIM, RYAN, SHAPIRO and LOISELLE, *JJ.
[161 Conn. 235] RYAN, Associate Justice.
On February 15, 1966, the defendant filed a statement of compensation in the Superior Court which stated that certain premises belonging to the plaintiffs were included within the area of a redevelopment plan of the defendant and set the amount of compensation to be paid for the premises at $50,000. The plaintiffs are the Connecticut Railway and Lighting Company, owner of the land in question and holder of franchises to serve the New Britain area with electric power, and The Connecticut Light and Power Company, lessee of the land and franchises. They appealed to the Superior Court from the statement of compensation and the case was referred to a state referee. From the referee's judgment making an award of $68,000 the plaintiffs have appealed to this court.
The following facts were found: The property taken by the defendant consisted of a parcel of land on the south side of Church Street and the east side of Herald Square in the city of New Britain, on which was located an electric substation and switching station comprised of a one-story and basement brick, steel and concrete building and various items of electrical equipment. The property was known as the Church Street substation. For the purposes of this matter the parties and the state referee considered the interests of the plaintiffs to be one and the same. The fair value of the land and buildings on the date of the taking was $68,000, and none of the parties disputes the award of this amount for [161 Conn. 236] the land and building. The Church Street substation was a portion of the plaintiffs' facilities used to distribute electric power in the area. Electric power is generated at generating stations and transmitted at high voltages to bulk power stations near the areas where the power is to be consumed. At bulk power stations the voltage is reduced and the electric power is further transmitted to smaller substations at the location of the load to be served. At these smaller substations the voltage of the electric power is further reduced, and it is distributed through overhead or underground electric lines to the consumers of electric power. In New Britain the Black Rock substation is the bulk power station, and the Church Street substation was one of a dozen or more substations receiving power from the Black Rock substation. The Church Street substation supplied electric power to the downtown area of New Britain and to large industrial plants located in that area and all of such power passed through the substation. Electric power reached the Church Street substation from the Black Rock station by means of four 15,000-volt underground electric lines. From the Church Street substation electric power was distributed to customers by means of underground electric lines, some operating at 15,000 volts and some at 2300 volts. In 1966, in connection with the taking, the defendant commission ordered the plaintiffs to vacate the Church Street substation. If the plaintiffs had merely vacated the substation they would no longer have been able to serve the customers who had received electric power through the substation. In order to continue to serve such customers, it was necessary for the plaintiffs to make provision for the flow of
Page 364
electric power from the Black Rock station to the electric lines which had [161 Conn. 237] formerly received electric power through the Church Street substation. The plaintiffs did, in fact, install new facilities in the highways so that customers who had formerly received electric power through the Church Street substation could continue to receive electric power. The method adopted by the plaintiffs to serve such customers was the most economical and best engineered method to serve them. In addition to the facilities for distributing electric power to its customers, the Church Street substation contained equipment which controlled all of the street lights in downtown New Britain. As a result of the taking of the substation it was necessary for...
Hanson v. Commissioner of Transp. United States Supreme Court of Connecticut January 2, 1979 ...659-60, 363 A.2d 1094; Lynch v. West Hartford, 167 Conn. 67, 73, 355 A.2d 42; Connecticut Ry. & Lighting Co. v. Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362. The fact that this "before and after" rule of computation may have governed the commissioner's determination of damages......
City of Meriden v. Highway Com'r United States Supreme Court of Connecticut December 2, 1975 ...the market value of the property just prior to the taking. Connecticut Ry. & Lighting Co. v. [169 Conn. 660] Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362; Andrews v. Cox, 129 Conn. 475, 478, 29 A.2d 587. The difference, which is the diminution in market value sustained by the ......
City of Meriden v. Ives United States Supreme Court of Connecticut January 23, 1974 ...from Bauman v. Ross, 167 U.S. 548, 574, 17 S.Ct. 966, 42 L.Ed. 270; see also Connecticut Ry. & Lighting Co. v. Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362; Hollister v. Cox, 130 Conn. 389, 34 A.2d 633; 4A Nichols, Eminent Domain (3d Ed.) § 14.2. 'Damage to the remainder area ......
State By and Through Dept. of Highways v. City of Helena, 80-306 United States Montana United States State Supreme Court of Montana August 11, 1981 ...use of the streets. Jones v. Burns (1960), 138 Mont. 268, 357 P.2d 22; Connecticut Ry. & L. Co. v. New Britain Redev. Comm'n (1971), 161 Conn. 234, 287 A.2d 362; McQuillin, Municipal Corporations, §§ 34.72, 34.74(a), (1970 ed.). The fact that the governing body which requires the relocation......
4 cases
Hanson v. Commissioner of Transp. United States Supreme Court of Connecticut January 2, 1979 ...659-60, 363 A.2d 1094; Lynch v. West Hartford, 167 Conn. 67, 73, 355 A.2d 42; Connecticut Ry. & Lighting Co. v. Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362. The fact that this "before and after" rule of computation may have governed the commissioner's determination of damages......
City of Meriden v. Highway Com'r United States Supreme Court of Connecticut December 2, 1975 ...the market value of the property just prior to the taking. Connecticut Ry. & Lighting Co. v. [169 Conn. 660] Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362; Andrews v. Cox, 129 Conn. 475, 478, 29 A.2d 587. The difference, which is the diminution in market value sustained by the ......
City of Meriden v. Ives United States Supreme Court of Connecticut January 23, 1974 ...from Bauman v. Ross, 167 U.S. 548, 574, 17 S.Ct. 966, 42 L.Ed. 270; see also Connecticut Ry. & Lighting Co. v. Redevelopment Commission, 161 Conn. 234, 239, 287 A.2d 362; Hollister v. Cox, 130 Conn. 389, 34 A.2d 633; 4A Nichols, Eminent Domain (3d Ed.) § 14.2. 'Damage to the remainder area ......
State By and Through Dept. of Highways v. City of Helena, 80-306 United States Montana United States State Supreme Court of Montana August 11, 1981 ...use of the streets. Jones v. Burns (1960), 138 Mont. 268, 357 P.2d 22; Connecticut Ry. & L. Co. v. New Britain Redev. Comm'n (1971), 161 Conn. 234, 287 A.2d 362; McQuillin, Municipal Corporations, §§ 34.72, 34.74(a), (1970 ed.). The fact that the governing body which requires the relocation......
| https://case-law.vlex.com/vid/connecticut-ry-lighting-co-893788086 |
State ex rel Counsel for Discipline of the Nebraska Supreme Court v. Widtfeldt | Nebraska Supreme Court | 06-23-2006 | www.anylaw.com
Research the case of State ex rel Counsel for Discipline of the Nebraska Supreme Court v. Widtfeldt, from the Nebraska Supreme Court, 06-23-2006. AnyLaw is the FREE and Friendly legal research service that gives you unlimited access to massive amounts of valuable legal data.
State ex rel Counsel for Discipline of the Nebraska Supreme Court v. Widtfeldt
Original action. Judgment of suspension.
Hendry, C.J., Wright, Connolly, Gerrard, Stephan, and McCormack, JJ.
NATURE OF CASE
This case presents the review of the uncontested findings of the referee in an attorney disciplinary proceeding.
BACKGROUND
James Widtfeldt was admitted to the practice of law in Nebraska in 1978 and has a general practice in Holt County, Nebraska. He has previously been privately reprimanded for representing both sides of a tax case. He is currently under an order of indefinite suspension to be followed by a period of probation for filing irrelevant and abusive motions and pleadings in an unrelated case and for irrelevant and abusive written responses to the Counsel for Discipline reviewing that case. See State ex rel. Counsel for Dis. v. Widtfeldt, 269 Neb. 289, 691 N.W.2d 531 (2005).
The formal charges currently before us concern Widtfeldt's conduct in two separate probate proceedings (described separately in counts I and II) occurring prior to the current order of suspension. The formal charges alleged that Widtfeldt entered into agreement for, charged, or collected clearly excessive fees, in violation of Canon 2, DR 2-106(A), of the Nebraska Code of Professional Responsibility, and that he knowingly failed to disclose information or had knowingly made a false statement of law or fact during the proceedings, in violation of Canon 7, DR 7-102, of the Nebraska Code of Professional Responsibility. The Counsel for Discipline also charged Widtfeldt with violation of Canon 1, DR-102(A), of the Nebraska Code of Professional Responsibility which prohibits the violation of a disciplinary rule, engaging in conduct prejudicial to the administration of justice, or any other conduct that adversely reflects on the lawyer's fitness to practice law. After the appointment of the referee, a hearing was held at which Widtfeldt was present with counsel.
Count I: Marr Estate
Count I involved the probate proceedings of the estate of Rose M. Marr. The evidence at the hearing showed that Widtfeldt entered into an agreement with the personal representatives of the estate to represent them and to receive attorney fees in the amount of 8 percent of the non-probate and probate property. Widtfeldt later filed an inheritance tax worksheet with the county court, reflecting a gross estate value of $578,943.51 and an attorney fee of $46,434.22. The personal representatives paid Widtfeldt this amount from the estate assets, but the county court ultimately ordered the fees to be repaid to the estate. Widtfeldt complied with this order.
Widtfeldt testified at that hearing that in the past, his standard fee for estate cases was 2 percent of the gross estate, plus extra sums for extraordinary work. He attempted to explain the 8-percent figure as compensation for conservatorship work at 1 percent per year for 7 years, plus 1 percent for the estate work.
Widtfeldt admitted that a conservatorship was never actually filed and that the "conservatorship work" was done after Marr's death. This work involved doublechecking all the canceled checks issued by Marr's attorneys in fact pursuant to Marr's powers of attorney. Widtfeldt described his work as compiling "an account like a conservator." Widtfeldt testified that he did this pursuant to Marr's predeath wish that Widtfeldt conduct such a review informally, without court oversight, and that Widtfeldt wait to be paid out of the estate for such services. Widtfeldt did not have a formal written agreement with Marr to that effect. Widtfeldt was paid during Marr's lifetime for services such as the drafting of her will, and for a cancellation fee for not completing the guardianship-conservatorship which he had drafted for Marr.
The allegation of misrepresentation in the Marr estate stemmed from the fact that the personal representatives were also each initially afforded, through Widtfeldt, 8 percent of the estate under a similar theory of compensation for their past services to Marr. However, when the petition for their appointment was filed, Widtfeldt stated therein that they were not creditors of the estate. Widtfeldt explained that neither of the personal representatives had a formal compensation arrangement with Marr and that they had told him they were not creditors of the estate. Instead, the compensation was as per Marr's expressed wishes to Widtfeldt that they in fact later be generously compensated.
The referee found, by clear and convincing evidence, that Widtfeldt violated DR 2-106(A) by entering into an agreement for, charging, or collecting an illegal or clearly excessive fee. However, the referee concluded that he could not find by clear and convincing evidence that Widtfeldt had intentionally misled the county court in filing the personal representative applications as he did. The referee explained that the personal representatives' prior services were admittedly done partially out of friendship with Marr and that no terms of payment had been formally agreed upon. Thus, the referee did not find a "creditor" relationship.
Count II: Kollman Estate
Count II involved the estate of Walter Kollman and Widtfeldt's representation of its personal representatives. Widtfeldt entered into an agreement with the personal representatives for attorney fees in the amount of 5 percent of the estate, with a like percentage designated for the services of each personal representative. An inheritance tax worksheet was eventually presented to and signed by the personal representatives, setting forth a gross estate of $1,419,994.70, attorney fees of $100,999.74 (which was roughly 7 percent of the assets), and personal representatives' fees in the amount of $201,999.47. This sheet was presented to the county attorney, who informed Widtfeldt that he would not approve the worksheet and that Widtfeldt would have to obtain court approval for any such fees.
The worksheet was never filed with the court. Widtfeldt claimed that the reason he never filed this first worksheet was because it contained errors. He explained that there were mathematical errors, on which he did not elaborate. In addition, Widtfeldt testified that "tempers were fairly high." A litigator had been hired through him for the estate to handle litigation with certain heirs, and Widtfeldt explained that he thought that he was going to have to pay the litigator's expenses out of his own fees because the fees were being informally contested by one of the personal representatives.
Subsequently, Widtfeldt drafted or filed several different and conflicting motions for approval of his fees, ranging from 2 to 5 percent of the estate. Ultimately, the county court, noting that normal fees for estate actions in that area were 1 percent, awarded a 2-percent fee to Widtfeldt and ordered that any excess fees be refunded. Widtfeldt, pursuant to such order, refunded $28,398 of previously paid fees. The aforementioned litigator testified at the disciplinary hearing that a reasonable rate was between 2 to 3 percent.
The misrepresentation allegations of count II related to alleged false statements to the county court in Widtfeldt's pleadings regarding the scheduling of hearings. The Counsel for Discipline however, eventually conceded that Widtfeldt's testimony established that the misrepresentations were unintentional and were a result of administrative error.
The referee found with regard to the false pleadings allegation that the evidence failed to establish any violation. However, the referee found that Widtfeldt had violated DR 2-106(A) by charging, albeit without successfully collecting, an excessive fee.
Referee Recommendations
The referee recommended that Widtfeldt be publicly reprimanded and that his current indefinite suspension remain in full force and effect without modification. In so recommending, the referee noted that Widtfeldt failed to produce evidence that the events in question were isolated occurrences. The referee did take into consideration Widtfeldt's behavior at the hearing, which the referee described as "contrite and cooperative." At the same time, however, the referee noted that Widtfeldt did not actually admit to any wrongdoing. The referee also took into account Widtfeldt's previous reprimand and his current suspension.
No exceptions were filed to the referee's findings by either party to the proceeding. We sustained the Counsel for Discipline's motion for judgment on the pleadings as to the violations, but not as to the proposed discipline.
ASSIGNMENTS OF ERROR
In Widtfeldt's brief, he assigns that the referee erred (1) by finding that he contracted for, charged, or collected a clearly excessive fee in the Kollman estate and (2) in determining that Widtfeldt's conduct in the Kollman estate was cumulative of his conduct in the Marr estate.
ANALYSIS
Widtfeldt's brief focuses on count II and his allegation that he never really intended to collect the 7-percent fee found by the referee to be excessive. The Counsel for Discipline does not assert that any of the subsequent filings of either 2 or 5 percent were clearly excessive given the protracted litigation of the case, and the referee's findings appear to focus on the 7-percent figure.
Widtfeldt accordingly takes issue with the referee's recommendation that he be publicly reprimanded for his conduct related to the Kollman estate. Widtfeldt does not take issue with the referee's recommendation that his current status of indefinite suspension should continue or with the public reprimand in relation to the Marr estate.
[1,2] Under existing case law, the Nebraska Supreme Court is limited in its review to examining only those items to which the parties have taken exception. State ex. rel. Counsel for Dis. v. Petersen, ante p. 262, 710 N.W.2d 646 (2006). When no exceptions to the referee's findings of fact are filed by either party in a disciplinary proceeding, the Nebraska Supreme Court may, in its discretion, consider the referee's findings as final and conclusive. See, id.; Neb. Ct. R. of Discipline 10(L) (rev. 2005). In sustaining the Counsel for Discipline's motion for judgment on the pleadings, we have already concluded that Widtfeldt's conduct was in violation of DR 2-106(A) on two separate occasions. We consider Widtfeldt's arguments in his brief to this court to the extent that they are relevant to the appropriate sanction to be imposed from that conduct. We note that the conduct at issue in this case occurred prior to the September 1, 2005, effective date of the Nebraska Rules of Professional Conduct and is, thus, governed by the now-superseded Code of Professional Responsibility.
[3,4] To determine whether and to what extent discipline should be imposed in a lawyer discipline proceeding, the Nebraska Supreme Court considers the following factors: (1) the nature of the offense, (2) the need for deterring others, (3) the maintenance of the reputation of the bar as a whole, (4) the protection of the public, (5) the attitude of the respondent generally, and (6) the respondent's present or future fitness to continue in the practice of law. State ex rel. Counsel for Dis. v. Horneber,270 Neb. 951, 708 N.W.2d 620 (2006). Each attorney discipline case must be evaluated individually in light of its particular facts and circumstances. In addition, the propriety of a sanction must be considered with reference to the sanctions imposed in prior similar cases. State ex rel. Counsel for Dis. v. Widtfeldt, 269 Neb. 289, 691 N.W.2d 531 (2005).
The referee, in recommending a public reprimand, considered the case of State ex rel. Counsel for Dis. v. Palagi,269 Neb. 398, 693 N.W.2d 276 (2005), wherein we publicly reprimanded an attorney for having charged an excessive fee in a wrongful death matter. The attorney was also found to have improperly advanced financial assistance to a client and failed to return the property of clients. Other cases considering the issue of excessive fees are limited, and the circumstances in those cases also presented additional violations of the Code of Professional Responsibility. See, State ex rel. Special Counsel for Dis. v. Shapiro,266 Neb. 328, 665 N.W.2d 615 (2003); State ex rel. Counsel for Dis. v. Huston,262 Neb. 481, 631 N.W.2d 913 (2001); State ex rel. NSBA v. Miller, 258 Neb. 181, 602 N.W.2d 486 (1999); State ex rel. NSBA v. Kirshen, 232 Neb. 445, 441 N.W.2d 161 (1989).
Widtfeldt's current order of suspension is subject to reinstatement followed by a period of probation of not less than 1 year. In order to be reinstated under this order, we explained that he will need to establish that counseling has resulted in behavioral changes that will allow him to practice law within the disciplinary rules. At the disciplinary hearing considered in State ex rel. Counsel for Dis. v. Widtfeldt, supra,a psychologist concluded that although intelligent, Widtfeldt had narcissistic and obsessive-compulsive personality features which interfered with his ability to reason through certain issues. However, the psychologist opined that Widtfeldt could complete a plan to modify his behavior so that there was a much greater chance that problems would not reoccur.
[5] Neb. Ct. R. of Discipline 4 (rev. 2004) provides that misconduct shall be grounds for (1) disbarrment; (2) suspension; (3) probation in lieu of or subsequent to suspension, on such terms as we may designate; (4) censure and reprimand; (5) temporary suspension; or (6) private reprimand by the Committee on Inquiry or Disciplinary Review Board.
[6] In considering the appropriate discipline in this case, we are mindful of the fact that this is not the first instance of misconduct by Widtfeldt. Cumulative acts of attorney misconduct are distinguishable from isolated incidents and are therefore deserving of more serious sanctions. State ex rel. Counsel for Dis. v. Swanson,267 Neb. 540, 675 N.W.2d 674 (2004). Although Widtfeldt is currently suspended, we find that his cumulative acts of misconduct merit more of a sanction than is afforded by a public reprimand. We conclude that the appropriate discipline in this case for the two counts of violating DR 2-106(A) is a judgment of suspension for a period of 1 year.
CONCLUSION
We order that Widtfeldt should be and hereby is suspended from the practice of law in the State of Nebraska for a period of 1 year, effective immediately. Widtfeldt is directed to pay costs and expenses in accordance with Neb. Rev. Stat. §§ 7-114 and 7-115 (Reissue 1997) and Neb. Ct. R. of Discipline 23(B) (rev. 2001).
Judgment of Suspension
Miller-Lerman, J., not participating.
| https://www.anylaw.com/case/state-ex-rel-counsel-for-discipline-of-the-nebraska-supreme-court-v-widtfeldt/nebraska-supreme-court/06-23-2006/frg9TmYBTlTomsSB7XU0 |
Λp interactions in momentum range 300 to 1500 MeV/c
Download Citation | Λp interactions in momentum range 300 to 1500 MeV/c | A sample of approximately 250 Λp interactions has been obtained in the Λ-hyperon momentum range of about 300 to 500 MeV/c. An enhanced Λ-hyperon... | Find, read and cite all the research you need on ResearchGate
Λp interactions in momentum range 300 to 1500 MeV/c
March 1971
DOI: 10.1016/0550-3213(71)90076-9
Abstract
A sample of approximately 250 Λp interactions has been obtained in the Λ-hyperon momentum range of about 300 to 500 MeV/c. An enhanced Λ-hyperon production rate was obtained by exposing an internally-mounted platinum target to the incident 1.5 GeV/c meson beam. Cross sections and angular distributions are obtained for the reactions: Λp → Λp, Λp → Σop and Λp → Λpπo. In the elastic channel, no strong evidence is seen near the Σop threshold for the presence of a 3S1 resonance, which has been reported, although there is some evidence for a small enhancement in this mass region. There is evidence for the presence of P-waves and probably also D-waves above about 800 MeV/c, but not below this momentum.
... For the Y N and Y Y interactions, the old data were mainly either total cross sections or threshold parameters, which have relatively large uncertainties [12][13][14][15]
[16]
[17][18]. Only in the past two decades, differential cross sections were measured. ...
... The covariant ChEFT results obtained with cutoffs ranging from 550 to 700 MeV/c are presented as bands. In these figures, the cross section data [12,14,17,51] included in the fitting procedure are denoted by filled symbols, while for the high energy data
[16,
18,20,21,53,54] open symbols are used. For the sake of comparison, we also show the results from the Jülich'04 model (orange solid lines) [24] and the Nijmegen NSC97f potential (red dashed lines) [23], if available. ...
... We hope that the results presented in this work will stimulate more future experimental, theoretical, and lattice QCD studies.
[16]
. The additional curves are the theoretical predictions of the meson exchange models, NSC97a (red dashed lines) [23] and Jülich'04 (orange solid lines) [24]. ...
Test of the hyperon-nucleon interaction of the leading order covariant chiral effective field theory
Preprint
Jul 2021
Jing Song
Zhi-Wei Liu
Kai-Wen Li
Li-Sheng Geng
Motivated by the recent experimental measurements of differential cross sections of the $\Sigma^{-}p$ elastic scattering in the momentum range of $470$ to $850$ MeV$/c$ by the J-PARC E$40$ experiment, we extend our previous studies of $S=-1$ hyperon-nucleon interactions to relatively higher energies up to $900$ MeV$/c$ for both the coupled-channel $\Lambda p\rightarrow(\Lambda p, \Sigma^{+}n, \Sigma^{0}p)$, $\Sigma^{-}p\rightarrow(\Lambda n, \Sigma^{0}n, \Sigma^{-}p)$ and single-channel $\Sigma^{+}p\rightarrow\Sigma^{+}p$ reactions. We show that although the leading order covariant chiral effective field theory is only constrained by the low energy data, it can describe the high energy data very well, in particular, the J-PARC E40 differential cross sections. In particular, we predict a pronounced cusp structure close to the $\Sigma N$ threshold in the $\Lambda p\to \Lambda p$ reaction, which can be checked in the future using, e.g., the Femtoscopy technique. The predicted total and differential cross sections are of relevance for ongoing and planned experiments.
... The models for nucleon-nucleon interactions have been well established and strictly constrained based on more than 4000 measured data points in history [1,2], while the measurements for hyperon-nucleon and hyperon-hyperon interactions are insufficient since a stable, intense hyperon beam is difficult to experimentally realize resulting from the short life time of hyperons [5]. Actually, up to now, there are only 70 measured data points for hyperon-nucleon scattering and only one for hyperon-hyperon scattering [6][7][8]
[9]
[10][11][12][13][14][15][16][17][18], so that the theoretical study of hyperon-nucleon (hyperon-hyperon) interactions suffers a lot from a degree of ambiguity due to the lack of limitation from experiments. ...
... Most of the previous hyperon-nucleon scattering measurements (Λp → Λp, Σ − p → Σ − p, Λn, Σ 0 n, and Σ + p → Σ + p) were accomplished in the bubble chamber era of 1960s and 1970s [6][7][8]
[9]
[10] using hyperons with momenta less than 1 GeV/c 2 . After a gap of twenty years, an experimental group in KEK studied Σ + p and Σ − p elastic scattering processes with a scintillating fiber block [11,12], where the momentum of Σ ± hyperon is within [0.35, 0.75] GeV/c 2 , a little higher than that used in Ref [6]. ...
A novel method to study hyperon-nucleon interactions at BESIII
Preprint
Full-text available
Sep 2022
Jianping Dai
Hai-Bo Li
Han Miao
Jian-Yu Zhang
A novel method to study hyperon-nucleon/nuclei interactions at $e^+ e^-$ colliders represented by BESIII is proposed in this work. Utilizing the large quantity of hyperons produced by the decay of 10 billion $J/\psi$ and 2.7 billion $\psi(3686)$ collected at BESIII, hyperon-nucleon/nuclei interactions can be studied by the scattering between hyperons and nucleus in the dense objects of BESIII detectors, which makes it possible to measure the cross sections of several specific elastic or inelastic processes. The results will definitely benefit a lot for precisely probing the hyperon-nucleon interactions and provide the essential direct constraints for researching aspects including the internal structure of neutron stars and the unified model for baryon-baryon interactions. In addition, the desirable prospects in future Super Tau-Charm Factory (STCF) are discussed and estimated in this work as well.
... Very recently evidence of the threshold structure has been also observed in measurements of the Λp correlation function in pp collisions at T = 13 GeV by the ALICE Collaboration [17]. Let us mention that there are also data for the Λp elastic cross section itself in the ΣN threshold region
[18,
19]. However, in that case the energy resolution is rather poor so that no conclusion on a possible structure could be drawn [12]. ...
... The cross sections are the ones at zero momentum, but in calculations it is common practice [28] to evaluate the cross sections at a small non-zero momentum, namely p lab = 10 MeV/c. As mentioned already, available Λp cross sections in the ΣN threshold region
[18,
19] are afflicted by a poor momentum resolution and usually not taken into account in the fitting procedure. For a detailed description of the utilized Y N interactions (NLO13, NLO19, NSC97f) we refer the reader to the original publications [26][27][28]. ...
On the structure in the $\Lambda N$ cross section at the $\Sigma N$ threshold
Preprint
May 2021
J. Haidenbauer
Ulf-G Meissner
The complexity of threshold phenomena is exemplified on a prominent and long-known case - the structure in the $\Lambda p$ cross section (invariant mass spectrum) at the opening of the $\Sigma N$ channel. The mass splitting between the $\Sigma$ baryons together with the angular momentum coupling in the $^3S_1$-$^3D_1$ partial wave imply that, in principle, up to six channels are involved. Utilizing hyperon-nucleon potentials that provide an excellent description of the available low-energy $\Lambda p$ and $\Sigma N$ scattering data, the shape of the resulting $\Lambda p$ cross section is discussed and the poles near the $\Sigma N$ threshold are determined. Evidence for a strangeness $S=-1$ dibaryon is provided, in the form of a deuteron-like (unstable) $\Sigma N$ bound state. Predictions for level shifts and widths of $\Sigma^-p$ atomic states are given.
... The exper-imental cross sections are taken from Refs. [37] (filled circles), [38] (filled squares), [42,43] (open triangles),
[44]
(open squares), and [45] (open circles). The dotted vertical lines labeled with Σ + n and Σ 0 p indicate the thresholds of the pertinent ΣN channels while the new results are shown as cyan (light) bands. ...
... The dotted vertical lines labeled with Σ + n and Σ 0 p indicate the thresholds of the pertinent ΣN channels while the new results are shown as cyan (light) bands. In this figure and the following ones, Y N data included in the fitting procedure [37][38][39][40] are displayed by filled symbols, while for additional data at higher energies [42][43]
[44]
[45][46][47][48] open symbols are used. ...
Hyperon–nucleon interaction within chiral effective field theory revisited
Article
Full-text available
Ulf-G Meissner
A. Nogga
The \(\varLambda N\) and \(\varSigma N\) interactions are considered at next-to-leading order in SU(3) chiral effective field theory. Different options for the low-energy constants that determine the strength of the contact interactions are explored. Two variants are analysed in detail which yield equivalent results for \(\varLambda N\) and \(\varSigma N\) scattering observables but differ in the strength of the \(\varLambda N \rightarrow \varSigma N\) transition potential. The influence of this difference on predictions for light hypernuclei and on the properties of the \(\varLambda \) and \(\varSigma \) hyperons in nuclear matter is investigated and discussed. The effect of the variation in the potential strength of the \(\varLambda N\)-\(\varSigma N\) coupling (also called \(\varLambda -\varSigma \) conversion) is found to be moderate for the considered \(^3_\varLambda {{\mathrm{H}}}\) and \(^4_\varLambda \mathrm{He}\) hypernuclei but sizable in case of the matter properties. Further, the size of three-body forces and their relation to different approaches to hypernuclear interactions is discussed.
... The set of 52 YN-data was also fitted successfully, while having no bound states. This set comprises the usual standard set of 35 data employed in the older Nijmegen work on YN [18], plus higher energy Λp data
[19]
and the recently measured Σ + p cross sections of the KEK-PS E289 experiment [20,21], and the Σ − p cross sections [22]. Σ-nucleus interaction: All Nijmegen soft-core models seem to lack sufficient repulsion to give a (very) strong repulsive U Σ [23] in 9 Σ Be and 28 Σ S i. ...
... In Table 5 the ESC16 results of the fit for the Λp scattering data [36,37,
19]
are given. In Fig. 1 the fit to these data is shown together with the effective range approximation with two (I) and three (II) terms. ...
Extended-soft-core baryon-baryon model ESC16
Conference Paper
Jul 2019
Th. A. Rijken
M. M. Nagels
Y. Yamamoto
The most recent Nijmegen extended-soft-core ESC16 model for the baryon-baryon (BB) interactions of the SU(3) flavor-octet of baryons (N, Λ, Σ, and Ξ) is presented. The ESC model ESC16, as well as its predecessors ESC08 and ESC04, describe the nucleon-nucleon (NN), hyperon-nucleon (YN), and hyperon-hyperon (YY) interactions in a unified way using broken SU(3) symmetry. In this paper we outline the differences between ESC16 and ESC08c.
The parameters of the ESC models are established in a simultaneous fit to the NN and YN data, taking into account information about ΛΛ, ΞN, and Λ-hypernuclei in the form of constraints. In particular, the experimental indications for ΛΛ-attraction, Ξ-nuclear and Σ-nuclear well-depth were taken into account as much as possible. About 25 physical coupling parameters and 8 cut-off and diffractive masses, were searched. The obtained OBE-couplings and the F/(F+D) ratios can be well understood in the context of the quark-antiquark pair creation (QPC) mechanism.
The fit of the ESC-models to the NN- and YN- scattering data with a single set of parameters has achieved excellent results for the NN and YN data, and for the YY data in accordance with the experimental indications for ΛΛ. In the case of the most recent ESC model, called ESC16, the achievements are: (i) For the selected 4313 pp and np scattering data with energies 0 ≤ Tlab ≤ 350 MeV, the model reaches a fit having χ²/Ndata = 1.10. (ii) The deuteron binding energy and all of the NN scattering lengths are fitted very nicely. (iii) The YN data are described very well with χ²/Ndata = 1.11, giving at the same time good descriptions of the Λ, Σ, and Ξ nuclear well-depths. (iv) The model has no bound states for S = −1,−2,−3,−4. (v) The nuclear saturation, and well-depths UΣ, UΞ require important contributions from three-body forces.
... The results for NLO13 are shown as red (dark) bands while the new results are shown as cyan (light) bands. In this figure and the following ones, Y N data included in the fitting procedure [31][32][33][34] are displayed by filled symbols, while for additional data at higher energies [36][37]
[38]
[39][40][41][42] open symbols are used. ...
... The experimental cross sections are taken from Refs. [31] (filled circles), [32] (filled squares), [36,37] (open triangles),
[38]
(open squares), and [39] (open circles). The dotted vertical lines labeled with Σ + n and Σ 0 p indicate the thresholds of the pertinent ΣN channels. ...
Hyperon-nucleon interaction within chiral effective field theory revisited
Preprint
Jun 2019
J. Haidenbauer
Ulf-G Meissner
A. Nogga
The $\Lambda N$ and $\Sigma N$ interactions are considered at next-to-leading order in SU(3) chiral effective field theory. Different options for the low-energy constants that determine the strength of the contact interactions are explored. Two variants are analysed in detail which yield equivalent results for $\Lambda N$ and $\Sigma N$ scattering observables but differ in the strength of the $\Lambda N \to \Sigma N$ transition potential. The influence of this difference on predictions for light hypernuclei and on the properties of the $\Lambda$ and $\Sigma$ hyperons in nuclear matter is investigated and discussed. The effect of the variation in the potential strength of the $\Lambda N$-$\Sigma N$ coupling (also called $\Lambda -\Sigma$ conversion) is found to be moderate for the considered $^3_\Lambda \rm H$ and $^4_\Lambda \rm He$ hypernuclei but sizable in case of the matter properties. Further, the size of three-body forces and their relation to different approaches to hypernuclear interactions is discussed.
... Relying on SU (3) flavor symmetry or the SU(6) symmetry of the quark model, most coupling constants at the strange vertices can be related to nucleon-nucleon-meson coupling constants which are constrained by nucleon-nucleon scattering data. The remaining free parameters are optimised against the available hyperon-nucleon total cross section data [194][195]
[196]
[197][198]. All modern hyperon-nucleon potential models [199][200][201] successfully reproduce these data, notwithstanding the substantial differences in implementation between the different models. ...
... [194] ( ) and [195] (•), in (b) from Refs.
[196]
(•) and [204] ( ), in (c),(d) from [197] and in (e),(f) from [198]. The shaded band is the Jülich chiral EFT result [202], the solid curve is the Jülich '04 model [199], and the dashed curve is the Nijmegen NSC97f potential [205]. ...
Regge-plus-resonance approach to strangeness production from the deuteron
Thesis
Pieter Vancraeyveld
Electromagnetic production of strangeness plays a prominent role in our quest to chart the excitation spectrum of the nucleon. Despite the large body of high-quality p(g*,K)Y data, phenomenological analyses of these reactions have not led to an unequivocal outcome. The persistent lack of consensus on the role of different nucleon resonances in the reaction dynamics can be attributed in part to the important role played by non-resonant dynamics. In this dissertation, photon- and electron-induced kaon production off nucleons and deuterium is studied using an efficient reaction model developed at Ghent University, coined Regge-plus-resonance, that successfully reconciles an isobaric approach in the resonance region with Regge phenomenology at higher energies. The dominant non-resonant amplitudes are modelled in terms of K+(494) and K*+(892) t-channel Regge-trajectory exchange and are fixed by high-energy data. In a next step, this amplitude is extrapolated into the resonance region and refined by adding individual N* and Delta* terms in the s-channel. We show how the Regge-plus-resonance model, which is optimised to data obtained off proton targets, can be transformed to reliably describe all reactions with a kaon-hyperon pair in the final state. In addition to the study of strangeness production off the proton, it pays to consider the same reaction on more complex targets, such as the deuteron. In this dissertation quasi-free kaon production from the deuteron is investigated using the Regge-plus-resonance elementary operator within the relativistic plane-wave impulse approximation. In addition, the effects of the hyperon-nucleon final-state interaction are analysed using the non-relativistic one-boson-exchange model developed at Jülich as input. Numerical results for (semi-)inclusive and exclusive differential cross sections are presented and we investigate the formalism’s sensitivity to its different ingredients. The characteristic shape of the cross section is studied and distinct kinematic regions are identified where the 2H(g,K)YN reaction can be exploited to learn about elementary kaon production or hyperon-nucleon rescattering. Finally, model calculations are confronted with the first published 2H(g,K)YN data.
... To estimate these cross sections, we could use e.g. effective model calculations [61,62], however, for the first estimation, it is not necessary as there are some measurement data for the N interaction, which can be used for creating hypernuclei with one inside [63][64][65]
[66]
[67]. For double strange hypernuclei, where we have two -s the interaction could also play a role. ...
Hypernuclei production with a modified coalescence model in BUU transport calculations
Article
Full-text available
Apr 2023
EUR PHYS J A
Gábor Balassa
Gy. Wolf
In this paper, the usual momentum- and coordinate-space distance criteria for creating nuclear clusters in transport simulations are readdressed by using a dynamical, covariant description in an off-shell Boltzmann-Uehling-Uhlenbeck transport approach. The free parameter of this clustering scheme is the cluster formation time, which is fitted through the FOPI data of low energy charged cluster multiplicities in Au+Au collisions at 150 A MeV, and 400 A MeV incident energies. The coalescence model is used to estimate the yields of the $$^3$$ 3 H $$_\Lambda $$ Λ , $$^5$$ 5 H $$_{\Lambda \Lambda }$$ Λ Λ , $$^6$$ 6 He $$_{\Lambda \Lambda }$$ Λ Λ single and double strange hypernuclei in central Au+Au collisions between 2, and 20 A GeV incident energies, giving comparable results to estimations from other methods.
... 1. Data are from Refs.[55] (filled circles),[56] (filled squares),[68,69] (open triangles),
[70]
(open squares),[71] (open circles) and[6] (inverted triangles) ...
Hyperon–nucleon interaction in chiral effective field theory at next-to-next-to-leading order
Article
Full-text available
Mar 2023
EUR PHYS J A
Hoai Le
J. Haidenbauer
Ulf-G Meissner
A. Nogga
A hyperon–nucleon potential for the strangeness $$S=-1$$ S = - 1 sector ( $$\varLambda N$$ Λ N , $$\varSigma N$$ Σ N ) up to third order in the chiral expansion is presented. SU(3) flavor symmetry is imposed for constructing the interaction, however, the explicit SU(3) symmetry breaking by the physical masses of the pseudoscalar mesons and in the leading-order contact terms is taken into account. A novel regularization scheme is employed which has already been successfully used in studies of the nucleon–nucleon interaction within chiral effective field theory up to high orders. An excellent description of the low-energy $$\varLambda p$$ Λ p , $$\varSigma ^- p$$ Σ - p and $$\varSigma ^+ p$$ Σ + p scattering data is achieved. New data from J-PARC on angular distributions for the $$\varSigma N$$ Σ N channels are analyzed. Results for the hypertriton and $$A=4$$ A = 4 hyper-nuclear separation energies are presented. An uncertainty estimate for the chiral expansion is performed for selected hyperon–nucleon observables.
... 1. Data are from Refs.[54] (filled circles),[55] (filled squares),[67,68] (open triangles),
[69]
(open squares),[70] (open circles) and[5] (inverted triangles). ...
Hyperon-nucleon interaction in chiral effective field theory at next-to-next-to-leading order
Preprint
Jan 2023
Hoai Le
J. Haidenbauer
Ulf-G Meissner
A. Nogga
A hyperon-nucleon potential for the strangeness $S=-1$ sector ($\Lambda N$, $\Sigma N$) up to third order in the chiral expansion is presented. SU(3) flavor symmetry is imposed for constructing the interaction, however, the explicit SU(3) symmetry breaking by the physical masses of the pseudoscalar mesons and in the leading-order contact terms is taken into account. A novel regularization scheme is employed which has already been successfully used in studies of the nucleon-nucleon interaction within chiral effective field theory up to high orders. An excellent description of the low-energy $\Lambda p$, $\Sigma^- p$ and $\Sigma^+ p$ scattering data is achieved. New data from J-PARC on angular distributions for the $\Sigma N$ channels are analyzed. Results for the hypertriton and $A=4$ hyper-nuclear separation energies are presented. An uncertainty estimate for the chiral expansion is performed for selected hyperon-nucleon observables.
... Experimental data of the YN scatterings are, historically, rare, owing to the experimental difficulties regarding the short lifetime of hyperons [24][25]
[26]
[27][28][29][30][31][32]. For the intermediate energy, two experiments to measure the differential cross sections of the + p channel have been conducted [32,33]. ...
Measurement of differential cross sections for Σ+ p elastic scattering in the momentum range 0.44–0.80 GeV/ c
Article
Full-text available
Sep 2022
T. Nanamura
K. Miwa
J. K. Ahn
Koji Yoshimura
We performed a novel Σ+p scattering experiment at the J-PARC Hadron Experimental Facility. Approximately 2400 Σ+p elastic scattering events were identified from 4.9 × 107 tagged Σ+ particles in the Σ+ momentum range 0.44–0.80 GeV/c. The differential cross sections of the Σ+p elastic scattering were derived with much better precision than in previous experiments. The obtained differential cross sections were approximately 2 mb/sr or less, which were not as large as those predicted by the fss2 and FSS models based on the quark cluster model in the short-range region. By performing phase-shift analyses for the obtained differential cross sections, we experimentally derived the phase shifts of the 3S1 and 1P1 channels for the first time. The phase shift of the 3S1 channel, where a large repulsive core was predicted owing to the Pauli effect between quarks, was evaluated as $20^\circ \lt |\delta _{^3S_1}|\lt 35^\circ$. If the sign of $\delta _{^3S_1}$ is assumed to be negative, the interaction in this channel is moderately repulsive, as the Nijmegen extended-sort-core models predicted.
... However, the scattering experiment is not easy to be applied for hyperons because of their short lifetimes. There are scattering data for the p
[1]
reaction although the statistics are very limited, and no data exists for the n reaction. The n interaction has instead been estimated from the p interaction as measured by scattering experiments. ...
Study of the $$nn\Lambda $$ State and $$\Lambda n$$ Interaction at Jefferson Lab
Article
Full-text available
Mar 2022
FEW-BODY SYST
K. Itabashi
T. Akiyama
Yu Fujii
Guido Maria Urciuoli
An \(nn\Lambda \), which consists of two neutrons and a Lambda hyperon, is a multi-baryon system with no charge. Studying the \(nn\Lambda \) state would provide information about the \(\Lambda n\) interaction which has not been directly measured by a scattering experiment. The experiment (E12-17-003) was performed in order to search for the \(nn\Lambda \) state at Jefferson Lab. The \(nn\Lambda \) is expected to be produced by the \((e,e'K^+)\) reaction, which has sensitivity to both bound and resonance states if the natural width of the \(nn\Lambda \) is narrow enough to be observed as a peak. The experiment used gas targets of hydrogen and tritium for mass calibration and the \(nn\Lambda \) production, respectively. The mass calibration with \(\mathrm{H}(e,e'K^+) \Lambda /\Sigma ^0\) reactions gave the mass resolution of the \(\Lambda \) and \(\Sigma ^0\) each 3.5 \(\mathrm{MeV}/c^2\) FWHM, for the elementary reaction. A spectrum of \(\mathrm{^3 H}(e,e'K^+)X\) was obtained, and a simple model with a \(\Lambda n \) final state interaction was applied to reproduce the spectrum.
... On the other hand, the hyperon-proton scattering experiment was quite difficult experimentally due to the low intensity of the hyperon beam and its short lifetime. 36 cross section data of the Λp and Σp scatterings [215][216]
[217]
[218][219][220][221][222][223] were actually indispensable to construct the present BB interaction models. However the quality and quantity of these data are insufficient to impose a strict constraint on the theoretical models. ...
Extension of the J-PARC Hadron Experimental Facility: Third White Paper
Preprint
Full-text available
Oct 2021
Kazuya Aoki
H. Fujioka
Toshiyuki Gogami
Yasuo Yamamoto
The J-PARC Hadron Experimental Facility was constructed with an aim to explore the origin and evolution of matter in the universe through the experiments with intense particle beams. In the past decade, many results on particle and nuclear physics have been obtained at the present facility. To expand the physics programs to unexplored regions never achieved, the extension project of the Hadron Experimental Facility has been extensively discussed. This white paper presents the physics of the extension of the Hadron Experimental Facility for resolving the issues in the fields of the strangeness nuclear physics, hadron physics, and flavor physics.
... This is because the spin-flavor SU(6) quark model predict significantly characteristic potentials in the short-range region, such as significantly repulsive cores or attractive interactions depending on the spin and flavor configuration of the quarks in the system [5,6,7]. However, regarding hyperonproton scattering experiments, no experimental progress has been made from the experiments conducted throughout the 1970s in which hydrogen bubble chambers were employed [8,9,
10,
11,12,13,14]. This is owing to the experimental difficulties stemming from the low intensity of the hyperon [email protected] ( K. Miwa 2 ) ORCID(s): beam and its short lifetime. ...
Development and application of CATCH: A cylindrical active tracker and calorimeter system for hyperon-proton scattering experiments
Preprint
Full-text available
Sep 2021
Y. Akazawa
N. Chiga
N. Fujioka
H. Umetsu
In this study, we developed a new proton detector system called CATCH, which was designed for a scattering experiment involving a $\Sigma$ hyperon and a proton (J-PARC E40). CATCH is a cylindrical detector system covering an inner target that can be used to measure the trajectory and energy of a proton emitted from the target for the kinematic identification of a $\Sigma$p scattering event. It comprises a cylindrical fiber tracker (CFT), a bismuth germanate (BGO) calorimeter, and a plastic scintillator hodoscope (PiID), which are coaxially arranged from the inner to the outer sides. The CFT is a tracking detector consisting of 5,000 scintillation fibers, and it has two types of cylindrical layers in which the fibers are arranged in straight and spiral configurations. 24 BGO crystals are placed around the CFT to measure the kinetic energy of the recoil proton. The PiID is used to determine whether the recoil proton is stopped in the BGO calorimeter. We performed proton-proton (pp) and proton-carbon (pC) scattering experiments using an 80 MeV proton beam to evaluate the performance of CATCH. The total energy resolution for the recoil proton was 2.8 MeV in $\sigma$ for the entire angular region after the energy calibrations of the BGO calorimeter and the CFT. The angular resolution of the CFT was 1.27 degrees in $\sigma$ for the proton, and the time resolution was more than 1.8 ns in $\sigma$. We also developed an analysis method for deriving the cross section of the pp scattering using CATCH. The obtained relative differential cross section for the pp elastic scattering was consistent with that obtained by reliable partial wave analysis, and the systematic error was maintained at below 10%. These performance results satisfy our requirements for a reliable detection system for the $\Sigma$p scattering experiment conducted at J-PARC .
View
Show abstract
... The most important contribution of this method is the possibility to access experimentally systems with S ď´2, very challenging for scattering experiments. Although some constraints on the scattering parameters for ΛΛ have been obtained (with quite large uncertainties) [332], at the moment the data extracted from femtoscopy is used to compare Ref. [307] Ref. [308] Ref.
[313]
200 400 600 800 ...
Approaching nuclear interactions with lattice QCD
Preprint
Sep 2021
Marc Illa
Nuclei make up the majority of the visible matter in the Universe; obtaining a first principles description of the nuclear properties and interactions between nuclei directly from the underlying theory of the strong interaction, Quantum Chromodynamics (QCD), is one of the main goals of the nuclear physics community. Although the theory was established nearly fifty years ago, the complexities of QCD at low energies precludes analytical solutions of the simplest hadronic systems, let alone the features of the nuclear forces. In this thesis we follow the lattice QCD approach, according to which QCD is solved non-perturbatively in a discretized space-time via large-scale numerical calculations. Specifically, the interactions between two octet baryons, with strangeness ranging from 0 to -4, are studied at low energies with larger-than-physical quark masses, and the low-energy coefficients in pionless effective field thepry relevant for two-baryon interactions, including those responsible for SU(3) flavor-symmetry breaking, are constrained.
... Ground-state SUð3Þ octet hyperons (Λ, Σ þ;− , Ξ 0;− ) and their antiparticles have relatively long lifetimes (with a typical cτ of a few centimeters) and are essential for investigating several important physics questions, including hyperon-nucleon interaction and and the possible role of hyperons in neutron stars [5][6][7]. The relevant experimental studies started in the 1960s and have lasted for more than half a century [8][9][10][11]
[12]
[13][14][15][16][17], using π AE or K AE beams shot into bubble chambers or scintillating fiber (SciFi) targets. The statistics of these experiments are low, with typically a few tens to a few hundreds of observed events. ...
Cornucopia of Antineutrons and Hyperons from a Super J / ψ Factory for Next-Generation Nuclear and Particle Physics High-Precision Experiments
Article
Full-text available
Jun 2021
Chang-Zheng Yuan
Marek Karliner
In order to study the interactions and structure of various types of matter, one typically needs to carry out scattering experiments utilizing many different particles as projectiles. Whereas beams of e±, μ±, π±, K±, protons, antiprotons, and various heavy ions have been produced and have enabled many scientific breakthroughs, beams of antineutrons, hyperons (Λ, Σ, and Ξ) and their antiparticles are typically not easy to obtain. Here we point out and investigate a new high-quality source of these particles: a super-J/ψ factory with the capability of accumulating trillions of J/ψ decays each year. In the relevant J/ψ decays, the desired particle is produced together with other final-state particles that can be tagged. This allows accurate determination of the flux and momentum of the projectile, enabling unprecedented precision in the study of the corresponding interactions with a broad range of targets. These novel high-statistics sources of baryons and antibaryons with precisely known kinematics open fresh opportunities for applications in particle and nuclear physics, including antinucleon-nucleon interaction, a nonvalence ss¯ component of the nucleon, (anti)hyperon-nucleon interaction, OZI violation, (multistrange) hypernuclei, exotic light hadron spectroscopy, and many others, as well as calibration of Monte Carlo simulation for hadronic and medical physics.
... The measured scattering cross sections are characterised by large uncertainties and limited to hyperon momenta above p lab ∼100 MeV/c. In the region where the Σ + n and Σ 0 p channels open, which occurs around p lab ≈ 638 MeV/c, the momentum resolution of the existing data is very poor
[12,
13]. Thus it remains unclear whether there is any threshold structure in the pΛ cross section due to the coupling to the NΣ system. ...
Exploring the N$\Lambda$-N$\Sigma$ coupled system with high precision correlation techniques at the LHC
Preprint
Full-text available
Apr 2021
ALICE Collaboration
The interaction of $\Lambda$ and $\Sigma$ hyperons (Y) with nucleons (N) is strongly influenced by the coupled-channel dynamics. Due to the small mass difference of the $\rm N \Lambda$ and $\rm N \Sigma$ systems, the coupling strength of the $\rm N \Sigma\leftrightarrow N \Lambda$ processes is non-negligible and constitutes a crucial element in the determination of the N$\Lambda$ interaction. In this letter we present the most precise measurements on the interaction of p$\Lambda$ pairs, from zero relative momentum up to the opening of the $\rm N \Sigma$ channel. The correlation function in the relative momentum space for $\mathrm{p}\Lambda\oplus\overline{\mathrm{p}}\overline{\Lambda}$ pairs measured in high-multiplicity triggered pp collisions at $\sqrt{s}~=~13$ TeV at the LHC is reported. The opening of the inelastic N$\Sigma$ channels is visible in the extracted correlation function as a cusp-like structure occurring at relative momentum $k^{*}$ = 289 MeV/$c$. This represents the first direct experimental observation of the $\rm N \Sigma\rightarrow N \Lambda$ coupled channel in the p$\Lambda$ system. The correlation function is compared with recent chiral effective field theory calculations, based on different strengths of the $\rm N \Sigma\leftrightarrow N \Lambda$ transition potential. A weaker coupling, as possibly supported by the present measurement, would require a more repulsive three-body NN$\Lambda$ interaction for a proper description of the $\Lambda$ in-medium properties, which has implications on the nuclear equation of state and for the presence of hyperons inside neutron stars.
... In the 3 D 1 channel, both the N N and Λ c N interactions are weakly repulsive, while the ΛN interaction is quite small up to E c.m. ∼ 50 MeV, and then increases quickly, corresponding to the opening of the ΣN channel. Such a phenomenon has been observed in the experimental data
[43,
44] and our previous studies [29,41] that a cusp appears in the Λp → Λp cross section at the opening of the Σ + n channel. On the other hand, the N N and ΛN mixing angles are very similar up to E c.m. ∼ 50 MeV but the Λ c N mixing angle is negative and smaller in magnitude. ...
\Lambda_c N$ interaction in leading order covariant chiral effective field theory
Preprint
Oct 2020
Jing Song
Yang Xiao
Zhi-Wei Liu
Lisheng Geng
We study the $\Lambda_c N$ interaction in the covariant chiral effective field theory (ChEFT) at leading order. All the relevant low-energy constants are determined by fitting to the lattice QCD simulations from the HAL QCD Collaboration. Extrapolating the results to the physical point, we show that the $\Lambda_c N$ interaction is weakly attractive in the $^1S_0$ channel, but in the $^3S_1$ channel, it is only attractive at extremely low energies and soon turns repulsive for larger laboratory energy. Furthermore, we show that the neglect of the $^3S_1-{}^3D_1$ coupling provided by the leading order covariant ChEFT would result in an attractive interaction in the $^3S_1$ channel at the physical point, which coincides with the previous non-relatistic ChEFT study. As a byproduct, we predict the $^3D_1$ phase shifts and the mixing angel $\varepsilon_1$, which can be checked by future lattice QCD simulations. In addition, we compare the $\Lambda_c N$ interaction with the $\Lambda N$ and $NN$ interactions to study how the baryon-nucleon ($BN$) interactions evolve as a function of the baryon mass with the replacement of a light quark by a strange or charm quark in the baryon ($B$).
View
Show abstract
... Contrary to the nucleon-nucleon (N N ) interaction, the forces between strange baryons (Λ, Σ, Ξ) and nucleons are still poorly understood, not least because of the limited number and accuracy of available scattering data [1][2][3]
[4]
. At least with regard to the ΛN interaction the main features are roughly known due to the aforementioned scattering data but also from measurements and studies of hypernuclei [5,6]. ...
Exploring the $\Lambda$-deuteron interaction via correlations in heavy-ion collisions
Preprint
\Lambda$-deuteron two-particle momentum correlation functions, to be measured in high-energy heavy-ion collisions, are investigated. In particular, the question is addressed whether such correlations can serve as an additional and alternative source of information on the elementary $\Lambda N$ interaction. The study is performed within the Lednicky-Lyuboshits formalism, utilizing an effective range expansion for the two relevant $S$-wave $\Lambda d$ amplitudes with parameters taken from the literature. It is found that in collisions characterized by a large emitting source the $\Lambda d$ correlation function is predominatly sensitive to the quartet state ($^4S_{3/2}$). In contrast, for small source sizes the contribution from the doublet partial wave ($^2S_{1/2}$) could be significant. Though the latter is constrained by the hypertriton binding energy, its present experimental uncertainty impedes an accurate determination of the doublet amplitude and, in turn, complicates conclusions on the quartet state.
... The interactions of baryons are well known for pp pairs and pn pairs. Measurements were also performed for p pairs [23][24]
[25]
. Recently, a comparative study of the baryon-baryon and antibaryon-antibaryon interaction using Au-Au collisions at E-mail address: alice -publications @cern .ch. √ s NN = 200 GeV has been performed by the STAR experiment at the Relativistic Heavy Ion Collider and found that the pp interaction does not differ from the pp system [26]. ...
Measurement of strange baryon–antibaryon interactions with femtoscopic correlations
Article
Full-text available
PHYS LETT B
Susmita Acharya
Dagmar Adamova
S. P. Adhya
N. Zurlo
Two-particle correlation functions were measured for pp‾, pΛ‾, p‾Λ, and ΛΛ‾ pairs in Pb–Pb collisions at sNN=2.76 TeV and sNN=5.02 TeV recorded by the ALICE detector. From a simultaneous fit to all obtained correlation functions, real and imaginary components of the scattering lengths, as well as the effective ranges, were extracted for combined pΛ‾ and p‾Λ pairs and, for the first time, for ΛΛ‾ pairs. Effective averaged scattering parameters for heavier baryon–antibaryon pairs, not measured directly, are also provided. The results reveal similarly strong interaction between measured baryon–antibaryon pairs, suggesting that they all annihilate in the same manner at the same pair relative momentum k⁎. Moreover, the reported significant non-zero imaginary part and negative real part of the scattering length provide motivation for future baryon–antibaryon bound state searches.
... One of the goals of hypernuclear physics [1][2][3] is to relate hypernuclei observables with the underlying bare hyperonnucleon (Y N ) and hyperon-hyperon (Y Y ) interactions which, contrary to that between two nucleons (N N ), are still poorly known due to the limited number and accuracy of scattering data [4][5][6]
[7]
. Hypernuclei, therefore, constitute a valuable and complementary source of information to constrain better these interactions. ...
Structure of single-$\Lambda$ hypernuclei with chiral hyperon-nucleon potentials
Preprint
J. Haidenbauer
I. Vidaña
The structure of single-$\Lambda$ hypernuclei is studied using the chiral hyperon-nucleon potentials derived at leading order (LO) and next-to-leading order (NLO) by the J\"{u}lich--Bonn--Munich group. Results for the separation energies of $\Lambda$ single-particle states for various hypernuclei from $^5_{\Lambda}$He to $^{209}_{\,\,\,\,\,\Lambda}$Pb are presented for the LO interaction and the 2013 (NLO13) and 2019 (NLO19) versions of the NLO potentials. It is found that the results based on the LO potential show a clear tendency for overbinding while those for the NLO13 interaction underbind most of the considered hypernuclei. A qualitatively good agreement with the data is obtained for the NLO19 interaction over a fairly large range of mass number values when considering the uncertainty due to the regulator dependence. A small spin-orbit splitting of the $p$-, $d$-, $f$-, and $g$-wave states is predicted by all interactions, in line with the rather small values observed in pertinent experiments.
... Since the Λ(1520)-nucleon elastic cross section is expected to be small similar to the ΛN elastic cross section at these momenta
[22]
, we will neglect quasielastic Λ(1520)N rescatterings in the present study. Then, accounting for the absorption of the incident pion and Λ(1520) hyperon in nuclear matter as well as using the results given in [21], we represent the inclusive differential cross section for the production of Λ(1520) hyperons with vacuum momentum p Λ(1520) (or p Λ * ) on nuclei in the direct process (1) as follows: ...
Pion-induced production of $\Lambda(1520)$ hyperons on nuclei near threshold
Preprint
Full-text available
Oct 2019
E. Ya. Paryev
Yu. T. Kiselev
We study the pion-induced inclusive $\Lambda(1520)$ hyperon production from nuclei near threshold within a nuclear spectral function approach accounting for incoherent primary $\pi^-$ meson--proton ${\pi^-}p \to K^0\Lambda(1520)$ production processes. We calculate the absolute differential and total cross sections for the production of $\Lambda(1520)$ hyperons off carbon and tungsten nuclei at laboratory angles of 0$^{\circ}$--10$^{\circ}$, 10$^{\circ}$--45$^{\circ}$ and 45$^{\circ}$--85$^{\circ}$ by $\pi^-$ mesons with momentum of 1.7 GeV/c as well as their relative (transparency ratio) differential and integral yields from these nuclei within four scenarios for their total in-medium width. We demonstrate that these absolute observables, contrary to the relative ones, reveal some sensitivity to the $\Lambda(1520)$ in-medium width. Therefore, their measurement in a dedicated experiment at the GSI pion beam facility will allow to shed light on this width.
... The present world data sample for the process Λp → Λp consists of thirteen publications. [8,9,10,11,12,13,14,15,16,17,
18,
19,20] Table 1 summarizes the existing world data set for this process. There have been a total [9] π − p → ΛK 0 LH 2 BC 0.4-1.0 14 Groves [10] K − N → Λπ Propane BC 0.3-1.5 26 Beillière et al. [11] K − N → Λπ Freon BC 0.5-1.2 ...
Λp elastic scattering in the CLAS detector
Article
J.W. Price
for the CLAS Collaboration
The elastic scattering process Λp → Λp offers insights on multiple problems in nuclear physics. SU(3)F symmetry implies a close agreement between the Λp and pp scattering cross sections. The Λp elastic scattering cross section can also illuminate the structure of neutron stars. A data-mining project was started using multiple CLAS data sets taken for other purposes with photon beams on a long liquid hydrogen target. A Λ produced in a process such as γp → K⁺ Λ can interact with a second proton inside the target before either decaying or leaving the target. The good angular acceptance and momentum resolution of CLAS make it well-suited for this type of analysis, even though it was not designed for such a measurement. The scattered Λ can be identified from the π⁻p invariant mass. The four-vector of the initial Λ is then reconstructed in the process Xp → Λp, which shows a strong peak at the Λ mass with roughly twice the number of events as the existing world data sample. This observation opens up the possibility of other measurements using secondary beams of short-lived particles. This paper will discuss the current status of the analysis, and our plans for future work on this project.
... The interactions of baryons are well known for pp pairs, for pn pairs, as well as for the lightest baryonanti-baryon system, pp [22][23][24][25][26]. Measurements were also performed for pΛ pairs [27][28]
[29]
. The STAR Collaboration has recently performed a comparative study of the baryon-baryon and anti-baryon-antibaryon interaction in Au-Au collisions at √ s NN = 200 GeV and found that the pp interaction does not differ from the pp system [30]. ...
Measurement of $\rm p\overline{\Lambda}\oplus\overline{p}\Lambda$ and $\Lambda\overline{\Lambda}$ interactions with femtoscopic correlations in Pb$-$Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV and $\sqrt{s_{\rm NN}} = 5.02$ TeV
Preprint
Full-text available
Mar 2019
ALICE Collaboration
Femtoscopic correlation functions were measured for $\rm p\overline{p}$, $\rm p\overline{\Lambda}\oplus\overline{p}\Lambda$, and $\Lambda\overline{\Lambda}$ pairs, as a function of collision centrality, in Pb$-$Pb collisions at $\sqrt{s_{\rm NN}}=2.76$ TeV and $\sqrt{s_{\rm NN}}=5.02$ TeV recorded by the ALICE experiment at the LHC. A simultaneous fit to all obtained correlation functions was performed, maximising the precision and sensitivity to the strong interaction parameters for the selected baryon pairs. Real and imaginary components of the scattering lengths, as well as the effective ranges, were extracted for combined $\rm p\overline{\Lambda}\oplus\overline{p}\Lambda$ pairs and, for the first time, for $\Lambda\overline{\Lambda}$ pairs. Effective averaged scattering parameters for heavier baryon$-$anti-baryon pairs, not measured directly, are also provided. The results reveal similarly strong interaction between measured baryon$-$anti-baryon pairs, suggesting that they annihilate in the same manner as $\rm p\overline{p}$ at the same pair relative momentum $k^{*}$. Moreover, the reported significant non-zero imaginary part and negative real part of the scattering length open up a possibility for future baryon$-$anti-baryon bound state searches.
View
... However, the interaction involving baryons with strangeness is less understood. Data exist on Σ − p interaction for centerof-mass energy ( √ s) above 5 GeV and for pΛ interaction [5,
6,
7]. The existing experimental measurements are of limited quality. ...
Baryon-(anti-)baryon interaction cross-section measurement with femtoscopy technique in HIC
Conference Paper
Feb 2018
Adam Kisiel
... Nevertheless, contrary to the nucleon-nucleon (NN) interaction, which is fairly well known due to the large number of existing scattering data and measured properties of nuclei, YN and YY interactions are still poorly constrained. The experimental difficulties associated with the short lifetime of hyperons and the low-intensity beam fluxes have limited the number of ΛN and ΣN events to several hundred [4][5][6]
[7]
[8] and that of Ξ N to very few. In the case of the YY interaction, the situation is even worse because no scattering data exist at all. ...
Hyperons: the strange ingredients of the nuclear equation of state
Article
Full-text available
Sep 2018
Proc Math Phys Eng Sci
I. Vidaña
In this article we will review the role and properties of hyperons in finite and infinite nuclear systems. In particular, we will revise different production mechanisms of hypernuclei, as well as several aspects of hypernuclear $\gamma$-ray spectroscopy, and the weak decay modes of hypernuclei. Then we will discuss the construction of hyperon-nucleon and hyperon-hyperon interactions on the basis of the meson-exchange and chiral effective field theories. Recent developments based on the so-called V$_{low\,\, k}$ approach and lattice QCD will also be adressed. Finally, we will go over some of the effects of hyperons on the properties of neutron and proto-neutron stars with an emphasis on the so-called "hyperon puzzle", {\it i.e.,} the problem of the strong softening of the equation of state, and the consequent reduction of the maximum mass, induced by the presence of hyperons, a problem which has become more intringuing and difficult to solve due the recent measurements of $\sim 2M_\odot$ millisecond pulsars. We will discuss some of the solutions proposed to tackle this problem. We will also re-examine the role of hyperons on the cooling properties of newly born neutron stars and on the development of the so-called r-mode instability.
... This effect is related to the spin of the produced particles (1/2 versus 0). We hope for a confirmation of the slope of the invariant mass distribution, e.g., by the ATLAS or the ALICE collaboration. 2 The Λp total cross sections were measured in [38][39]
[40]
[41]. In [41] the average cross section was obtained σ tot (Λp) = 34.6 ± 0.4 mb in the hyperon momentum interval P lab = 6 − 21 GeV (which corresponds to √ s ∼ 4 − 6 GeV). ...
Central exclusive diffractive production of $p \bar{p}$ pairs in proton-proton collisions at high energies
Article
Full-text available
Jan 2018
P. Lebiedowicz
Otto Nachtmann
A. Szczurek
We consider the central exclusive production of the $p\bar{p}$ in the continuum and via resonances in proton-proton collisions at high energies. We discuss the diffractive mechanism calculated within the tensor-pomeron approach including both pomeron and reggeon exchanges. The theoretical results are compared with existing WA102 and ISR experimental data and predictions for planned or current experiments at RHIC and the LHC are presented. The distribution in ${\rm y}_{diff}$, the rapidity distance between proton and antiproton, is particularly interesting. We find a dip at ${\rm y}_{diff} = 0$ for the $p \bar{p}$ production, in contrast to the $\pi^{+}\pi^{-}$ and $K^{+}K^{-}$ production. We predict also the $p \bar{p}$ invariant mass distribution to be less steep than for the pseudoscalar dimeson pairs. We argue that these specific differences for the $p \bar{p}$ production with respect to the pseudoscalar meson pair production can be attributed to the proper treatment of the spin of produced particles. We discuss asymmetries which are due to interference of $C=+1$ and $C=-1$ amplitudes of $p \bar{p}$ production. We have also calculated the cross section for the $pp \to pp \Lambda \overline{\Lambda}$ reaction. Here, the cross section is smaller but the characteristic feature for $d\sigma/d{\rm y}_{diff}$ is predicted to be similar to $p \bar{p}$ production. The presence of resonances in the $p \bar p$ channel may destroy the dip at ${\rm y}_{diff} = 0$. This opens a possibility to study diffractively produced resonances. We discuss the observables suited for this purpose.
... Whereas the NN interaction is fairly well known due to the large number of existing scattering data, the Y N and Y Y ones are still poorly constrained. Experimental difficulties due to the short lifetime of hyperons and the low-intensity beam fluxes have limited the number of N and N scattering events to several hundred [57][58][59]
[60]
[61] and that of N events to very few. In the case of the Y Y interaction, the situation is even worse because no scattering data exist at all. ...
Hypernuclei and massive neutron stars
Article
Jun 2017
M. Fortin
Sidney Avancini
Constança Providência
I. Vidaña
Background: The recent accurate measurement of the mass of two pulsars close to or above 2M⊙ has raised the question of whether such large pulsar masses allow for the existence of exotic degrees of freedom, such as hyperons, inside neutron stars.
View
... It is then necessary to understand how well theory is able to account for experimental results, discriminating among different interaction models. The standard hyperon-nucleon (YN) database comprises 35 selected Λp low-energy scattering data and some ΛN and N data at higher energies
[5]
for a total of 52 YN scattering data. In comparison the Nijmegen NN scattering database [6] includes over 4300 NN data in the range 0-350 MeV. ...
Benchmark Results for Few-Body Hypernuclei
Article
Full-text available
Mar 2017
FEW-BODY SYST
F. Ferrari Ruffino
Nir Barnea
Sergio Deflorian
Francesco Pederiva
The Non-Symmetrized Hyperspherical Harmonics method (NSHH) is introduced in the hypernuclear sector and benchmarked with three different ab-initio methods, namely the Auxiliary Field Diffusion Monte Carlo method, the Faddeev-Yakubovsky approach and the Gaussian Expansion Method. Binding energies and hyperon separation energies of three- to five-body hypernuclei are calculated by employing the two-body $\Lambda$N component of the phenomenological Bodmer-Usmani potential, and a hyperon-nucleon interaction simulating the scattering phase shifts given by NSC97f. The range of applicability of the NSHH method is briefly discussed.
... Whereas the NN interaction is fairly well known due to the large number of existing scattering data, the YN and YY ones are still poorly constrained. Experimental difficulties due to the short lifetime of hyperons and the low intensity beam fluxes have limited the number of ΛN and ΣN scattering events to several hundreds [53][54][55]
[56]
[57], and that of ΞN events to very few. In the case of the YY interaction the situation is even worse because no scattering data exists at all. ...
(No) neutron star maximum mass constraint from hypernuclei
Article
Full-text available
Jan 2017
M. Fortin
Sidney Avancini
Constança Providência
I. Vidaña
(Abridged) The recent measurement of the mass of two $2\, M_\odot$ pulsars has raised the question whether such large masses allow for the existence of exotic degrees of freedom, such as hyperons, inside neutron stars. In the present work we will investigate how the existing hypernuclei properties may constrain the neutron star equation of state and confront the neutron star maximum masses obtained with equations of state calibrated to hypernuclei properties with the astrophysical $2\,M_\odot$ constraint. The study is performed using a relativistic mean field approach to describe both the hypernuclei and the neutron star equations of state. A set of five models consistent with $2\,M_\odot$ for a purely nucleonic composition are employed. The $\Lambda$-meson couplings are determined for all the models considered. Hyperonic stars with the complete baryonic octet are studied, restricting the coupling of the $\Sigma$ and $\Xi$ hyperons to the $\omega-$, $\rho-$ and $\sigma-$mesons due to the lack of experimental data, and maximum star masses calculated for unified equations of state. We conclude that the currently available hypernuclei experimental data and the lack of constraints on the asymmetric equation of state of nuclear matter at high densities do not allow to further constrain the neutron star matter equation of state using the recent $2\, M_\odot$ observations. It is also shown that the $\Lambda$ potential in symmetric nuclear matter takes a value $\sim 30-32$ MeV at saturation for the $g_{\omega \Lambda}$ coupling given by the SU(6) symmetry, close to values generally used in the literature. However, the $\Lambda$ potential in $\Lambda$ matter varies between -16 and -8 MeV taking for vector mesons couplings the SU(6) values, at variance with generally employed values between $-1$ and $-5$ MeV.
... On the contrary, the possible Σ * (1380) state with J P = 1/2 − is decaying to πΛ in relative S -wave, which will give enhancement at the near threshold. As one can see in Fig. 3, thanks to the contribution from Σ * (1380) state, we can reproduce the experimental data taken from Ref.
[15]
for all of the beam energies. Thus, we find a natural source for the near threshold enhancement of the Λp → Λpπ 0 reaction coming from the possible Σ * (1380) state which decays to πΛ in the S -wave. ...
Baryon Resonances in the Strangeness Production
Conference Paper
Full-text available
May 2016
Ju-Jun Xie
En Wang
Jia-Jun Wu
We have studied the $N^*(2120)$, $\Delta^*(1940)$, and the possible $\Sigma^*(1380)$ resonances in the $\gamma p \to K^+ \Lambda(1520)$, $pp \to n K^+ \Sigma(1385)$, and $\Lambda p \to \Lambda p \pi^0$ reactions within the resonance model and the effective Lagrangian approach. It is shown that when the contributions from these baryonic states were considered, the current experimental measurement could be well reproduced. In addition, we also demonstrate that the angular distributions provide direct information of these reactions, which could be useful for the investigation of those states and may be tested by future experiments.
... On the contrary, the possible Σ * (1380) state with J P = 1/2 − is decaying to πΛ in relative S -wave, which will give enhancement at the near threshold. As one can see in Fig. 3, thanks to the contribution from Σ * (1380) state, we can reproduce the experimental data taken from Ref.
[15]
for all of the beam energies. Thus, we find a natural source for the near threshold enhancement of the Λp → Λpπ 0 reaction coming from the possible Σ * (1380) state which decays to πΛ in the S -wave. ...
Baryon resonances in the strangeness production
We have studied the $N^*(2120)$, $\Delta^*(1940)$, and the possible
$\Sigma^*(1380)$ resonances in the $\gamma p \to K^+ \Lambda(1520)$, $pp \to n
K^+ \Sigma(1385)$, and $\Lambda p \to \Lambda p \pi^0$ reactions within the
resonance model and the effective Lagrangian approach. It is shown that when
the contributions from these baryonic states were considered, the current
experimental measurement could be well reproduced. In addition, we also
demonstrate that the angular distributions provide direct information of these
reactions, which could be useful for the investigation of those states and may
be tested by future experiments.
Exploring the NΛ–NΣ coupled system with high precision correlation techniques at the LHC
The interaction of Λ and Σ hyperons (Y) with nucleons (N) is strongly influenced by the coupled-channel dynamics. Due to the small mass difference of the NΛ and NΣ systems, the sizable coupling strength of the NΣ↔NΛ processes constitutes a crucial element in the determination of the NΛ interaction. In this letter we present the most precise measurements on the interaction of pΛ pairs, from zero relative momentum up to the opening of the NΣ channel. The correlation function in the relative momentum space for pΛ⊕p‾Λ‾ pairs measured in high-multiplicity triggered pp collisions at s=13 TeV at the LHC is reported. The opening of the inelastic NΣ channels is visible in the extracted correlation function as a cusp-like structure occurring at relative momentum k⁎=289MeV/c. This represents the first direct experimental observation of the NΣ↔NΛ coupled channel in the pΛ system. The correlation function is compared with recent chiral effective field theory calculations, based on different strengths of the NΣ↔NΛ transition potential. A weaker coupling, as possibly supported by the present measurement, would require a more repulsive three-body NNΛ interaction for a proper description of the Λ in-medium properties, which has implications on the nuclear equation of state and for the presence of hyperons inside neutron stars.
Test of the hyperon-nucleon interaction within leading order covariant chiral effective field theory
Motivated by the recent experimental measurements of differential cross sections of the Σ−p elastic scattering in the momentum range of 470 to 850MeV/c by the J-PARC E40 experiment, we extend our previous studies of S=−1 hyperon-nucleon interactions to relatively higher energies up to 900MeV/c for both the coupled-channel Λp→(Λp,Σ+n,Σ0p), Σ−p→(Λn,Σ0n,Σ−p) and single-channel Σ+p→Σ+p reactions. We show that although the leading order covariant chiral effective field theory is only constrained by the low energy data, it can describe the high energy data reasonably well, in particular, the J-PARC E40 differential cross sections. The predicted cusp structure close to the ΣN threshold in the Λp→Λp reaction agrees with the latest ALICE observation as well as with the results of the next-to-leading order heavy baryon chiral effective theory. On the other hand, the comparison with the latest CLAS data on the Λp cross sections between 0.9 and 2.0 GeV/c clearly indicates the need for higher order chiral potentials for such high momenta. This is also the case for the latest J-PARC data on the Σp→Λn differential cross sections. Nevertheless, even for these cases, the predictions are in qualitative agreement with the data, albeit with large uncertainties, implying that the predicted total and differential cross sections are of relevance for ongoing and planned experiments.
Precise Measurement of Differential Cross Sections of the Σ − p → Λ n Reaction in Momentum Range 470 – 650 MeV / c
The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470<p_{Σ}(MeV/c)<550 and 550<p_{Σ}(MeV/c)<650, respectively. These results show a drastic improvement compared with past measurements of the hyperon-proton scattering experiments. They will play essential roles in updating the theoretical models of the baryon-baryon interactions.
Development and application of CATCH: A cylindrical active tracker and calorimeter system for hyperon–proton scattering experiments
In this study, we developed a new proton detector system called CATCH, which was designed for a scattering experiment involving a Σ hyperon and a proton (J-PARC E40). CATCH is a cylindrical detector system covering an inner target that can be used to measure the trajectory and energy of a proton emitted from the target for the kinematic identification of a Σp scattering event. It comprises a cylindrical fiber tracker (CFT), a bismuth germanate (BGO) calorimeter, and a plastic scintillator hodoscope (PiID), which are coaxially arranged from the inner to the outer sides. The CFT is a tracking detector consisting of 5,000 scintillation fibers, and it has two types of cylindrical layers in which the fibers are arranged in straight and spiral configurations. 24 BGO crystals are placed around the CFT to measure the kinetic energy of the recoil proton. The PiID is used to determine whether the recoil proton is stopped in the BGO calorimeter . We performed proton– proton (pp) and proton–carbon (pC) scattering experiments using an 80 MeV proton beam to evaluate the performance of CATCH. The total energy resolution for the recoil proton was 2.8 MeV in σ for the entire angular region after the energy calibrations of the BGO calorimeter and the CFT. The angular resolution of the CFT was 1.27 degrees in σ for the proton, and the time resolution was more than 1.8 ns in σ. We also developed an analysis method for deriving the cross section of the pp scattering using CATCH. The obtained relative differential cross section for the pp elastic scattering was consistent with that obtained by reliable partial wave analysis, and the systematic error was maintained at below 10%. These performance results satisfy our requirements for a reliable detection system for the Σp scattering experiment conducted at J-PARC.
\Lambda -\alpha $$ Potential by Folding $$\Lambda $$-Nucleon Interaction with Realistic $$\alpha $$ Wave Function
We construct a folding potential between the \(\alpha \) and \(\Lambda \) particles based on underlying nucleon-nucleon and hyperon-nucleon interactions. Starting from a phenomenological \(\Lambda \)-N potential and a Gaussian form of the \(\alpha \)-particle wave function we obtain the \(\alpha \)-\(\Lambda \) potential and with this potential the binding energy of \(^5_\Lambda \)He is (3.10 MeV), which is consistent with recent experimental data \(3.12 \pm 0.02\) MeV. When in turn an exact solution of the four-body Faddeev-Yakubovsky equation for the \(\alpha \)-particle calculated with the CDBonn, Nijmegen or Argonne V18 realistic nucleon-nucleon potential is used and the phenomenological Gaussian \(\Lambda \)-N potential is replaced by the realistic (e.g. Nijmegen NSC97f) potential approximated by a rank-1 separable form, then \(^5_\Lambda \)He is overbound. In particular, its binding energy given by the folding potential generated with the \(\alpha \) particle wave function based on the CDBonn potential is 7.47 MeV. Although the rank-1 separable \(\Lambda \)-N potential reproduces the exact scattering length and the effective range of the original \(\Lambda \)-N potential, the \(\Lambda \)-\(\alpha \) folding potential results from these \(\Lambda \)-N potential give a large binding energy of \(^5_\Lambda \)He .
Measurement of the differential cross sections of the Σ−p elastic scattering in momentum range 470 to 850 MeV/c
A high statistics Σp scattering experiment is performed at the J-PARC Hadron Experimental Facility. Momentum-tagged Σ−s running in a liquid hydrogen target are accumulated by detecting the π−p→K+Σ− reaction with a high intensity π− beam of 20 M/spill. The differential cross sections of the Σ−p elastic scattering were derived with a drastically improved accuracy by identifying approximately 4500 events from 1.72×107Σ−. The derived differential cross section shows a clear forward-peaking angular distribution for a Σ− momentum range from 470 to 850 MeV/c. The accurate data will impose a strong constraint on the theoretical models of the baryon-baryon interactions.
On the structure in the $\Lambda N$ cross section at the $\Sigma N$ threshold
The complexity of threshold phenomena is exemplified on a prominent and long-known case - the structure in the cross section (invariant mass spectrum) at the opening of the channel. The mass splitting between the baryons together with the angular momentum coupling in the - partial wave imply that, in principle, up to six channels are involved. Utilizing hyperon-nucleon potentials that provide an excellent description of the available low-energy and scattering data, the shape of the resulting cross section is discussed and the poles near the threshold are determined. Evidence for a strangeness dibaryon is provided, in the form of a (unstable) bound state in the vicinity of the threshold. Predictions for level shifts and widths of atomic states are given.
Neutron stars and the nuclear equation of state
We review the current status and recent progress of microscopic many-body approaches and phenomenological models, which are employed to construct the equation of state of neutron stars. The equation of state is relevant for the description of their structure and dynamical properties, and it rules also the dynamics of core-collapse supernovae and binary neutron star mergers. We describe neutron star matter assuming that the main degrees of freedom are nucleons and hyperons, disregarding the appearance of quark matter. We compare the theoretical predictions of the different equation-of-state models with the currently available data coming from both terrestrial laboratory experiments and recent astrophysical observations. We also analyse the importance of the nuclear strong interaction and equation of state for the cooling properties of neutron stars. We discuss the main open challenges in the description of the equation of state, mainly focusing on the limits of the different many-body techniques, the so-called “hyperon puzzle,” and the dependence of the direct URCA processes on the equation of state.
Λ c N interaction in leading-order covariant chiral effective field theory
Dec 2020
Li-Sheng Geng
Jing Song
Yang Xiao
Zhi-Wei Liu
We study the ΛcN interaction in the covariant chiral effective field theory (ChEFT) at leading order. All the relevant low-energy constants are determined by fitting to the lattice QCD simulations from the HAL QCD Collaboration. Extrapolating the results to the physical point, we show that the ΛcN interaction is weakly attractive in the S01 channel, but in the S13 channel it is only attractive at extremely low energies and soon turns repulsive for larger laboratory energy. Furthermore, we show that the neglect of the S13−D13 coupling provided by the leading-order covariant ChEFT would result in an attractive interaction in the S13 channel at the physical point, which coincides with the previous nonrelativistic ChEFT study. As a byproduct, we predict the D13 phase shifts and the mixing angel ɛ1, which can be checked by future lattice QCD simulations. In addition, we compare the ΛcN interaction with the ΛN and NN interactions to study how the baryon-nucleon (BN) interactions evolve as a function of the baryon mass with the replacement of a light quark by a strange or charm quark in the baryon (B).
Exploring the Λ -deuteron interaction via correlations in heavy-ion collisions
J. Haidenbauer
Λ-deuteron two-particle momentum correlation functions, to be measured in high-energy heavy-ion collisions, are investigated. In particular, the question is addressed whether such correlations can serve as an additional and alternative source of information on the elementary ΛN interaction. The study is performed within the Lednicky-Lyuboshits formalism, utilizing an effective range expansion for the two relevant S-wave Λd amplitudes with parameters taken from the literature. It is found that in collisions characterized by a large emitting source the Λd correlation function is predominantly sensitive to the quartet state (S3/24). In contrast, for small source sizes the contribution from the doublet partial wave (S1/22) could be significant. Though the latter is constrained by the hypertriton binding energy, its present experimental uncertainty impedes an accurate determination of the doublet amplitude and, in turn, complicates conclusions on the quartet state.
Hadron physics at J-PARC
Mar 2020
PROG PART NUCL PHYS
H. Ohnishi
F. Sakuma
T. Takahashi
The aim of the hadron physics research programs conducted at J-PARC is to explore the structure of hadronic matter using the world’s highest-intensity meson beams. Since the first beam was extracted at the hadron experimental facility (HEF) in February 2009, a wide variety of physics experiments have been proposed and performed to address open questions regarding quantum chromodynamics (QCD) at low energy. The high-intensity K− and high-momentum beams available at J-PARC open a new era in hadron and nuclear physics, in which strange and charm quarks play an important role. We review the programs focused on addressing the hadron structure as strongly interacting composite particles, the origin of hadron mass, and interactions between hadrons under broken flavor SU(3) symmetry.
Structure of single-$$\varLambda $$Λ hypernuclei with chiral hyperon–nucleon potentials
The structure of single-\(\varLambda \) hypernuclei is studied using the chiral hyperon-nucleon potentials derived at leading order (LO) and next-to-leading order (NLO) by the Jülich–Bonn–Munich group. Results for the separation energies of \(\varLambda \) single-particle states for various hypernuclei from \(^5_{\varLambda }\hbox {He}\) to \(^{209}_{\,\,\,\,\,\varLambda }\hbox {Pb}\) are presented for the LO interaction and the 2013 (NLO13) and 2019 (NLO19) versions of the NLO potentials. It is found that the results based on the LO potential show a clear tendency for overbinding while those for the NLO13 interaction underbind most of the considered hypernuclei. A qualitatively good agreement with the data is obtained for the NLO19 interaction over a fairly large range of mass number values when considering the uncertainty due to the regulator dependence. A small spin-orbit splitting of the p-, d-, f-, and g-wave states is predicted by all interactions, in line with the rather small values observed in pertinent experiments.
Pion-induced production of Λ(1520) hyperons on nuclei near threshold
NUCL PHYS A
We study the pion-induced inclusive Λ(1520) hyperon production from nuclei near threshold within a nuclear spectral function approach accounting for incoherent primary π− meson–proton π−p→K0Λ(1520) production processes. We calculate the absolute differential and total cross sections for the production of Λ(1520) hyperons off carbon and tungsten nuclei at laboratory angles of 0∘–10∘, 10∘–45∘ and 45∘–85∘ by π− mesons with momentum of 1.7 GeV/c as well as their relative (transparency ratio) differential and integral yields from these nuclei within four scenarios for their total in-medium width. We demonstrate that these absolute observables, contrary to the relative ones, reveal some sensitivity to the Λ(1520) in-medium width. Therefore, their measurement in a dedicated experiment at the GSI pion beam facility will allow to shed light on this width.
Extended-soft-core baryon-baryon model ESC16. II. Hyperon-nucleon interactions
Article
Apr 2019
M. M. Nagels
Th. A. Rijken
Y. Yamamoto
Background: The Nijmegen extended-soft-core (ESC) models describe the nucleon-nucleon (NN), hyperon-nucleon (YN), and the S=−2 hyperon-hyperon/nucleon (YY/ΞN) interactions in a unified way using broken SU(3) symmetry. The potentials consist of local and nonlocal potentials due to (i) one-boson exchanges (OBE), which are the members of nonets of pseudoscalar, vector, scalar, and axial-vector mesons, (ii) two pseudoscalar exchange (TPS), (iii) meson-pair exchange (MPE), and (iv) diffractive exchanges. Both the OBE and pair vertices are regulated by Gaussian form factors producing potentials with a soft behavior near the origin. Broken SU(3) symmetry serves to connect the NN, YN, and YY channels. In particular, the meson-baryon coupling constants are calculated via SU(3) using the coupling constants of the NN analysis as input. The assignment of the cutoff masses for the baryon-baryon-meson (BBM) vertices is dependent on the SU(3) classification of the exchanged mesons for OBE and a similar scheme for MPE.
Recent development in theoretical studies of hyperon-nucleon interaction
Jan 2018
Li Kaiwen
Ren Xiulei
Lisheng Geng
Long Bingwei
VII.2 Cross section data
Chapter
Jan 1988
A. Baldini
Flaminio Vincenzo
W. G. Moorhead
D. R. O. Morrison
Summary This document is part of Subvolume B of Volume 12 ‘Total Cross-Sections for Reactions of High Energy Particles’ of Landolt-Börnstein - Group I Elementary Particles, Nuclei and Atoms.
View
Leading order covariant hyperon-nucleon interactions in chiral effective field theory
CHINESE PHYS C
Bing-Wei Long
Xiu-Lei Ren
Lisheng Geng
We apply a recently proposed covariant power counting to study strangeness $S=-1$ $\Lambda N-\Sigma N$ interactions in chiral effective field theory. At leading order, Lorentz invariance introduces 12 low energy constants in contrast to the Weinberg counting based on na\"ive dimensional analysis, where only five appear. The Kadyshevsky equation is adopted to resum the potential in order to account for the non-perturbative nature of hyperon-nucleon interactions. A fit to the $36$ hyperon-nucleon scattering data yields $\chi^2\simeq 17$ , which is comparable with the sophisticated phenomenological models and the next-to-leading order Weinberg approach. The results hint that a more efficient formulation of the hyperon-nucleon interaction can be achieved in covariant chiral effective field theory, in agreement with the results in the nucleon-nucleon sector using a similar framework.
Strangeness $S=-1$ hyperon-nucleon scattering at leading order in the covariant Weinberg's approach
Xiu-Lei Ren
Lisheng Geng
Inspired by the success of covariant baryon chiral perturbation theory in the one baryon sector and in the heavy-light systems, we explore the relevance of relativistic effects in the construction of the strangeness $S=-1$ hyperon-nucleon interaction using chiral perturbation theory. Due to the non-perturbative nature of the hyperon-nucleon interaction, we follow the covariant Weinberg's approach recently proposed by Epelbaum and Gegelia to sum the leading order chiral potential using the Kadyshevsky equation (Epelbaum, 2012) in this exploratory work. By fitting the five low-energy constants to available experimental data, we find that the cutoff dependence is mitigated compared with the results obtained in the Weinberg's approach for both partial wave phase shifts and the description of experimental data. Nevertheless, at leading order, the description of experimental data remains quantitatively similar. We discuss in detail the cutoff dependence of the partial wave phase shifts and cross sections in the Weinberg's approach and in the covariant Weinberg's approach.
Show abstract
Show more
| https://www.researchgate.net/publication/229284549_Lp_interactions_in_momentum_range_300_to_1500_MeVc |
Cypress canker disease in Italy: biology, control possibilities and genetic improvement for resistance
Download Citation | Cypress canker disease in Italy: biology, control possibilities and genetic improvement for resistance | The life cycle of Seiridium cardinale, the principal symptoms of the cypress canker disease, the results of chemical control, and the research... | Find, read and cite all the research you need on ResearchGate
Cypress canker disease in Italy: biology, control possibilities and genetic improvement for resistance
Forest Pathology 11(5‐6):340 - 347
DOI: 10.1111/j.1439-0329.1981.tb00104.x
Authors:
P. Raddi
A. Panconesi
Abstract
The life cycle of Seiridium cardinale, the principal symptoms of the cypress canker disease, the results of chemical control, and the research directed toward genetic improvement of Italian cypress for resistance to the canker are described.
... A genetic improvement program of C. sempervirens for resistance to CCD has been carried out in Europe since the 1970s
(Raddi and Panconesi, 1981;
Danti et al., 2011), due to this species' valuable role in the landscape and its multifunctionality, especially in Mediterranean countries (Xenopoulos et al., 1990;Della Rocca et al., 2007;Farahmand, 2020). As a result, a series of canker-resistant varieties of C. sempervirens have been patented (Panconesi and Raddi, 1990;Danti et al., 2006Danti et al., , 2013b. ...
Ultrastructure of Terpene and Polyphenol Synthesis in the Bark of Cupressus sempervirens After Seiridium cardinale Infection
Article
Full-text available
May 2022
DELLA ROCCA Gianni
Alessio Papini
Isabella Posarelli
Salvatore Moricca
Cypress Canker Disease (CCD) pandemic caused by Seiridium cardinale is the major constraint of many Cupressaceae worldwide. One of the main symptoms of the disease is the flow of resin from the cankered barks. While inducible phloem axial resin duct-like structures (PARDs) have recently been characterized from an anatomical point of view, their actual resin production is still being debated and has never been demonstrated. Although the involvement of polyphenolic parenchyma cells (PP cells) in the bark of Cupressus sempervirens after S. cardinale infection was revealed in one of our previous studies using light microscopy, their evolution from the phloem parenchyma cells is yet to be clarified. This study investigated functional and ultrastructural aspects of both PARD-like structures and PP cells by means of more in-depth light (LM) and fluorescence microscopy (FM) combined with histochemical staining (using Sudan red, Fluorol Yellow, NADI Aniline blue black, and Toluidine blue staining), in addition to Transmission Electron Microscope (TEM). Two-year-old stem sections of a C. sempervirens canker-resistant clone (var. “Bolgheri”), artificially inoculated with S. cardinale , were sampled 5, 7, 14, 21, and 45 days after inoculation, for time-course observations. FM observation using Fluorol yellow dye clearly showed the presence of lipid material in PARD-like structures lining cells of the cavity and during their secretion into the duct space/cavity. The same tissues were also positive for NADI staining, revealing the presence of terpenoids. The cytoplasm of the ducts' lining cells was also positive for Sudan red. TEM observation highlighted the involvement of plastids and endoplasmic reticulum in the production of terpenoids and the consequent secretion of terpenoids directly through the plasma membrane, without exhibiting vesicle formation. The presence of a high number of mitochondria around the area of terpenoid production suggests that this process is active and consumes ATP. The LM observations showed that PP cells originated from the phloem parenchyma cells (and possibly albuminous cells) through the accumulation of phenolic substances in the vacuole. Here, plastids were again involved in their production. Thus, the findings of this work suggest that the PARD-like structures can actually be considered PARDs or even bark traumatic resin ducts (BTRD).
... In the last 60 years, cultivation of cypress has been limited by cypress canker disease, a lethal disease caused by the introduced fungal pathogen Seiridum cardinale, which caused epidemics throughout the Mediterranean region resulting in significant economic and environmental losses (Danti and Della Rocca 2017;Graniti 1998). To overcome this constraint, a cypress genetic improvement programme has been conducted since the 1970s to select canker resistant varieties of cypress with different characteristics for multiple uses
(Raddi and Panconesi, 1981;
Santini and Di Lonardo, 2000;Danti et al. 2006Danti et al. , 2013. ...
Determination of extractive content in Cupressus sempervirens wood through a NIRS-PLSR model and its correlation with durability
Article
Aug 2021
INT BIODETER BIODEGR
Sabrina Palanti
Ana Alves
Jose Rodrigues
Roberto Danti
The objective of this study was the development of a NIRS (Near InfraRed Spectroscopy) and PLSR (Partial Least Square Regression) model for quantitatively determining extractives, in four clones of the Italian cypress Cupressus sempervirens. Extractives were correlated to the fungal resistance of wood samples evaluated with a non-standard procedure based on the mass loss of mini-blocks. PLSR regression models based on NIRS gave good predictions of extractives content with RPD (Residual Prediction Deviation) equal or above 2.7, suggesting that NIRS-PLSR procedure could be used for the characterization of cypress wood. Total extractives were significantly different among heartwood and sapwood but not among clones. Both inner and outer heartwood of the four C. sempervirens clones were resistant to three brown rot fungi. Minimal differences were found among clones in the mass loss of the heartwood samples, while significant inter-clonal differences emerged in the mass loss of sapwood samples. Intra-clonal variation was detected for sapwood samples and only in one of the four tested clones. The correlation between durability and extractives content was significant only if sapwood was added to heartwood in the dataset. Nevertheless, the high durability observed in the examined clones encourages selection of these cypress genotypes for wood production.
... sempervirens) was enforced recently by a serious disease outbreak (bark canker, caused by the fungus Seiridium cardinale) that has been threatening the plant species since the middle of the last century (Danti et al. 2013a). This work finally yielded canker-tolerant clones (Danti et al. 2013b;
Raddi and Panconesi 1981)
. Like other conifers, C. sempervirens is not an efficient species for micropropagation by axillary bud proliferation starting from adult material (Giovanelli and De Carlo 2007). ...
The endangered Saharan cypress (Cupressus dupreziana): do not let it get into Charon’s boat
Article
Full-text available
Feb 2020
PLANTA
Jana Lábusová
Hana Konradova
Helena Lipavská
Main conclusion
The current state-of-the-art creates a sound basis for the preservation of unique species Cupressus dupreziana provided that targeted effort and care is devoted to the accomplishment of multiplication protocols.
Abstract
This review is to summarize known data on Cupressus dupreziana-specific characteristics, including abiotic stress resistance, and natural reproduction, and estimates the possibilities of ex situ conservation with an emphasis on the cultivation in vitro of this endangered species. As there is only limited information about the cultivation of C. dupreziana in vitro, we have included relevant data on the related species Cupressus sempervirens, where micropropagation techniques are well established, along with other information on species with similar fates and life strategies—Saharan olive Olea europaea subsp. laperrinei and myrtle Myrthus nivellei. The aim of this work is to enhance general understanding and to promote an interest in this relict plant species to contribute to more wide-ranging studies and to increase its chance of preservation. Besides others, reducing the number of species threatened with extinction is an essential and immediate task as high genetic variability of ecosystems is crucial for their stability under changing climatic conditions.
... Many species causing tree canker, previously known as Coryneum were transferred to other genera e.g. Seiridium, Seimatosporium and Wilsonomyces (Sutton 1980
, Raddi and Panconesi 1981
, Marin-Felix et al. 2017. Recently, research has clarified the taxonomic position of the family Coryneaceae based on morphological and molecular data (Rossman et al., 2015;Senanayake et al., 2017;Wijayawardene et al., 2018). ...
Coryneum heveanum sp. Nov. (Coryneaceae, Diaporthales) on twigs of Para rubber in Thailand
Article
Full-text available
Dec 2018
Chanokned Senwanna
Kevin Hyde
Rungtiwa Phookamsak
Ratchadawan Cheewangkoon
During studies of microfungi on para rubber in Thailand, we collected a new Coryneum species on twigs which we introduce herein as C.heveanum with support from phylogenetic analyses of LSU, ITS and TEF1 sequence data and morphological characters. Coryneumheveanum is distinct from other known taxa by its conidial measurements, number of pseudosepta and lack of a hyaline tip to the apical cell.
View
... Additionally, in terms of the response of Monterey cypress to S. cardinale infections, artificial inoculation campaigns conducted in Italy and France also revealed a substantial lack of intraspecific variability in the resistance response to the pathogen. All young stems were completely girdled by the induced cankers, and trees were not able to survive the inoculation (16,30,
31)
. ...
The Epidemic Spread of Seiridium cardinale on Leyland Cypress Severely Limits Its Use in the Mediterranean
Article
Jan 2015
PLANT DIS
DELLA ROCCA Gianni
Sara Barberini
Roberto Danti
Pecchioli Annalisa
Leyland cypress (× Hesperotropsis leylandii) is a fast-growing conifer used in most temperate regions as an ornamental tree for hedges and screens, and is one of the most commercially important trees in Europe. In recent years, severe diebacks and mortality due to cypress canker have been observed on Leyland cypress plantations in Southern Europe. This study was conducted to evaluate (i) the spread and impact of cypress canker caused by Seiridium cardinale in plantations of a sample area of 1,250 km2 in central Italy, (ii) the response of the most commonly grown Leyland cypress varieties to artificial inoculation with to S. cardinal, and (iii) the pathogenicity of S. cardinale isolates obtained from Leyland cypress. Of the 1,411 surveyed trees, 11.4% had been killed by cypress canker and 43.9% of the living trees were affected by the disease. The number of diseased or dead trees and the percentage of cankered trunks was significantly correlated with the mean trunk diameter of the plantations. Six months after inoculation, the size of developed cankers was significantly different among the inoculated Leyland cypress cultivars but all of them showed markedly larger cankers than the C. sempervirens canker-resistant control clone. All of the tested S. cardinale isolates obtained from Leyland cypress also caused cankers on Cupressus sempervirens when inoculated as conidial suspensions or mycelia. Leyland cypress is highly prone to contract cypress canker in the Mediterranean due to its high susceptibility to S. cardinale infections, low genetic variability among the grown cultivars, and cracks which form on fast-growing trunks, favoring entry of the fungus into the inner bark and the occurrence of infections.
... Melanisation has important roles in both pathology and ecology of fungal pathogens (Bell and Wheeler, 1986;Butler et al., 2001). These findings are in agreement with the appearance of resting mycelium often found in dead cypress wood (raddi and
Panconesi, 1981
), which along with chlamydospores, presumably aids in fungal survival and longevity under unfavourable conditions. Along with abundance of lipid-rich organelles (a form of stored chemical energy), all the observed histochemical modifications are part of known adaptation mechanisms for microorganisms when shifts in either osmotic or water potential occur as response to many different stressors (Gharieb and Gadd, 2004;Gangwar et al., 2006;Magan, 2007). ...
In vitro ecology of Seiridium cardinale and allied species: The effect of solute stress and water potential on fungal growth
Article
Full-text available
May 2011
Elena Turco
Bruno Mori
Paolo Raddi
Defining the potential implications of global climate change on Mediterranean forest ecosystems requires a basic knowledge on the ecology of fungal pathogens under conditions that would stress host plants. The Mediterranean cypress (Cupressus sempervirens)-Seiridium spp. pathosystem represents an important case study. In the last century, epidemics of cypress canker have killed historical plantations and the decades-long host resistance will probably break down in the future as a result of both host and pathogen adaptation to increasing temperature and decreasing summer precipitation. In this study, the effect of osmotic water stress on mycelial growth of Seiridium cardinale, S. unicorne and S. cupressi in culture was examined and compared to that of Diplodia cupressi, which is a pathogen of cypress known to be favoured by host water stress. Growth responses were evaluated on potato sucrose agar amended with KCl or NaCl to give water potentials in the range of -0.34 to -15 MPa. Mycelial growth decreased with decreasing water potential and ceased at -15 MPa, although the mycelium remained alive. Histochemical analysis conducted on S. cardinale grown at -12 MPa revealed melanization and thickening of hyphal walls, in addition to abundance of lipid-rich organelles. These results suggest that the three Seiridium spp. might survive drying cycles in cypress wood, but their tolerance is different. Successful survival strategies may partly result from changes in mycelium structure. Furthermore, S. unicorne was positively stimulated by a water potential of -3 MPa, suggesting that it may have high adaptive potential for life in a drier Mediterranean ecosystem, which is predicted to occur under scenarios of global warming.
... Although intraspecific variation in the response of B. coccinea to C. melanocraspeda was mainly skewed to highly susceptible trees, there would be the potential for the conservation of diversity through single-tree selection for resistance and breeding. Intraspecific resistance has been identified and deployed in a range of canker-host interactions, including: Seiridium-cypress
(Raddi and Panconesi 1981)
; Cryphonectria-chestnut (Kubisiak et al. 1997); Sirococcusbutternut (Michler et al. 2005) and Chrysoporthe-eucalypt (da Silva Guimarães et al. 2010). Of the Banksia spp. ...
Genetic, morphological and pathogenic diversity in the canker pathogen Cryptodiaporthe melanocraspeda on Banksia
Article
Full-text available
May 2015
AUSTRALAS PLANT PATH
Bryan Leslie Shearer
Colin Crane
Diversity within and between Cryptodiaporthe melanocraspeda populations on Banksia spp. and variation in susceptibility within B. coccinea that resulted from pathogen-induced selection, was investigated. Genetic distances between C. melanocraspeda isolate populations were much less than those between Cryptodiaporthe spp. Spore size and rates of lesion extension of isolate populations of C. melanocraspeda formed continua that reflected intraspecific variation within a species. There were two isozyme groups amongst the populations of C. melanocraspeda from different Banksia hosts. Populations of C. melanocraspeda from the five geographic clusters could be divided into three geographic isozyme groups. Pycnidiospore size of populations of C. melanocraspeda isolates from different Banksia hosts formed a continuum from relatively short-thin spores for isolates from B. sessilis and relatively long-wide spores for isolates from B. baxteri. The rate of lesion extension formed a continuum, with ranking of isolates from slowest to fastest rates differing on the four hosts inoculated. Isolate populations varied in their pattern of adaptation to local Banksia host populations. Although intraspecific variation in the response of B. coccinea to C. melanocraspeda was mainly skewed to highly susceptible trees, there would be the potential for the conservation of diversity through single-tree selection for resistance and breeding.
... Additionally, in terms of the response of Monterey cypress to S. cardinale infections, artificial inoculation campaigns conducted in Italy and France also revealed a substantial lack of intraspecific variability in the resistance response to the pathogen. All young stems were completely girdled by the induced cankers, and trees were not able to survive the inoculation (16,30,
31)
. ...
The epidemic spread of Seiridium cardinale canker on Leyland cypress strongly limits its use in the Mediterranean area.
Article
Full-text available
Aug 2014
PLANT DIS
Roberto Danti
Sara Barberini
A. Pecchioli
DELLA ROCCA Gianni
Leyland cypress (x Hesperotropsis leylandii) is a fast-growing conifer used in most temperate regions as an ornamental tree for hedges and screens, and is one of the most commercially important trees in Europe. In recent years severe diebacks and mortality due to cypress canker have been observed on Leyland cypress plantations in Southern Europe. This study was conducted to evaluate: i) the spread and impact of cypress canker caused by S. cardinale in plantations of a sample area of 1250 km2 in central Italy; ii) the response of the most commonly-grown Leyland cypress varieties to artificial inoculation with to S. cardinale; iii) the pathogenicity of S. cardinale isolates obtained from Leyland cypress. Of the 1411 surveyed trees 11.4% had been killed by cypress canker and 43.9% of the living trees were affected by the disease. The number of diseased or dead trees and the percentage of cankered trunks was significantly correlated with the mean trunk diameter of the plantations. Six months after inoculation the size of developed cankers was significantly different among the inoculated Leyland cypress cultivars, but all of them showed markedly larger cankers than the C. sempervirens canker-resistant control clone (P < 0.01). All of the tested S. cardinale isolates obtained from Leyland cypress also caused cankers on Cupressus sempervirens when inoculated as conidial suspensions or mycelia. Leyland cypress is highly prone to contract cypress canker in the Mediterranean due to its high susceptibility to S. cardinale infections, low genetic variability among the grown cultivars and cracks which form on fast-growing trunks favoring entry of the fungus into the inner bark and the occurrence of infections.
... (i) a group of exotic forest pathogens (Phytophthora spp., with particular focus on P. ramorum in California; Rizzo et al. 2005), (ii) a native pathogen on an exotic host (Seiridium cardinale on Monterey cypress planted outside its distributional range in California;
Raddi and Panconesi 1981;
Smith 2010), (iii) an exotic pathogen-native host combination that has the potential to become an exotic pathogenexotic host combination in other parts of the world (Fusarium circinatum on Pinus radiata in California; Wingfield et al. 2008), and (iv) a case of an exotic pathogen (Heterobasidion irregulare) interacting with a closely related native pathogen (H. annosum) in Italy (Asiegbu et al. 2005;Garbelotto et al. 2010). ...
Impacts of exotic forest pathogens on Mediterranean ecosystems: Four case studies
Article
May 2012
M. Garbelotto
Marco Pautasso
Mediterranean ecosystems are hotspots of biodiversity. Because of a coincidence of high species richness and human presence,
Mediterranean biodiversity is particularly threatened by processes such as habitat degradation, fragmentation and loss, pollution,
climate change and introduction of invasive species. Invasive tree pathogens are among the problematic exotic species of California,
Chile, the Mediterranean, South Africa and Australia. In this review, we provide an update on a selection of non-native tree
pathogens currently posing a threat in Mediterranean ecosystems. The impact of exotic forest pathogens range from large-scale
tree and shrub mortality in native ecosystems (Phytophthora ramorum on the West Coast of the USA) to disruption of plantations of exotic (e.g., Seiridium cardinale on planted Monterey cypress in California, Fusarium circinatum on Monterey pine worldwide) and native trees (introduction of the North American Heterobasidion irregulare in stone pine woodland in Italy). Genetic analyses are instrumental in improving our understanding and management of these
outbreaks. There is a need for more empirical data on how novel pathosystems are likely to develop under novel climates, as
well as interdisciplinary collaborations among forest pathologists, theoretical modellers and climatologists. The magnitude
of the observed effects of some exotic tree diseases makes it important to try and minimize the risk of the inadvertent movement
of plant pathogens when planning assisted migration activities to enable plant species to cope with rapid climate change.
KeywordsBiodiversity–Forest health–Geographical genetics–Global change–Host susceptibility–Landscape epidemiology–Multiple trade-offs–Sudden Oak Death–Transmission rates–Tree fungal pathogens
... In the last 20 years the spread of cypress cortical cancer, a dangerous disease caused by the parasite Seiridium cardinale (Wag.), has produced extensive damage and has given rise to a large-scale breeding program to select for cancer-tolerant clones
(Raddi and Panconesi 1981)
. Cutting prop- agation is an important tool in this program, for it allows a high replication rate of the improved genotypes while avoiding rootstock influence, typical of grafted plants. ...
Cutting propagation of common cypress (Cupressus sempervirens L.)
Article
Mar 1995
Maurizio Capuana
Maurizio Lambardi
Effects of genotype, collection date, auxin treatment, crown position and artificial chilling on rooting and subsequent vegetative growth of Cupressus sempervirens L. softwood cuttings taken from 13-year-old plants were evaluated. Three different clones (318, 296 and 22) previously selected for resistance to cypress cortical cancer caused by Seiridium cardinale were used. In all these clones, both the IBA treated and the untreated cuttings showed seasonal periodicity of rooting. Untreated cuttings rooted best when collected in April (up to 49% for the best clone, i.e. 296) and rooted very poorly in July and October. Auxin treatments appeared unable to overcome this periodicity, as the cuttings taken in July and October did not respond to IBA stimulation. However, in January and April, IBA treatments enhanced adventitious root formation of poorly rooting clones (318 and 22), as well as of clone 296, which performed best (89%) when cuttings were treated in April with 1.5% IBA. Cuttings of each clone collected in the lower third of the crown of the donor trees showed a significantly higher rooting percentage, when compared with those from the upper third. A 4-week post-severance chilling treatment (4C) significantly enhanced the rooting capacity of cuttings taken in January, while a longer chilling treatment (8 weeks) had a negative effect. The subsequent growth of the rooted cuttings was not affected by either the crown position of the severed cuttings, or the genotype.
... Since the 1970s, a serious disease, named the "cypress canker" and caused by the fungus Seiridium cardinale, started to spread over large Mediterranean areas and led to extensive damage in forests, nurseries and ornamental plantations, the disease becoming a factor strongly limiting cypress planting. So devastating were the losses incurred that large-scale breeding programmes, founded by the European Union, were initiated in several Mediterranean countries, mainly Italy, Greece and France
(Raddi & Panconesi, 1981;
Xenopoulos, 1990;Teissier du Cros et al., 1991). As results of these efforts, canker-resistant clones have been recently patented (between the others, "Florentia", "Etruria", "Agrimed 1" and "Bolgheri"). ...
Micropropagation of Mediterranean cypress (Cupressus sempervirens L.)
Chapter
Jan 2007
A. Giovanelli
A. De Carlo
The “Mediterranean” or “common” cypress (Cupressus sempervirens L.) is a tall tree (up to 30 m in height), belonging to the genus Cupressus, Family Cupressaceae. The Genus includes as much as 25 species (Ducrey et al., 1999), largely diffused in the Mediterranean
basin, in Asia and in North America. Of them, the Mediterranean cypress is by far the most important and widespread species
in the Mediterranean area. It is native to Northern Persia, as well as Syria, Turkey, Cyprus and several Greek islands. However,
during the Roman Empire it was introduced into all the Mediterranean countries, where it can now be considered naturalised.
The cypress is monoecious, and bears male and female strobili (cones) separately at the end of short branchlets. Depending
on the crown branch habit, the species is divided into two varieties, i.e.: - C. sempervirens var. horizontalis, the most common in natural areas, characterised by spreading branches and a broad conical crown; - C. sempervirens var. pyramidalis (= var. fastigiata), the most popular for ornamental use because of its erect branches, parallel to the trunk, which give the tree its typical
columnar shape.
New Threat to Lemon Cypress (Cupressus macrocarpa cv. Goldcrest) in Turkey: Seiridium cardinale
Article
Full-text available
Figen Mert
Arjin Ondes
Sibel Dervis
Lemon cypress (Cupressus macrocarpa cv. Goldcrest) is a coniferous Cuppressaceae tree and is popular in urban landscapes of Turkey. In July 2021, dark-brown elongated bark lesions and resin exuding cracks with die-back symptoms were observed on the main stem of young C. macrocarpa cv. Goldcrest trees in a private house garden in the central district of Çanakkale Province of Turkey. Fungal isolations made from the margin of cankers of trees consistently yielded flat colonies with dense floccose aerial mycelium that were first off-white and grayish olive-green in some parts or in older cultures. Based on the morphological characteristics of obtained isolates, molecular analyses of the ITS rDNA region of a representative isolate, and pathogenicity tests on 4-year-old C. macrocarpa cv. Goldcrest plants, the causal agent was identified as Seiridium cardinale (Wagener) Sutton & Gibson. This is, to the best of our knowledge, the first report of S. cardinale causing canker on C. macrocarpa in Turkey.
Different Polyphenolic Parenchyma Cell and Phloem Axial Resin Duct-Like Structure Formation Rates in Cupressus sempervirens Clones Infected with Seiridium cardinale
PLANT DIS
DELLA ROCCA Gianni
Isabella Posarelli
Federica Morandi
Alessio Papini
The aim of this study was the characterization of constitutive and induced defence mechanisms in the bark tissues of Cupressus sempervirens before and after infection with the bark fungus Seiridium cardinale that is responsible for Cypress Canker Disease. The time-course development of polyphenolic parenchyma cells (PP cells) and phloem axial resin ducts PARDs(PARD) like structures) in the phloem was investigated in two C. sempervirens clones, one resistant and one susceptible to the disease, through anatomycal and hystologycal observations carried out by light microscope during a 19 days trial. PP cells were constitutively more abundant in the canker resistant clone compared to the susceptible clone, while PARDsPARD-like structures were not present in the bark of untreated plants of both clones. PP cells increased in both clones as a response to infection, but in the resistant clone they were more abundant 5 and 12 days after inoculation. Following inoculation, PARDsPARD-like structures appeared in the phloem after 5 days in the resistant clone and only after 12 days in the susceptible clone. Even the number of secretory cells (surrounding the PARDsPARD-like structures) was higher in the R clone 5 and 12 days after inoculation compared to the S clone. These observations demonstrate a faster phloem response of the resistant clone in the early phase of the infection. This may slow down initial growth of the fungus contributing to the resistance mechanism.
Two-dimensional electrophoretic analysis of proteins associated with somatic embryogenesis development in Cupressus sempervirens L.
Dec 2007
Anne Sallandrouze
Mireille Faurobert
M.E.I. Maataoui
Henri Espagnac
Two-dimensional gel electrophoretic analysis and histological studies were performed on somatic embryos in cypress. Embryogenic cultures were obtained from in vitro culture of immature seeds. On a modified Murashige and Skoog (MS) medium they showed an intense and repetitive cleavage polyembryogenesis phenomenon which maintained them in a continuous proliferating status instead of undergoing a complete embryogenic development. Only the addition of bovine serum albumin to the culture allowed somatic embryo development and maturation. Major histological differences were noticed between developing and nondeveloping embryogénie cultures. Attempts to find proteins that could be associated with developmental stages of somatic embryos have been achieved. Proteins were extracted and analyzed by two-dimensional electrophoresis from nondeveloping embryogenic cultures (SO) and from embryogenic cultures at three different stages of somatic embryo development: small size and rounded shape embryos (S1), increased size embryos with a well-developed suspensor (S2) and embryos with two well-separated cotyledons (S3). The results revealed some qualitative and quantitative protein variations between the two cultures. Some could be connected with the induction of pro-embryo differentiation whereas others should be more related to the mechanisms involved in somatic embryo development and maturation. Specific polypeptides associated with the presence of bovine serum albumin (BSA) in the medium have been detected.
Relations hôte-parasite dans le couple Cupressus-Coryneum cardinale Wag
Jan 1984
Agronomie
Jacques PONCHET
Claudine ANDRÉOLI
Frédéric FERRERO
Résultats de l'action commune de recherche sur le chancre cortical du cyprès1
Apr 2008
J. PONCHET
Un gros effort de méthodologie a permis de standardiser les techniques d'inoculation et de notation du chancre cortical du cyprès selon les stades de son évolution: en phase I, l'agressivité de Seiridium cardinale; en phase II, la réaction de l'hôte et les néoformations tissulaires. Réalisés sur de jeunes arbres, les tests permettent de juger le comportement en 2 ou 3 ans, ce qui est relativement rapide. Les réactions anatomiques à l'infection (néocollenchyme, barrière de suber) caractérisent la capacité de résistance. La sélection et l'amélioration génétique, menées conjointement en Grèce, en Italie et en France, progressent de façon accélérée et de nombreux clones ont déjàété mis en collection chez plusieurs espèces de cyprès. La variabilité du pouvoir pathogène de S. cardinale est, jusqu'à présent, très faible, quelques différences d'agressivité ont été notées pour la zone méditerranéenne. S. cardinale est présent très tôt sur les cônes et les graines de cyprès, sa transmission par la semence peut être inhibée. La chimiothérapie, avec quatre pulvérisations annuelles au bénomyl ou au carbendazime, est efficace mais seulement préventive, onéreuse et limitée à des applications ornementales.
A distribution map for Seiridium cardinale causing the cypress canker disease in Greece
Article
Full-text available
Jun 2007
FOREST PATHOL
S. Xenopoulos
S. Diamandis
The first distribution map of Seiridium (Coryneum) cardinale (Wag.) Sutton and Gibson which causes the cypress canker in Greece is given. A recent survey all over the country has shown that S. W. Greece and the Ionian islands are already under heavy attack whereas in central and N. Greece and the island of Krete only restricted spots have been found. Strict sanitation measures are imposed to prevent building up and diffusion of the disease.
Pathogenicity of some isolates of Seiridium (Coryneum) cardinale, agent of cypress canker disease
Jun 2007
FOREST PATHOL
P. Raddi
A. Panconesi
Ramets of 200 clones of Cupressus sempervirens were inoculated with 6 isolates of Seiridium cardinale. No significant differences were found among isolates, while there were highly significant differences among clones when length and width of canker were assumed as discriminating traits.
Natural Occurrence of Seiridium cardinale on Thuja in Germany
May 2008
J PHYTOPATHOL
I. Urbasch
Seiridium cardinale (Wagener) Sutton & Gibson (syn. Coryneum cardinale Wagener) is the most dangerous parasitic fungus of cypress and other Gupressaceae, already appearing in epidemic proportions, especially in the mediterranean area. Recently (in 1989, 1990 and 1991) this pathogen has been detected in the northern part of Germany (Hamburg and Schleswig-Holstein) naturally infecting Thuja.
The geographical distribution and the progressive spread of S. cardinale is reviewed. Diagnostic features of the fungus, modes of host penetration, principal symptoms of the disease, ways of dispersal and control methods are described.
Possible causal factors for the recently observed occurrence of 5. cardinale in the north of Germany are discussed.
View
Histopathologie du chancre cortical du cyprès à Seiridium cardinale
FOREST PATHOL
J. Ponchet Et
Claudine Andréoli
Histopathology of cankers on Cupressus caused by Seiridium cardinale. The purpose of this work was to understand host defense reactions of cypress trees against S. cardinale canker to improve selection of clones resistant to the disease. Following infection, bark recovery depends on the neophellogenic efficiency to build a necrophylactic periderm (NP) that compartmentalizes the diseased tissue. The thicker the NP the more resistant the bark. Neophellogenic activity can be estimated by measuring the thickness of constitutive phelloderm of the bark of trees from natural plantings or seedlings. Potentially resistant clones having phelloderms thicker than 100μm will be selected for further experiments.
Organogenesis and somatic embryogenesis in Cupressus sempervirens
Feb 1995
Maurizio Lambardi
Indra S. Harry
D. Menabeni
Trevor A Thorpe
Adventitious buds of Cupressus sempervirens L., were formed on excised mature embryos cultured for 10 days on half-strength Quoirin and Lepoivre medium (1/2QP) with 10 M N6-benzyladenine. For shoot development, embryos were transferred to 1/2QP without growth regulators. Axillary shoot formation and rooting occurred spontaneously as adventitious shoots aged and transfer intervals were increased. Embryogenic tissue was obtained from immature embryos on induction media consisting of von Arnold and Eriksson (AE) or Gupta and Durzan (DCR) salts with 10 or 20 M 2,4-dichlorophenoxyacetic acid. Cultures were maintained on DCR with 5 M -naphthaleneacetic acid and 5 M BA.
Platanus × acerifolia genotypes surviving to inoculation with Ceratocystis platani (the agent of canker stain): First screening and molecular characterization
Article
Sep 2009
Massimo Pilotti
Angela Brunetti
Lorenza Tizzani
O. Marani
Canker stain, caused by the fungus Ceratocystis platani, is a destructive disease in Platanus spp. It has been recently proved that resistant accessions can be produced and grown in Europe. However, additional resistant
genotypes are still needed in order to avoid the onset of virulent pathogen strains favoured by the selection pressures exerted
by genetically homogeneous resistant plane tree plantings. In this study we present the results of two parallel experiments
performed on 975 accessions of P.×acerifolia seedlings and P.×acerifolia clones derived by cutting propagation from mature trees grown in the urban environments. The selection process was based
on inoculation with C. platani and yielded 13 accessions that showed different types of resistant reactions and survived in a stable manner thoughout the
period of observation. Selected accessions were characterised by sequencing the rDNA-ITS region and by developing PCR procedures
capable of detecting P. orientalis and P. occidentalis
LEAFY homoeologues. These molecular analyses enabled us to confirm the identification of the species, its hybrid origin and to
assess an evident genetic variability among the accessions, which therefore have to be considered as different genotypes.
Effect of some leaf essential oil phenotypes in coastal redwood on the growth of several fungi with endophytic stages
Nov 1991
BIOCHEM SYST ECOL
Francisco Javier Espinosa-García
Experiments assessed the effect of four foliar essential oil phenotypes from a coastal redwood (Sequoia sempervirens) population on isolates of six fungus species with leaf endophytic stages. The hypothesis tested was that leaf essential oil phenotypes would have differential effects in vitro on these endophytic species. Another objective was to determine whether differences in response to redwood essential oils existed among pathogens isolated from redwood and a mutalistic endophtye never isolated from redwood. These species were: Botrytis cinerea, an opportunist generalist pathogen able to attack redwood; Pestalotiopsis funerea, Phomopsis occulta and Seiridium juniperi, actual or potential conifer pathogens isolated as leaf endophytes in redwood; Cryptosporiopsis abietna, a common conifer endophyte with uncertain ecological status isolated from redwood; and Meria parkeri, a mutalistic endophyte known only from Douglas fir. The four essential oil phenotypes were uniformly inhibitory for some species and differentially so for others. Susceptibility to the four phenotypes varied widely within and among fungus species. The conifer-specific pathogens were the least susceptible and the Douglas fir endophyte the most; the other two displayed intermediate susceptibility. The diversity of responses by these fungus species suggests that these redwood terpenoids may have a differential intra- and interspecific importance in preventing pathogenic activity in the species found within redwood foilage.
| https://www.researchgate.net/publication/229798290_Cypress_canker_disease_in_Italy_biology_control_possibilities_and_genetic_improvement_for_resistance |
Generalized Pustular Psoriasis | Consultant360
Clinical Updates
Ongoing updates of key clinical trial advances and new study data for common conditions.
By Lisa Kuhns, PhD
Published May 15, 2023.
Introduction Etiology Screening and Diagnosis Treatment and Management Conclusion References
Introduction
Generalized pustular psoriasis (GPP) is a severe and rare inflammatory skin disorder that can potentially be life-threatening. This condition is characterized by recurring episodes of inflamed, red, and tender skin with widespread pustules all over the body, accompanied by systemic symptoms such as fever, chills, headache, rapid pulse rate, loss of appetite, nausea, and muscle weakness. 1 These flare-ups can affect large areas of the body and can last for several weeks before spontaneous remission occurs, leading to partial or complete clearance of the skin. 2 GPP most commonly affects adults, although the condition may sometimes develop in children too. 2 It is estimated that GPP affects fewer than 5000 individuals in the United States. 1
Etiology
GPP is a complex condition that arises from a combination of genetic and environmental factors. As a genetic disorder, several mutations have been linked to the development of GPP. One such mutation is found in the IL36RN gene, which results in a deficiency of the interleukin-36 receptor antagonist (IL-36Ra). 3,4 This deficiency leads to the expression of pro-inflammatory cytokines, which are regulated by transcription factor NF-kB and MAPK. These cytokines include IL-8, CXCL1-3, IL-1, and IL-36, which form a cycle of inflammation. IL-8 and CXCL1-3 are potent neutrophil chemokines that upregulate their expression, causing neutrophils to infiltrate the skin pustules and leading to systemic inflammation in patients with GPP. 4
While IL36RN mutations are the most common genetic cause of GPP, mutations in other genes like CARD14 , AP1S3 , and MPO have also been associated with this condition, although at a lower prevalence. 5 The CARD14 gene, also known as CARMA2 , is responsible for encoding caspase recruitment domain family member 14 (CARD14). This process mediates the activation of TRAF2-dependent NF-κB signaling in keratinocytes. While mutations in the CARD14 gene are believed to be involved in GPP progression, the exact correlation between CARD14 gene mutations and the onset of GPP requires further investigation. 4 The AP1S3 gene encodes the core subunit σ1C of adaptor protein complex 1 (AP-1), which stabilizes AP-1 heterotetramers involved in vesicular trafficking between the trans-Golgi network and endosomes. Studies have shown that loss-of-function mutations in the AP1S3 gene can also be relevant to GPP. 4 In 2020, myeloperoxidase (MPO) deficiency was identified as a genetic risk factor for GPP. 6 Mutations in the MPO gene, which encodes MPO, have been identified as playing a role in the pathogenesis of GPP. 4
Several factors can trigger or worsen GPP, including infections, medication use, psychological stress, and hypocalcemia. 5 Medication-related triggers are common, including steroid withdrawal, antimalarials, beta-blockers, angiotensin-converting enzyme inhibitors, and lithium. Other triggers include pregnancy, menstruation, upper respiratory tract infections, and bacterial infections. 5 Recently, a study has reported a link between COVID-19 infection and the subsequent diagnosis or worsening of GPP, with an average time of 19 days between COVID-19 infection and the eruption of pustules. 7
Screening and Diagnosis
Physicians should suspect the condition in patients with an acute onset of erythema and pustulosis and evaluate it by correlating clinicopathologic findings from physical examination, patient history, review of symptoms, and histopathology. 8 GPP is characterized by a sudden onset of widespread, inflamed skin with sterile pustules, accompanied by systemic symptoms such as fever and malaise. Patients with GPP may also exhibit mucosal findings such as a geographic or fissured tongue, cheilitis, and ocular involvement. 8 Although a history of concurrent or previous psoriasis may assist in diagnosis, not all patients have a history of the condition. A thorough history is crucial as GPP can be triggered by several patient specific factors. 8 GPP may be associated with various medical conditions such as infections including Epstein-Barr virus or varicella-zoster virus, Turner syndrome, hypoparathyroidism, hypocalcemia, allogeneic stem cell transplantation, rheumatoid arthritis, and cardiomyopathy. 8
The classification and diagnosis of GPP present challenges, and consensus guidelines with clear definitions and diagnostic criteria have been proposed by international groups. In 2017, the European Rare and Severe Psoriasis Expert Network (ERASPEN) published diagnostic criteria that define GPP as primary, macroscopically visible, and sterile epidermal pustules on non-acral skin. These guidelines state that GPP can occur with or without systemic inflammation, with or without psoriasis vulgaris, and may be either relapsing (>1 episode) or persistent (>3 months). 9 The Japanese Dermatological Association (JDA) published diagnostic criteria for GPP in 2018, based on four factors: (1) systemic symptoms such as fever or fatigue; (2) systemic or extensive flush accompanied by multiple sterile pustules; (3) histological evidence of neutrophilic subcorneal pustules, characterized by Kogoj spongiform pustules; and (4) recurrence of these clinical and histologic findings. In Japan, a definitive diagnosis of GPP can be made in patients who meet all four criteria, and GPP should be suspected in those who meet criteria 2 and 3. 10
The evidence base for these guidelines for GPP diagnosis is limited due to the rarity of the condition and lack of large-scale clinical trials. Recently, a global Delphi panel study was conducted to gain further insights into the diagnosis of GPP. 11 The study found a consensus among the panelists that the ERASPEN and JDA diagnostic criteria can be used to classify and define GPP, respectively.
Several laboratory tests are helpful in diagnosing GPP, including complete blood cell count, erythrocyte sedimentation rate, C-reactive protein levels, and blood chemistries. In cases where genetic testing is available, screening for IL36RN mutations is recommended for GPP diagnosis, while screening for other mutations associated with GPP may also be considered. 11
When diagnosing GPP, experts agree that a histopathologic examination of a skin biopsy is useful in differential diagnoses to confirm the diagnosis. The histologic features of GPP include neutrophilic subcorneal pustules characterized by Kogoj spongiform pustules, intense neutrophilic epidermal and dermal infiltration, intraepidermal pustules, and Munro micro-abscesses. 11 The panel agree that parakeratosis, acanthosis, hyperkeratosis, elongation of rete ridges, diminished stratum granulosum, and capillary dilation of the papillary dermis are histologic findings of plaque psoriasis, which may also be present in GPP. 11
Treatment and Management
Treatment options for GPP include topical, biological, and non-biological therapies. However, there is a lack of well-established treatment guidelines due to limited evidence for their effectiveness and the absence of large clinical trials. Treatment plans for GPP often involve inpatient admission and supportive care, and the choice of treatment should be individualized based on the patient's specific comorbidities and the severity of their disease. 5
Spesolimab, an anti-IL-36R antibody, is currently the only medication specifically approved for the treatment of GPP by the FDA. 12 The approval was based on the results of the randomized phase II EFFISAYIL trial, which demonstrated that 54% of individuals treated with spesolimab showed no visible pustules compared with 6% taking the placebo. However, it is important to note that spesolimab has been associated with risk of infections and systemic medication reactions. 13 To address this, EFFISATYI 2 is currently investigating the long-term management of patients with GPP using spesolimab. 14
Investigations are currently being conducted on other therapies that target the anti-IL-36 pathway for GPP treatment. In particular, imsidolimab is being evaluated in the phase III GEMINI1 trial, which aims to assess its safety and effectiveness in comparison with a placebo among adult patients with GPP. 15 Furthermore, small molecule anti-IL-36 therapies like the endothelin receptor A antagonist ambrisentan (A-552) and interleukin-1 receptor accessory protein (IL-1RAcP) antibodies may serve as potential future therapies for GPP management, but additional studies are required to determine their long-term safety and efficacy. 5
According to the treatment guidelines developed by the American Academy of Dermatology and National Psoriasis Foundation, biological therapies such as adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, and infliximab are listed as potential options for treating GPP. 16 Non-biological therapies, such as methotrexate and cyclosporine, are also recommended. 17 In addition, phototherapy may be used in conjunction with methotrexate. 18
Conclusion
GPP is a rare and severe skin condition characterized by painful and disfiguring pustules, which pose a threat to the patient's life. Treatment options have historically been limited because of a lack of clinical trials, mainly due to the low survival rate of the disease and the limited number of cases diagnosed. However, recent research has provided new insights into the pathogenesis of GPP, leading to the development of a new FDA-approved GPP-specific medication. Despite this progress, further research is necessary to identify additional biologic treatment options for GPP and establish effective long-term management strategies for chronic GPP.
References
Generalized pustular psoriasis. National Center for Advancing Translational Sciences. Updated February 2023. Accessed April 25, 2023. https://rarediseases.info.nih.gov/diseases/12819/generalized-pustular-psoriasis
Generalized pustular psoriasis. National Psoriasis Foundation. Accessed April 25, 2023. https://www.psoriasis.org/generalized-pustular-psoriasis/
Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet . 2011;89(3):432-437. doi:10.1016/j.ajhg.2011.07.022.
Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic basis of generalized pustular psoriasis (review). Int J Mol Med . 2021;47(6):1-12. doi:10.3892/ijmm.2021.4951.
Kodali N, Blanchard I, Kunamneni S, Lebwohl MG. Current management of generalized pustular psoriasis. Exp Dermatol . Published online February 13, 2023. doi:10.1111/exd.14765.
Haskamp S, Bruns H, Hahn M, et al. Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases. Am J Hum Genet . 2020;107(3):527-538. doi:10.1016/j.ajhg.2020.07.001.
Goyal PK, Mohammed TO, Mahmoud A, Zaidi AJ, Nguyen CV. COVID-19 infection leading to acute pustular dermatoses. Arch Dermatol Res . 2023;315(4):685-697. doi:10.1007/s00403-022-02450-z.
Ly K, Beck KM, Smith MP, Thibodeaux Q, Bhutani T. Diagnosis and screening of patients with generalized pustular psoriasis. Psoriasis (Auckl) . 2019;9:37-42. doi:10.2147/PTT.S181808.
Navarini AA, Burden AD, Capon F, et al; ERASPEN Network. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol . 2017;31(11):1792-1799. doi:10.1111/jdv.14386.
Fujita H, Terui T, Hayama K, et al; The Japanese Dermatological Association Guidelines Development Committee for the Guidelines for the Management and Treatment of Generalized Pustular Psoriasis. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235-1270. doi:10.1111/1346-8138.114523.
Puig L, Choon SE, Gottlieb AB, et al. Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management. J Eur Acad Dermatol Venereol . 2023;37(4):737-752. doi:10.1111/jdv.18851.
Spevigo prescribing information. Food and Drug Administration. Updated September 2022. Accessed April 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761244s000lbl.pdf
Bachelez H, Choon SE, Marrakchi S, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med . 2021;385(26):2431-2440. doi:10.1056/NEJMoa2111563.
Morita A, Choon SE, Bachelez H, et al. Design of EffisayilTM 2: a randomized, double-blind, placebo-controlled study of spesolimab in preventing flares in patients with generalized pustular psoriasis. Dermatol Ther . 2023;13(1):347-359. doi:10.1007/s13555-022-00835-6.
A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of imsidolimab (ANB019) in the treatment of adult subjects with generalized pustular psoriasis. Clinicaltrials.gov. April 29, 2022. Accessed April 25, 2023. Clinicaltrials.gov identifier NCT05352893. https://clinicaltrials.gov/ct2/show/NCT05352893
Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol . 2019;80(4):1029-1072. doi:10.1016/j.jaad.2018.11.057.
Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486. doi:10.1016/j.jaad.2020.02.044.
Elmets CA, Lim HW, Stoff B, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy. J Am Acad Dermatol . 2019;81(3):775-804. doi:10.1016/j.jaad.2019.04.042.
| https://www.consultant360.com/clinical-updates/generalized-pustular-psoriasis?page=1%3Fpage=3%3Fpage=9%3Fpage=2%3Fpage=7 |
Charara Branch Post Office, Bangana 07, Una, Himachal Pradesh
Get Charara post office address, pincode, phone number, Charara speed post tracking, saving scheme and location map.
Charara Post Office, Bangana
Charara Post Officeis located at Charara, Bangana, Unaof Himachal Pradesh state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Charara POis 174307. This Postoffice falls under Una postal division of the Himachal Pradesh postal circle. The related head P.O. for this branch office is Una head post office and the related sub-post office (S.O.) for this branch office is Bangana post office.
Charara dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Charara. The official website fo this PO is http://www.indiapost.gov.in.
Types of Post Offices
are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Charara P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Charara Post Office & Its Pin Code
Branch Office Information
Charara Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Charara Post Office Recruitment
Location Map
Contact Details
About India Post
Charara Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Charara Post Office has the Postal Index Number or Pin Code 174307. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Charara PO Pincode 174 307
The first digit of 174307 Pin Code '1' represents the region, to which this Post Office of Charara belongs to. The first two digits of the Pincode '17' represent the sub region, i.e, Himachal Pradesh. The first 3 digits '174' represent the post-office revenue district, i.e, Una. The last 3 digits, i.e, '307' represent the Charara Delivery Branch Office.
Branch Office Information
The Charara Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Una, which falls under Shimla Hq region. The circle name for this PO is Himachal Pradesh and it falls under Bangana Taluka and Una District. The state in which this Dakghar is situated or located is Himachal Pradesh. The related head postoffice is Una post office and the related sub post office is Bangana post-office. The phone number of Charara post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Una Postal Region Shimla Hq Postal Circle Himachal Pradesh Town / City / Tehsil / Taluka / Mandal Bangana District Una State Himachal Pradesh Related Sub PO Bangana Sub Office Related Head PO Una Head Post Office
Charara Post Office Services
Traditionally the primary function of Charara post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Charara P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Charara and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Charara Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Charara can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Charara peoples and nearby living people. The premium services provided by Charara Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Charara customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Charara Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Charara postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Charara postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Charara people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Charara post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Charara customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Charara customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Charara postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Charara can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Charara area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Charara postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Charara postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/- and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 08:00 AM or 09:00 AM or 10:00 AM and the closing time is 04:00 PM or 05:00 PM or 06:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Charara Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Charara people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Charara Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Charara postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Charara Post Office Recruitment
For latest Charara post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Charara Branch Post Office is located in Charara, Bangana, Una.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc.services in Charara Post Office, can be resolved at Charara Branch Post Office. You can send letters to "Postmaster, Charara Branch Post Office, Charara, Bangana, Una, Himachal Pradesh, India, Pincode: 174 307". The official website of the Berhampur University Sub Office is http://www.indiapost.gov.in.
Charara Branch Office
Address: Charara Branch Post Office, Charara, Bangana, Una , Himachal Pradesh , India
Pin Code: 174307
Website: www.indiapost.gov.in
About India Post
India Postis a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the Indiawith over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Charara Post Office Summary
Dak Ghar Name Charara Branch Post Office Pincode 174307 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Una Postal Region Shimla Hq Postal Circle Himachal Pradesh Location Charara Town / City / Tehsil / Taluka / Mandal Bangana District Una State Himachal Pradesh Country India Related Sub Office Bangana Sub Office Related Head Office Una Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
Previous Dak Ghar Jassana Post Office
Other Post Offices
| https://www.postoffices.co.in/himachalpradesh-hp/charara-bangana-07-una/ |
Bremsstrahlung Shielding from Electron Trapping in Dielectrics
Download Citation | Bremsstrahlung Shielding from Electron Trapping in Dielectrics | A study is made of utilizing electron trapping in dielectrics as a means of reducing bremsstrahlung in spacecrafts at synchronous altitude. Traps... | Find, read and cite all the research you need on ResearchGate
Article
Bremsstrahlung Shielding from Electron Trapping in Dielectrics
April 1971
Nuclear Technology10(3)
DOI: 10.13182/NT71-A30966
Source
NTRS
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
D. L. Hollis
D. L. Hollis
Abstract
A study is made of utilizing electron trapping in dielectrics as a means of reducing bremsstrahlung in spacecrafts at synchronous altitude. Traps retain electrons, and large internal electric fields are induced within the dielectric. Electrons penetrating the insulating material can lose most of their kinetic energy to the electric field with a subsequent decrease in energy loss to bremsstrahlung. This acts to reduce bremsstrahlung production. It also lowers the average radiation energy of that which is produced, with consequent increase in probability of absorption by the wall. Breakdown phenomenon causes the shielding effect of the trapped electrons to be cyclic. A thin layer of dielectric material on the external surface of a spacecraft should provide an effective, light, and inexpensive shield against bremsstrahlung while not interfering with any of the system functions. Electron-trap shielding is applicable not only to space, but wherever a dielectric-charge layer is allowed to accumulate.
Space-charge storage in polymer dielectrics irradiated with fast electrons
Article
Dec 1984
Radiat Phys Chem
O.B. Evdokimov
Yu.A. Solovyov
Well-known theoretical models of space charge storage in polymer dielectrics irradiated with fast electrons are analysed in this paper. A phenomenological model based on the assumption of instantaneous time-independent equilibrium between the trapped and free carrier concentrations is considered. The results of model equation solutions for various ratios of electron path to dielectric thickness are given.
Reduction of the dose rate of electron radiation behind layers of charged dielectrics
Article
Feb 1993
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vladimir Vladimirovich Tsetlin
T. K. Pavlushkina
V. I. Red'ko
sample. Glass samples with an average atomic number 10 _ 2 were used in our work. The glass samples were prepared in the form of 0.5-10 mm thick disks with a diameter of 40 mm and were placed on the path of the electron beam which was incident in normal direction on a flat surface of the disk. A dosimeter, which was shielded from the incidence of electrons scattered in the accelerator structure, was mounted behind the irradiated sample in direct contact with its rear surface. The sensitive element of the dosimeter consisted of a diamond detector in the form of a 300/xm thick plate with a surface of 0.2 cm 2 and with both shut-off and injection contacts sputtered onto the plane surfaces of the disk [11]. The detector facilitated many hours of irradiation of the materials without any noticeable degradation of the parameters of the sensitive part. During the irradiation of the materials, the current incident on the sample was continuously monitored. The shielding properties of the materials were studied in various test series which differed by sets of samples of different thicknesses, the energy spectruml and the electron beam current. The energy spectrum of the incident beam was determined with the absorption technique of [12] and usually had a normal distribution with a relative half-width not exceeding 20%. In order to assess the shielding effect produced by the space charge in the sample, the dose rate behind plates of a conductive material, in which any accumulation of electric charge was impossible, was measured in each series of experiments along with measurements involving irradiated dielectric samples. An aluminum alloy as material closest to the glasses examined in regard to atomic number and specific weight was used. A comparison of the measurements revealed that under equal irradiation conditions and equal thicknesses, the dose rates produced by the transmitted electrons behind the glass plates and the alloy plates were almost identical at the beginning of the irradiation. Differences were observed when the plate thickness exceeded the maximum range of the incident electrons, i.e., when the measured dose rate was produced by the bremsstrahlung generated by particles inside the plates. In this case the dose rate behind the aluminum alloy sample was 1.6 times greater than the dose rate behind the glass plates; this can be explained by the alloy's atomic number, which exceeds the medium atomic number of the glass.
Radiation-shield characteristics of dielectric layers carrying an electric space charge
Article
Feb 1993
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vladimir Vladimirovich Tsetlin
O. A. Maznitsyna
<here is a image 0843231f8101fe41-ab8eb90faeba403d> Vyacheslav Shurshakov
Vitreous Radioelectrets: Materials for Shielding Spacecraft Against Radiation (Review)
Article
May 2001
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vladimir Vladimirovich Tsetlin
T. K. Pavlushkina
<here is a image ded77d452db13e0f-545b24f61df5177b> Lydia Dmitrievna Bogomolova
Using the EPR method, it was established that the main centers of negative charge accumulation are electroactive phosphor-oxygen ion radical P of the electron type. The majority of the considered phosphate glasses are capable of accumulating such a charge. However, the most effective one among the alkaline-earth modifiers is magnesium. The results obtained make it possible to develop with a great degree of reliability the compositions and technology of inorganic glasses with a prescribed set of service properties.
Bremsstrahlung reduction by dielectric trapping
Article
Jan 1976
J. J. Wade
D. L. Hollis
A mathematical model is used to analyze the effects of trapped negative charges in a dielectric absorber on bremsstrahlung production from low to moderate energy electrons. Significant changes in the bremsstrahlung spectra are predicted when the induced field due to trapped electrons is sufficiently large. Experiments with T1‐204 and an electron accelerator as electron sources indicate that bremsstrahlung reduction does occur, although the effect is limited by radiation‐induced conductivity.
Bremsstrahlung Production in Thick Aluminum and Iron Targets by 0.5- to 3.0MeV Electrons
Article
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Leo Baggerly
W. E. Dance
B. J. Farmer
J. H. Johnson
Space Electron Radiation Shielding-Bremsstrahlung and Electron Transmission
Article
Jul 1965
G. D. Magnuson
A. W. McReynolds
An analysis of energetic space radiation and dose rates
Article
M. O. Burrell
J. W. Watts
J. J. Wright
| https://www.researchgate.net/publication/23575843_Bremsstrahlung_Shielding_from_Electron_Trapping_in_Dielectrics |
If you had to leave your country and could live anywhere else, where would you go ? [Archive] - Eupedia Forum
Recently a Gallup poll asked people in which country they wished to live if there were no barrier. Surprisingly only 38% of respondents replied that they were happy where were. The country where people were most happy where they were was Australia (66%). However the most popular destination to live was still the USA. I would like to ask the question differently. Let's suppose that for some reason you had to leave your country, but could choose to live anywhere else. where would you go and
If you had to leave your country and could live anywhere else, where would you go ?
Recently a Gallup poll asked people in which country they wished to live if there were no barrier. Surprisingly only 38% of respondents replied that they were happy where were. The country where people were most happy where they were was Australia (66%). However the most popular destination to live was still the USA.
I would like to ask the question differently. Let's suppose that for some reason you had to leave your country, but could choose to live anywhere else. where would you go and why ?
Well from 1st of January,Romanians are getting working rights everywhere in European Union.But I would not really go to work outside Romania,since I do not like to be despised,as it is usually happens to Romanians which go to work and live in European Union.Where I would go to work,if I could would be US,Canada or Russia (not in Sankt-Petersburg,anyway,in Russia).These societies are not treating people bad,if they are not native from there.
Recently a Gallup poll asked people in which country they wished to live if there were no barrier. Surprisingly only 38% of respondents replied that they were happy where were. The country where people were most happy where they were was Australia (66%). However the most popular destination to live was still the USA.
I would like to ask the question differently. Let's suppose that for some reason you had to leave your country, but could choose to live anywhere else. where would you go and why ?
Even though this country has some problems, I can't imagine living anywhere other than Canada. But if I had to leave? Most of my ancestors came from Britain, but I wouldn't want to live in Britain with its right wing politics and failing economy. Some of my ancestors are from Germany but I don't know what part of Germany and I don't speak German, so I probably wouldn't go there. I think I would go to New Zealand, since I hear that it's a very livable country and it has good hiking trails and still has some wilderness areas, even though it's a fairly small place. And I really like seafood, lamb and apples, three things that New Zealand seems to be famous for.
Even though this country has some problems, I can't imagine living anywhere other than Canada. But if I had to leave? Most of my ancestors came from Britain, but I wouldn't want to live in Britain with its right wing politics and failing economy. Some of my ancestors are from Germany but I don't know what part of Germany and I don't speak German, so I probably wouldn't go there. I think I would go to New Zealand, since I hear that it's a very livable country and it has good hiking trails and still has some wilderness areas, even though it's a fairly small place. And I really like seafood, lamb and apples, three things that New Zealand seems to be famous for.
Do you really think that New Zealand is faring better economically than Britain ? The GDP per capita (PPP) of New Zealand is lower than that of Italy or Spain. A recent study (http://www.theguardian.com/business/2013/dec/26/britain-europe-top-economy-by-2030) predicts that the British economy will outgrow other West European ones and overtake Germany's by 2030.
Do you really think that New Zealand is faring better economically than Britain ? The GDP per capita (PPP) of New Zealand is lower than that of Italy or Spain. A recent study (http://www.theguardian.com/business/2013/dec/26/britain-europe-top-economy-by-2030) predicts that the British economy will outgrow other West European ones and overtake Germany's by 2030.
I will admit that my thinking is subjective, based on anecdotal evidence. Britain to me seems like a very crowded place, very expensive, with a lot of big city blight, crime and poverty. Although it has some very nice rural areas, it's very expensive to buy a house in any part of the country where I would want to live. And I have relatives in Britain, and they all seem to think that the quality of life has deteriorated there, with growing poverty, crime and social inequity, and the National Health Service is deteriorating. I've never been to New Zealand, but I know several people who have, and they all seem to like it, and say that it's a very safe, pleasant place with fresh air and a good climate. Whereas the UK seems to have a lot of social problems, and it seems to me that life there is not very good for people in big cities with a low or average income (i.e., most people).
I tried to find some actual statistics so I could compare Britain to New Zealand, although you've probably heard that saying that there are lies, damned lies and statistics. According to the UN, the GDP of New Zealand for 2012 was $38,3999 US compared to $39,367 for the UK, so that the UK GDP is only slightly higher. The same list of statistics show Germany at $41,866, Italy at $33,069 and Spain at $28,278. So according to these statistics, there isn't a lot of difference in income between NZ and the UK, and NZ is more prosperous than Italy or Spain. However, there are no doubt other statistics that show a different result.
A person should go where they're happy (or happier than anywhere else). So it's good to choose a country that offers all kinds of environments. Canada has a good mix of multi-ethnic big cities with vibrant social scene and rural areas where nobody bothers you. Although, most rural areas and small-cities are boring to the point where most multi-generation locals have left them.
Do you really think that New Zealand is faring better economically than Britain ? The GDP per capita (PPP) of New Zealand is lower than that of Italy or Spain. A recent study (http://www.theguardian.com/business/2013/dec/26/britain-europe-top-economy-by-2030) predicts that the British economy will outgrow other West European ones and overtake Germany's by 2030.That study putting Englands economy above Germany's by 2030 sounded more like a wishfull thinking than science based. It supposed euro currancy weakened to the point that everyone hated it and its population decreased to levels of Britain. Both of them are false. Both of them are factors that can be reversed. German economy is industrial based, which means they will always produce. For the moment they are way stronger than Britan industrially. Everyone should stay in hus own country. If I had to choose one I ould go to Mexico.
could I get my own island, and invite some nice women from time to time ?
could I get my own island, and invite some nice women from time to time ?
When I was younger, I would have liked the idea of my very own tropical island, to share only with two or three dozen attractive women. But now that I'm older, I don't think I could do justice to the opportunity any more. In any case, I think the idea was to decide what country you'd live in if you had about the same income you have now, which for me would be middle class. Buying my own island would be out of my reach. And I happen to like living in a town that's big enough to have a few good bookstores, coffee shops and restaurants but small enough to have a farmer's market, with the countryside not too far away. Certainly a middle class income can buy you such a life in Canada and also, I think, in New Zealand. But I think it's more expensive to have a life like that in Europe, especially in Britain, because it's so crowded. In my experience, towns there tend to either have expensive real estate (e.g., St Albans) or are run down and neglected (e.g., most English seaside towns). But if I had a lot of money, I would probably pick somewhere in Europe, because European countries have a much older and stronger cultural heritage than countries like Canada, New Zealand and Australia (and I would never move to Australia because I don't like hot weather). If I could afford to buy my own castle, perhaps I would pick Saltsburg - I've never been there but everything I've read about the place makes it sound very interesting. In that case, I would want to learn the language - even though I could find many people who would speak to me in English if it's anything like the rest of Europe, I would try to fit in with the locals.
Britain or France
Britain or FranceBritain is good TDE, but France is much warmer, believe me...:smile:Also, welcome to Eupedia.
Britain is good TDE, but France is much warmer, believe me...:smile:Also, welcome to Eupedia.
Thank you very much :)
| https://www.eupedia.com/forum/archive/index.php/t-29396.html?s=56ac34557f66dabcdc8552015aa689be |
Act 052 of 1974 : Conservation of Foreign Exchange and Prevention of Smuggling Activities Act, 1974 | CaseMine
Get full details of Act 052 of 1974 : Conservation of Foreign Exchange and Prevention of Smuggling Activities Act, 1974 on CaseMine.
Act 052 of 1974 : Conservation of Foreign Exchange and Prevention of Smuggling Activities Act, 1974
Department
Department of Revenue
Ministry
Text
Preamble
Conservation of Foreign Exchange and Prevention of Smuggling Activities Act, 1974 1
[Act 52 of 1974 as amended by Acts 35 of 1975, 20 of 1976, 90 of 1976, 58 of 1984, 23 of 1987, 46 of 1988, 27 of 1990, 52 of 1993 and 15 of 1996] [13th December, 1974]
An Act to provide for preventive detention in certain cases for the purposes of conservation and augmentation of foreign exchange and prevention of smuggling activities and for matters connected therewith
Whereas violations of foreign exchange regulations and smuggling activities are having an increasingly deleterious effect on the national economy and thereby a serious adverse effect on the security of the State;
And whereas having regard to the persons by whom and the manner in which such activities or violations are organised and carried on, and having regard to the fact that in certain areas which are highly vulnerable to smuggling, smuggling activities of a considerable magnitude are clandestinely organised and carried on, it is necessary for the effective prevention of such activities and violations to provide for detention of persons concerned in any manner therewith;
Be it enacted by Parliament in the Twenty-fifth Year of the Republic of India as follows:-
1 Received the assent of the President on December 13, 1974, published in the Gazette of India, Extra., Part II, Section 1, dated 13th December, 1974, pp. 761-767.
Section 1. Short title, extent and commencement
1. Short title, extent and commencement.-(1) This Act may be called the Conservation of Foreign Exchange and Prevention of Smuggling Activities Act, 1974.
(2) It extends to the whole of India.
(3) It shall come into force on such date (being a date not later than the twentieth day of December, 1974), as the Central Government may, by notification in the Official Gazette, appoint. 1
1 The Act came into force on 19th December, 1974, vide G.S.R. 690(E), dated 16-12-1974.
Section 2. Definitions
2. Definitions.- In this Act, unless the context otherwise requires,-
( a) "appropriate Government" means, as respects a detention order made by Central Government or by an Officer of the Central Government or a person detained under such order, the Central Government and as respects a detention order made by a State Government or by an officer of a State Government or a person detained under such order, the State Government;
( b) "detention order" means an order made under Section 3;
( c) "foreigner" has the same meaning as in the Foreigners Act, 1946 (31 of 1946);
( d) "Indian customs waters" has the same meaning as in clause (28) of Section 2 of the Customs Act, 1962 (52 of 1962);
( e) "smuggling" has the same meaning as in clause (39) of Section 2 of the Customs Act, 1962 (52 of 1962), and all its grammatical variations and cognate expressions shall be construed accordingly;
( f) "State Government", in relation to a Union territory, means the administrator thereof;
( g) any reference in this Act to a law which is not in force in the State of Jammu and Kashmir shall, in relation to that State, be construed as a reference to the corresponding law, if any, in force in that State.
Section 3. Power to make orders detaining certain persons
3. Power to make orders detaining certain persons.-(1) The Central Government or the State Government or any officer of the Central Government, not below the rank of Joint Secretary to that Government, specially empowered for the purposes of this section by that Government, or any officer of a State Government, not below the rank of a Secretary to that Government, specially empowered for the purposes of this section by that Government may, if satisfied, with respect to any person (including a foreigner), that, with a view to preventing him from acting in any manner prejudicial to the conservation or augmentation of foreign exchange or with a view to preventing him from-
( i) smuggling goods, or
( ii) abetting the smuggling of goods, or
( iii) engaging in transporting or concealing or keeping smuggled goods, or
( iv) dealing in smuggled goods otherwise than by engaging in transporting or concealing or keeping smuggled goods, or
( v) harbouring persons engaged in smuggling goods or in abetting the smuggling of goods,
it is necessary so to do, make an order directing that such person be detained.
1[Provided that no order of detention shall be made on any of the grounds specified in this sub-section on which an order of detention may be made under Section 3 of the Prevention of Illicit Traffic in Narcotic Drugs and Psychotropic Substances Act, 1988 or under Section 3 of the Jammu and Kashmir Prevention of Illicit Traffic in Narcotic Drugs and Psychotropic Substances Ordinance, 1988 (J&K Ordinance 1 of 1988).]
(2) When any order of detention is made by a State Government or by an officer empowered by a State Government, the State Government shall, within ten days, forward to the Central Government a report in respect of the order.
(3) For the purposes of clause (5) of Article 22 of the Constitution, the communication to a person detained in pursuance of a detention order of the grounds on which the order has been made shall be made as soon as may be after the detention, but ordinarily not later than five days, and in exceptional circumstances and for reasons to be recorded in writing, not later than fifteen days, from the date of detention.
1 Added by Act 46 of 1988, S. 15 (w.e.f. 4-7-1988)
Section 4. Execution of detention orders
4. Execution of detention orders.-A detention order may be executed at any place in India in the manner provided for the execution of warrants of arrest under the Code of Criminal Procedure, 1973 (2 of 1974).
Section 5. Power to regulate place and conditions of detention
5. Power to regulate place and conditions of detention.-Every person in respect of whom a detention order has been made shall be liable-
( a) to be detained in such place and under such conditions including conditions as to maintenance, interviews or communication with others, discipline and punishment for breaches of discipline, as the appropriate Government may, by general or special order, specify; and
( b) to be removed from one place of detention to another place of detention, whether within the same State or in another State by order of the appropriate Government:
Provided that no order shall be made by a State Government under clause ( b) for the removal of a person from one State to another State except with the consent of the Government of that other State.
Section 5-A. Grounds of detention severable
1[ 5-A. Grounds of detention severable.-Where a person has been detained in pursuance of an order of detention under sub-section (1) of Section 3 which has been made on two or more grounds, such order of detention shall be deemed to have been made separately on each of such grounds and accordingly-
( a) such order shall not be deemed to be invalid or inoperative merely because one or some of the grounds is or are-
( i) vague,
( ii) non-existent,
( iii) non relevant,
( iv) not connected or not proximately connected with such person, or
( v) invalid for any other reason whatsoever,
and it is not therefore possible to hold that the Government or officer making such order would have been satisfied as provided in sub-section (1) of Section 3 with reference to the remaining ground or grounds and made the order of detention;
( b) the Government or officer making the order of detention shall be deemed to have made the order of detention under the said sub-section (1) after being satisfied as provided in that sub-section with reference to the remaining ground or grounds.]
1 Inserted by the Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1975 (35 of 1975), S. 2 (w.e.f. 1-7-1975).
Section 6. Detention orders not to be invalid or inoperative on certain grounds
6. Detention orders not to be invalid or inoperative on certain grounds.-No detention order shall be invalid or inoperative merely by reason-
( a) that the person to be detained thereunder is outside the limits of the territorial jurisdiction of the Government or the officer making the order of detention, or
( b) that the place of detention of such person is outside the said limits.
Section 7. Powers in relation to absconding persons
7. Powers in relation to absconding persons.-(1) If the appropriate Government has reason to believe that a person in respect of whom a detention order has been made has absconded or is concealing himself so that the order cannot be executed, that Government may-
( a) make a report in writing of the fact to a Metropolitan Magistrate or a Magistrate of the first class having jurisdiction in the place where the said person ordinarily resides; and thereupon the provisions of Sections 82, 83, 84 and 85 of the Code of Criminal Procedure, 1973 (2 of 1974), shall apply in respect of the said person and his property as if the order directing that he be detained were a warrant issued by the Magistrate;
( b) by order notified in the Official Gazette direct the said person to appear before such officer, at such place and within such period as may be specified in the order; and if the said person fails to comply with such direction, he shall, unless he proves that it was not possible for him to comply therewith and that he had, within the period specified in the order, informed the officer mentioned in the order of the reason which rendered compliance therewith impossible and of his whereabouts, be punishable with imprisonment for a term which may extend to one year or with fine or with both.
(2) Notwithstanding anything contained in the Code of Criminal Procedure, 1973 (2 of 1974), every offence under clause ( b) of sub-section (1) shall be cognisable.
Section 8. Advisory Boards
8. Advisory Boards.- For the purposes of sub-clause ( a) of clause (4), and sub-clause ( c) of clause (7), of Article 22 of the Constitution,-
( a) the Central Government and each State Government shall, whenever necessary, constitute one or more Advisory Boards each of which shall consist of a Chairman and two other persons possessing the qualifications specified in sub-clause ( a) of clause (4) of Article 22 of the Constitution;
( b) save as otherwise provided in Section 9, the appropriate Government shall, within five weeks from the date of detention of a person under a detention order make a reference in respect thereof to the Advisory Board constituted under clause ( a) to enable the Advisory Board to make report under sub-clause ( a) of clause (4) of Article 22 of the Constitution;
( c) the Advisory Board to which a reference is made under clause ( b) shall after considering the reference and the materials placed before it and after calling for such further information as it may deem necessary from the appropriate Government or from any person called for the purpose through the appropriate Government or from the person concerned, and if in any particular case, it considers it essential so to do or if the person concerned desires to be heard in person, after hearing him in person, prepare its report specifying in a separate paragraph thereof its opinion as to whether or not there is sufficient cause for the detention of the person concerned and submit the same within eleven weeks from the date of detention of the person concerned;
( d) when there is a difference of opinion among the members forming the Advisory Board, the opinion of the majority of such members shall be deemed to be the opinion of the Board;
( e) a person against whom an order of detention has been made under this Act shall not be entitled to appear by any legal practitioner in any matter connected with the reference to the Advisory Board, and the proceedings of the Advisory Board and its report, excepting that part of the report in which the opinion of the Advisory Board is specified shall be confidential;
( f) in every case where the Advisory Board has reported that there is in its opinion sufficient cause for the detention of a person, the appropriate Government may confirm the detention order and continue the detention of the person concerned for such period as it thinks fit and in every case where the Advisory Board has reported that there is in its opinion no sufficient cause for the detention of the person concerned, the appropriate Government shall revoke the detention order and cause the person to be released forthwith.
Section 9. Cases in which and circumstances under which persons may be detained for periods longer than three months without obtaining the opinion of Advisory Board
1[ 9. Cases in which and circumstances under which persons may be detained for periods longer than three months without obtaining the opinion of Advisory Board.-(1) Notwithstanding anything contained in this Act, any person (including a foreigner) in respect of whom an order of detention is made under this Act at any time before the 2 3[31st day of July, 1999], may be detained without obtaining, in accordance with the provisions of sub-clause ( a) of clause (4) of Article 22 of the Constitution, the opinion of an Advisory Board for a period longer than three months but not exceeding six months from the date of his detention, where the order of detention has been made against such person with a view to preventing him from smuggling goods or abetting the smuggling of goods or engaging in transporting or concealing or keeping smuggled goods and the Central Government or any officer of the Central Government, not below the rank of an Additional Secretary to that Government, specially empowered for the purposes of this section by that Government, is satisfied that such person-
( a) smuggles or is likely to smuggle goods into, out of or through any area highly vulnerable to smuggling; or
( b) abets or is likely to abet the smuggling of goods into, out of or through any area highly vulnerable to smuggling; or
( c) engages or is likely to engage in transporting or concealing or keeping smuggled goods in any area highly vulnerable to smuggling,
and makes a declaration to that effect within five weeks of the detention of such person.
Explanation 1.-In this sub-section, "area highly vulnerable to smuggling" means-
( i) the Indian customs waters contiguous to 4[the State of Goa, Gujarat, Karnataka, Kerala, Maharashtra and Tamil Nadu and the Union Territories of Daman and Diu and Pondicherry];
( ii) the inland area fifty kilometres in width from the coast of India falling within the territories of [the States of Goa, Gujarat, Karnataka, Kerala, Maharashtra and Tamil Nadu and the Union territories of Daman and Diu and Pondicherry;]
( iii) the inland area fifty kilometres in width from the India-Pakistan border in the States of Gujarat, Jammu and Kashmir, Punjab and Rajasthan;
( iv) the customs airport of Delhi; and
( v) such further or other Indian customs waters, or inland area not exceeding one hundred kilometres in width from any other coast or border of India, or such other customs station, as the Central Government may, having regard to the vulnerability of such waters, area or customs station, as the case may be, to smuggling, by notification in the Official Gazette, specify in this behalf.
Explanation 2.-For the purposes of Explanation 1, "customs airport" and "customs station" shall have the same meaning as in clauses (10) and (13) of Section 2 of the Customs Act, 1962 (52 of 1962), respectively.
(2) In the case of any person detained under a detention order to which the provisions of sub-section (1) apply, Section 8 shall have effect subject to the following modifications, namely:-
( i) in clause ( b), for the words "shall, within five weeks", the words "shall, within four months and two weeks" shall be substituted;
( ii) in clause ( c),-
(1) for the words "the detention of the person concerned", the words "the continued detention of the person concerned" shall be substituted;
(2) for the words "eleven weeks", the words "five months and three weeks" shall be substituted;
( iii) in clause ( f), for the words "for the detention", at both the places where they occur, the words "for the continued detention" shall be substituted.]
1 Substituted by Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1984 (58 of 1984), S. 2 (w.e.f. 13-7-1984).
2 Substituted for "31st day of July, 1993" by Act 53 of 1993, S. 2 (w.e.f. 30-6-1993).
3 Substituted for "31st day of July 1996" by Act 15 of 1996, S. 2.
4 Substituted by Act 23 of 1987, S. 2 (w.e.f. 2-7-1987)
Section 10. Maximum period of detention
10. Maximum period of detention.-The maximum period for which any person may be detained in pursuance of any detention order to which the provisions of Section 9 do not apply and which has been confirmed under clause ( f) of Section 8 shall be 1[a period of one year from the date of detention or the specified period, whichever period expires later] and the maximum period for which any person may be detained in pursuance of any detention order to which the provisions of Section 9 apply and which has been confirmed under clause ( f) of Section 8 read with sub-section (2) of Section 9 shall be 2[a period of two years from the date of detention or the specified period, whichever period expires later]:
Provided that nothing contained in this section shall affect the power of the appropriate Government in either case to revoke or modify the detention order at any earlier time.
3[ Explanation.-In this section and in Section 10-A, "specified period" means the period during which the Proclamation of Emergency issued under clause (1) of Article 352 of the Constitution on the 3rd day of December, 1971 and the Proclamation of Emergency issued under that clause on the 25th day of June, 1975, are both in operation.]
1 Substituted temporarily for the words "one year from the date of detention" for the duration of the Proclamation of Emergency of 3-12-1971 and 25-6-1975 by Act 20 of 1976, S. 3, (w.e.f. 12-12-1975).
2 Substituted temporarily for the words "two years from the date of detention", for the duration of the Proclamation of Emergency of 3-12-1971 and 25-6-1975 by Act 20 of 1976, S. 3 (w.e.f. 12-12-1975).
3 Inserted temporarily for the duration of the Proclamation of Emergency of 3-12-1971 and 25-6-1975 by S. 3, (w.e.f. 12-12-1975).
Section 10-A. Extension of period of detention
1[ 10-A. Extension of period of detention.-(1) Notwithstanding anything contained in any other provision of this Act, the detention of every person detained under a detention order which has been confirmed under clause ( f) of Section 8 before the commencement of the Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1976, and which is in force immediately before such commencement shall, unless his detention has been continued by the appropriate Government under the said clause for a period shorter than one year from the date of his detention, continue until the expiry of a period of one year from the date of his detention under such order or until the expiry of the specified period, whichever period expires later:
Provided that nothing contained in this sub-section shall affect the power of the appropriate Government to revoke or modify such detention order at any earlier time.
(2) Notwithstanding anything contained in any other provision of this Act, the detention of every person detained under a detention order which has been confirmed under clause ( f) of Section 8 read with sub-section (2) of Section 9 before the commencement of the Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1976, and which is in force immediately before such commencement, shall, unless his detention has been continued by the appropriate Government under the said clause ( f) read with the said sub-section (2), for a period shorter than two years from the date of his detention, continue until the expiry of a period of two years from the date of his detention under such order or until the expiry of the specified period, whichever period expires later:
Provided that nothing contained in this sub-section shall affect the power of the appropriate Government to revoke or modify such detention order at any earlier time.]
1 Inserted by Act 20 of 1976, S. 3 (w.e.f. 12-12-1975).
Section 11. Revocation of detention orders
11. Revocation of detention orders.-(1) Without prejudice to the provisions of Section 21 of the General Clauses Act, 1897 (10 of 1897), a detention order may, at any time, be revoked or modified-
( a) notwithstanding that the order has been made by an officer of a State Government, by that State Government or by the Central Government;
( b) notwithstanding that the order has been made by an officer of the Central Government or by a State Government, by the Central Government.
(2) The revocation of a detention order shall not bar the making of another detention order under Section 3 against the same person.
Section 12. Temporary release of persons detained
12. Temporary release of persons detained.- 1[(1) The Central Government may, at any time, direct that any person detained in pursuance of a detention order made by that Government or an officer subordinate to that Government or by a State Government or by an officer subordinate to a State Government, may be released for any specified period either without condition or upon such conditions specified in the direction as that person accepts, and may, at any time, cancel his release.
(1-A) A State Government may, at any time, direct that any person detained in pursuance of a detention order made by that Government or by an officer subordinate to that Government may be released for any specified period either without condition or upon such conditions specified in the direction as that person accepts, and may, at any time, cancel his release.]
(2) In directing the release of any person [under sub-section (1) or sub-section (1-A), the Government directing the release], may require him to enter into a bond with sureties for the due observance of the conditions specified in the direction.
(3) Any person released under 2[sub-section (1) or sub-section (1-A)] shall surrender himself at the time and place, and to the authority, specified in the order directing his release or cancelling his release, as the case may be.
(4) If any person fails without sufficient cause to surrender himself in the manner specified in sub-section (3), he shall be punishable with imprisonment for a term which may extend to two years, or with fine, or with both.
(5) If any person released under 3[sub-section (1) or sub-section (1-A)] fails to fulfil any of the conditions imposed upon him under the said sub-section or in the bond entered into by him, the bond shall be declared to be forfeited and any person bound thereby shall be liable to pay the penalty thereof.]
4[(6) Notwithstanding anything contained in any other law and save as otherwise provided in this section, no person against whom a detention order made under this Act is in force shall be released whether on bail or bail bond or otherwise.]
1 Substituted by Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1976 (20 of 1976), S. 4. (w.e.f. 12-12-1975).
2 Substituted by Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1976 (20 of 1976), S. 4.
3 Substituted by Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1976 (20 of 1976), S. 4.
4 Inserted by the Conservation of Foreign Exchange and Prevention of Smuggling Activities (Amendment) Act, 1975 (35 of 1975), S. 3. (w.e.f. 1-7-1975).
Section 13. Protection of action taken in good faith
13. Protection of action taken in good faith.- No suit or other legal proceedings shall lie against the Central Government or a State Government and no suit, prosecution or other legal proceedings shall lie against any person, for anything in good faith done or intended to be done in pursuance of this Act.
Section 14. Repeal
14. Repeal.- The Maintenance of Internal Security (Amendment) Ordinance, 1974 (11 of 1974), shall, on the commencement of this Act, stand repealed and accordingly the amendments made in the Maintenance of Internal Security Act, 1971 (26 of 1971), by the said Ordinance shall, on such commencement, cease to have effect.
| https://www.casemine.com/act/in/5a979da54a93263ca60b71c3 |
A Phase I, Open-Label, Dose-Escalation Study of CC-11006 In Subjects With Low- or Intermediate-1 Risk Myelodysplastic Syndromes
A Phase I, Open-Label, Dose-Escalation Study of CC-11006 In Subjects With Low- or Intermediate-1 Risk Myelodysplastic Syndromes.
Log in
A Phase I, Open-Label, Dose-Escalation Study of CC-11006 In Subjects With Low- or Intermediate-1 Risk Myelodysplastic Syndromes
Trial Phase: Phase 1 Minimum Age: 18 Years Maximum Age: N/A
Enrollment Status: Not Enrolling Gender: Both Conditions: Myelodysplastic Syndrome
About
Details
Locations
Trial Information
A Phase I, Open-Label, Dose-Escalation Study of CC-11006 In Subjects With Low- or Intermediate-1 Risk Myelodysplastic Syndromes
Inclusion Criteria
Study Population Key Inclusion Criteria
- Age greater than 18 years.
- Able to understand and voluntarily sign an informed consent form.
- A diagnosis of de novo myelodysplastic syndrome (MDS) of at least 12 weeks duration,
with one of the following subtypes (See WHO Classification and Criteria for
Myelodysplastic Syndromes).
1. Refractory anemia (RA)
2. Refractory cytopenia with multilineage dysplasia (RCMD)
3. Refractory anemia with ring sideroblasts (RARS)
4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
(RCMD-RS)
5. Refractory anemia with excess blasts (RAEB-1 [5-9% blasts])
6. RAEB-2 (10%-19% blasts)
7. MDS-Unclassified (MDS-U)
8. MDS with chromosome 5q deletion (MDS 5q-)
- At least two hemoglobins < 9 g/dL (untransfused) or transfusion-dependence defined as
requiring at least 4 units of RBCs in the 56 days prior to Study Day 1 (start of
CC-11006 treatment).
- Tried and failed one or more conventional first-line treatments for MDS with anemia
including Revlimid®, recombinant erythropoietins, 5-azacitidine, decitibine or other
associated therapies.
- More than 28 days (from Study Day 1) must have elapsed since any previous treatment
(including Revlimid®) for MDS with anemia, other than transfusion(s).
- An ECOG Performance status of 0, 1 or 2 • Able to adhere to the study visit schedule
and other protocol requirements.
- Females of childbearing potential (FCBP)† must agree to use two reliable forms of
contraception simultaneously or to practice complete abstinence from heterosexual
intercourse for at least 28 days before starting study drug, while on study drug,
during dose interruptions, and 28 days after the last dose of study drug. The two
methods of reliable contraception must include one highly effective method (i.e.
intrauterine device, hormonal [birth control pills, injections, or implants], tubal
ligation, partner's vasectomy) and one additional effective (barrier) method (i.e.
latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified
provider of contraceptive methods, if needed.
Before starting study drug:
- FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior
to starting study drug. The first test must be performed within 10 - 14 days and the
second negative pregnancy test within 24 hours prior to the start of study drug. The
subject may not receive study drug until the Investigator has verified a negative
pregnancy test.
- Will be counseled about pregnancy precautions, potential risks of fetal exposure.
Male Subjects:
- Must agree to use a latex condom during any sexual contact with females of
childbearing potential during study drug treatment, during dose interruptions, and
for at least 28 days following discontinuation of study drug even if they have
undergone a successful vasectomy.
- Agree to abstain from donating semen or sperm while taking study drug and for 28 days
after stopping study drug.
While on study and during dose interruptions:
- FCBP with regular cycles must agree to have pregnancy tests weekly for the first 28
days and then every 28 days while on study drug, during dose interruptions and at day
28 day following discontinuation of study drug. If menstrual cycles are irregular,
the pregnancy testing must occur every 14 days.
- The subject may not receive study drug until the Investigator has verified a negative
pregnancy test.
- No more than a 28-day supply of study drug is to be dispensed at a time.
- In addition to the required pregnancy testing, the Investigator must confirm with
FCBP that they are continuing to use the two reliable methods of birth control at
each visit.
- Counseling about pregnancy precautions must be done at a minimum of every 28 days.
Subjects must be reminded of the potential risks of fetal exposure at each visit and
to not share drug.
- Pregnancy testing and counseling must be performed if a subject missed her period or
if there is any abnormality in her pregnancy test or in her menstrual bleeding.
Study drug treatment must bediscontinued during this evaluation.
- Females must agree to abstain from breastfeeding while on study, during dose
interruptions and for 28 days after last dose of study drug.
Male Subjects:
-Counseling not to share drugs, donate blood, sperm or semen, and on contraceptive use,
including counseling on emergency contraception must be done at a minimum of every 28
days.
Upon discontinuation of study drug:
- Pregnancy test will be performed for FCBP at study termination and at day 28 after
last dose of study drug.
- Females must agree to abstain from breastfeeding for 28 days after last dose of study
drug.
- Male and FCBP subjects must follow all birth control requirements as those required
while on study drug for 28 days after last dose of study drug.
- Both males and females must agree to abstain from donating blood or ova (for females)
while taking study drug and for 28 days after stopping study drug.
- Males must not donate sperm or semen for 28 days after last dose of study
drug.
If pregnancy does occur during treatment, study drug must be immediately discontinued. Key
Exclusion Criteria
- Myelosclerosis (or myelofibrosis) occupying more than 30% of marrow space.
- Bone marrow blast ≥ 20 %.
- The following laboratory abnormalities:
1. Absolute neutrophil count (ANC) < 500 cells/L (0.5 x 109/L)
2. Platelet count < 50,000/L (50 x 109/L)
3. Serum creatinine > 2.0 mg/dL (177 mol/L)
4. Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)
5. Serum total bilirubin > 2 x the ULN secondary to hemolysis in the absence of any
known intrinsic liver disease
- A history of active tuberculosis requiring treatment within the previous 3 years (of
Study Day 1) or opportunistic infections, including but not limited to evidence of
active cytomegalovirus, active Pneumocystis carinii, or atypical mycobacterium
infection, etc., or documented HIV infection, within the previous 6 months (of Study
Day 1). Subjects with evidence of an old tuberculosis infection without documented
adequate therapy are also excluded.
- A history of active non-hematopoietic malignancy, or a similar diagnosis within 3
years of Study Day 1 (except basal cell or squamous cell carcinoma of the skin or
cervical carcinoma in situ).
- A history of venous thromboembolism.
- Clinically significant anemia due to factors such as iron, B12 or folate
deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding (if a
marrow aspirate is not evaluable for storage iron, transferrin saturation must be >
20 % and serum ferritin not less than 50 ng/mL).
- Any clinically significant pulmonary, cardiac, vascular, endocrine, hepatic,
neurological, gastrointestinal or genitourinary disease unrelated to underlying
hematological disorder.
- Any life-threatening or active infection requiring parenteral antibiotic therapy.
- Chromosome abnormalities common to de novo acute myelogenous leukemia (AML), i.e.,
t(8:21), t(15;17), and inv (16).
- Known hepatitis-B surface antigenemia or positive hepatitis-C antibodies.
- Known HIV-1 positivity.
- Greater than Grade 2 neuropathy.
- Any medical condition, including the presence of laboratory abnormalities, which
would place the subject at unacceptable risk if he/she were to participate in the
study or confounds the ability to interpret data from the study.
- Any other serious medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from signing the informed consent form.
- Pregnant or lactating females.
- Subjects who require ongoing treatment with corticosteroids.
- Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not
commercially available) for the treatment of MDS within 28 days of the first day of
study drug treatment.
- Recombinant human erythropoietin (rHuEPO) therapy within 28 days of the first day of
study drug treatment.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum Tolerated Dose of CC-11006
Outcome Time Frame:
2 cohorts
Safety Issue:
Yes
Principal Investigator
Alan List, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
H. Lee Moffitt Cancer Center and Research Institute
Authority:
United States: Food and Drug Administration
Study ID:
CC-11006-MDS-001
NCT ID:
NCT00458159
Start Date:
May 2007
Completion Date:
December 2008
Related Keywords:
Myelodysplastic Syndrome
CC-11006
RA
MDS
Celgene
RCMD-RS
RARS
RAEB-1
Low-or Intermediate-1-Risk Myelodysplastic Syndrome (MDS)
Myelodysplastic Syndromes
Preleukemia
Name Location MD Anderson Cancer Center Houston, Texas 77030-4096 H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida 33612 Indiana University Medical Center Indianapolis, Indiana 46202 The Cleveland Clinic Foundation Cleveland, Ohio Center for Cancer and Blood Disorders Bethesda, Maryland 20817 New York Presbyterian Hospital-Weill Cornell Medical College New York, New York 10021 Wake Forest University School of Medicine Bowman Gray Campus, Comprehensive Cancer Center Winston-Salem, North Carolina 27157-1082
| http://www.knowcancer.com/cancer-trials/NCT00458159/ |
IJERPH | Free Full-Text | Effective Strategies for Monitoring and Regulating Chemical Mixtures and Contaminants Sharing Pathways of Toxicity
Traditionally, hazardous chemicals have been regulated in the U.S. on a one-by-one basis, an approach that is slow, expensive and can be inefficient, as illustrated by a decades-long succession of replacing one type of organohalogen flame retardants (OHFRs) with another one, without addressing the root cause of toxicity and associated public health threats posed. The present article expounds on the need for efficient monitoring strategies and pragmatic steps in reducing environmental pollution and adverse human health impacts. A promising approach is to combine specific bioassays with state-of-the-art chemical screening to identify chemicals and chemical mixtures sharing specific modes of action (MOAs) and pathways of toxicity (PoTs). This approach could be used to identify and regulate hazardous chemicals as classes or compound families, featuring similar biological end-points, such as endocrine disruption and mutagenicity. Opportunities and potential obstacles of implementing this approach are discussed.
Effective Strategies for Monitoring and Regulating Chemical Mixtures and Contaminants Sharing Pathways of Toxicity
by Arjun K. Venkatesan and Rolf U. Halden *
Center for Environmental Security, The Biodesign Institute, Global Security Initiative, Arizona State University, Tempe, AZ 85287, USA
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2015 , 12 (9), 10549-10557; https://doi.org/10.3390/ijerph120910549
Received: 26 June 2015 / Revised: 31 July 2015 / Accepted: 25 August 2015 / Published: 28 August 2015
(This article belongs to the Special Issue Hazardous Waste and Human Health-2015 )
Abstract
:
Traditionally, hazardous chemicals have been regulated in the U.S. on a one-by-one basis, an approach that is slow, expensive and can be inefficient, as illustrated by a decades-long succession of replacing one type of organohalogen flame retardants (OHFRs) with another one, without addressing the root cause of toxicity and associated public health threats posed. The present article expounds on the need for efficient monitoring strategies and pragmatic steps in reducing environmental pollution and adverse human health impacts. A promising approach is to combine specific bioassays with state-of-the-art chemical screening to identify chemicals and chemical mixtures sharing specific modes of action (MOAs) and pathways of toxicity (PoTs). This approach could be used to identify and regulate hazardous chemicals as classes or compound families, featuring similar biological end-points, such as endocrine disruption and mutagenicity. Opportunities and potential obstacles of implementing this approach are discussed.
Keywords:
environmental monitoring
;
flame retardants
;
regulatory framework
;
chemical mixtures
;
toxicity
Graphical Abstract
1. Introduction
Today, more than 84,000 chemicals are included in the U.S. Toxic Substances Control Act (TSCA) inventory, and approximately 10% of these chemicals are associated with cancer [ 1 , 2 ]. The majority of current environmental and biological monitoring strategies rely on chemical analysis of individual target compounds. Similarly, today’s chemical regulations in the U.S. and many other countries worldwide target specific chemicals rather than groups of compounds posing threats via specific pathways of toxicity that result in shared adverse outcomes in human health. Contrary to the single-chemical scenarios that inform risk assessments today, people in everyday life get exposed to multiple chemicals, which may exert cumulative effects on humans or interact in unpredictable ways via chemical interactions [ 1 ]. One major concern with chemical mixtures is the possibility of inducing synergistic effects, whose overall effects exceed the sum of adverse impacts caused by individual exposures. Synergistic effects resulting from the inhalation of radon progeny and smoking, and exposure to asbestos and smoking have been documented for lung cancer incidents [ 3 , 4 ]. Two classic approaches to address toxicity resulting from chemical mixtures are concentration addition (CA) and independent action (IA), for which information on both the individual chemical toxicity and concentration of the chemical in the respective mixture of interest is needed [ 5 , 6 ]. For example, the standard method for assessing mixture toxicity and exposures of dioxin-like compounds makes use of Toxic Equivalency Factors (TEF). This methodology expresses the composite chemical risk resultant from complex mixtures of dioxin-like compounds (polychlorinated/polybrominated dioxins, furans and biphenyls), in a single value, using as a benchmark the most toxic form of dioxin, i.e. , 2,3,7,8-tetrachlorodibezo- p -dioxin (TCDD). The approach assumes that all dioxin-like compounds exhibit a similar profile of effect on the aryl hydrocarbon receptor (AhR), and that the effects are additive. However, research has shown that the presence of certain congeners (e.g., PCB 153) in mixtures antagonized the effects of TCDD, highlighting some major limitations for the use of additive TEF approach [ 7 ]. In addition, these approaches of estimating toxicity require extensive ecotoxicological data for individual chemicals and a thorough characterization of the chemical mixtures. An added concern is the presence of unknown production impurities in chemicals and unrecognized transformation products for which no current methods of detection are available, with these toxic analogs contributing to the observed toxicity.
One important class of chemicals that exhibit mixture toxicity in the environment is the group of organohalogen flame retardants (OHFRs), particularly the various congeners of polybrominated diphenyl ethers (PBDEs). Among these, the large number of congeners, their varying toxicity (depending on the degree of halogenation), the possibility of inter-transformation of congeners from a higher to a lower halogenation state, and presence of impurities (such as dioxins and furans), make monitoring and legislative actions for OHFRs exceptionally complicated. Managing this group of problematic chemicals has proven to be a challenge, as indicated by 45 years of still ongoing legislative actions for PBDEs. Relevant challenges and legislative initiatives are highlighted in the following, using OHFRs as an illustrative case study of lessons learned from monitoring practices and chemical regulations.
2. Organohalogen Flame Retardants and Current Regulations
Many OHFRs are known to be persistent, bioaccumulative and toxic, while also having been detected globally in the environment, in wildlife, and in human populations [ 8 ]. Following these concerns, two major commercial formulations of flame retardants, namely penta- and octa-brominated diphenyl ethers (BDEs), were banned by the European Union (EU) in 2002; the fully brominated deca-BDE later also was banned from use in electrical and electronic applications within the EU in 2008 [ 9 , 10 ]. In the U.S., penta- and octa-BDEs were voluntarily phased-out in 2005 and deca-BDE sales were expected to cease by the end of 2013, with definitive numbers still pending. Regulating brominated flame retardants is and has been an ongoing challenge for the past 45 years, ever since their widespread use began in the 1970s ( Figure 1 ). Even after ban and phase-out initiatives, many products manufactured with penta- through deca-BDEs prior to regulatory actions remain in use today. Replacement chemicals now finding their way into commerce are structurally similar to the original, now banned or phased-out compounds; not surprisingly, they show similar characteristics, including persistence, bioaccumulation potential and toxicity in the environment [ 9 , 11 ]. In general, all these chemicals feature one or more benzene rings with varying degrees of halogenation, a basic chemical structure endowing banned polychlorinated biphenyls (PCBs) and carcinogenic polychlorinated dibenzo- p -dioxins with their marked toxicity and endocrine disrupting characteristics. Four decades after being banned in the U.S., PCBs still are detected in most environments, wildlife and human populations, and BDE formulations are on a trajectory to persist for many decades following their recent ban [ 12 , 13 ]. In addition, the realization has set in more recently, that these mass produced OHFRs are transformed in the environment abiotically and biotically to various toxic transformation products, such as mono- and polyhydroxylated congeners of the manufactured parent compound [ 14 , 15 , 16 ]. Furthermore, structurally related impurities of similar toxicity have been known for quite some time to be present in commercial grade flame retardants used in the manufacturing of consumer products [ 17 ].
Figure 1. Timeline of legislative initiatives for brominated flame retardants spanning half a century of widespread use in industries. EU: European Union; OECD: Organisation for Economic Co-operation and Development; OSPAR: Oslo and Paris Conventions for the Protection of the Marine Environment of the North-East Atlantic; PBB: polybrominated biphenyls; PBDE: polybrominated diphenylether; POP: persistent organic pollutant; TBBPA: tetrabromobisphenol A; WHO: World Health Organization.
The solution to the problem of persistent chemical pollution ultimately is to curtail the use and production of compounds sharing a structural and functional similarity to known hazardous compounds. The futility of making minor modifications to the carbon backbone or halogen substitution pattern of persistent OHFRs and then hoping for a different, better outcome has been demonstrated over and over again. Pragmatic and prudent steps for reducing the unwanted environmental pollution and adverse human health impacts these chemicals pose include:
Avoiding the use of flame retardants in consumer products that do not pose a significant fire hazard in the first place;
Avoiding the use of flame retardants that resemble in molecular size and structure their harmful predecessors;
Developing for use in products that absolutely require them, next-generation flame retardants featuring the following characteristics while still delivering the desired flame retardation qualities:
○
covalently bound to the consumer products to minimize release and exposure, wherever possible and practical;
○
large molecular size (e.g., polymers) that limits and ideally precludes uptake by biota following environmental release [ 18 ];
○
absence of size and shape characteristics contributing to affinity and binding to human and animal receptors, thereby reducing the risk of toxicity, for example, of endocrine disruption via binding to hormone receptors.
A recent study by our group featured the use of municipal sewage sludge (a solid byproduct of wastewater treatment) for identifying and prioritizing persistent and bioaccumulative chemicals. Eight top priority chemicals of high abundance and bioaccumulative potential were identified; these included five organohalogens of which three were brominated flame retardants (BFRs) [
19
]. The BFRs were the third most abundant group of chemicals detected in nationally representative U.S. sewage sludges (among 239 compounds surveyed), suggesting their widespread use and ongoing exposures of human populations and wildlife. Also, the study revealed that among 55 potentially bioaccumulative chemicals detectable in sewage sludge, 93% were halogenated. It is well known that the replacement of hydrogen with halogen atoms is positively correlated with an increase in the chemical’s hydrophobicity, persistence and toxicity [
20
]. Our analysis of compounds included in the U.S. Safe Drinking Water Act of the U.S. EPA showed that 74 percent of regulated organic compounds carry at least one and more frequently multiple halogen substituents.
With these facts firmly established, the following question arises: why are we continuing to design, manufacture and use organohalogen compounds that are known to be hazardous as a class or family? Instead of regulating individual formulations like penta- or octa-BDEs and replacing those with similar formulations like deca-BDE, a more proactive and protective strategy is required in chemical safety management. There is a need to recognize and circumvent the root cause that endows organic compounds, such as OHFRs, with the widely manifested potential for adverse effects, specifically persistence, bioaccumulation potential and toxicity.
3. Future Monitoring Strategies
Future monitoring approaches can pave the way to creating and enforcing better regulations. They should include both chemical analyses and specific bioassays to identify anthropogenic chemical agents eliciting unwanted and unnecessary toxicity in the environment. These agents then could be targeted by more effective regulations zeroing in on chemical groups featuring similar modes of action (MOAs) and pathways of toxicity (PoTs). Techniques that identify specific interactions of chemical mixtures with human receptors or biological end-points (e.g., binding to thyroid hormone receptor and resultant endocrine disruption) will allow for an identification of biologically active groups of chemical in the environment. Examples of such approaches include effects-directed analysis (EDA), toxicity identification evaluation (TIE) and other pathway-based cellular and molecular assays [
21
,
22
,
23
]. EDA uses bioassays (typically
in vitro
) as tools to narrow down and sensitively detect organic chemical mixtures in the environment that contribute to an observed and measureable toxic effect. This is achieved by fractionation based on physical-chemical properties of the components to reduce the complexity of contaminant mixtures in the sample into prioritized sub-groups. TIE relies on whole-organism (e.g., daphnids, mysids) toxicity testing to enable a characterization of chemical mixtures into sub-classes, followed by identification and validation. EDA has the advantage of having high specificity in toxicant identification, since specific biological endpoints are studied via
in vitro
testing. Whereas TIE lacks specificity due to whole organism testing, it does however consider toxicant bioavailability considerations in the analysis. Currently, the U.S. EPA requires chemical testing from manufacturers and processors only if: (
i
) a chemical may present an unreasonable risk of injury to human health or environment; (
ii
) the chemical is produced in a substantial quantity that could result in significant environmental releases and human exposures; and/or (
iii
) the available data is inadequate [
24
]. However, these criteria may exclude many chemicals of low production volume, other transformation products, unidentified chemicals and chemical mixtures that might be of significant concern to human health and the environment. Hence, incorporating EDA/TIE like bioassays into monitoring programs would be a prudent and promising approach to identify risks of injury to human health or the environment from chemical mixtures including unknowns, whose occurrence and harmful potential cannot be established purely on the basis of chemical monitoring of singular compounds.
The U.S. EPA’s Computational Toxicology (CompTox) research aims to integrate advances in molecular biology, toxicology, and computer science to overcome limitations of traditional laboratory animal-based toxicity tests and to help prioritize chemicals through high-throughput screening assays via Toxicity Forecaster (ToxCast). This program relies on cell-based bioassays for screening of chemicals and to develop predictive models for health outcomes [ 25 ]. Application of such cell-based bioassays for water quality assessment has been successfully carried out in the past [ 26 , 27 , 28 ]. One study tested six endpoints of particular importance to human and environmental health (genotoxicity, estrogenicity, neurotoxicity, phytotoxicity, dioxin-like activity, and non-specific cell toxicity) to establish the efficacy of different water treatment barriers [ 26 ]. The authors applied the concept of TEQ by selecting one reference compound in each of the tests. The study concluded the bioanalytical tools to be reproducible and robust, and found the TEQ approach to be useful for assessing the removal of micro-pollutants in various treatment steps. Another recent study examined the suitability of cell-based bioassays to benchmark water quality and tested 103 unique in vitro bioassays, including induction of xenobiotic metabolism, specific and reactive modes of toxic action, as well as activation of adaptive stress response pathways and system responses [ 28 ]. The study concluded that an ideal battery of bioassays should include sensitive bioassays covering a wide range of cellular toxicity pathways for effective water quality assessment. The widely applied AhR activation endpoint was found to be a relevant indicator of presence of chemicals and was suggested to be included in any routine battery of tests. Specific receptor-mediated modes of action—including effects related to estrogenic, glucocorticoid and antiandrogenic pathways—showed the most promise for water quality screening applications. Additionally, the study identified oxidative stress response as a highly sensitive and selective indicator of environmental pollution [ 28 ].
Once a toxic hazard has been established from use of the above screening tools, the key to successful characterization of chemical or chemical mixtures are analytical tools such as liquid/gas chromatography-mass spectrometry (LC/GC-MS) as well as computer-based tools for chemical structure elucidation. Non-target analysis by GC-MS in scan mode followed by mass spectral analysis using database searches can aid in identifying the unknowns present in the mixture that may significantly contribute to the observed toxicity. Structural elucidation and chemical identification can be aided greatly by using high resolution mass spectrometry (HRMS) [
29
]. In addition to instrumental techniques, programs such as quantitative structure-activity relationship (QSAR) have also been used in the past to predict and estimate the toxicity of chemical mixtures [
30
]. Although the latter tool can aid in identifying similar MOA of chemicals, the output from QSAR depends on proper input parameters and fails to address the problem of mixtures. Whereas this restricts the quantitative application of QSARs in environmental monitoring, the approach is quite useful for prioritizing and identifying chemicals that share common MOA. Combining EDA-like strategies with
in silico
analytical tools can further complement the traditional analysis of target compounds in environmental matrices. Combining these approaches then enables an identification and quantitation of harmful effect exerted by both single chemicals (including manufacturing byproducts and chemical degradates of commercial formulations) and chemical mixtures (like BFRs and other structurally similar organohalogens) featuring similar modes of toxic action. Such information then could inform both the design and regulation of industrial chemicals as well as enforcement of regulations leveled for environmental and human health protection [
31
]. However, bioassays are expensive and cannot replace the traditional monitoring approach when used in isolation. These tests should be included to identify chemicals causing an observed toxicity in environmental samples or where there is a high probability of toxicity to environmental end points, e.g., soils amended with contaminated sewage sludge and surface water receiving wastewater inputs. Though incorporating such techniques for regular monitoring is difficult and not economically feasible, testing samples yearly or biennially will benefit the regulatory community in prioritizing contaminants for future monitoring needs and to evaluate the effectiveness of legislative actions.
4. Conclusions
Polybrominated mono and bi-nuclear aromatic flame retardants of low molecular weight are prone to pose significant environmental and human health risks, no matter what minor modifications are made to the structure of their carbon backbone and its halogen substitution pattern. Learning from past failures and improving on existing monitoring strategies is a necessity for creating and implementing an effective regulatory framework and, ultimately, for designing more sustainable chemicals. Discontinuing unnecessary uses of brominated flame retardants and developing non-halogenated alternatives may serve as the starting point for arriving at safer, greener and more sustainable consumer products. Fire retardation has essential applications in society but does not need to come at the expense of contaminating and harming the environment and human populations for multiple generations into the future. Analytical chemists and toxicologists have an opportunity to aid in the transition toward a more sustainable chemical future, by devising assays that capture multiple bad chemical players and that provide a composite measure for the toxicity these exert. Inclusion of such assays in routine monitoring and regulatory framework may provide opportunities to avoid harmful chemicals that are similar to legacy toxicants and to shorten the time taken for legislative actions, which on average takes some 14 years following first reports of significant risks posed [
32
].
Acknowledgments
This project was supported in part by Award Numbers R01ES015445 and R01ES020889 from the National Institute of Environmental Health Sciences (NIEHS). It further was supported by the Virginia G. Piper Charitable Trust by award number LTR 05/01/12. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIEHS or the National Institutes of Health (NIH).
Author Contributions
Arjun Venkatesan wrote the first draft of the manuscript. Rolf Halden conceived the original idea for the article and supervised manuscript preparation.
Conflicts of Interest
The authors declare no conflict of interest.
References
Carpenter, D.O.; Arcaro, K.; Spink, D.C. Understanding the human health effects of chemical mixtures. Environ. Health Perspect. 2002 , 110 (Supplement 1), 25–42. [ Google Scholar ] [ CrossRef ] [ PubMed ]
U.S. EPA. TSCA Chemical Substance Inventory: Basic Information. Available online: http://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/basic.html (accessed on 25 August 2015).
Morrison, H.; Villeneuve, P.; Lubin, J.; Schaubel, D. Radon-progeny exposure and lung cancer risk in a cohort of Newfoundland fluorspar miners. Radiat. Res. 1998 , 150 , 58–65. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Erren, T.C.; Jacobsen, M.; Piekarski, C. Synergy between asbestos and smoking on lung: Cancer risks. Epidemiology 1999 , 10 , 405–411. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Backhaus, T.; Faust, M. Predictive environmental risk assessment of chemical mixtures: A conceptual framework. Environ. Sci. Technol. 2012 , 46 , 2564–2573. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Monosson, E. Chemical Mixtures: Considering the evolution of toxicology and chemical assessment. Environ. Health Perspect. 2005 , 113 , 383–390. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wölfle, D. Interactions between 2,3,7,8-TCDD and PCBs as Tumor Promoters: Limitations of TEFs. Teratog. Carcinog. Mutagen. 1997 , 17 , 217–224. [ Google Scholar ] [ CrossRef ]
Birnbaum, L.S.; Staskal, D.F. Brominated Flame Retardants: Cause for Concern? Environ. Health Perspect. 2004 , 112 , 9–17. [ Google Scholar ] [ CrossRef ]
Cox, P.; Efthymiou, P. Directive 2003/11/EC of the European Parliament and of the Council of February 6 2003 Amending for the 24th Time Council Directive 76/669/EEC Relating to Restrictions on the Marketing and use of Certain Dangerous Substances and Preparations (Pentabromodiphenyl Ether, Octabromodiphenyl Ether). Off. J. Eur. Union. OJ. L. 2003 , 42 , 45–46. [ Google Scholar ]
Covaci, A.; Harrad, S.; Abdallah, M.A.; Ali, N.; Law, R.J.; Herzke, D.; de Wit, C.A. Novel brominated flame retardants: A review of their analysis, environmental fate and behaviour. Environ. Int. 2011 , 37 , 532–556. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wu, J.; Guan, Y.; Zhang, Y.; Luo, X.; Zhi, H.; Chen, S.; Mai, B. Several current-use, non-PBDE brominated flame retardants are highly bioaccumulative: Evidence from field determined bioaccumulation factors. Environ. Int. 2011 , 37 , 210–215. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Breivik, K.; Sweetman, A.; Pacyna, J.M.; Jones, K.C. Towards a global historical emission inventory for selected PCB congeners—A mass balance approach: 3. An update. Sci. Total Environ. 2007 , 377 , 296–307. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Frederiksen, M.; Vorkamp, K.; Thomsen, M.; Knudsen, L.E. Human internal and external exposure to PBDEs—A review of levels and sources. Int. J. Hyg. Environ. Health 2009 , 212 , 109–134. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Meerts, I.A.; Letcher, R.J.; Hoving, S.; Marsh, G.; Bergman, A.; Lemmen, J.G.; van der Burg, B.; Brouwer, A. In vitro estrogenicity of polybrominated diphenyl ethers, hydroxylated PDBEs, and polybrominated bisphenol a compounds. Environ. Health Perspect. 2001 , 109 , 399–407. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Dingemans, M.M.; van den Berg, M.; Westerink, R.H. Neurotoxicity of brominated flame retardants: (In) direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environ. Health Perspect. 2011 , 119 , 900–907. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wiseman, S.B.; Wan, Y.; Chang, H.; Zhang, X.; Hecker, M.; Jones, P.D.; Giesy, J.P. Polybrominated diphenyl ethers and their hydroxylated/methoxylated analogs: Environmental sources, metabolic relationships, and relative toxicities. Mar. Pollut. Bull. 2011 , 63 , 179–188. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hanari, N.; Kannan, K.; Miyake, Y.; Okazawa, T.; Kodavanti, P.R.S.; Aldous, K.M.; Yamashita, N. Occurrence of polybrominated biphenyls, polybrominated dibenzo-p-dioxins, and polybrominated dibenzofurans as impurities in commercial polybrominated diphenyl ether mixtures. Environ. Sci. Technol. 2006 , 40 , 4400–4405. [ Google Scholar ] [ CrossRef ] [ PubMed ]
U.S. EPA. Draft: An Alternatives Assessment for the Flame Retardant Decabromodiphenyl Ether (DecaBDE). Available online: http://www.epa.gov/oppt/existingchemicals/pubs/actionplans/aa-for-deca-full-version.pdf (accessed on 25 August 2015).
Venkatesan, A.K.; Halden, R.U. Wastewater treatment plants as chemical observatories to forecast ecological and human health risks of manmade chemicals. Sci. Rep. 2014 , 4. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Manahan, S.E. Green Chemistry and the Ten Commandments of Sustainability ; ChemChar Research: Columbia, Missouri, MO, USA, 2011. [ Google Scholar ]
Burgess, R.M.; Ho, K.T.; Brack, W.; Lamoree, M. Effects-directed analysis (EDA) and toxicity identification evaluation (TIE): Complementary but different approaches for diagnosing causes of environmental toxicity. Environ. Toxicol. Chem. 2013 , 32 , 1935–1945. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hartung, T. From Alternative Methods to a New Toxicology. Eur. J. Pharm. Biopharm. 2011 , 77 , 338–349. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hewitt, L.M.; Marvin, C.H. Analytical Methods in environmental effects-directed investigations of effluents. Mutat Res Rev Mutat Res. 2005 , 589 , 208–232. [ Google Scholar ] [ CrossRef ] [ PubMed ]
U.S. EPA. Chemical Testing & Data Collection. Available online: http://www.epa.gov/oppt/chemtest/ (accessed on 25 August 2015).
Kavlock, R.; Chandler, K.; Houck, K.; Hunter, S.; Judson, R.; Kleinstreuer, N.; Knudsen, T.; Martin, M.; Padilla, S.; Reif, D. Update on EPA’s ToxCast program: Providing high throughput decision support tools for chemical risk management. Chem. Res. Toxicol. 2012 , 25 , 1287–1302. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Macova, M.; Toze, S.; Hodgers, L.; Mueller, J.F.; Bartkow, M.; Escher, B.I. Bioanalytical tools for the evaluation of organic micropollutants during sewage treatment, water recycling and drinking water generation. Water Res. 2011 , 45 , 4238–4247. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Escher, B.I.; Leusch, F. Bioanalytical Tools in Water Quality Assessment ; IWA Publishing: London, UK, 2012. [ Google Scholar ]
Escher, B.I.; Allinson, M.; Altenburger, R.; Bain, P.A.; Balaguer, P.; Busch, W.; Crago, J.; Denslow, N.D.; Dopp, E.; Hilscherova, K. Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays. Environ. Sci. Technol. 2013 , 48 , 1940–1956. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Krauss, M.; Singer, H.; Hollender, J. LC-high resolution MS in environmental analysis: From target screening to the identification of unknowns. Anal. Bioanal. Chem. 2010 , 397 , 943–951. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Altenburger, R.; Nendza, M.; Schüürmann, G. Mixture Toxicity and its Modeling by Quantitative Structure-Activity Relationships. Environ. Toxicol. Chem. 2003 , 22 , 1900–1915. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kostal, J.; Voutchkova-Kostal, A.; Anastas, P.T.; Zimmerman, J.B. Identifying and designing chemicals with minimal acute aquatic toxicity. Proc. Natl. Acad. Sci. 2015 , 112 , 6289–6294. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Halden, R.U. Epistemology of Contaminants of Emerging Concern and Literature Meta-Analysis. J. Hazard. Mater. 2015 , 282 , 2–9. [ Google Scholar ] [ CrossRef ] [ PubMed ]
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Venkatesan, A.K.; Halden, R.U. Effective Strategies for Monitoring and Regulating Chemical Mixtures and Contaminants Sharing Pathways of Toxicity. Int. J. Environ. Res. Public Health 2015, 12, 10549-10557.
https://doi.org/10.3390/ijerph120910549
AMA Style
Venkatesan AK, Halden RU. Effective Strategies for Monitoring and Regulating Chemical Mixtures and Contaminants Sharing Pathways of Toxicity. International Journal of Environmental Research and Public Health. 2015; 12(9):10549-10557.
https://doi.org/10.3390/ijerph120910549
Chicago/Turabian Style
Venkatesan, Arjun K., and Rolf U. Halden. 2015. "Effective Strategies for Monitoring and Regulating Chemical Mixtures and Contaminants Sharing Pathways of Toxicity" International Journal of Environmental Research and Public Health12, no. 9: 10549-10557.
https://doi.org/10.3390/ijerph120910549
| https://www.mdpi.com/1660-4601/12/9/10549 |
Conservative Interventions for Treating Clavicle Fractures in Adults - Full Text View - ClinicalTrials.gov
Conservative Interventions for Treating Clavicle Fractures in Adults
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02398006 Recruitment Status : Unknown Verified March 2015 by Mario Lenza, Hospital Israelita Albert Einstein. Recruitment status was: Not yet recruiting First Posted : March 25, 2015 Last Update Posted : March 25, 2015
Sponsor:
Hospital Israelita Albert Einstein
Mario Lenza, Hospital Israelita Albert Einstein
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
Background: Fracture of the clavicle is common accounting for 2.6% to 4 % of all fractures, with an overall incidence of 36.5 to 64 per 100,000 per year. Around 80% of clavicle fractures occur in the middle third of the clavicle. There is a lack of evidence of randomised controlled trials assessing the best treatment of these fractures. The objective of this study is to evaluate the effects (benefits and harms) of conservative interventions: figure-of-eight bandage versus sling for the treating middle third clavicle fractures. Methods/Design: this project has been designed as a single-centre, parallel-group randomised controlled trial that will compare figure-of-eight bandage versus sling. The investigators aim to recruit 110 adults, aged 18 years or older, with an acute (less than 10 days) middle third clavicle fracture. Primary outcomes will be function or disability measured by DASH questionnaire; the secondary outcomes will be: modified UCLA score pain, treatment failure, adverse events and numbers returning to previous activities. Data analysis: the chi-square test will be used to analyse the results of categorical variables, and Student t-test will be used to compare groups with respect to the numerical variables. The Student t-test is used to compare the clinical outcome of each group at 1, 2 and 4 weeks and at 6 and 12 months after the intervention. The significance level of 5% (alpha = 0.05) is used for all statistical tests such that tests have a value of less than 0.05 are considered statistically significant. Discussion: According to current evidence there is very limited evidence from two single trials only regarding the effectiveness of different methods of conservative interventions for treating clavicle fractures. This study is one of the first randomised controlled trials following the CONSORT statements designed to compare two conservative methods for treating clavicle fractures (figure-of-eight versus sling).
Condition or disease Intervention/treatment Phase Fracture of Clavicle Other: a standard arm sling Other: a figure-of-eight bandage Not Applicable
Detailed Description:
Whilst there are several options for conservative treatment for middle third clavicle fractures, only two randomised controlled published in the 80s attempted to determine the effects of different methods for conservative treatment for middle third clavicle fractures. Thus, a pragmatic trial design has been chosen as it can directly inform clinical practice; our inclusion criteria will reflect the variety in patient presentations that would be encountered by general orthopaedic surgeons in the clinical setting. The current trial includes design characteristics known to minimise bias. Participants will be assigned using a concealed random procedure, assessments and data analysis will be blinded and we will use the intention-to-treat analysis.
Study Design
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for study information Study Type : Interventional
(Clinical Trial) Estimated Enrollment : 110 participants Allocation: Randomized Intervention Model: Single Group Assignment Masking: Single (Outcomes Assessor) Primary Purpose: Treatment Official Title: Figure-of-eight Bandage Versus Arm Sling for Treating Middle Third Clavicle Fractures in Adults: Study Protocol for a Randomised Controlled Trial Study Start Date : April 2015 Estimated Primary Completion Date : September 2016 Estimated Study Completion Date : December 2017
U.S. FDA Resources
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Active Comparator: Group 1: a standard arm sling Group 1: the orthopaedic surgeon will apply a standard arm sling that will be used for four weeks; however, during these weeks, participants will be encouraged to discard the sling when their pain has subsided. After four weeks the same orientations of group 1 will be done to this group. Other: a standard arm sling Closed reduction (re-aligning the fragments of the fracture) will be not performed because the reduced position is practically impossible to maintain. Active Comparator: Group 2: a figure-of-eight bandage Group 2: a figure-of-eight bandage will be used for four weeks, and every week the participants will return to check and adjust the immobilisation. In this way, the dominant hand can remain free and simple activities will be allowed (writing, keyboarding and other). After four weeks, participants will be encouraged to discard the bandage, but load bearing will not be allowed before osseous consolidation (around 10 weeks). Other: a figure-of-eight bandage Closed reduction (re-aligning the fragments of the fracture) will be not performed because the reduced position is practically impossible to maintain.
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Function or disability will be measured by DASH - Disability of the Arm, Shoulder, and Hand questionnaire [ Time Frame: 12 months ]
Function or disability will be measured by DASH - Disability of the Arm, Shoulder, and Hand questionnaire validated and translated into Portuguese in Brazil, the final score of the DASH questionnaire will be converted to a percentage via the following formula: Scoring = [Sum of answers n/n - 1] X 25, where n is the number of complete answers. The two optional modules will not be measured. The value obtained will be directly proportional to the percentage of impairment of the limb function.
Secondary Outcome Measures
:
Modified University of California at Los Angeles (modified - UCLA) [ Time Frame: 12 months ]
Modified University of California at Los Angeles (modified - UCLA), validated and translated into Portuguese in Brazil.
Pain measured on a 0 to 100 using visual analogue scale (VAS) [ Time Frame: 12 months ]
Pain measured on a 0 to 100 using visual analogue scale (VAS) (with 0 indicating no pain and 100 indicating the maximum pain). As reported in the literature, a clinically important change will be considered as a 30% or more change in pain score.
Treatment failure measured by the number of participants who have undergone or are being considered a surgical intervention [ Time Frame: 12 months ]
Treatment failure measured by the number of participants who have undergone or are being considered a surgical intervention (e.g. symptomatic non-union or malunion with intractable pain). Although studies evaluating patients with fractures without displacement reported low rates of nonunion (about 0.03%), studies with patients with displaced fractures found nonunion rates of up to 15%. Therefore, we expect between 5 and 10% of our participants might provide symptomatic nonunion during follow-up. Patients who experience this complication during follow-up study will be treated surgically with open reduction and internal fixation with pre-contoured locking plate counted down the superior surface of the clavicle and bone grafting when necessary.
Adverse events measured by: a) Cosmetic result: perception of deformity or asymmetric result (dichotomous data); b) Asymptomatic non-union (i.e. the fracture has not healed radiographically with no pain); c) Stiffness/restricted of range of shoulder movement (compared with contralateral side).
Numbers returning to previous activities (work, sport, activities of daily living), including time to return. [ Time Frame: 12 months ]
Numbers returning to previous activities (work, sport, activities of daily living), including time to return.
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Adults aged 18 years or older and 65 years or less with middle third clavicle fracture,
Acute fracture (less than 10 days), we will include all types of middle third clavicle fractures (non-displaced and displaced fractures),
No medical contraindication to proposed methods of immobilisation,
Understanding of Portuguese language and written informed consent.
Exclusion Criteria:
Pathological fracture,
Open fracture,
Neurovascular injury on physical examination,
Associated head injury (Glasgow Coma Scale score of <12),
Ipsilateral upper limb fractures and/or dislocation(except hand and fingers),
History of frozen shoulder,
Previous disease in the limb that could influence the results (e.g. rheumatoid arthritis),
Inability to comply with follow-up (inability to read or complete forms).
Contacts and Locations
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02398006
Contacts
Layout table for location contacts Contact: Mario Lenza, PhD 55 11 21511444 [email protected] Contact: Mario Ferretti, PhD 55 11 21511444 [email protected]
Sponsors and Collaborators
Hospital Israelita Albert Einstein
Investigators
Layout table for investigator information Principal Investigator: Mario Lenza, PhD Hospital Israelita Albert Einstein
More Information
Lenza M, Taniguchi LF, Ferretti M. Figure-of-eight bandage versus arm sling for treating middle-third clavicle fractures in adults: study protocol for a randomised controlled trial. Trials. 2016 May 4;17(1):229. doi: 10.1186/s13063-016-1355-8.
Layout table for additonal information Responsible Party: Mario Lenza, Dr, Hospital Israelita Albert Einstein ClinicalTrials.gov Identifier: NCT02398006 History of Changes Other Study ID Numbers: HIAE orthopaedics First Posted: March 25, 2015 Key Record Dates Last Update Posted: March 25, 2015 Last Verified: March 2015
Keywords provided by Mario Lenza, Hospital Israelita Albert Einstein:
Clavicle [mh] Fracture Healing [mh] Fractures, Bone [mh] Treatment outcome [mh] Conservative treatment [tw]
Additional relevant MeSH terms:
Layout table for MeSH terms Fractures, Bone Wounds and Injuries
U.S. National Library of Medicine
U.S. National Institutes of Health
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/ct2/show/study/NCT02398006 |
SB898.DOC
A BILL FOR AN ACT
making appropriations for collective bargaining cost
items.
BE IT ENACTED BY THE LEGISLATURE OF THE STATE OF HAWAII:
PART
I
SECTION 1. There are appropriated or
authorized from the sources of funding indicated below to Program Planning,
Analysis, and Budgeting (BUF 101) the following sums or so much thereof as may
be necessary to fund for fiscal biennium 2013-2015 all collective bargaining
cost items contained in the agreements negotiated with the exclusive bargaining
representatives of collective bargaining unit 4:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
Special
Funds -0- -0-
Federal
Funds -0- -0-
Other
Funds -0- -0-
SECTION 2. Funds appropriated or authorized by
this part shall be allotted by the director of finance to the appropriate state
departments in the respective fiscal year for expenditure for the purposes of
this part.
PART
II
SECTION 3. There are appropriated or authorized
from the sources of funding indicated below to Program Planning, Analysis, and
Budgeting (BUF 101) the following sums or so much thereof as may be necessary
to fund for fiscal biennium 2013-2015 the salary increases and other cost
adjustments authorized by chapter 89C, Hawaii Revised Statutes, for state
officers and employees in the executive branch who are excluded from collective
bargaining and belong to the same compensation plans as those officers and
employees within collective bargaining unit 4:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
Special
Funds -0- -0-
Federal
Funds -0- -0-
Other
Funds -0- -0-
SECTION 4. Funds appropriated or authorized by
this part shall be allotted by the director of finance to the appropriate state
departments in the respective fiscal year for expenditure for the purposes of
this part.
PART III
SECTION 5. There are appropriated or
authorized from the sources of funding indicated below to Administration (JUD
601) the following sums or so much thereof as may be necessary to fund for
fiscal biennium 2013-2015 all collective bargaining cost items in the
agreements negotiated with the exclusive bargaining representatives of
collective bargaining unit 4:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
Special
Funds -0- -0-
SECTION 6. Funds appropriated
or authorized by this part shall be allotted by the chief justice in the
respective fiscal year for expenditure for the purposes of this part.
PART
IV
SECTION
7. There are appropriated or authorized from the source of funding indicated
below to Administration (JUD 601) the following sums or so much thereof as may
be necessary to fund for fiscal biennium 2013-2015 salary increases and other
cost adjustments authorized by chapter 89C, Hawaii Revised Statutes, for state
officers and employees of the judiciary who are excluded from collective
bargaining and belong to the same compensation plans as those officers and
employees within collective bargaining unit 4:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
Special
Funds -0- -0-
SECTION 8. Funds appropriated or authorized by
this part shall be allotted by the chief justice in the respective fiscal year
for expenditure for the purposes of this part.
PART
V
SECTION 9. There is appropriated or authorized
from the source of funding indicated below to Hospital Care –- Hawaii Health
Systems Corporation (HTH 210) the following sums or so much thereof as may be
necessary to fund for fiscal biennium 2013-2015 all collective bargaining cost
items in agreements with the exclusive bargaining representatives of collective
bargaining unit 4 assigned to the Hawaii health systems corporation:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
SECTION 10. Funds appropriated or authorized
by this part shall be allotted by the director of finance to the Hawaii health
systems corporation in the respective fiscal year for expenditure for the
purposes of this part.
PART
VI
SECTION 11. There is appropriated or
authorized from the source of funding indicated below to Hospital Care – Hawaii
Health Systems Corporation (HTH 210) the following sums or so much thereof as
may be necessary to fund for fiscal biennium 2013-2015 the salary increases and
other cost adjustments authorized by chapter 89C, Hawaii Revised Statutes, for
state officers and employees assigned to the Hawaii health systems corporation
who are excluded from collective bargaining:
FY
2013-2014 FY 2014-2015
General
Funds -0- -0-
SECTION 12. Funds appropriated or authorized
by this part shall be allotted by the director of finance to the Hawaii health
systems corporation in the respective fiscal year for expenditure for the
purposes of this part.
PART
VII
SECTION 13. Salary increases and cost
adjustments provided in this Act for any officer or employee whose compensation
is paid, in whole or in part, from federal, special, or other funds shall be
paid wholly or proportionately, as the case may be, from the respective funds.
SECTION 14. Funds appropriated or authorized
by this Act that are not expended or encumbered by June 30, 2014, and June 30,
2015, of the respective fiscal years, shall lapse as of those dates.
SECTION 15. This Act shall take effect on July
1, 2013.
INTRODUCED BY: _____________________________
Report Title:
Cost Items; Collective Bargaining; Unit 4
Description:
Provides fund authorization and appropriations for Unit 4
collective bargaining cost items and their excluded counterparts for fiscal
biennium 2013-2015, including all collective bargaining cost items in the
agreements negotiated between the State and the bargaining unit
representative. Effective July 1, 2013.
The
summary description of legislation appearing on this page is for informational
purposes only and is not legislation or evidence of legislative intent.
| https://www.capitol.hawaii.gov/sessions/session2013/bills/SB898_.HTM |
[lbo-talk] Voter support for same-sex marriage bans declining
Doug Henwood dhenwood at panix.com
Tue Dec 5 14:55:36 PST 2006 Previous message: [lbo-talk] Nepal's comrades tie a party knot
Next message: [lbo-talk] Flirting With Fascism on CNN Headline News
Messages sorted by: [ date ] [ thread ] [ subject ] [ author ]
Search LBO-Talk Archives
Limit search to: Subject & Body Subject Author
Sort by:
Date Rank Author Subject
Reverse Sort
[report: < http://www.thetaskforce.org/downloads/Egan_Sherrill_06.pdf >]
Voter support for same-sex marriage bans declining, study finds
Ballot measures' appeal diminishes in states with fewer evangelical
Christians;
marriage initiatives did not help Republican Senate candidates in 2006
WASHINGTON, Dec. 5 — Bans on same-sex marriage performed more poorly
in the November 2006 elections than in the past, in part due to their
declining appeal in states with smaller "born-again" Christian
populations, according to a study released today by the National Gay
and Lesbian Task Force Policy Institute. If current trends hold, such
bans would fail at the ballot box in many of the states that have not
yet considered same-sex marriage initiatives.
Same-sex marriage bans passed with an average of 64 percent of voter
support in all states in 2006, down from a similar figure of 71
percent in 2004. But support has fallen even more dramatically in
states where those identifying themselves as born-again or
evangelical Christians make up an identifiable minority of residents,
according to the report.
Same-sex marriage ballot questions did not help Republican Senate
candidates, even though minimum wage initiatives appeared to help
Democratic Senate candidates, the study found. Three in four lesbian,
gay and bisexual (LGB) voters backed a Democrat for the U.S. House of
Representatives in 2006, about the same as the 77 percent of LGB
voters who backed John Kerry in 2004.
The study, Same-sex marriage initiatives and lesbian, gay and
bisexual voters in the 2006 elections, was written by Patrick Egan of
Princeton University and Kenneth Sherrill of Hunter College.
Egan and Sherrill's analysis of 2006 election returns and data from
the National Election Pool exit poll, which asks voters if they are
"gay, lesbian or bisexual" but does not ask about gender identity,
found that:
* While the vote on the marriage initiatives is best explained by
partisan and ideological variables, declining support for marriage
bans can also be explained somewhat by the measures' diminishing
appeal in states with fewer voters identifying as "born-again"
Christians.
* If current trends hold, marriage bans would fail — or just barely
pass — in many of the states that have yet to hold such referenda.
* There is no evidence that the presence of marriage bans on the
ballot in 2006 helped Republican Senate candidates.
* In 2006, lesbian, gay and bisexual (LGB) voters for the most part
looked demographically like the rest of the electorate, with two
major exceptions — LGB voters were much younger and more urban than
other voters.
* As in previous elections, LGB voters exhibited distinctive voting
behavior. They continued to vote overwhelmingly (75 percent) for
Democratic candidates and took liberal positions on the major issues
of the day. Only Jewish voters (87 percent) and black voters (89
percent) voted for Democrats at higher rates than LGB voters.
"While banning same-sex marriage remains popular in states with many
religious conservatives, support is waning in places with more
tolerant religious traditions," said study co-author Patrick Egan, a
visiting scholar at Princeton University. "It may be that these
states have political environments in which gay rights advocates have
become better able to get their messages across to voters."
"The days of winning national elections on the backs of gay people
appear to be over," said Kenneth Sherrill of Hunter College's
political science department and an author of the study. "Contrary to
conventional wisdom, marriage initiatives did not give President Bush
a lift in 2004. They were of no more help to Republicans running for
Senate in 2006."
The data also indicate that, in terms of family heritage and other
demographic variables, we should expect LGB Americans to be as
Republican as anyone else. But as in previous elections, LGB voters
overwhelmingly identified as Democrats (52 percent) and as liberals
(43 percent). Almost half of LGB voters said that the Bush
administration made them feel "angry."
"This study demonstrates — yet again — that gay voters are a loyal,
core and essential part of the Democratic base," said Matt Foreman,
executive director of the National Gay and Lesbian Task Force. "We
look forward to working with the new Congress to move forward on long-
stalled priorities for our community, including nondiscrimination and
hate crimes protections."
-30- The mission of the National Gay and Lesbian Task Force is to build
the political power of the lesbian, gay, bisexual and transgender
(LGBT) community from the ground up. We do this by training
activists, organizing broad-based campaigns to defeat anti-LGBT
referenda and advance pro-LGBT legislation and building the
organizational capacity of our movement. Our Policy Institute, the
movement's premier think tank, provides research and policy analysis
to support the struggle for complete equality and to counter right-
wing lies. As part of a broader social justice movement, we work to
create a nation that respects the diversity of human expression and
identity and creates opportunity for all. Headquartered in
Washington, D.C., we also have offices in New York City, Los Angeles,
Miami, Minneapolis and Cambridge. The Task Force is a 501(c)(3)
corporation incorporated in Washington, D.C. Contributions to the
Task Force are tax-deductible to the full extent allowed by law. (C)
2005–2006 National Gay and Lesbian Task Force. 1325 Massachusetts Ave
NW, Suite 600, Washington, DC 20005. Phone 202.393.5177. Fax
202.393.2241. TTY 202.393.2284.
theTaskForce at theTaskForce.org. Previous message: [lbo-talk] Nepal's comrades tie a party knot
Next message: [lbo-talk] Flirting With Fascism on CNN Headline News
Messages sorted by: [ date ] [ thread ] [ subject ] [ author ]
More information about the lbo-talk
mailing list | http://mailman.lbo-talk.org/2006/2006-December/024221.html |
Is right to property a civil right?
Is right to property a civil right? Right to Property ceased to be a fundamental right with the 44th Constitution...
Is right to property a civil right?
Table of contents:
Is right to property a civil right?
Can eminent domain be stopped?
What are the 5 legal interests in land?
What is a fee simple property?
Is a fee simple estate inheritable?
What is the main difference between a license and an easement?
What Freehold means?
What's a fee simple title?
What is the difference between freehold and fee simple?
What is freehold fee simple?
What is a fee simple land lease?
Are condominiums fee simple?
Is right to property a civil right?
Right to Propertyceased to be a fundamental rightwith the 44th Constitution Amendment in 1978. It was made a Constitutional rightunder Article 300A. Article 300A requires the state to follow due procedure and authority of law to deprive a person of his or her private property.
Can eminent domain be stopped?
The only way to stop eminent domainis to challenge the government's right to take. You canonly do this if the government's proposed taking does not meet the requirements for public necessity or public purpose.
What are the 5 legal interests in land?
There are various legal interests in land under the LPA as follows.
Legal easements, rights and privileges. Legal easements are rights attached to one piece of land , entitling the occupy to do something over another's property. ...
Rentcharges. ...
Charge by way of legal mortgage. ...
Rights of entry.
What is a fee simple property?
What Is Fee SimpleAbsolute Ownership? The best form of real property ownershipis fee simpleabsolute, sometimes called a freehold, which means that the owner or owners can do whatever they like with the property, subject only to encumbrances like liens, or local guidelines, such as zoning, taxation or criminal laws.
Is a fee simple estate inheritable?
The fee simpleabsolute is inheritable; the life estateis not. A fee simpleabsolute is the most extensive interest in real property that an individual can possess because it is limited completely to the individual and his heirs, assigns forever, and is not subject to any limitations or conditions.
What is the main difference between a license and an easement?
Thus, a licenseis simply a permitor privilege to do what would otherwise be considered an unlawful trespass. An easement, on the other hand, is a nonpossessory interest in theland of another. This is an important distinctionin that an easementis an “interest in land,” not a mere contract right.
What Freehold means?
The freeholder of a property owns it outright, including the land it's built on. If you buy a freehold, you're responsible for maintaining your property and land, so you'll need to budget for these costs. Most houses are freeholdbut some might be leasehold – usually through shared-ownership schemes.
What's a fee simple title?
Fee simplerefers to how people own real estate. Say you buy a home in the United States from a seller. In the vast majority of cases, you will now have whatis known as fee simple ownershipof this property. With fee simple, you take full and complete ownershipof a piece of land and any buildings that sit on it.
What is the difference between freehold and fee simple?
A freehold estateis an estatein which you have exclusive rights to enjoy the possession of a property for an undefined length of time. In contrast, a less than freehold estateis held for a fixed, defined period. Fee simpleabsolute is the greatest interest in aparcel of land that one can possibly own.
What is freehold fee simple?
Freeholdland (or fee simple) provides people with the most complete form of ownership of that land, in perpetuity. It allows the land holder to deal with the land including selling, leasing, licensing or mortgaging the land, subject to compliance with applicable laws such as planning and environment laws.
What is a fee simple land lease?
What Does Fee SimpleMean? Fee simpleownership is the absolute ownership of real property, in which the owner holds unconditional power over the land, as well as any improvements — including buildings — that sit on it.
Are condominiums fee simple?
Fee simpleis a legal term describing the most common and absolute type of property ownership. ... Owners of single-family residences have fee simpleownership, but condoand many townhouse owners don't, since they own only their individual unit, not the land on which the development is built.
Is therapeutic cloning safe?
| https://philosophy-question.com/library/lecture/read/251814-is-right-to-property-a-civil-right |
Clock and Reset Design Based on SOC Chip System
Download Citation | Clock and Reset Design Based on SOC Chip System | Starting from optimization of methodologies and circuit design, a reset method and a clock-reset circuit based on system-on-chip(SOC) was... | Find, read and cite all the research you need on ResearchGate
Clock and Reset Design Based on SOC Chip System
April 2017
Bandaoti Guangdian/Semiconductor Optoelectronics 38(2):293-298
DOI: 10.16818/j.issn1001-5868.2017.02.029
Authors:
Abstract
Starting from optimization of methodologies and circuit design, a reset method and a clock-reset circuit based on system-on-chip(SOC) was proposed. The design of modules including off-chip button reset circuit, on-chip power-on circuit, crystal oscillator control circuit, on-chip RC low frequency clock circuit, channel pulse generation circuit, frequency division delay circuit, clock switching circuit and asynchronous reset synchronous release circuit were presented. A specific reset method was established and a clock reset circuit applicable to SOC was formed on the basis of the circuit modules above. The clock reset system combines off-chip reset button and on-chip power-on reset, forming a multiple reset design, which is more intelligent than using single reset button and of more reliability compared to using power-on reset only. In addition, an on-chip RC clock oscillation circuit was used in the clock reset circuit to realize the chip delay reset, therefore not only the correct initialization of registers was guaranteed during the reset period, but also consistent normal working condition of the whole chip under the stable oscillating clock was ensured. Compared with the traditional clock reset circuit, the clock reset system is convenient and guarantees the reliability of system initialization and operation. © 2017, Editorial Office of Semiconductor Optoelectronics. All right reserved.
Research of Rotor Position Detection for Sensorless BLDCM without Hardware Filter Circuit
A rotor position detection method based on the state of chip's registers and the features of freewheeling time when motor is commutating was presented for the sensorless control system of Brushless DC(BLDC) motors with no hardware filter circuit. The interference of PWM switching noise and the noise of freewheeling can be avoided by detecting the effective range of non-conducting phase's terminal ... [Show full abstract] voltage and delaying an appropriate time to avoid the noise of freewheeling. The method does not need the complex hardware filter and detection circuit, and it also does not need the complex algorithms, so the method has advanced practicability. The theoretical derivation proves the correctness of the method, and the control results are given under different PWM duty cycles and loads in the experiment, which confirms the validity of the presented method. © 2017, The editorial office of Transaction of China Electrotechnical Society. All right reserved.
4509008 Method of concurrently testing each of a plurality of interconnected integrated circuit chip...
Disclosed is a design discipline, or approach, in the form of circuitry and a test method, or methodology which obviates the problems of the prior art and allows testing of each individual chip and interchip connections of a plurality of interconnected chips contained on or within a high density packaging structure. This testing is accomplished without the need for and utilization of test ... [Show full abstract] equipment having a precision probe and a high precision step and repeat mechanism. CPA is a method and circuit design discipline that, where followed, will result in a testable multichip package given that each logical component is testable and the design is synchronous in nature. The CPA discipline is able to accomplish this by making use of shift register latches on the chips or functional island periphery. These latches are used to indirectly observe and/or control the synchronous network, in many ways replicating the stuckfault test environment under which tests were generated at the lower subcomponent level of assembly. One method, full CPA, offers the ability to apply these tests to all full CPA chips on the multichip package simultaneously or in unison, thus reducing manufacturing tester time. An additional benefit is the ease of testing intercomponent connections.
Single event effect experiment on SoC using pulsed laser
In order to evaluate the effectiveness of pulse laser experiment aiming at the single event effect of SoC (System on Chip), an experiment system was established based on a 65 nm SoC. The methods of coordinate setting, focusing on source and compensation about ΔZ on flip chip integrated circuit were proposed and employed. Pulsed laser tests were carried on static random access memory, register ... [Show full abstract] file, RapidIO and Dice flip-flop. The results indicate that SRAM is the most sensitive area and the results on these modules are consistent with the corresponding results under heavy-ion experiment. Therefore, the pulse laser is suitable for single-event effect researches on large-scale integrated circuit designed with nanometer technology.
A mixed EFL I<sup>2</sup>L digital telecommunication integrated circuit
A bipolar digital telecommunications circuit has been designed in the OXIL technology as part of a VLSI upgrade of an existing digital switching circuit. The chip is unique in its exploitation of the OXIL oxide isolated process which allows both high gain "up" and "down" devices used for I<sup>2</sup>L and EFL (emitter function logic), respectively. This allowed the circuit designers to tailor ... [Show full abstract] power consumption, circuit speed, and gate density as needed. In particular, the high speed properties of EFL were utilized in the control section to provide accurate timing signals and satisfy tight propagation delay requirements in the register section. I<sup>2</sup>L, because of its greater density and low power, was used in the gate intensive register sections. Another novel feature of this device was the treatment of bus lines (up to 250 fanout) such as clock, clear, etc., in the I<sup>2</sup>L sections. The common multiline I<sup>2</sup>L drive problem has been overcome here by using high drive translators from EFL circuitry and a single pullup resistor per bus line to provide switched currents to all gates on that line.
Fabrication and Circuits Design of Flexible MEMS Flow Sensor
Combinatorial Aspects of Lower Power Clock Layout Synthesis in VLSI Synchronous Circuits
In a synchronous VLSI design, carrying the heaviest load and switching at high frequency, clock distribution is a major source of power dissipation. Also, circuit speed and chip area have been an important consideration and the delay on the longest path (phase delay) through combinational logic, and the maximum skew among the synchronizing components should be minimized. There have been active ... [Show full abstract] research in the area of high-performance and low-power clock routing. This paper gives an overview of a number of combinatorial aspects and highlights the state of the art of currently active research areas on low power clock tree synthesis. Promising future directions and open problems are also investigated. 1 Introduction Reduction in power consumption without sacrificing processing speed is increasingly important objective in integrated circuit design nowadays. One reason is the requirement of longer battery life for the growing class of personal computing devices, such as portable d...
A 9 bit 34 MS/s SAR Analog-to-Digital Converter in 130 nm SiGe BiCMOS
A 9 bit 34 MS/s successive approximation register (SAR) analog-to-digital converter (ADC) is presented. The successive approximation is realized with a switched-capacitor digitalto- analog converter (SC-DAC) which is very power efficient. The switching control and SAR are implemented with special flip-flops that have two delay inputs. The classical switching algorithm is extended to be capable of ... [Show full abstract] deriving one additional bit. The ADC is implemented in a 130 nm SiGe BiCMOS technology. The chip size is 2.1??0.7 mm2 while the ADC core only occupies 0.3??0.2 mm2. At a conversion rate of 22 MS/s the SNDR and SFDR are 49.3 dB and 59.8 dB with a low frequency input. For Nyquist frequency, SNDR and SFDR are 48.7 dB and 59.0 dB. The effective resolution bandwidth (ERBW) is 30 MHz. The ADC consumes 3.3 mW from a 1.3 V supply and has a FoM of 630 fJ/conv. step at 22 MS/s.
| https://www.researchgate.net/publication/317829254_Clock_and_Reset_Design_Based_on_SOC_Chip_System |
Diagnostics | Free Full-Text | Risk Factors of In-Hospital Mortality in Non-Specialized Tertiary Center Repurposed for Medical Care to COVID-19 Patients in Russia
The purpose of our study is to investigate the risk factors of in-hospital mortality among patients who were admitted in an emergency setting to a non-specialized tertiary center during the first peak of coronavirus disease in Moscow in 2020. The Federal Center of Brain and Neurotechnologies of the Federal Medical and Biological Agency of Russia was repurposed for medical care for COVID-19 patients from 6th of April to 16th of June 2020 and admitted the patients who were transported by an ambulance with severe disease. In our study, we analyzed the data of 635 hospitalized patients aged 59.1 ± 15.1 years. The data included epidemiologic and demographic characteristics, laboratory, echocardiographic and radiographic findings, comorbidities, and complications of the COVID-19, developed during the hospital stay. Results of our study support previous reports that risk factors of mortality among hospitalized patients are older age, male gender (OR 1.91, 95% CI 1.03–3.52), previous myocardial infarction (OR 3.15, 95% CI 1.47–6.73), previous acute cerebrovascular event (stroke, OR = 3.78, 95% CI 1.44–9.92), known oncological disease (OR = 3.39, 95% CI 1.39–8.26), and alcohol abuse (OR 6.98, 95% CI 1.62–30.13). According to the data collected, high body mass index and smoking did not influence the clinical outcome. Arterial hypertension was found to be protective against in-hospital mortality in patients with coronavirus pneumonia in the older age group. The neutrophil-to-lymphocyte ratio showed a significant increase in those patients who died during the hospitalization, and the borderline was found to be 2.5. CT pattern of “crazy paving” was more prevalent in those patients who died since their first CT scan, and it was a 4-fold increase in the risk of death in case of aortic and coronal calcinosis (4.22, 95% CI 2.13–8.40). Results largely support data from other studies and emphasize that some factors play a major role in patients’ stratification and medical care provided to them.
Risk Factors of In-Hospital Mortality in Non-Specialized Tertiary Center Repurposed for Medical Care to COVID-19 Patients in Russia
by Anton Kondakov * , Alexander Berdalin , Vladimir Lelyuk , Ilya Gubskiy and Denis Golovin
Radiology and Clinical Physiology Research Center, Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency, 117997 Moscow, Russia
Author to whom correspondence should be addressed.
Diagnostics 2021 , 11 (9), 1687; https://doi.org/10.3390/diagnostics11091687
Received: 25 August 2021 / Revised: 11 September 2021 / Accepted: 13 September 2021 / Published: 15 September 2021
(This article belongs to the Section Diagnostic Microbiology and Infectious Disease )
Abstract
The purpose of our study is to investigate the risk factors of in-hospital mortality among patients who were admitted in an emergency setting to a non-specialized tertiary center during the first peak of coronavirus disease in Moscow in 2020. The Federal Center of Brain and Neurotechnologies of the Federal Medical and Biological Agency of Russia was repurposed for medical care for COVID-19 patients from 6th of April to 16th of June 2020 and admitted the patients who were transported by an ambulance with severe disease. In our study, we analyzed the data of 635 hospitalized patients aged 59.1 ± 15.1 years. The data included epidemiologic and demographic characteristics, laboratory, echocardiographic and radiographic findings, comorbidities, and complications of the COVID-19, developed during the hospital stay. Results of our study support previous reports that risk factors of mortality among hospitalized patients are older age, male gender (OR 1.91, 95% CI 1.03–3.52), previous myocardial infarction (OR 3.15, 95% CI 1.47–6.73), previous acute cerebrovascular event (stroke, OR = 3.78, 95% CI 1.44–9.92), known oncological disease (OR = 3.39, 95% CI 1.39–8.26), and alcohol abuse (OR 6.98, 95% CI 1.62–30.13). According to the data collected, high body mass index and smoking did not influence the clinical outcome. Arterial hypertension was found to be protective against in-hospital mortality in patients with coronavirus pneumonia in the older age group. The neutrophil-to-lymphocyte ratio showed a significant increase in those patients who died during the hospitalization, and the borderline was found to be 2.5. CT pattern of “crazy paving” was more prevalent in those patients who died since their first CT scan, and it was a 4-fold increase in the risk of death in case of aortic and coronal calcinosis (4.22, 95% CI 2.13–8.40). Results largely support data from other studies and emphasize that some factors play a major role in patients’ stratification and medical care provided to them.
Keywords:
COVID-19
;
risk factors
;
arterial hypertension
;
computed tomography
;
body mass index
1. Introduction
1.1. Background
COVID-19 became the first pandemic infection in the 21st century. As of 31st of August 2021, 215,714,824 people were infected with SARS-CoV-2 virus and 4,490,753 have died. Despite the high priority of response measures, established by most of the countries, SARS-CoV-2 still is spreading in different regions, with a tendency to increase the number of infected [ 1 ].
Coronaviruses are enveloped, single-stranded RNA viruses, that are commonly found in people and other mammals and cause respiratory, gastrointestinal, and neurologic diseases. The most common coronaviruses cause symptoms of the common cold in the immunocompetent population. SARS-CoV-2 is the third coronavirus to cause severe disease and spread all over the world in the last two decades. The first one was the virus of severe acute respiratory syndrome (SARS) that appeared in Foshan in China and caused the SARS-CoV pandemic 2002–2003. The next one was called Middle Eastern respiratory syndrome (MERS), which appeared on the Arabian Peninsula in 2012. Current SARS-CoV-2 virions have a diameter from 60 to 140 nm and characteristic spikes with a length of 9–12 nm, making them look like a stellar corona [
2
].
SARS-CoV-2 has been found to have a higher transmission rate, compared to SARS and MERS. Its basic reproduction number (R0) was previously reported to be 3.32 (95% CI 3.24–3.39), and the incubation period is about 5.24 days (95% CI: 3.97–6.50), with variation in time of symptom appearance across countries [ 3 ]. In other studies, basic reproduction number has been found to be 2.21 (95% CI 1.86–2.63) in Western Europe [ 4 ], 5.9 (95% CI 4.7–7.5) in the USA [ 5 ], and 4.08 (95% CI 3.09–5.39) at the global level [ 6 ].
In the earliest stage, SARS-CoV-2 is targeted to nasal cavities’ epithelium, bronchial epithelium, and alveolocytes, which is realized by the binding of a virus’ S-protein to a receptor of angiotensin-converting enzyme type 2 (ACE2) on the cellular surface. Although it was thought that an increase in the number of ACE2, caused by ACE inhibitors and angiotensin receptor blockers (ARB), increases susceptibility to the infection, large groups of investigators found no link between these medications and risks of infection or in-hospital mortality. For example, in a Dutch research on 4480 patients with COVID-19, previous treatment with inhibitors of ACE and ARB has not influenced the mortality rate [
7
]. Research on comparison of ACE inhibitors and ARB with a frequency of positive SARS-CoV-2 polymerase chain reaction tests among 18,472 patients resulted in no significant association between them and supported the practice of treatment with these types of medications during the COVID pandemic [
8
].
In the later stages of the infection process, when virus replication speeds up, the integrity of the epithelial-endothelial barrier becomes weaker. Besides epithelial cells, SARS-CoV-2 infects endothelial cells of lung capillaries, which leads to an increase in inflammatory reaction and influx of monocytes and neutrophils. The autopsy on these stages of the disease shows diffuse thickening of an alveolar wall with mononuclear and macrophagic infiltration of airspaces, with endothelialitis. During the infectious process, the interstitial inflammatory infiltrates and concurrent edema are visualized by CT as ground-glass opacities (GGO). The evolution of the infiltration process leads to lung edema, which fills up alveolar airspace and forming of hyaline membranes, which corresponds to the early stage of acute respiratory distress syndrome [
2
,
3
].
In summary, endothelial barrier impairment, alveolar-to-capillary oxygen transmission, and oxygen diffusion are characteristic parts of COVID pneumonia. Along with that, COVID-19 may cause lymphopenia by infecting and causing necrosis of T-lymphocytes.
Classical clinical symptoms of COVID-19 are fever (38.1–39.0 °C), cough, and fatigue, and most often complication is acute respiratory distress syndrome (ARDS). It had been found that fever over 39.0 °C, shortness of breath, and anorexia are more often in critically ill patients [ 3 ].
In severe cases of COVID-19 rapid activation of coagulation and consumption of blood coagulation factors occurs [ 9 ]. It is recognized that the pathophysiology of coagulation disturbances in COVID-19 mostly relies on some complicated interactions between proinflammatory cytokines, platelet activation, and downregulation of natural anti-coagulation system on the one side and endothelial dysfunction, von-Willebrand factor secretion, and complement activation on the other [ 10 ]. Inflamed lung parenchyma and damaged lung endothelium may cause the microthrombi formation and lead to a higher frequency of thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and arterial thrombosis (e.g., in case of ischemic infarction and limb ischemia) in severely ill patients. To date, it had been found that coagulopathy in the case of coronavirus infection has characteristics of both disseminated intravascular coagulation (DIC) syndrome and local thrombotic events [ 11 , 12 ]. It is also reported that in some cases, due to imbalance in platelet production and consumption, some patients have an increased risk of bleeding complications but this condition is thought to be rare [ 10 ].
1.2. Risk Factors of Lethality and Severe Course of COVID-19
The combination of different COVID-19 patient characteristics leads to a different course of the disease that varies from asymptomatic to severe and may cause need in respiratory assistance and even death [ 13 , 14 ]. Thus, identification of risk factors of severe course of the disease is very valuable for timely hospital admission and precise patient status monitoring.
For the identification of these risk factors many studies were performed, a short review of their main results is presented below. Lack of standard study protocol, different inclusion criteria, and various treatment strategies result in different risk factors. This can be overcome by a unified protocol of data collection and analysis which has yet to be developed.
In a systematic review, Yewei Xie et al. showed that one of the risk factors of a COVID-19 patient’s death is the patient’s gender. In the overall analysis, males have a 35% higher chance of death compared to women (fatality rate ratio was found to be 1.35, with a 95% CI 1.35–1.35), and this tendency was shown in all regions and age groups. Moreover, the fatality rate ratio for males to females is higher in the younger age group (2.74, 95% CI 2.66–2.82, in the age group younger than 60 years) compared to older patients (1.83, 95% CI 1.82–1.83, in the age group 60 years and older) [ 3 ]. Similar results were found in the meta-analysis by Vignesh Chidambaram et al. [ 15 ], with a fatality rate ratio of 1.45 (95% CI 1.23–1.71). Despite few conflicting results [ 16 ], the male gender is recognized as a major risk factor of death [ 17 ] and risk factor of ICU admission [ 18 ] in other studies.
Age is an undeniable risk factor of severe course and death in coronavirus infection, with an increase in the probability of death in the older population [ 3 , 15 , 17 , 19 , 20 ]. Older age is an independent risk factor of severe course and mortality in coronavirus pneumonia (in general, patients older than 75 years had a 13-fold increase of risk of death (95% CI 9.13–17.85) compared to patients younger than 65 years). This effect can be partially explained by interfering comorbidities, which are more common in the older population [ 21 ].
There are conflicting results about smoking status and the risk of mortality in COVID. In the early report of Constantine Vardavas and Katerina Nikitara, there was a negative influence of smoking status shown on the outcome of coronavirus pneumonia, based on limited data [
22
]. However, in a systematic review, Giuseppe Lippi and Brandon Michael Henry found no statistically significant difference among the risk of mortality for smokers and non-smokers (OR 1.69; 95% CI 0.41–6.92) [
23
]. In a recent review on a link between smoking status and risk of severe course of COVID-19 it was shown that smokers have a higher chance of critical illness (OR 1.58; 95% CI 1.16–2.15) and death (OR 1.35; 95% CI 1.12–1.62). Similarly, it was reported that former smokers have a higher risk of critical illness and death (OR 2.48; 95% CI 1.64–3.77 and 2.58; 95% CI 2.15–3.09, respectively) [
24
].
The influence of high body mass index (BMI) on severity and mortality is often mentioned in different articles. In a meta-analysis of 22 studies, it was found that BMI was higher in severe and critically ill patients compared to mild disease (average difference was 2.48 kg/m
2
, 95% CI 2.00–2.96 kg/m
2
). In addition, obesity in patients with COVID-19 was associated with negative outcomes (OR 1.683, 95% CI 1.408–2.011), which were defined as severe disease, the need for intensive care, the use of invasive mechanical ventilation, or disease progression. Obesity as a risk factor was more pronounced in younger patients (odds ratio 3.30 vs. 1.72). In this analysis, obesity did not increase the risk of hospital mortality (odds ratio 0.89, 95% CI 0.32–2.51) [
25
]. On the other hand, a review based on data from the AHA register of cardiovascular diseases showed that a high body mass index is a risk factor for patient death in a medical institution: the risk ratio for III obesity class was 1.26 (95% CI 1.00–1.58). The need for mechanical ventilation was also higher in overweight and obese patients I–III classes (odds ratio 1.28 [95%CI 1.09–1.51], 1.54 [1.29–1.84], 1.88 [1.52–2.32], and 2.08 [1.68–2.58], respectively) [
26
].
Comorbidities significantly worsen the patient’s prognosis. Already in the early stages of the pandemic, links between hypertension, cardiovascular disease, chronic kidney disease, and diabetes have been demonstrated [
27
]. These conclusions were confirmed by subsequent studies. In a recent systematic review and meta-analysis by Maryam Honardoost et al., it was shown that disease severity was significantly higher among patients with a history of cerebrovascular diseases (odds ratio 4.85, 95% CI: 3.11–7.57), cardiovascular diseases (OR 4.81 95% CI: 3.43–6.74), chronic lung diseases (4.19, 95% CI: 2.84–6.19), malignancies (OR 3.18, 95% CI: 2.09–4.82), diabetes (OR 2.61, 95% CI: 2.02–3.3), and arterial hypertension (OR 2.37, 95% CI: 1.80–3.13) [
28
].
Biochemical blood test abnormalities in patients with severe infection are noteworthy. Older adults were reported to have higher levels of low-density lipoproteins, a larger width of red blood cell distribution, and higher levels of the D-dimer than other age groups, suggesting that these patients were more likely to have impaired blood clotting function [ 29 ].
Another coagulation system status marker, platelet count, was also considered as an independent risk factor. It should be noted that according to the meta-analysis by G. Lippi et al., thrombocytopenia was a predictor of the development of severe disease, while the weighted average difference in the number of platelets between patients with mild and severe coronavirus infection was −31 × 10
9
/L (95% CI ranges from−35 to −29 × 10
9
/L), and when comparing patients with a mild course of the disease and deceased patients, the weighted average difference increases to −48 × 10
9
/L (95% CI ranges from −57 to −39 × 10
9
/L), and the risk ratio of severe disease in patients with thrombocytopenia was found to be 5.1 (95% CI 1.8–14.6) [
30
].
In addition to these parameters, it is necessary to include a widespread and easily accessible marker of the severity of the process—lymphopenia, which is accompanied by leukocytosis and neutrophilia [
31
]. Based on numerous data A.-P. Yang et al. suggested using the neutrophil-to-lymphocyte ratio (NLR) as a predictive marker of the severe course of the disease [
32
]. It was shown that high values of this marker are independently associated with a severe course of the disease (risk 2.46, 95% CI 1.98–4.57), and the threshold value is 3.3 [
32
]. The data were also confirmed in the paper by J. Liu, but the threshold value of this parameter for discriminating patients into high- and low-risk groups was reduced to 3.13, with 50% of patients in the higher NLR group suffering from critically severe disease [
33
].
In biochemical blood tests, the most significant predictive parameters of severe disease were elevated levels of C-reactive protein (weighted mean difference 42.7 mg/L, 95% CI 31.12–54.28), lactate dehydrogenase (weighted mean difference 137.4 U/L, 95% CI 105.5–169.3), procalcitonin (weighted mean difference 0.07 ng/mL, 95% CI 0.05–0.10), ALT (weighted mean difference 5.12 U/L, 95% CI 0.82–9.42), AST (weighted mean difference 8.51 U/L, 95% CI 5.01–12.01), and creatinine (weighted mean difference 4.57 µmol/L, 95% CI 0.64–8.50) [ 34 ].
CT analysis uses a semi-quantitative scale for assessing lung tissue involvement, according to which the degree of damage to each lobe of the lung is determined on a 5-point scale, then all points are summed up to get a total damage score, giving a total score ranging from 0 to 25 points [ 35 ].
According to the results of published studies, this summary assessment is the independent risk factor for a severe course and unfavorable outcome of the disease. At the same time, with a total score of more than 18, the risks of death were higher both in the univariate analysis (HR, 8.33; 95% CI, 3.19–21.73) and in the multivariate analysis (HR, 3.74; 95% CI, 1.10–12.77), that was done with 130 patients [ 36 ]. Similar data are presented in other studies (in patient cohorts ranging from 128 to 572 participants), both in semi-quantitative and quantitative assessment of lung tissue involvement [ 37 ].
When studying specific CT patterns of the disease, it was shown that the presence of mosaic perfusion is predictive for the development of a severe course of the disease, while the presence of an air bronchogram, the location and structure of areas of reduced pneumatization of lung tissue (ground-glass opacities—GGO), and the presence of thickened vascular bundles did not show such relationships [
38
]. According to N. Lassau et al., the peripheral location of sites of reduced pneumatization of the pulmonary parenchyma is a predictor of a milder course of infection, while the symptom of “crazy paving” (GGO and thickened interlobular septa) and the prevalence of the disease in the lungs are predisposing factors for the severe course of the disease [
39
].
The main findings of some of the aforementioned studies are summarized in Table 1 .
Table 1. Summary of the main risk factors of COVID-19 severe outcome or death reported in the literature.
In the Russian population, Youri Kirillov et al. previously reported their data based on retrospective cohort analysis of electronic medical records of 1487 deceased patients with RT-PCR confirmed COVID-19. According to their report, the median age for lethal outcome was 71 years of age among males and 78 for females. Arterial hypertension was reported in 81% of their cases, diabetes mellitus was found to be a comorbidity in 37% of cases. About 12% of deceased patients had cancer [ 40 ].
Thus, there are data on various risk factors for severe coronavirus infection. In this article, we present the results of our analysis of the intrahospital COVID-19 course collected during the work in March–July 2020. The presented data on the patient population will complement the knowledge about the disease and allow us to develop tactics for the distribution of patients, stratification of their risk level, and algorithms for maintenance therapy.
2. Materials and Methods
2.1. Patients
We analyzed the database containing a total of 635 patients who were treated at the Federal Center of Brain research and Neurotechnologies, repurposed for Health Care for COVID-19 in the spring of 2020. In total, more than 700 patients passed through our center, but some of them refused to be hospitalized, were transferred to other medical organizations, and some were not confirmed to have coronavirus pneumonia. Of those included in the analysis, a total of 53 patients (8.3%) died.
Among the patients included in the study, 351 (55.3%) men and 284 (44.7%) women were included. The mean age was 59.1 ± 15.1 years, including 57.0 ± 15.1 years for men and 61.8 ± 14.6 years for women.
Total of 56 patients reported smoking (8.8%—lower than recently published data on prevalence of current smoking in Russia [
41
]), while 10 patients (1.6%) did not complete this form in the questionnaire and were excluded from the analysis of smoking risk assessment. Arterial hypertension was detected in 318 patients (50.1%—corresponds to previously reported data about the general Russian population [
42
]), myocardial infarction—in 50 patients (7.9%), 25 patients had a stroke before (3.9%), COPD was found in 41 patients (6.5%), 18 patients suffered bronchial asthma (2.8%), 32 patients were admitted with known cancer after treatment (5%), 97 patients (15.3%) suffered from well-controlled diabetes mellitus (this is higher than in corresponding age group of the general Russian population that was reported before [
43
]). In a hospital setting, if necessary, correction of antihypertensive, hypoglycemic, protective, and other permanent therapy was performed.
Patients were transferred to our Center by ambulance on the basis of proximity of their location to the Center, and clinical condition (decreased blood oxygen saturation, severe symptoms of pneumonia) under supervision of Moscow Ambulance and Emergency Care station named after A.S. Puchkov. Unfortunately, we could find no published statistics on gender and age of hospitalized COVID-19 patients in Russia, but in our opinion, patients enrolled in this study reflect the general population of Moscow.
The study was approved by the local ethics committee by the Federal Center of Brain research and Neurotechnologies (project RF-COVID, approved on 5 July 2021). The study was conducted in accordance with the Declaration of Helsinki Ethical Principles. Upon admission, all patients included signed an informed consent that their data may be anonymized and used for aims of scientific research and publication.
2.2. Methods of Examination
Within the standard protocol of examination at admission, blood saturation was determined in patients using a pulse oximeter MD300 C2 (Beijing Choice Electronic Tech Co., Ltd., Beijing, China), blood was withdrawn for standard clinical and biochemical analysis with a determination of the complete blood count (CBC), erythrocyte sedimentation rate (ESR), and hematocrit. Transaminases, lactate dehydrogenase, total protein, glucose, creatinine, urea, total cholesterol, and C-reactive protein were measured in all patients. During the hospital treatment process, the blood tests were determined by clinical necessity.
Depending on the severity of the clinical condition, patients were assigned to the wards with the possibility of oxygen therapy (the need for oxygen therapy was 56.3%), or to intensive care units for artificial ventilation (the need for mechanical ventilation was 9.4%) and correction of the patients’ condition. Patients were treated following the constantly updated recommendations of the Ministry of Health.
According to the indications, transthoracic echocardiography was performed on a Philips Epiq 7G ultrasound scanner (Philips Ultrasound, Inc., Bothell, WA, USA) using a sector multi-frequency matrix sensor with a frequency of 1–5 MHz according to the standard protocol with the registration of the end-systolic and end-diastolic volume, stroke volume, Simpson ejection fraction, and systolic pressure in the pulmonary artery.
At admission and during treatment, patients underwent chest CT scans (Optima CT660, General Electric, Boston, MA, USA), and all CT scans for each patient were divided into three groups—performed at the beginning, in the middle (in dynamics), and end of admission (last CT performed in chronological order). The CT protocol consisted of scanning the patient’s chest at the height of maximum inspiration with a voltage of 120 kV and a tube current of 100–350 mA. Image reconstruction was performed with a slice thickness of 0.625 mm. In some cases, when a patient was admitted from an outpatient CT center, the results of the CT study provided by the patient were used. A total of 1519 CT scans were included in the analysis (from 1 to 7 studies per patient, an average of 3.5 per patient). The analysis of the studies was carried out by experienced radiologists of the Federal Center of Brain Research and Neurotechnologies, who received special training.
The probability of viral etiology of the lesion was estimated by the system similar to RSNA recommendations [
44
], which is based on the visual assessment of characteristic features. However, in the system used there were four categories: no signs of viral pneumonia, and low, medium, and high probability of viral etiology. The severity of the lung damage was determined by the CT0-CT4 scale, which was recommended by the health authorities in Moscow to unify the interpretation of studies and later confirmed by the temporary recommendations of the Russian Society of Radiology (RSR) [
45
,
46
] and by summing up the score of the severity of the lesion for each segment of the lungs on the scale CT-SS [
47
].
The prevailing types of changes, the condition of other organs of the chest and upper abdomen were evaluated. The predominant types of changes (GGO, “crazy paving”, consolidation, curvilinear opacities, and reticular changes) were evaluated according to a self-produced scale, assigning each of the signs a score from 0 to 3, depending on the visual severity. In the subsequent analysis, the scores were converted to percentages as follows: the scores were summed up and the percentage contribution of each feature to the total score was determined.
The distribution of lesion foci was defined as peripheral, peribronchovascular (central), or mixed. The presence of emphysematous changes, lymphadenopathy, pleural effusion, changes in the trachea, the degree of expansion of the aortic root and pulmonary trunk according to CT data, and the presence of calcified plaques were also evaluated.
2.3. Statistical Methods
Statistical analysis was performed using the software packages SPSS Statistics version 23.0 (IBM, Armonk, NY, USA) and R software version 3.3.2 (R Core team, Vienna, Austria) [
48
]. The null hypothesis was rejected at a significance level of
p
< 0.05. For the description of scale variables, the arithmetic means and standard deviation were used, unless otherwise specified, for nominal variables, the frequency and proportion (in percent) were used. The distribution of scale variables was assessed by frequency histograms evaluation. For nominal dependent variables frequencies comparison between categories of independent (grouping) variables were performed using the criterion χ
2
Pearson or the exact Fischer criterion. For scale dependent variables, analysis was made using ANOVA followed by pairwise comparisons using the Dunnet method or (if the distribution of the variable did not match the normal one)—Kruskal–Wallis criteria with pairwise comparisons by the Mann–Whitney criterion (using Bonferroni multiplicity adjustment). The effect of individual independent variables on patient survival was evaluated using the Kaplan–Mayer log-rank criterion. After identifying potential confounders and predictors using the methods described above, the exact identification of variables that affect the unfavorable outcome probability of coronavirus infection was performed using binary logistic regression.
3. Results and Discussion
3.1. Epidemiologic Risk Factors
In our study, an unfavorable prognosis was recognized as a fatal outcome, so the main goal of the study was to predict intrahospital mortality.
Deceased patients were significantly older than those who recovered (mean age 69.08 ± 13.50 vs. 58.20 ± 14.93, p < 0.0005), that corresponds to results of other studies [ 15 , 19 , 20 ]. As in other studies, men also had a higher risk of death—OR 1.97 (95% CI 1.07–3.62, p = 0.030). This is also consistent with data from other large studies with reasonable variation in risk [ 3 , 15 ]. Due to the revealed heterogeneities, the analysis was further adjusted for gender and age.
When adjusting for age, the difference in mortality among men and women over and under 59 years old is different. Risk of death in males over 59 years old is slightly, but insignificantly, higher than in women, OR 1.83 (95% CI 0.92–3.62), p = 0.081. Among people with an age below the median (59 years), men were at higher risk of death (in that group 12 out of 13 registered cases of death were male). OR of death in males under 59 years old is 8.32 (95% CI 1.07–64.75), p = 0.018. This observation reproduces data from previously published studies [ 3 ].
In contrast to the results of other published studies, patients did not significantly differ in body mass index (29.60 ± 6.12 among those who recovered versus 27.99 ± 5.11 among those who died, p = 0.104), which contradicts the data of broader studies. At the same time, the risk of death non-linearly depends on the body mass index and the lowest risk is noted at the level of BMI = 23.7, increasing at the level above and below this value [ 49 ], so the curve is J-shaped, and the average BMI in our study, both for survivors and deceased patients, lies in a much higher zone. This can be explained by the fact that a high BMI is associated with a higher risk of hospitalization, and during selection, our in-hospital study included overweight patients with a higher frequency. In addition, an increase in intrahospital mortality was observed with a BMI of more than 30 kg/m 2 [ 50 ] or 35 kg/m 2 [ 51 ], that is, in different classes of obesity, but there is evidence that being overweight (and not obese) does not affect the mortality of patients with coronavirus [ 52 ]. There is also the “obesity paradox”, which shows that obese individuals have a lower mortality rate for various diseases, including pneumonia [ 53 ], which may be caused by both a higher level of attention from the medical staff and some other factors. If the limit value between overweight and normal weight is consistently set at 25, 30, 35, and 40 kg/m 2 (according to obesity classes I, II, and III) there was no significant risk for overweight patients in our study.
Among the two groups of patients studied, the frequency of smoking did not significantly differ (8.9% in recovered group vs. 10.2% in deceased group,
p
= 0.798), but in our study, only the fact of current smoking was recorded, without taking into account the duration and intensity of smoking, which could affect the analysis result and lead to a contradiction with the available data [
22
]. In addition, the same relationship between smoking and the risk of severe viral pneumonia and mortality, as in our study, has been demonstrated before [
23
]. Even age-adjusted, smoking status had no significance as a risk factor among our patients.
The patients who died were slightly more likely to drink excessive alcohol (5.9% vs. 0.9%, p = 0.021), OR was 7.13 (95% CI 1.65–30.72, p = 0.0084), which is consistent with the data of previous studies [ 54 ], however, there is a wide variability of parameters related to the frequency and intensity of alcohol consumption and that requires careful data interpretation and further research, although a high risk of ARDS among long-term alcohol users has been demonstrated even before the pandemic began [ 55 ].
Excessive alcohol consumption, as reported by patients, preserves its prognostic value in different age groups (OR 14.18, 95% CI 2.34–85.90,
p
= 0.0039 in the younger age group), and if age-adjusted this parameter becomes more significant. Self-reported excessive alcohol consumption is not a reliable indicator because patients tend to report less amounts of alcohol consumption. The noteworthy, negative influence of high alcohol consumption on the frequency of ARDS in patients with coronavirus pneumonia was reported earlier [
56
], and its mechanism was probably realized through the dysfunction of the alveolar epithelium, alcohol-induced oxidative stress, and dysfunction of alveolar macrophages [
57
].
The main results of epidemiological risk factors analysis are shown in the Table 2 .
Table 2. Summary of key findings among epidemiological risk factors.
3.2. Comorbidities
Arterial hypertension did not affect survival in the overall analysis of the sample (survivability log-rank test,
p
= 0.33), however, when adjusted for age, patients with arterial hypertension had a significantly better prognosis than patients without it in the age group older than 59 years (OR = 0.37, 95% CI 0.19–0.73,
p
= 0.003). This unexpected result was also noted in the large-scale epidemiological study E. Williamson et al. [
58
], which reported no effect of hypertension on the risk of death in the general sample, as well as its positive impact on survival in the older age group (more than 70 years) after applying age adjustments. Studies of this phenomenon require an in-depth study of the mutual influence of many factors, including concomitant therapy of patients.
The survival rate was analyzed both in the general population and in groups younger and older than 59 years. Arterial hypertension did not influence the risk of death in coronavirus in the young cohort in our study (patients under median age of 59 years were regarded as young in our study), while in elder patients arterial hypertension was a protective factor. The Kaplan–Meyer analysis of survival in the older age group of patients with or without arterial hypertension is presented on Figure 1 .
Figure 1.
Kaplan–Meyer analysis of survival in age group older than 59 years in patients with and without arterial hypertension. Green line represents patients with arterial hypertension, blue line—patients without arterial hypertension.
Thus, the presence of arterial hypertension significantly reduces the chances of dying from coronavirus in the survival analysis. This finding may be linked with the higher frequency of observation of previously diagnosed arterial hypertension, and, accordingly, the longer duration of its treatment. However, there is mixed evidence that common antihypertensive drugs (ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta-blockers) may have a neutral or positive effect in case of coronavirus infection [ 59 ].
The presence of a previous myocardial infarction (18.9% in the group of deceased versus 6.9% in the group of survivors,
p
= 0.005) significantly worsened the prognosis of the outcome of the disease. The odds ratio of death is 3.15 (95% CI 1.47–6.73). Similarly, the prognosis of the disease is affected by a history of stroke (11.3% in the fatal group versus 3.3% in the recovered group,
p
= 0.013), OR = 3.78 (95% CI 1.44–9.92). The presence of cancer significantly increased the risk of an unfavorable outcome, it occurred in 13.2% of the deceased versus 4.3% of the recovered patients,
p
= 0.012. The ratio of the chances of death was found to be 3.39 (95% CI 1.39–8.26).
After age adjustment previous MI, stroke, and oncologic diseases had a negative effect on patients’ survival (Mantel-Haenszel common odds ratio estimate, OR = 2.14, 95% CI 0.97–4.7,
p
= 0.06; OR = 2.67, 95% CI 1.01–7.11,
p
= 0.048; OR = 2.74, 95% CI 1.10–6.82,
p
= 0.03, respectively). COPD and bronchial asthma were not found to be significant risk factors of mortality after age adjustment, as well as other diseases.
The worse prognosis in the case of concomitant diseases is due to both the general deterioration of the patient’s condition and some specific effects of these diseases on the outcome of viral pneumonia caused by a coronavirus, e.g., a transmitted coronavirus infection causes direct damage to the myocardium because of hemodynamic disorders or hypoxemia, concomitant myocarditis, stress cardiomyopathy, microvascular damage, and the development of thrombosis due to hypercoagulation or systemic inflammation (cytokine storm). Hypercoagulation, hypoxemia, and systemic inflammation can also be destabilizing coronary artery plaques, rendering them vulnerable, which can provoke vascular catastrophes in both the cerebral and coronary bed, which will be more difficult to tolerate due to the presence of previous damage to the brain and myocardium, respectively.
Data from various sources show that the probability of a serious illness and death COVID-19 is higher in adult patients with cancer, especially with hematological diseases and lung cancer, as well as in the elderly and other concomitant diseases [ 58 , 60 , 61 ]. This may be due to various reasons, including ongoing chemoradiotherapy, which leads to a decrease in the number of patients treated and the rate of appearance of formed blood elements, including red blood cells necessary for oxygen transport in hypoxia, and white blood cells involved in the formation of an immune response.
The presence of bronchial asthma (3.8% vs. 2.7%,
p
= 0.656), atrial fibrillation (13.2% vs. 8.1%,
p
= 0.189), diabetes mellitus (11.3% vs. 15.6%,
p
= 0.438), viral hepatitis, thyroid diseases, and systemic autoimmune diseases were also not associated with more frequent deaths.
Summary of main mentioned above comorbidities, regarded as a risk factor, is shown in Table 3 .
Table 3. Summary of key findings in analysis of comorbidities as a risk factor.
3.3. Complications
In the deceased patients, the complication rate was many times higher, but the presence of complications did not mean an unambiguous fatal outcome.
DIC syndrome was observed in 7 patients with fatal outcomes (13.2%) and in 7 recovered patients (1.2%), OR of death among the patient groups was 12.50 (95% CI 4.20–37.17,
p
= 0.0001). Sepsis, by the groups, was observed in 29 and 3 patients, respectively (54.7% and 0.5%), OR of death was 233.20 (95% CI 66.36–819.58,
p
= 0.0001). Deep venous thrombosis was detected in 15 and 3 patients, respectively (28.3 vs. 0.5%), OR 76.18 (95% CI 21.13–274.64,
p
= 0.0001).
Pulmonary embolism during treatment occurred in 13 dead patients and 5 recovered patients (24.5% and 0.9%, respectively), OR 37.5 (95% CI 12.74–110.45, p = 0.0001).
The development of ARDS was an unfavorable prognostic sign: all 25 patients with this complication died (47.2% of the patients who died).
Acute myocardial infarction occurred only in 3 patients with a fatal outcome (5.7%), as well as pneumothorax/pneumomediastinum (3 patients, 5.7%).
Registered hemorrhagic complications were not associated with mortality (1 patient in the group of deaths and 2 patients in the group of survivors, p = 0.230).
3.4. Laboratory Testing
The deceased patients had significantly lower hemoglobin levels (130.10 vs. 139.11,
p
= 0.001; average values are indicated hereafter), red blood cell count (4.26 vs. 4.67,
p
< 0.0005), and hematocrit (39.03 vs. 41.68,
p
< 0.0005). Given that with the development of prolonged respiratory failure, the number of red blood cells increases as compensation (due to a decrease in the concentration of oxygen in the kidneys and an increase in the production of erythropoietin), this phenomenon is not quite usual. This observation is generally consistent with the literature data—anemia in coronavirus infection is often observed and correlates with unfavorable outcomes [
62
].
The explanation for this phenomenon lies in a combination of general hypoxia (including bone marrow hypoxia) and a systemic inflammatory reaction that reduces the lifetime of red blood cells. A decrease in the level of hemoglobin should worsen hypoxia due to respiratory failure, it is also possible that the level of hemoglobin (or the number of RBC), and the dynamics of this indicator may be a good predictor of an unfavorable outcome, testing this hypothesis, however, requires a separate study.
The leukocytes’ count was significantly higher in patients who later died (8.38 vs. 6.34,
p
< 0.0005), and the number of band neutrophils were also higher (12.43 vs. 5.36,
p
< 0.0005), as well as the count of segmented neutrophils (not significant, 66.71 vs. 58.50). It is worth noting that this trend could be associated with the addition of a bacterial infection.
On the other hand, the number of platelets and lymphocytes is slightly lower (also non-significant—161.41 vs. 181.76 for platelets,
p
= 0.073; 8.69 vs. 12.14 for lymphocytes,
p
= 0.111). The ESR level, the number of monocytes, and eosinophils did not differ between groups.
The ratio of neutrophils to lymphocytes was calculated retrospectively, considering the published data. This criterion turned out to be prognostically significant: with a value of more than 2.5, the survival rate of patients was much lower, as it is presented in Figure 2 .
Figure 2. Survival rate in patients’ groups depending on NLR. Blue line represents survival of patients with NLR less or equal than 2.5, green line—patients with NLR more than 2.5.
Among patients in the recovered group, the median of this ratio was also lower than in the group of patients with a fatal outcome—2.13 [IQR 0.97; 3.76], and in those who died-4.19 [IQR 1.04; 3.91]. These results are graphically presented in Figure 3 .
Figure 3. Median and CI of NLR in survivors and deceased patients. NLR is markedly higher in deceased patients’ group. Median is represented with circle; error bars show 95% CI.
In the biochemical analysis of blood, it was noteworthy that patients with a fatal outcome had lower levels of total protein (64.74 vs. 71.00,
p
< 0.0005), as well as higher levels of blood glucose (7.61 vs. 6.93,
p
= 0.046), creatinine (94.00 vs. 85.03,
p
= 0.025), and C-reactive protein (153.02 vs. 69.57,
p
< 0.0005). The levels of procalcitonin, a marker of bacterial infection, were not significantly different between groups (1.34 vs. 0.13,
p
= 0.117).
In quantitative blood tests, it was noted that the significance of high creatinine and glucose levels does not affect the outcome (85.0 vs. 94.0,
p
= 0.179 and 6.9 vs. 7.6,
p
= 0.130, respectively). This may be explained by higher levels of glucose and creatinine in the elder population.
Among the main vital signs, a statistically significant difference was found in the frequency of respiratory movements (25.63 in those who subsequently died, 22.04 in those who recovered,
p
= 0.001). Blood pressure, body temperature, and heart rate were almost identical.
3.5. Echocardiography
According to echocardiography data, there was a tendency to decrease the ejection fraction and stroke volume in the group of fatal outcomes versus the group of recovered patients (57.56 vs. 60.53, p = 0.055 and 64.38 vs. 73.73, p = 0.043, respectively), but these values lie in the region of borderline statistical significance. There is a dramatic difference in systolic pressure in the pulmonary artery (53.00 in deceased patients versus 37.61 in recovered patients, p < 0.0005) that may be caused by an increase in pulmonary vascular resistance due to endothelitis and pulmonary embolism. Careful analysis of this indicator is required, together with analysis of the functional state of the right ventricle and other modalities for assessing the risk of death and thromboembolic complications.
3.6. Radiology
CT scans at every time point (for the initial study, CT in dynamics, and at the last CT scan) demonstrated “crazy paving” as the most pronounced type of changes in the deceased patients, the median value of severity of this type of changes was 22.2% [IQR 0.0–37.5], and in the group of surviving patients—0% [IQR 0.0–25.0] (
p
< 0.0005).
GGO on primary CT were less typical for deceased patients than for those who recovered—37.5 [IQR 20.0–50.0] vs. 42.9 [IQR 25.0–60.0] (
p
= 0.007). However, this shift can be explained by the fact that severe patients, admitted at later stages of the disease, when GGO transforms into zones of consolidation, were more likely to die. This is confirmed by the increase in the severity of the consolidation and “crazy paving” pattern in these patients.
On dynamic CT, patients with a fatal outcome had less prevalence of curvilinear consolidations 0.0 [IQR 0.0–11.1] and reticular changes 5.0 [0.0–15.5] than the surviving patients (14.3 [IQR 0.0–20.0] and 14.3 [IQR 0.0–25.0],
p
= 0.003 and
p
= 0.018, respectively). Probably, these changes are observed in the resolution stage of pneumonia, which was not achieved by deceased patients due to the development of ARDS, or massive consolidations. On the last CT scan performed, “crazy paving” also prevails in deceased patients, reticular changes are less pronounced 11.8 [IQR 0.0–22.2] vs. 25.0 [IQR 0.0–33.3] in survivors (
p
= 0.001) and curvilinear consolidations 9.1 [IQR 0.0–14.3] vs. 16.7 [IQR 0.0–28.6] in survivors (
p
= 0.001). At the same time, consolidations in deceased patients are more pronounced—29.3 [IQR 18.2–37.5] versus 16.7 [IQR 0.0–33.3] (
p
= 0.004). The “crazy paving” pattern is associated with filling the alveoli with exudate and associated thickening of the interlobular and intralobular interstitium, which creates linear strands over the GGO [
63
]. There are studies in which the appearance of “crazy paving” was assessed as a risk factor, but in the paper of Q. Lei et al. [
64
] this pattern was not identified as significant. On the other hand, there are data that this pattern can be used as a predictive one [
65
], and this is confirmed, among other things, by the results of our analysis.
With CT at all time points, both on the sum of points and the CT0–CT4 scale, the changes were more pronounced in severe patients (in all cases,
p
< 0.0005), and both methods of semiquantitative assessment of lung parenchyma involvement resulted in similar risk estimation.
CT changes that were more characteristic for the deceased patients included the measured diameter of the pulmonary trunk, which was significantly larger at all CT scans in these patients than in those who recovered (median 30 [IQR 28.0–34.0] mm vs. 28 [IQR 26.0–30.0] mm at the first CT scan, 32 [IQR 29.0–33.0] vs. 28 [IQR 26.0–30.0] on dynamic CT, 30 [IQR 28.0–34.0] vs. 28 [IQR 26.0–30.0] on the last CT, in every case
p
< 0.0005).
Patients with a severe course also had a predominant mixed and diffuse location of the GGO and zones of consolidation, not limited to the peripheral distribution, as was the case in recovered patients (
p
= 0.0001).
In patients with fatal outcome, hydrothorax was recorded more often than in recovered: at the first CT scan, OR = 3.10, 95% CI 1.34–7.16,
p
= 0.0082, with CT in the dynamics of OR = 3.26, 95% CI 1.35–7.89,
p
= 0.0087, and at the last CT scan OR = 7.09, 95% CI 3.43–14.7,
p
= 0.0001. The increased frequency of this syndrome is probably linked with the development of pulmonary edema and ARDS in the final stages of the disease with an unfavorable outcome.
Lymphadenopathy with enlarged lymph nodes over 10 mm along the short axis was slightly more common in the group of patients with a fatal outcome during primary CT (9.6% had multiple enlarged lymph nodes, 25.0%—single enlarged lymph node, 65.4%—had no lymphadenopathy) than in the group of patients who recovered (1.5%, 15.9%, 82.7%). Similar changes became more pronounced in CT during treatment (16.0% had multiple enlarged lymph nodes, 32.0%—single, 52.0%—without lymphadenopathy) than in the group of patients who recovered (2.9%, 15.3%, 81.8%). The proportion of patients with lymphadenopathy of varying severity increased slightly at the last CT scan performed in the group of fatal outcomes (13.9%, 41.7%, 44.4%), in the recovered group, the distribution was 0.9%, 17.8%, and 81.3%. It is worth noting that in this case, the last CT scan performed for recovered patients was performed shortly before discharge, while for deceased patients, the last CT scan was performed at the height of the disease. Reactive inflammatory changes in the lymph nodes can be observed in patients without severe lung damage [
66
].
Cardiomegaly was more common among the deceased patients’ group. Thus, at the first CT scan, 32.7% of this group had an increase in the size of the heart according to CT data, while in the group of recovered patients it was 16.9% (
p
= 0.005). When analyzing the obtained data, an OR of 2.38 was found (95% CI 1.28–4.43,
p
= 0.0062). In the dynamic CT study, this ratio did not change significantly (36.0% and 17.9%, respectively), OR 2.57 (95% CI 1.07–6.16,
p
= 0.034). At the last CT scan, 36.1% of the deceased patients’ group had an increase in the size of the heart according to CT data, while in the group of recovered patients it was 18.4% (
p
= 0.011). When analyzing the obtained data, OR 2.50 was found (95% CI 1.21–5.15,
p
= 0.0128). Thus, there was no increase in the number of cases of cardiomegaly during treatment, but it was a risk factor of mortality.
Calcified atherosclerotic plaques in the aorta can become a matrix for the formation of thrombi in the event of a violation of the integrity of their capsule, which can cause vascular thromboembolism. At primary CT, aortocalcinosis was observed in 78.8% of patients in the group of a fatal outcome and 46.9% of patients in the recovered group (
p
= 0.0001). The odds ratio was 4.22 (95% CI 2.13–8.40,
p
= 0.0001). Similar ratios were maintained for dynamic CT (52.4% and 24.0%,
p
= 0.007) and final CT (54.6% and 25.0%, respectively,
p
= 0.001). Similarly, coronary arteriosclerosis was detected, prevailing in the group of patients with a fatal outcome in primary CT (75.0%) versus 41.8% in the group of surviving patients. The odds ratio, in this case, was 4.84 (95% CI 2.23–10.50,
p
= 0.0001).
Thus, the presence of calcified plaques can be a predictor of the fatal outcome of coronavirus infection, which reflects the conversion of plaques into a vulnerable state on the hypoxemic background, a systemic inflammatory reaction, and a general metabolic disorder.
The significance of qualitative signs on CT scans does not change after age adjustment, including the remaining significance of aortocalcinosis as a risk factor of fatal outcomes.
3.7. Overall Regression Model
After pairwise comparison most significant risk factors were added to the regression model.
In our model of logit regression with Wald test following parameters were included: protein level in biochemical blood test (OR 0.888 [95% CI 0.825–0.956],
p
= 0.002), pulmonary trunk diameter as it was shown by CT (OR 1.179 [95% CI 1.049–1.326],
p
= 0.006), “crazy paving” severity on CT (OR 1.028 [95% CI 1.007–1.048],
p
= 0.008), summed severity score of lung involvement (OR 1.166 [95% CI 1.087–1.250],
p
< 0.0005), history of arterial hypertension (OR 0.384, [95% CI 0.157–0.940],
p
= 0.012), history of MI (OR 4.248, [95% CI 1.310–13.768],
p
= 0.024), and history of stroke (OR 8.986, [95% CI 1.701–47.464],
p
= 0.016). Pseudo R-squared for overall model was found to be 0.445, Hosmer–Lemeshow goodness of fit test showed
p
= 0.673.
The ROC curve for the summary predictive model is shown in Figure 4 , and the final results table are provided in Table 4 . The area under the curve is 0.890 (95% CI 0.833–0.948), which corresponds to excellent model quality.
Figure 4. The ROC curve for the overall regression model. AUC is 0.89, which corresponds to the excellent quality of the model.
Table 4. The results table for the final overall regression model.
The severity of lung involvement on CT scans and severity of lung injury patterns indicates lung injury, characteristic of severe disease course, causing hypoxemia and systemic inflammatory reaction. Dysfunction in coagulation factors may cause microthrombosis in lung vessels, which aggravates gas exchange in the lungs.
History of previous cardiovascular events, such as MI and stroke, and coronaroaortocalcinosis indicates that vessel walls are already vulnerable and local disturbances in partial oxygen pressure and coagulation system in the blood leads to a higher frequency of complications and death in these patients. The protective effect of arterial hypertension is probably linked with the aforementioned antihypertensive medical therapy and higher attention of medical staff to elder patients.
4. Conclusions
In our analysis, data from other studies were partially confirmed. Patient mortality is increased with age, male gender, history of MI, stroke, and oncological diseases. On the other hand, arterial hypertension has a protective effect in case of coronavirus infection against mortality in hospitalized patients, especially in the elder group of patients, that may be linked with medical therapy for that condition.
When evaluating blood tests, attention should be drawn to the neutrophil–leukocyte ratio, which has predictive properties in relation to in-hospital mortality at a value above 2.5. Anemia and lymphopenia were more common in deceased patients.
According to CT data, CT scans at any time point, including those performed upon admission of the patient, had a predictive value, which is of great diagnostic value. A particularly significant risk factor is the diffuse location of the lesions, as well as the “crazy paving” appearance associated with thickening of the pulmonary interstitium, most likely on the background of edema.
It is worth noting that our study had its limitations because not the entire population of infected patients was studied, but exclusively those hospitalized in our tertiary non-specialized center—patients with a clinically more pronounced course of coronavirus infection. The results of the work can be used in the triage of hospitalized patients, including to determine those who need intensive oxygen therapy in connection with concomitant diseases.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Acknowledgments
We thank our colleagues from the Federal Center of Brain Research and Neurotechnologies who treated patients with novel coronavirus disease during 2020, and thus laid the foundation for the study and made its completion possible. We are also immensely grateful to the director of FCBRN Vsevolod Belousov, neurophysiologist and functional diagnostics physician Yulia Voronkova, radiologists Maxim Shorikov and Mikhail Beregov for their comments on an earlier version of the manuscript, although any errors are our own and should not tarnish the reputations of these esteemed persons.
Conflicts of Interest
The authors declare no conflict of interest.
References
Weekly Epidemiological Update on COVID-19—31 August 2021. Available online: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---31-august-2021 (accessed on 11 September 2021).
Wiersinga, W.J.; Rhodes, A.; Cheng, A.C.; Peacock, S.J.; Prescott, H.C. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020 , 324 , 782–793. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Xie, Y.; Wang, Z.; Liao, H.; Marley, G.; Wu, D.; Tang, W. Epidemiologic, Clinical, and Laboratory Findings of the COVID-19 in the Current Pandemic: Systematic Review and Meta-Analysis. BMC Infect. Dis. 2020 , 20 , 640. [ Google Scholar ] [ CrossRef ]
Locatelli, I.; Trächsel, B.; Rousson, V. Estimating the Basic Reproduction Number for COVID-19 in Western Europe. PLoS ONE 2021 , 16 , e0248731. [ Google Scholar ] [ CrossRef ]
Ke, R.; Romero-Severson, E.; Sanche, S.; Hengartner, N. Estimating the Reproductive Number R 0 of SARS-CoV-2 in the United States and Eight European Countries and Implications for Vaccination. J. Theor. Biol. 2021 , 517 , 110621. [ Google Scholar ] [ CrossRef ]
Yu, C.-J.; Wang, Z.-X.; Xu, Y.; Hu, M.-X.; Chen, K.; Qin, G. Assessment of Basic Reproductive Number for COVID-19 at Global Level. Medicine 2021 , 100 , e25837. [ Google Scholar ] [ CrossRef ]
Fosbøl, E.L.; Butt, J.H.; Østergaard, L.; Andersson, C.; Selmer, C.; Kragholm, K.; Schou, M.; Phelps, M.; Gislason, G.H.; Gerds, T.A.; et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use with COVID-19 Diagnosis and Mortality. JAMA 2020 , 324 , 168–177. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mehta, N.; Kalra, A.; Nowacki, A.S.; Anjewierden, S.; Han, Z.; Bhat, P.; Carmona-Rubio, A.E.; Jacob, M.; Procop, G.W.; Harrington, S.; et al. Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 , 5 , 1020–1026. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Tang, N.; Li, D.; Wang, X.; Sun, Z. Abnormal Coagulation Parameters Are Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia. J. Thromb. Haemost. 2020 , 18 , 844–847. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Vajari, M.K.; Shirin, M.; Pourbagheri-Sigaroodi, A.; Akbari, M.E.; Abolghasemi, H.; Bashash, D. COVID-19-related Coagulopathy: A Review of Pathophysiology and Pharmaceutical Management. Cell Biol. Int. 2021 , 45 , 1832–1850. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Levi, M.; Thachil, J. Coronavirus Disease 2019 Coagulopathy: Disseminated Intravascular Coagulation and Thrombotic Microangiopathy-Either, Neither, or Both. Semin. Thromb. Hemost. 2020 , 46 , 781–784. [ Google Scholar ] [ CrossRef ]
Levi, M. COVID-19 Coagulopathy vs. Disseminated Intravascular Coagulation. Blood Adv. 2020 , 4 , 2850. [ Google Scholar ] [ CrossRef ]
Wu, Z.; McGoogan, J.M. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention. JAMA 2020 , 323 , 1239–1242. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Clinical Spectrum|COVID-19 Treatment Guidelines. Available online: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/ (accessed on 23 February 2021).
Chidambaram, V.; Tun, N.L.; Haque, W.Z.; Gilbert Majella, M.; Kumar Sivakumar, R.; Kumar, A.; Hsu, A.T.W.; Ishak, I.A.; Nur, A.A.; Ayeh, S.K.; et al. Factors Associated with Disease Severity and Mortality among Patients with COVID-19: A Systematic Review and Meta-Analysis. PLoS ONE 2020 , 15 , e0241541. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Dehingia, N.; Raj, A. Sex Differences in COVID-19 Case Fatality: Do We Know Enough? Lancet Glob. Health 2021 , 9 , e14–e15. [ Google Scholar ] [ CrossRef ]
Petrilli, C.M.; Jones, S.A.; Yang, J.; Rajagopalan, H.; O’Donnell, L.; Chernyak, Y.; Tobin, K.A.; Cerfolio, R.J.; Francois, F.; Horwitz, L.I. Factors Associated with Hospital Admission and Critical Illness among 5279 People with Coronavirus Disease 2019 in New York City: Prospective Cohort Study. BMJ 2020 , 369 , m1966. [ Google Scholar ] [ CrossRef ]
Suleyman, G.; Fadel, R.A.; Malette, K.M.; Hammond, C.; Abdulla, H.; Entz, A.; Demertzis, Z.; Hanna, Z.; Failla, A.; Dagher, C.; et al. Clinical Characteristics and Morbidity Associated with Coronavirus Disease 2019 in a Series of Patients in Metropolitan Detroit. JAMA Netw. Open 2020 , 3 , e2012270. [ Google Scholar ] [ CrossRef ]
Siordia, J.A. Epidemiology and Clinical Features of COVID-19: A Review of Current Literature. J. Clin. Virol. 2020 , 127 , 104357. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rod, J.E.; Oviedo-Trespalacios, O.; Cortes-Ramirez, J. A Brief-Review of the Risk Factors for COVID-19 Severity. Revista Saúde Pública 2020 , 54 , 60. [ Google Scholar ] [ CrossRef ]
Ho, F.K.; Petermann-Rocha, F.; Gray, S.R.; Jani, B.D.; Katikireddi, S.V.; Niedzwiedz, C.L.; Foster, H.; Hastie, C.E.; Mackay, D.F.; Gill, J.M.R.; et al. Is Older Age Associated with COVID-19 Mortality in the Absence of Other Risk Factors? General Population Cohort Study of 470,034 Participants. PLoS ONE 2020 , 15 , e0241824. [ Google Scholar ] [ CrossRef ]
Vardavas, C.I.; Nikitara, K. COVID-19 and Smoking: A Systematic Review of the Evidence. Tob. Induc. Dis. 2020 , 18 , 20. [ Google Scholar ] [ CrossRef ]
Lippi, G.; Henry, B.M. Active Smoking Is Not Associated with Severity of Coronavirus Disease 2019 (COVID-19). Eur. J. Intern. Med. 2020 , 75 , 107–108. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Umnuaypornlert, A.; Kanchanasurakit, S.; Lucero-Prisno, D.E.; Saokaew, S. Smoking and Risk of Negative Outcomes among COVID-19 Patients: A Systematic Review and Meta-Analysis. Tob. Induc. Dis. 2021 , 19 , 1–13. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chu, Y.; Yang, J.; Shi, J.; Zhang, P.; Wang, X. Obesity Is Associated with Increased Severity of Disease in COVID-19 Pneumonia: A Systematic Review and Meta-Analysis. Eur. J. Med. Res. 2020 , 25 , 64. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hendren, N.S.; De Lemos, J.A.; Ayers, C.; Das, S.R.; Rao, A.; Carter, S.; Rosenblatt, A.; Walchok, J.; Omar, W.; Khera, R.; et al. Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19: Results from the American Heart Association COVID-19 Cardiovascular Disease Registry. Circulation 2021 , 143 , 135–144. [ Google Scholar ] [ CrossRef ]
Wang, X.; Fang, X.; Cai, Z.; Wu, X.; Gao, X.; Min, J.; Wang, F. Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis. Research 2020 , 2020 , 2402961. [ Google Scholar ] [ CrossRef ][ Green Version ]
Honardoost, M.; Janani, L.; Aghili, R.; Emami, Z.; Khamseh, M.E. The Association between Presence of Comorbidities and COVID-19 Severity: A Systematic Review and Meta-Analysis. Cerebrovasc. Dis. 2021 , 50 , 132–140. [ Google Scholar ] [ CrossRef ]
Wang, J.; Guo, S.; Zhang, Y.; Gao, K.; Zuo, J.; Tan, N.; Du, K.; Ma, Y.; Hou, Y.; Li, Q.; et al. Clinical Features and Risk Factors for Severe Inpatients with COVID-19: A Retrospective Study in China. PLoS ONE 2020 , 15 , e0244125. [ Google Scholar ] [ CrossRef ]
Lippi, G.; Plebani, M.; Henry, B.M. Thrombocytopenia Is Associated with Severe Coronavirus Disease 2019 (COVID-19) Infections: A Meta-Analysis. Clin. Chim. Acta 2020 , 506 , 145–148. [ Google Scholar ] [ CrossRef ]
Pourbagheri-Sigaroodi, A.; Bashash, D.; Fateh, F.; Abolghasemi, H. Laboratory Findings in COVID-19 Diagnosis and Prognosis. Clin. Chim. Acta 2020 , 510 , 475–482. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Yang, A.P.; Liu, J.P.; Tao, W.Q.; Li, H.M. The Diagnostic and Predictive Role of NLR, d-NLR and PLR in COVID-19 Patients. Int. Immunopharmacol. 2020 , 84 , 106504. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Liu, J.; Liu, Y.; Xiang, P.; Pu, L.; Xiong, H.; Li, C.; Zhang, M.; Tan, J.; Xu, Y.; Song, R.; et al. Neutrophil-to-Lymphocyte Ratio Predicts Critical Illness Patients with 2019 Coronavirus Disease in the Early Stage. J. Transl. Med. 2020 , 18 , 260. [ Google Scholar ] [ CrossRef ]
Ou, M.; Zhu, J.; Ji, P.; Li, H.; Zhong, Z.; Li, B.; Pang, J.; Zhang, J.; Zheng, X. Risk Factors of Severe Cases with COVID-19: A Meta-Analysis. Epidemiol. Infect. 2020 , 148 . [ Google Scholar ] [ CrossRef ] [ PubMed ]
Li, K.; Fang, Y.; Li, W.; Pan, C.; Qin, P.; Zhong, Y.; Liu, X.; Huang, M.; Liao, Y.; Li, S. CT Image Visual Quantitative Evaluation and Clinical Classification of Coronavirus Disease (COVID-19). Eur. Radiol. 2020 , 30 , 4407–4416. [ Google Scholar ] [ CrossRef ][ Green Version ]
Francone, M.; Iafrate, F.; Masci, G.M.; Coco, S.; Cilia, F.; Manganaro, L.; Panebianco, V.; Andreoli, C.; Colaiacomo, M.C.; Zingaropoli, M.A.; et al. Chest CT Score in COVID-19 Patients: Correlation with Disease Severity and Short-Term Prognosis. Eur. Radiol. 2020 , 30 , 6808–6817. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kanne, J.P.; Bai, H.; Bernheim, A.; Chung, M.; Haramati, L.B.; Kallmes, D.F.; Little, B.P.; Rubin, G.; Sverzellati, N. COVID-19 Imaging: What We Know Now and What Remains Unknown. Radiology 2021 , 299 , E262–E279. [ Google Scholar ] [ CrossRef ]
Yu, Y.; Wang, X.; Li, M.; Gu, L.; Xie, Z.; Gu, W.; Xu, F.; Bao, Y.; Liu, R.; Hu, S.; et al. Nomogram to Identify Severe Coronavirus Disease 2019 (COVID-19) Based on Initial Clinical and CT Characteristics: A Multi-Center Study. BMC Med. Imaging 2020 , 20 , 111. [ Google Scholar ] [ CrossRef ]
Lassau, N.; Ammari, S.; Chouzenoux, E.; Gortais, H.; Herent, P.; Devilder, M.; Soliman, S.; Meyrignac, O.; Talabard, M.P.; Lamarque, J.P.; et al. Integrating Deep Learning CT-Scan Model, Biological and Clinical Variables to Predict Severity of COVID-19 Patients. Nat. Commun. 2021 , 12 , 634. [ Google Scholar ] [ CrossRef ]
Kirillov, Y.; Timofeev, S.; Avdalyan, A.; Nikolenko, V.N.; Gridin, L.; Sinelnikov, M.Y. Analysis of Risk Factors in COVID-19 Adult Mortality in Russia. J. Prim. Care Community Health 2021 , 12 . [ Google Scholar ] [ CrossRef ]
Shkolnikov, V.M.; Churilova, E.; Jdanov, D.A.; Shalnova, S.A.; Nilssen, O.; Kudryavtsev, A.; Cook, S.; Malyutina, S.; McKee, M.; Leon, D.A. Time Trends in Smoking in Russia in the Light of Recent Tobacco Control Measures: Synthesis of Evidence from Multiple Sources. BMC Public Health 2020 , 20 , 378. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Erina, A.M.; Rotar, O.P.; Solntsev, V.N.; Shalnova, S.A.; Deev, A.D.; Baranova, E.I.; Konradi, O.A.; Boytsov, S.A.; Shlyakhto, E.V. Epidemiology of Arterial Hypertension in Russian Federation—Importance of Choice of Criteria of Diagnosis. Kardiologiia 2019 , 59 , 5–11. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Dedov, I.; Shestakova, M.; Benedetti, M.M.; Simon, D.; Pakhomov, I.; Galstyan, G. Prevalence of Type 2 Diabetes Mellitus (T2DM) in the Adult Russian Population (NATION Study). Diabetes Res. Clin. Pract. 2016 , 115 , 90–95. [ Google Scholar ] [ CrossRef ][ Green Version ]
Simpson, S.; Kay, F.U.; Abbara, S.; Bhalla, S.; Chung, J.H.; Chung, M.; Henry, T.S.; Kanne, J.P.; Kligerman, S.; Ko, J.P.; et al. Radiological Society of North America Expert Consensus Document on Reporting Chest CT Findings Related to COVID-19: Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. Radiology 2020 , 2 , e200152. [ Google Scholar ] [ CrossRef ][ Green Version ]
Morozov, S.P.; Andreychenko, A.E.; Blokhin, I.A.; Gelezhe, P.B.; Gonchar, A.P.; Nikolaev, A.E.; Pavlov, N.A.; Chernina, V.Y.; Gombolevskiy, V.A. MosMedData: Data Set of 1110 Chest CT Scans Performed during the COVID-19 Epidemic. Digit. Diagn. 2020 , 1 , 49–59. [ Google Scholar ] [ CrossRef ]
Sinitsyn, V.E.; Tyurin, I.E.; Mitkov, V.V. Consensus Guidelines of Russian Society of Radiology (RSR) and Russian Association of Specialists in Ultrasound Diagnostics in Medicine (RASUDM) «Role of Imaging (X-Ray, CT and US) in Diagnosis of COVID-19 Pneumonia» (Version 2). J. Radiol. Nucl. Med. 2020 , 101 , 72–89. [ Google Scholar ] [ CrossRef ]
Yang, R.; Li, X.; Liu, H.; Zhen, Y.; Zhang, X.; Xiong, Q.; Luo, Y.; Gao, C.; Zeng, W. Chest CT Severity Score: An Imaging Tool for Assessing Severe COVID-19. Radiology 2020 , 2 , e200047. [ Google Scholar ] [ CrossRef ][ Green Version ]
RC Team. R: A Language and Environment for Statistical Computing ; RC Team: Firminy, France, 2016. [ Google Scholar ]
Kompaniyets, L.; Goodman, A.B.; Belay, B.; Freedman, D.S.; Sucosky, M.S.; Lange, S.J.; Gundlapalli, A.V.; Boehmer, T.K.; Blanck, H.M. Body Mass Index and Risk for COVID-19—Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death—United States, March–December 2020. MMWR 2021 , 70 , 355–361. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Du, Y.; Lv, Y.; Zha, W.; Zhou, N.; Hong, X. Association of Body Mass Index (BMI) with Critical COVID-19 and in-Hospital Mortality: A Dose-Response Meta-Analysis. Metabolism 2021 , 117 , 154373. [ Google Scholar ] [ CrossRef ]
Palaiodimos, L.; Kokkinidis, D.G.; Li, W.; Karamanis, D.; Ognibene, J.; Arora, S.; Southern, W.N.; Mantzoros, C.S. Severe Obesity Is Associated with Higher In-Hospital Mortality in a Cohort of Patients with COVID-19 in the Bronx, New York. Metabolism 2020 , 108 , 154262. [ Google Scholar ] [ CrossRef ]
Al-Salameh, A.; Lanoix, J.P.; Bennis, Y.; Andrejak, C.; Brochot, E.; Deschasse, G.; Dupont, H.; Goeb, V.; Jaureguy, M.; Lion, S.; et al. The Association between Body Mass Index Class and Coronavirus Disease 2019 Outcomes. Int. J. Obes. 2021 , 45 , 700–705. [ Google Scholar ] [ CrossRef ]
Nie, W.; Zhang, Y.; Jee, S.H.; Jung, K.J.; Li, B.; Xiu, Q. Obesity Survival Paradox in Pneumonia: A Meta-Analysis. BMC Med. 2014 , 12 , 61. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Saengow, U.; Assanangkornchai, S.; Casswell, S. Alcohol: A Probable Risk Factor of COVID-19 Severity. Addiction 2021 , 116 , 204–205. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Simou, E.; Leonardi-Bee, J.; Britton, J. The Effect of Alcohol Consumption on the Risk of ARDS: A Systematic Review and Meta-Analysis. Chest 2018 , 154 , 58–68. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Lassen, M.C.H.; Skaarup, K.G.; Sengeløv, M.; Iversen, K.; Ulrik, C.S.; Jensen, J.U.S.; Biering-Sørensen, T. Alcohol Consumption and the Risk of Acute Respiratory Distress Syndrome in COVID-19. Ann. Am. Thorac. Soc. 2020 , 18 , 1074–1076. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Simet, S.M.; Sisson, J.H. Alcohol’s Effects on Lung Health and Immunity. Alcohol Res. 2015 , 37 , 199. [ Google Scholar ]
Williamson, E.J.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D.; Inglesby, P.; et al. Factors Associated with COVID-19-Related Death Using OpenSAFELY. Nature 2020 , 584 , 430–436. [ Google Scholar ] [ CrossRef ]
Kjeldsen, S.E.; Narkiewicz, K.; Burnier, M.; Oparil, S. Potential Protective Effects of Antihypertensive Treatments during the COVID-19 Pandemic: From Inhibitors of the Renin-Angiotensin System to Beta-Adrenergic Receptor Blockers. Blood Press. 2021 , 30 , 1–3. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Giannakoulis, V.G.; Papoutsi, E.; Siempos, I.I. Effect of Cancer on Clinical Outcomes of Patients with COVID-19: A Meta-Analysis of Patient Data. JCO Glob. Oncol. 2020 , 6 , 799–808. [ Google Scholar ] [ CrossRef ]
Wang, Q.; Berger, N.A.; Xu, R. Analyses of Risk, Racial Disparity, and Outcomes among US Patients with Cancer and COVID-19 Infection. JAMA Oncol. 2021 , 7 , 220. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Faghih Dinevari, M.; Somi, M.H.; Sadeghi Majd, E.; Abbasalizad Farhangi, M.; Nikniaz, Z. Anemia Predicts Poor Outcomes of COVID-19 in Hospitalized Patients: A Prospective Study in Iran. BMC Infect. Dis. 2021 , 21 , 170. [ Google Scholar ] [ CrossRef ] [ PubMed ]
De Wever, W.; Meersschaert, J.; Coolen, J.; Verbeken, E.; Verschakelen, J.A. The Crazy-Paving Pattern: A Radiological-Pathological Correlation. Insights Imaging 2011 , 2 , 117–132. [ Google Scholar ] [ CrossRef ][ Green Version ]
Lei, Q.; Li, G.; Ma, X.; Tian, J.; fan Wu, Y.; Chen, H.; Xu, W.; Li, C.; Jiang, G. Correlation between CT Findings and Outcomes in 46 Patients with Coronavirus Disease 2019. Sci. Rep. 2021 , 11 , 1103. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Gholamzadeh Baeis, M.; Mozafari, A.; Movaseghi, F.; Yadollahzadeh, M.; Sohrabi, A.; Reza Masjedi, M. The Crazy-Paving Pattern in Chest CT of Coronavirus Disease 2019 Patients; an Alarming Sign for Hospitalization. Available online: https://assets.researchsquare.com/files/rs-105075/v1/4c5a74a3-1ad4-4a6b-aa57-21a052dfed30.pdf?c= (accessed on 6 April 2021).
Karimi-Galougahi, M.; Yousefi-Koma, A.; Khalili, N.; Bakhshayeshkaram, M.; Haseli, S. Transient 18 FDG-Avid Hilar Lymph Node on PET/CT Imaging in Asymptomatic COVID-19. IDCases 2020 , 22 , e00981. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Figure 1. Kaplan–Meyer analysis of survival in age group older than 59 years in patients with and without arterial hypertension. Green line represents patients with arterial hypertension, blue line—patients without arterial hypertension.
Figure 2. Survival rate in patients’ groups depending on NLR. Blue line represents survival of patients with NLR less or equal than 2.5, green line—patients with NLR more than 2.5.
Figure 3. Median and CI of NLR in survivors and deceased patients. NLR is markedly higher in deceased patients’ group. Median is represented with circle; error bars show 95% CI.
Figure 4. The ROC curve for the overall regression model. AUC is 0.89, which corresponds to the excellent quality of the model.
Table 1. Summary of the main risk factors of COVID-19 severe outcome or death reported in the literature.
Risk Factor N Effect Size Reference Gender (male) n/a 53 countries FRR 1.35 † (95% CI 1.35–1.35) [ 3 ] 16,422 * FRR 1.45 † (95% CI 1.23–1.71) [ 15 ] Age 470,034 65–74 years: RR 4.27 † (95% CI 3.03–6.03) Over 75 years: RR 12.77 † (95% CI 9.13–17.85) [ 21 ] Smoking 1549 * RR = 2.4 ‡ (95% CI: 1.43–4.04) [ 22 ] 1399 * OR 1.69 ‡ (95% CI 0.41–6.92) [ 23 ] 369,287 * OR 1.35 † (95% CI 1.12–1.62) [ 24 ] Body mass index 12,591 * 0.89 † (95% CI 0.32–2.51) [ 25 ] 7606 OR 1.26 † (95% CI 1.00–1.58) [ 26 ] Comorbidities cerebrovascular diseases 6270 * OR 4.85 ‡ (95% CI 3.11–7.57) [ 22 ] cardiovascular diseases OR 4.81 ‡ (95% CI 3.43–6.74) chronic lung diseases OR 4.19 ‡ (95% CI 2.84–6.19) malignancies OR 3.18 ‡ (95% CI 2.09–4.82) diabetes OR 2.61 ‡ (95% CI 2.02–3.3) arterial hypertension OR 2.37 ‡ (95% CI 1.80–3.13) Thrombocytopenia 1779 * RR 5.1 ‡ (95% CI 1.8–14.6) [ 30 ] NLR (more than 3.3) 93 RR 2.46 ‡ (95% CI 1.98–4.57) [ 32 ] C-reactive protein 5872 * WAD 42.7 mg/L ‡ (95% CI 31.12–54.28) [ 34 ] ALT WAD 5.12 U/L ‡ (95% CI 0.82–9.42) AST WAD 8.51 U/L ‡ (95% CI 5.01–12.01 Creatinine WAD 4.57 µmol/L ‡ (95% CI 0.64–8.50) CT semi-quantitative scale 130 HR 8.33 † (95% CI 3.19–21.73) [ 36 ] CT “crazy paving” sign 217 OR 0.661 ‡ (95% CI 0.147–2.974) [ 38 ]
N—number of patients in the study, if available; FRR—fatality rate ratio, RR—risk ratio; OR—odds ratio; WMD—weighted mean difference; CI—confidence interval; NLR—neutrophil –to-leucocyte ratio, ALT—alanine aminotransferase, AST—aspartate aminotransferase; CT—computed tomography. Number of patients marked with an asterisk (*) shows overall number of patients included in the meta-analysis. Effect size marked with † indicates risk of death, while ‡ designation stands for risk of the severe course of the disease.
Table 2. Summary of key findings among epidemiological risk factors.
Risk Factor N R N D OR Gender (m vs. f) Male 314 37 1.97 * (95% CI 1.07–3.62) Female 268 16 Gender (m vs. f, aged 59 or more) Male 125 25 1.83 (95% CI 0.92–3.62) Female 137 15 Gender (m vs. f, under 59 years old) Male 189 12 8.32 * (95% CI 1.07–64.75) Female 131 1 Body mass index <25 124 11 0.78 (95% CI 0.38–1.60) ≥25 420 29 Body mass index <30 323 27 0.70 (95% CI 0.36–1.39) ≥30 221 13 Current smoking Yes 51 5 1.17 (95% CI 0.44–3.08) No 525 44 Alcohol abuse (self-reported) Yes 5 3 7.13 * (95% CI 1.65–30.72) No 570 48
N R —number of patients who had the risk factor in recovered group; N D —number of deceased patients who had the risk factor, OR—odds ratio. OR marked with an asterisk (*) are statistically significant.
Table 3. Summary of key findings in analysis of comorbidities as a risk factor.
Risk Factor N R N D OR Arterial hypertension Yes 294 24 0.81 (95% CI 0.46–1.43) No 288 29 Arterial hypertension (for patients over 59 years) Yes 191 20 0.37 * (95% CI 0.19–0.73) No 71 20 Arterial hypertension (for patients under 59 years) Yes 103 4 0.94 (95% CI 0.28–3.11) No 217 9 Myocardial infarction (in history) Yes 40 10 3.15 * (95% CI 1.48–6.73) No 542 43 Stroke (in history) Yes 19 6 3.78 * (95% CI 1.44–9.92) No 563 47 Malignancy (in history) Yes 25 7 3.39 * (95% CI 1.39–8.26) No 557 46
N R —number of patients who had the risk factor in recovered group; N D —number of deceased patients who had the risk factor, OR—odds ratio. OR marked with asterisk (*) are statistically significant ( p < 0.05).
Table 4. The results table for the final overall regression model.
B Significance Level OR 95% CI for OR Low High Protein level in biochemical blood test −0.119 0.002 0.888 0.825 0.956 Pulmonary trunk diameter 0.165 0.006 1.179 1.049 1.326 “Crazy paving” severity on CT 0.027 0.008 1.028 1.007 1.048 Summed severity score of lung involvement 0.153 <0.0005 1.166 1.087 1.250 No history of arterial hypertension 1.422 0.012 4.146 1.371 12.536 No history of MI −1.564 0.024 0.209 0.054 0.812 No history of stroke −2.420 0.016 0.089 0.012 0.635 Constant −0.371 0.913 0.690
B—value for the logistic regression equation for predicting the dependent variable from the independent variable, OR—odds ratio, CI—confidence interval.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).
MDPI and ACS Style
Kondakov, A.; Berdalin, A.; Lelyuk, V.; Gubskiy, I.; Golovin, D. Risk Factors of In-Hospital Mortality in Non-Specialized Tertiary Center Repurposed for Medical Care to COVID-19 Patients in Russia. Diagnostics 2021, 11, 1687.
https://doi.org/10.3390/diagnostics11091687
AMA Style
Kondakov A, Berdalin A, Lelyuk V, Gubskiy I, Golovin D. Risk Factors of In-Hospital Mortality in Non-Specialized Tertiary Center Repurposed for Medical Care to COVID-19 Patients in Russia. Diagnostics. 2021; 11(9):1687.
https://doi.org/10.3390/diagnostics11091687
Chicago/Turabian Style
Kondakov, Anton, Alexander Berdalin, Vladimir Lelyuk, Ilya Gubskiy, and Denis Golovin. 2021. "Risk Factors of In-Hospital Mortality in Non-Specialized Tertiary Center Repurposed for Medical Care to COVID-19 Patients in Russia" Diagnostics11, no. 9: 1687.
https://doi.org/10.3390/diagnostics11091687
| https://www.mdpi.com/2075-4418/11/9/1687/xml |
Browsing Open Access Subvention Fund Articles by Title
LTE Spectrum Sharing Research Testbed: Integrated Hardware, Software, Network and Data
Marojevic, Vuk ; Nealy, Randall ; Reed, Jeffrey H. ( ACM, 2017-10 )
This¹ paper presents Virginia Tech’s wireless testbed supporting research on long-term evolution (LTE) signaling and radio frequency (RF) spectrum coexistence. LTE is continuously refined and new features released. As the ...
Lysine and sulfur amino acid requirements of broiler chicks over short time periods within the starter phase
Sarsour, Albaraa Hisham ; Persia, Michael E.
Six experiments were conducted to validate the hypothesis that Lys and SAA requirements decrease within the starter phase using 3-d periods from 2 to 11 d of age. In the first 3 experiments, 7 diets were generated by adding ...
A Machine Learning Framework to Infer Time-of-Use of Flexible Loads: Resident Behavior Learning for Demand Response
Afzalan, Milad ; Jazizadeh, Farrokh ( IEEE, 2020-06-26 )
Load shapes obtained from smart meter data are commonly utilized to understand daily energy use patterns for adaptive operations in applications such as Demand Response (DR). However, they do not provide information on the ...
Machine Learning-Enabled 30-Day Readmission Model for Stroke Patients
Darabi, Negar ; Hosseinichimeh, Niyousha ; Noto, Anthony ; Zand, Ramin ; Abedi, Vida ( Frontiers Media, 2021-03-31 )
Background and Purpose: Hospital readmissions impose a substantial burden on the healthcare system. Reducing readmissions after stroke could lead to improved quality of care especially since stroke is associated with a ...
Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints
Menarim, Bruno C. ; Gillis, Kiersten H. ; Oliver, Andrea ; Ngo, Ying ; Werre, Stephen R. ; Barrett, Sarah H. ; Rodgerson, Dwayne H. ; Dahlgren, Linda A. ( 2020-11-26 )
Synovitis is a major component of osteoarthritis and is driven primarily by macrophages. Synovial macrophages are crucial for joint homeostasis (M2-like phenotype), but induce inflammation (M1-like) when regulatory functions ...
Magnetic resonance imaging-guided Treatment of equine Distal interphalangeal Joint collateral ligaments: 2009–2014
White, Nathaniel A. III ; Barrett, Jennifer G. ( Frontiers, 2016-09-05 )
Objectives: To determine the outcome of treating distal interphalangeal joint collateral ligament (DIJCL) desmopathy using magnetic resonance imaging (MRI)-guided ligament injection. Methods: Medical records of 13 adult ...
Magnetic Sensing with Ferrofluid and Fiber Optic Connectors
Homa, Daniel S. ; Pickrell, Gary R. ( Mdpi Ag, 2014-02-25 )
A simple, cost effective and sensitive fiber optic magnetic sensor fabricated with ferrofluid and commercially available fiber optic components is described in this paper. The system uses a ferrofluid infiltrated extrinsic ...
Mainstreaming environmental education for architects: the need for basic literacies
Grant, Elizabeth J. ( Ubiquity Press, 2020 )
What are recent architectural graduates perceptions about the level of knowledge required of interns entering architectural practice and suitability of architectural education? Research is presented that examines recent ...
Mammalian Brain Development is Accompanied by a Dramatic Increase in Bipolar DNA Methylation
Sun, M.-A. ; Sun, Z. ; Wu, X. ; Rajaram, V. ; Keimig, D. ; Lim, J. ; Zhu, H. ; Xie, H. ( Nature Publishing Group, 2016-09-02 )
Mapping the Celebrity Endorsement of Branded Food and Beverage Products and Marketing Campaigns in the United States, 1990–2017
Zhou, Mi ; Rajamohan, Srijith ; Hedrick, Valisa E. ; Rincón-Gallardo Patiño, Sofía ; Abidi, Faiz ; Polys, Nicholas F. ; Kraak, Vivica ( MDPI, 2019-10-04 )
Celebrity endorsement used to promote energy-dense and nutrient-poor (EDNP) food and beverage products may contribute to poor dietary habits. This study examined celebrity endorsement of branded food and beverage products ...
Mapping the Distribution Pattern of Gentrification near Urban Parks in the Case of Gyeongui Line Forest Park, Seoul, Korea
Kwon, Yoonku ; Joo, Shinha ; Han, Soyoung ; Park, Chan ( MDPI, 2017-02-09 )
The objective of this study was to map the distribution pattern of gentrification, showing the adverse effect of urban parks. The study adopted the perspective that urban parks, which have thus far been featured in urban ...
Mathematical modelling of the use of insecticide-treated nets for elimination of visceral leishmaniasis in Bihar, India
Fortunato, Anna K. ; Glasser, Casey P. ; Watson, Joy A. ; Lu, Yongjin ; Rychtář, Jan ; Taylor, Dewey ( The Royal Society Publishing, 2021-05-24 )
Visceral leishmaniasis (VL) is a deadly neglected tropical disease caused by a parasite Leishmania donovani and spread by female sand flies Phlebotomus argentipes. There is conflicting evidence regarding the role of ...
Mathematical Models of Localized Muscle Fatigue: Sensitivity Analysis and Assessment of Two Occupationally-Relevant Models
Rashedi, Ehsan ; Nussbaum, Maury A. ( PLOS, 2015-12-14 )
Muscle fatigue models (MFM) have broad potential application if they can accurately predict muscle capacity and/or endurance time during the execution of diverse tasks. As an initial step toward facilitating improved MFMs, ...
Maximality Theorems on the Sum of Two Maximal Monotone Operators and Applications to Variational inequality Problems
Asfaw, Teffera M. ( Hindawi, 2016-08-11 )
Let 𝑋 be a real locally uniformly convex reflexive Banach space with locally uniformly convex dual space 𝑋∗. Let 𝑇 : 𝑋 ⊇ 𝐷(𝑇)→
2𝑋 ∗ and 𝐴 : 𝑋 ⊇ 𝐷(𝐴) → 2𝑋
∗ be maximal monotone operators.The maximality of the ...
mD-Resilience: A Multi-Dimensional Approach for Resilience-Based Performance Assessment in Urban Transportation
Khaghani, Farnaz ; Jazizadeh, Farrokh ( MDPI, 2020-06-15 )
As demonstrated for extreme events, the resilience concept is used to evaluate the ability of a transportation system to resist and recover from disturbances. Motivated by the high cumulative impact of recurrent perturbations ...
The meaning(s) of place: Identifying the structure of sense of place across a social–ecological landscape
Rajala, Kiandra F. ; Sorice, Michael G. ; Thomas, Valerie A. ( Wiley, 2020-05-04 )
1. Sense of place holds promise to understand how people perceive and respond to social and ecological change; however, using this concept to explore vulnerability and adaptation first depends on identifying the multiple ...
A measured energy use, solar production, and building air leakage dataset for a zero energy commercial building
Agee, Philip ; Nikdel, Leila ; Roberts, Sydney ( 2021-11-23 )
This paper provides an open dataset of measured energy use, solar energy production, and building air leakage data from a 328 m(2) (3,531 ft(2)) all-electric, zero energy commercial building in Virginia, USA. Over two years ...
Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury
Cash, Alison ; Theus, Michelle H. ( MDPI, 2020-05-08 )
Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation ...
MedFuseNet: An attention-based multimodal deep learning model for visual question answering in the medical domain
Sharma, Dhruv ; Purushotham, Sanjay ; Reddy, Chandan K. ( Nature Portfolio, 2021-10-06 )
Medical images are difficult to comprehend for a person without expertise. The scarcity of medical practitioners across the globe often face the issue of physical and mental fatigue due to the high number of cases, inducing ...
Medical Students' Knowledge and Perception of Deep Brain Stimulation
Saway, Brian F. ; Monjazeb, Sanaz ; Godbe, Kerilyn ; Anwyll, Tessa ; Kablinger, Anita S. ; Witcher, Mark R. ( 2021-03 )
BACKGROUND: Deep brain stimulation (DBS) is a well-established neurosurgical procedure commonly used in movement and psychiatric disorders. Its widespread clinical implementation, however, may not be commensurate with ...
| http://vtechworks.lib.vt.edu/handle/10919/71752/browse?rpp=20&offset=514&etal=-1&sort_by=1&type=title&starts_with=S&order=ASC |
(PDF) Technical Report for A Joint User Scheduling and Trajectory Planning Data Collection Strategy for the UAV-assisted WSN
PDF | Unmanned aerial vehicles (UAVs) are usually dispatched as mobile sinks to assist data collection in large-scale wireless sensor networks (WSNs).... | Find, read and cite all the research you need on ResearchGate
Technical Report for A Joint User Scheduling and Trajectory Planning Data Collection Strategy for the UAV-assisted WSN
Xindi Wang
Lei Deng
Abstract and Figures
Unmanned aerial vehicles (UAVs) are usually dispatched as mobile sinks to assist data collection in large-scale wireless sensor networks (WSNs). However, when considering the limitations of UAV's mobility and communication capabilities in a large-scale WSN, some sensor nodes may run out of storage space as they fail to offload their data to the UAV for an extended period of time. To minimize the data loss caused by the above issue, a joint user scheduling and trajectory planning data collection strategy is proposed in this letter, which is formulated as a non-convex optimization problem. The problem is further divided into two sub-problems and solved sequentially. Simulation results show that the proposed strategy is more effective in minimizing data loss rate than other strategies.
An illustration of (a) the application scenario; (b) the constructed circular areas {Cm(i)|m ∈ {1, · · · , 5}} based on SN i and SN k. …
Figures - available via license: Creative Commons Attribution 4.0 International
Discover the world's research
25+ million members
1
T echnical Report for A Joint User Scheduling and
T rajectory Planning Data Collection Strategy for the
U A V -assisted WSN
Xindi W ang, Chi-Tsun Cheng, Lei Deng, Xiaojing Chen, Fu Xiao
Abstract —Unmanned aerial vehicles (UA Vs) are usually dis-
patched as mobile sinks to assist data collection in large-scale
wireless sensor networks (WSNs). However , when considering the
limitations of UA V’s mobility and communication capabilities in a
large-scale WSN, some sensor nodes may run out of storage space
as they fail to offload their data to the UA V for an extended period
of time. T o minimize the data loss caused by the above issue,
a joint user scheduling and trajectory planning data collection
strategy is proposed in this letter , which is formulated as a non-
convex optimization problem. The pr oblem is further divided
into two sub-problems and solved sequentially . Simulation results
show that the proposed strategy is more effective in minimizing
data loss rate than other strategies.
Index T erms —unmanned aerial vehicle, trajectory planning,
user scheduling.
I. I NTRODUCTION
By introducing an unmanned aerial vehicle (UA V) as a
mobile sink into large-scale wireless sensor networks (WSNs),
efficient and effectiv e data collections can be achieved for sen-
sor nodes (SNs) that are deployed in hard-to-reach non-urban
areas. In this way, the U A V can establish direct communication
links through the Line of Sight (LoS) air-to-ground channels
to the served SNs, and thus the communication quality and
the lifetime of the WSN can both be improved.
UA V -assisted WSNs have attracted growing interest in re-
cent years. The existing works mainly focus on optimizing the
UA V trajectory and SNs’ running parameters to improve the
network performances. Zeng et al. [1], [2] formulate the UA V
trajectory planning as a non-convex optimization problem, and
solve it by a successive optimization method. Zhan et al. [3]–
[5] further incorporate other critical parameters of wireless
communications into their optimization process, including
the status of the SNs, communication outage probability,
error estimation, etc., and propose a variety of UA V path
planning strategies accordingly . Furthermore, not limited to
WSNs, UA Vs have been widely applied to various wireless
communication scenarios [7]–[9], and yield promising results.
However , considering that a UA V with limited mobility and
communication capabilities can only serve a finite number of
SNs at a time, user (i.e. SN) scheduling is therefore a critical
issue for WSNs consisting of a large number of SNs, which
may cause some SNs to lose the data they just sampled due
to storage exhaustion [10] as they cannot offload their data
to the UA V for a long time. Such a critical issue has often
been ignored in previous studies by assuming either 1 ) that
the UA V can communicate with all SNs in the scenario all the
time [1], [2], [6]–[8]; 2 ) that the UA V only serve one user (SN)
at a time [3]–[5], [9], which are not always valid in real-life
applications.
T o fill the above research gap, a joint user scheduling and
trajectory planning data collection strategy for a UA V-assisted
large-scale WSN is proposed in this letter, which is e xecuted
in a time-division manner . At each time slot, a UA V will
schedule the users (i.e. SNs) to communicate with at the next
time slot and determine the next way-point to collect the data
from the involv ed SNs. Meanwhile, the orthogonal frequency
division multiple access (OFDMA) technology is also consid-
ered in the UA V -SNs communication processes, which enables
concurrent multi-SN transmissions through flexible bandwidth
allocation. Specially, dif ferent from existing OFDMA-WSN
studies [11], [12] that focus on optimizing the allocation of
wireless resource blocks (e.g. communication channels) in a
static network scenario, the communication system changes
all the time as the UA V moves in this letter, which can be
treated as an important complement to existing OFDMA-WSN
researches.
II . S Y ST EM M O DE L AN D P ROB LE M F OR MU LATI ON
A. System Model
Consider an area of interest (AoI) where | Ω all | SNs are
randomly and evenly distributed. For each SN i in the AoI,
its location (i.e. L i = [ L x ( i ) , L y ( i )] ∈ R 2 × 1 ) is fixed and
has been prestored in the UA V . The data queue length of SN
i at time slot t , denoted as B i ( t ) , depends on both the data
sampling rate (i.e. s ) and the data uploading throughput with
the UA V (i.e. T hr i ( t ) ), which is given as
B i ( t ) = min { B i ( t − 1) + s − T hr i ( t ) , B } . (1)
Notice that if the queue length B i ( t ) exceeds the storage
capacity B , the data sampled later will be discarded due to
the storage exhaustion. In addition, it is assumed that the data
queue of SN i can be estimated by the UA V based on the
known sampling rate and the historical communication records
with each SN.
In order to facilitate analysis, the behaviors of the UA V
during the entire data collection process is modeled in a time-
division manner, so that the trajectory of the U AV can be
represented as a serial of way-point coordinates { L u ( t ) } T
t =1 ,
of which L u ( t ) = [ L ux ( t ) , L uy ( t )] denotes the way-point
coordinate of the UA V projected on the ground at the t -th
time slot (obtained through the equipped GPS), and the flight
arXiv:2103.00753v1 [cs.NI] 1 Mar 2021
2
duration T of the UA V in a data collection task should meet
the following condition, namely
T ≤ T e , (2)
where T e is the maximum flight time of the UA V . Meanwhile,
the displacement of the UA V from the t − 1 -th time slot to the
t -th time slot is governed by
d ( t ) = || L u ( t ) − L u ( t − 1) || ≤ V max × τ, (3)
where V max denotes the maximum speed of the UA V and τ
is the interval of adjacent time slots.
Assume that the UA V is flying at the constant altitude H ,
and the projected distance between the UA V and SN i at
time slot t is measured as d u,i ( t ) = || L i − L u ( t ) || . Thus the
communication rate of SN i at time slot t can be expressed as
r i ( t ) = W log 2 (1 + α i
p
σ 2
i ( H 2 + d 2
u,i ( t )) ) , (4)
where α i denotes the real-time reference channel power gain at
d u,i = 1 m in time slot t and p denotes the transmission power
that is configured as the same value initially . In addition, due
to the fact that the distance between the SNs communicating
with the UA V is relatively close and τ in (3) is short enough,
the channel status (i.e. σ 2
i ) between each UA V -SN communi-
cation link is assumed to be the same and remain unchanged
throughout a time slot. Therefore, it is also assumed that any
SN i can establish a reliable communication connection with
the UA V whenever
d u,i ( t ) ≤ d c , (5)
where d c is the average effecti ve communication distance †
between SN and UA V projected on the 2D plane.
Meanwhile, by adopting OFDMA technology, the U AV
orthogonal resource blocks in advance, of which the bandwidth
allocated to each communication SN is W (in (4)). In this way,
the UA V using OFDMA technology can support concurrent
data transmissions with up to n surrounding SNs that meet
the condition in (5) at each time slot t , which is formulated
as
| Ω o ( t ) | ≤ n, ∀ t, (6)
where Ω o ( t ) denotes the set of SNs chosen by the UA V to
communicate with at time slot t . So, the throughput of SN i
at time slot t is given by
T hr i ( t ) = min { r i ( t ) τ c , B i ( t ) } , ∀ i ∈ Ω o ( t ) , (7)
in which τ c denotes the duration of a data communication
process within one time slot, which is assumed that τ c τ .
† A UA V-ground communication link is considered reliable if r i ( t ) ≥ ,
and given the same environment, the rate threshold mainly depends on the
communication distance.
B. Problem F ormulation
Under the considered application scenario § , each SN i ∈
Ω all will first store the sampled data in the storage with data
queue length B i ( t ) , and wait for the UA V to perform the
data collection task. However , when considering the physical
limitations of the UA V in maneuvering (i.e. the constraints
(2), (3)) and communication capacities (i.e. the constraints (5),
(6)) in a large-scale AoI, it can be expected that only a group
of SNs can communicate with the UA V at the same time,
which may cause some SNs to discard the data just sampled
due to exhaustion of storage space [10] because they cannot
communicate with the UA V for a long time. The amount of
data be discarded by SN i at the t -th time slot is given by
D i ( t ) = max { 0 , B i ( t − 1) + s − B } . (8)
Therefore, our goal is to design a data collection strategy for
the UA V -assisted WSN to minimize the data loss rate η due
to storage exhaustion during the entire data collection task,
which is given as
P1 : min η =
T
X
t =1 X
i ∈ Ω all
D i ( t )
s ∗ T
s.t. (1) − (7) .
III. A N E FFIC IE NT S T RATE GY T O S OLVE P RO BL EM P1
For the sake of non-conv exity of the objective function and
constraints ((4), (6)), it is hard to solve problem P1 using
general optimization methods. In this section, we proposed a
joint U ser scheduling and T rajectory planning S trategy (named
as UTS) to approximate solve problem P1 in an efficient way ,
in which the original problem will be divided into two sub-
problems and solved successively .
Assume the location of the UA V at time slot t − 1 is given as
L u ( t − 1) . T o reduce the amount of data loss at time slot t (i.e.
P i ∈ Ω all D i ( t ) ), the most intuitive way is regarding SNs with
the smallest sum of available storage space within the current
coverage area as the communication objects (i.e. Ω o ( t ) ) at the
next time slot t , and then finding the optimal next waypoint
(i.e. L u ( t ) ) to achieve the maximum data throughput with the
SNs in Ω o ( t ) for further releasing their storage space, which
can be modeled as sub-problem sP1 and sub-problem sP2,
respectively .
A. Solve Sub-Problem sP1
Searching for a SN set which is within the coverage range
(i.e. jointly considering the moving capability (3) and the
reliable communication distance (5)) of the UA V and owns the
smallest sum of available storage space under the constraints
of communication resources (i.e. (6)) at time slot t is the goal
of problem sP1, which is formulated as
sP1 :Ω o ( t ) = arg min X ( B − B i ( t )) , (9)
s.t. (1) , (3) , (5) , (6) .
§ Notice that our work can also extended to the scenario with the prob-
abilistic LoS channel model [13], [14]. However , due to the page limit,
corresponding details are given in section IV of our technical report[].
3
However , due to the fact that problem sP1 cannot be solved
efficiently using general optimization methods, a heuristic-
based method is considered here to obtain a sub-optimal
solution with a reasonable computational complexity . First of
all, the location constraints of SNs in Ω o ( t ) (i.e. (3) and (5))
are re-expressed as following forms, namely
|| L i − L u ( t − 1) || ≤ V max × τ + d c , ∀ i ∈ Ω o ( t ) . (10)
|| L i − L u ( t ) || ≤ d c , ∀ i ∈ Ω o ( t ) . (11)
Therefore, with a given L u ( t − 1) , problem sP1 can be
rephrased as the following geometry problem sP1*:
Problem sP1*: With a given big circular area C b with
L u ( t − 1) as its center and V max τ + d c as its radius (see
(10) ), how to get an optimal circular area C s with d c as
its radius (see (11) ) inside C b which covers at most n SNs
(see (6) ) with the smallest sum of available storage space.
Then, the set of the involved n SNs ar e regarded as the
Ω o ( t ) that we are searching for . The graphical illustration is
shown in Fig. 1(a) † .
Instead of traversing virtually infinite number of smaller
circles with radius d c inside C b , an efficient search method
is proposed, which constructs several alternativ e circular areas
with radius d c and picks out the one with the best performance.
Then, SNs within the chosen optimal circular area are set as
a sub-optimal solution of problem sP1*, which is graphically
represented in Fig. 1(b). Meanwhile, the corresponding pseudo
code of the proposed search method is given in Algorithm. 1.
Algorithm 1 An Efficient Search Strategy
1: Initialization: Ω opt ( i ) = ∅ : the constructed SN set with
respect to SN i ; Ω d max − dc : the set of SNs which are
within distance V max × τ − d c from L u ( t − 1) .
2: for each SN i in Ω d max − dc do
3: Find the partner SN (denoted as SN k ) for SN i , and
then put SNs { i, k } → Ω opt ( i ) .
4: Construct the search region F ( i ) based on the SN i
and SN k .
5: Find the optimal circular area C ∗ ( i ) with radius as d c
inside F ( i ) , and put the top n − 2 SNs with the smallest
available storage space from C ∗ ( i ) into Ω opt ( i ) .
6: end for
7: Output: Pick out the SN set Ω o ( t ) from { Ω opt ( i ) | i ∈
Ω d max − dc } based on (9).
follows.
Step 3 :The main idea in this step is to find a SN (denoted
as SN k ) that owns the smallest available storage space and
also can communicate with the UA V together with each SN i ∈
Ω d max − dc , which can be formulated as the following problem,
namely
SN k ← arg min ( B − B j ( t )) ,
s.t. || L i − L j || ≤ 2 d c . (12)
† In order to facilitate the analysis, it is assumed that V max τ is larger
than d c here. However , even for some special cases where V max τ is smaller
than d c , it is only necessary to update the SN set Ω d max − dc and its related
definition mentioned in Algorithm. 1 as Ω d max : the set of SNs which are
within distance V max × τ from L u ( t − 1)
Note that (12) is a necessary condition that a SN j can
communicate with the UA V with the SN i in the time slot t ,
which is adopted here to expand the search range as much as
possible.
Step 4 : The main idea in this step is to construct a
search region F ( i ) that clarifies the range of SNs that can
communicate with the UA V together with SN i and SN k .
At first, two big circular areas are constructed with the
coordinates of SN i and SN k (i.e. L i and L k ) as their centers
as the two biggest black circles in Fig. 1(b). Then, according
to (12), it is straightforward to prove that SNs located in the
overlapping area (denoted as O ( i ) ) of the constructed two
circles can communicate with the UA V either with SN i or
SN k . The overlapping area O ( i ) is shown as the blue area in
Fig. 1(b).
Proposition 1: With the given distance between SN i
and SN k , i.e., d i,k = || L i − L k || , any SN j attempting to
communicate with a UA V simultaneously with SN i and SN
k must meet the condition
max min { d j,i , d j,k } ≤ s 1
4 d 2
i,k + ( d c + r d 2
c − 1
4 d 2
i,k ) 2 ,
(13)
where d j,i denotes the distance between SN j and SN i .
Proof: It is straightforward to prove the abov e result by
the Pythagorean theorem.
Fig. 1. An illustration of (a) the application scenario; (b) the constructed
Here we denote the both end regions of O ( i ) , i.e., the gaps
between O ( i ) and the circles of radii d c passing through SN
i and SN k at the same time, as D 1 ( i ) or D 2 ( i ) (shown in
Fig. 1). According to Proposition 1 , it is easy to prove that
the SNs located in D 1 ( i ) or D 2 ( i ) cannot communicate with
UA V together with SNs i and k . Therefore, the search region
F ( i ) can be obtained by F ( i ) , O ( i ) − D 1 ( i ) − D 2 ( i ) .
Step 5 : The main idea in this step is to obtain an
optimal circular area C ∗ ( i ) inside the search region F ( i ) ,
and then put the top n − 2 SNs with the smallest available
storage space from C ∗ ( i ) into Ω opt ( i ) . In order to reduce the
computational complexity and cover the area of F ( i ) as much
as possible, here we construct five alternativ e circular areas,
i.e., { C m ( i ) | m ∈ { 1 , · · · , 5 }} with radius d c inside the region
F ( i ) , and select the one with the best performance. Among
{ C m ( i ) | m ∈ { 1 , · · · , 5 }} , C 1 ( i ) and C 2 ( i ) denote the circular
areas with distinct centers while touching both SN i and SN k
simultaneously. Then, C 3 ( i ) (or C 4 ( i )) is denoted as a circular
area that touch SN k (or i ) and with its corresponding center
being collinear with SN i (or k ). C 5 ( i ) is the circular area with
its center located at the midpoint of SNs i and k . Based on
L i and L ( k ) , the center coordinates of areas C 1 ( i ) and C 2 ( i )
L x ( i, k ) = L x ( i ) + L x ( k )
2 ∓ V L y ( i ) − L y ( k )
d i,k
,
L y ( i, k ) = L y ( i ) + L y ( k )
2 ± V L x ( i ) − L x ( k )
d i,k
,
in which V = q | d 2
c − 1
4 d 2
i,k | , and the center coordinates of
areas C 2 ( i ) and C 3 ( i ) are respectively deriv ed as
L x ( i, k ) = M ( L x ( i ) , L x ( k )) ∓ d c ∗ | L x ( i ) − L x ( k ) |
d i,k
,
L y ( i, k ) = M ( L y ( i ) , L y ( k )) ± d c ∗ | L y ( i ) − L y ( k ) |
d i,k
,
in which M ( ) ∈ { max ( ) , min ( ) } . Note that the selection of
the above operators (i.e. ∓ and functions { max ( ) , min ( ) } )
are determined by the relative positions between SN i and SN
k , which can be obtained by simple geometry calculations.
Meanwhile, note that if the distance between SNs i and k is
equal to 2 d c , then the aforementioned area, i.e. { C m ( i ) | m ∈
{ 1 , · · · , 5 }} will be merged into one.
Finally, set the circular area that has the smallest sum
of available storage space from its top n − 2 SNs from
{ C m ( i ) | m ∈ { 1 , · · · , 5 }} as C ∗ ( i ) .
F Computational complexity analysis: step 2 requires
O ( N R ) to traverse all SNs in Ω d max − dc , of which N R rep-
radius of V max × τ − d c . Step 3 requires O ( N r ) to search for
the partner SN, in which N r represents the average number
of SNs in a circular area with a radius of d c . Step 4 only
involves simpl e calculations. Step 5 requires O ( N 2
r ) to sort the
SNs in each generated circular area C m ( i ) , m ∈ { 1 , · · · , 5 } ,
and requires O (5) to pick the one with the best performance.
Finally, step 7 requires O ( N R ) to obtain the optimal SN
set from { Ω opt ( i ) | i ∈ Ω d max − dc } by comparing the sum of
available storage space.
In summary, the computational comple xity of the proposed
search method is O ( N R × ( N r + 5 ∗ N 2
r + 5) + N R ) , which is
considered as practical and highly desirable for the application
scenarios under studied in this letter.
B. Solve Sub-Problem sP2
After obtaining the SN set Ω o ( t ) by executing Algorithm 1 ,
sub-problem sP2 is to get the optimal way-point for the UA V
at the t -th time slot with the given location L u ( t − 1) , so that
the maximum data throughput between the UA V and SNs in
Ω o ( t ) can be obtained. The problem sP2 is formulated as
sP2 : max
i ∈ Ω o ( t )
r i ( t ) τ c
s.t. (3) − (4) , (7) . (14)
By substituting (4) into the above problem, the objective
function can be expressed as
max
L u ( t ) X
i ∈ Ω o ( t )
W log 2 (1 + α i
p
σ 2
i ( H 2 + d 2
u,i ( t )) ) τ c
⇒ max
L u ( t ) X
i ∈ Ω o ( t )
W log 2 (1 + α i
p
σ 2
i ( H 2 + || L i − L u ( t ) || 2 ) ) τ c .
(15)
Obviously , function (15) is convex with respect to d 2
instead of the next way-point of the UA V (i.e. L u ( t ) ). Mean-
while, due to the fact that the first order T aylor expansion of
a convex function is the global under -estimator at any point,
thus we expand r i ( t ) = W log 2 (1 + α i p
σ 2
i ( H 2 + d 2
u,i ( t )) ) in (15)
with an initial point d 2
i,ui ( t ) = || L i − L ui ( t ) || 2 in terms of the
first-order T aylor expansion as
r i ( t ) = r i ( t, L ui ( t )) + r 0
i ( t, L ui ( t )) ∗ ∆ d ( t ) + ε, (16)
in which
r i ( t, L ui ( t )) = W log(1 + α i
p
σ 2
i ( H 2 + || L i − L ui ( t ) || 2 ) ) ,
r 0
i ( t, L ui ( t )) = − W
log 2 ( e ) σ 2
i α i p
σ 4
1 + α i p
σ 2
i ( H 2 + || L i − L ui ( t ) || 2 )
,
∆ d ( t ) = || L i − L u ( t ) || 2 − || L i − L ui ( t ) || 2 .
Here, if we substitute (16) without item ε into original
problem, sP2 will be transformed to a convex optimization
problem (denoted as sP2*) with respect to L u ( t ) due to the
fact that other items are all constants with the initial point
d i,ui ( t ) . Therefore, problem sP2* can be solved by using
general convex optimization methods.
Meanwhile, to reduce the impact of ignoring ε when
transforming sP2 to sP2*, an intuitive method is to choose
an initial coordinate L ui ( t ) which is very likely to be
close to the optimal coordinate L u ( t ) , so that the ε =
P ∞
n =2
r n
i ( t,d ui ( t ))
n ! ∆ d ( t ) n can be negligible as ∆ d ( t ) tends to
0 . Therefore, considering the scheduled SN set Ω o ( t ) obtained
by Algorithm. 1, one can initialize L ui ( t ) as the mean of the
distances from the UA V to all SNs in Ω o ( t ) are balanced and
shorter than d c .
5
IV. E XTENSION IN P RO BAB IL IS TI C L O S C HANNELS
Here we discuss how to further extend this letter to prob-
abilistic LoS channel scenarios. In this case, the waypoint
of the UA V in time slot t should be updated to q u ( t ) =
[ L u ( t ) , L uz ( t )] T ∈ R 3 × 1 in a given 3-D space. Then, as
designed in [13], [14], the LoS probability at each time slot t
can be modeled as a function of the UA V -SN elevation angle,
which can be expressed in the form of
P ( c L
k,t = 1) = 1
1 + αe − b ( θ k,t − α ) , (17)
where θ k,t denotes the angel between the UA V and SN k in
time slot t , which is given by
θ k,t = 180
π arctan ( L uz ( t )
|| L i − L u ( t ) || ) , (18)
where α and β are modeling parameters to be specified. Then,
the corresponding NLoS probability can be obtained by
P ( c L
k,t = 1) . (19)
In this case, the large-scale channel power gain between the
UA V and SN k in the time slot t , including both the path loss
and shadowing, can be modeled as
h k,t = c L
k,t h L
k,t + (1 − c L
k,t ) h N
k,t , (20)
where
h L
k,t = β 0 d − α L
k,t , h N
k,t = µβ 0 d − α N
k,t (21)
denote the channel power gains in LoS and NLoS cases,
respectively . Meanwhile, d k ,t can be calculated as
d k,t = p || L i − L u ( t ) || 2 + L 2
uz ( t ) . (22)
Considering that the goal of this letter is to design a data
collection strategy for the UA V-assisted WSN to minimize the
data loss rate η due to storage exhaustion during the entire
will schedule a set of SNs (denoted as Ω o ( t ) ) which owns the
smallest sum of available storage space under the constraints
of communication resources (i.e. (6)), and then searches for
the next optimal waypoint (i.e. q u ( t ) ) of the UA V to maximize
the data transmission throughput based on the probability LoS
channel model. Obviously , the former issue can still be solved
by the Algorithm 1 we designed, while the latter issue can be
modeled as the following optimization problem.
P2 : max
q u ( t ) X
i ∈ Ω o ( t )
r i ( t ) τ c ,
s.t. (3) , (4) , (7) , (20) , (23)
where
r i ( t ) = W log 2 (1 + α h i,t p
σ 2
i Γ ) . (24)
The problem P2 can be solved by methods proposed in [13],
[14].
V . N UMERICAL R E SU LTS
A simulated UA V -assisted WSN application scenario has
been developed to validate the performances of the proposed
a fixed altitude to ground H = 20 m and its maximal speed
V max = 30 m/s, and a WSN with | Ω all | = 200 SNs being
uniformly and randomly distributed in a square AoI. For each
SN deployed in AoI, the initial length of the data queue follows
a Poisson distribution with λ = 10 kbits, and the storage ca-
pacity is B = 30 kbits. The parameters of the communication
model are configured as follows, i.e., bandwidth W = 5 MHz,
noise power δ 2 = − 100 dBm, transmission power p = 0 . 05 W ,
the reference channel power gain α i follows a random uniform
distribution with range [-55dB, -50dB], the average ef ficient
communication radius d c = 10 m, the number of wireless
resources n = 4 , the duration of each time slot is τ = 1 s
where τ c = 0 . 1 s, and the maximum flight time of the UA V
T e = 600 s.
For benchmarking, a R andom F light S trategy ( RFS ) and
a G reedy F light S trategy ( GFS ) have been introduced in
the simulations, in which RFS chooses the next way-point
randomly, and then sets the adjacent SNs with the smallest sum
of available storage space as the communication objects. In
contrast, GFS chooses the location of the SN with the smallest
available storage space within the feasible moving area as
its next way-point, and then selects the communication SNs
between the strategies mainly focus on the following three
aspects, namely sampling rate (Fig. 2 (a)), scene scale (Fig. 2
(b)), and running time (Fig. 2 (c)).
As shown in the above simulation results, the proposed UTS
shows significant advantages in reducing data loss in multiple
scenarios. Compared with RFS without the user scheduling
process and GFS with the single-SN greedy scheduling, UTS
considers searching for a group of SNs with the greatest
overall data loss risk for communication scheduling before
performing data collection tasks, which is especially important
for a large-scale WSN. In addition, UTS also optimizes each
waypoint in the trajectory to increase the data throughput with
the scheduled SNs, which leads to the throughput of the UTS
at each waypoint being nearly 3 times of those in the other
two strategies. In this way , more storage space of involved
SNs is released and the efficiency of data collection mission
can also be guaranteed.
VI . C ONCLUSION
In this letter, a U A V-assisted data collection strate gy has
been proposed, which takes into account the user scheduling
and trajectory planning of the UA V to reduce the data loss
rate in the large-scale WSN. Simulation results have shown
performance than those with other strategies under tests.
R EFERENCES
[1] Y . Zeng, R. Zhang, and T. J. Lim, “Throughput maximization for UA V en-
abled mobile relaying systems,” IEEE T ransactions on Communications ,
vol. 64, no. 12, pp. 4983-4996, 2016.
6
Fig. 2. The data loss rate vs. (a) area of AoI with sampling rate s = 100 bit/s over 500 time slot, (b) sampling rate in a 100 × 100 m 2 scenario over 600
consecutive time slots, (c) running time with sampling rate s = 120 bit/s in a 100 × 100 m 2 scenario from 300 individual simulations.
[2] Y . Zeng and R. Zhang, “Energy-efficient UA V communication with
trajectory optimization,” IEEE T ransactions on Wireless Communications ,
vol. 16, no. 6, pp. 3747–3760, 2017.
[3] C. Zhan and G. Y ao, “Energy efficient estimation in wireless sensor
network with unmanned aerial vehicle,” IEEE Access , v ol. 7, pp. 63519-
63530, 2019.
[4] C. Zhan, Y . Zeng and R. Zhang, “Energy-efficient data collection in
UA V enabled wireless sensor network,” IEEE W ireless Communications
Letters , vol. 7, no. 3, pp. 328-331, 2018.
[5] C. Zhan, Y. Zeng and R. Zhang, “T rajectory design for distributed
estimation in UA V-enabled wireless sensor network, ” IEEE Transactions
on V ehicular T echnology , vol. 67, no. 10, pp. 10155-10159, 2018.
[6] X. Jiang, Z. Wu, Z. Y in, W. Y ang and Z. Yang, “T rajectory and com-
munication design for UA V-relayed wireless networks, ” IEEE Wireless
[7] W. W ang et al. , “Joint precoding optimization for secure SWIPT in UA V-
aided NOMA networks,” IEEE T ransactions on Communications , vol. 68,
no. 8, pp. 5028-5040, 2020.
[8] X. Liu et al. , “Placement and power allocation for NOMA-UA V net-
works,” IEEE W ireless Communications Letters , vol. 8, no. 3, pp. 965-
968, 2019.
[9] F. Cheng et al. , “U AV trajectory optimization for data offloading at the
edge of multiple cells,” IEEE T ransactions on Vehicular T echnology , vol.
67, no. 7, pp. 6732-6736, 2018.
[10] Z. Li, Y . Jiang, Y. Gao, L. Sang and D. Y ang, “On buffer-constrained
throughput of a wireless-powered communication system, ” IEEE Journal
on Selected Areas in Communications , vol. 37, no. 2, pp. 283-297, 2019.
[11] H. Y ang, D. Deng and K. Chen, “Performance analysis of IEEE 802.11ax
UL OFDMA-based random access mechanism,” GLOBECOM 2017 ,
Singapore, pp. 1-6, 2017.
[12] J. Ren, S. Y ue, D. Zhang, Y . Zhang and J. Cao, “Joint channel
assignment and stochastic energy management for RF-powered OFDMA
WSNs,” IEEE T ransactions on Vehicular T echnology , vol. 68, no. 2,
pp. 1578-1592, 2019.
[13] C. Y ou and R. Zhang, “Hybrid Offline-Online Design for UA V-Enabled
Data Harvesting in Probabilistic LoS Channels,” IEEE T ransactions on
Wireless Communications , v ol. 19, no. 6, pp. 3753-3768, 2020.
[14] B. Duo, Q. Wu, X. Y uan and R. Zhang, “Anti-Jamming 3D Trajectory
Design for UA V-Enabled W ireless Sensor Networks Under Probabilistic
LoS Channel,” IEEE T ransactions on Vehicular T echnology , vol. 69, no.
12, pp. 16288-16293, 2020.
ResearchGate has not been able to resolve any citations for this publication.
Energy Efficient Estimation in Wireless Sensor Network With Unmanned Aerial Vehicle
Article
Full-text available
May 2019
Cheng Zhan
Guo Yao
Distributed estimation is a typical application of wireless sensor network (WSN), where a set of sensor nodes (SNs) collaboratively estimate some parameters of interest from noisy measurements. Recently, unmanned aerial vehicle (UAV) enabled WSN has attracted significant interest, since the UAV can collect data energy-efficiently due to its high mobility. In this paper, we consider the joint optimization of UAV trajectory design and SNs’ transmission bits allocation for estimating an unknown parameter in UAV-enabled WSN, and the objective is to minimize the total energy consumption of all SNs under the constraint that the mean square error (MSE) of estimation is below a target threshold. The joint optimization problem is formulated with a mixed-integer non-convex programming, which is difficult to solve in general. As such, an efficient iterative algorithm is proposed to solve it by applying the block coordinate descent and successive convex optimization techniques. A low-complexity and systematic initialization scheme is also proposed for the trajectory design and transmission bits allocation based on the trade-off structure on the number of visited SNs for estimation. Extensive simulation results are provided to demonstrate the significant performance gains in terms of total energy consumption of all SNs as compared to other benchmark schemes.
Anti-Jamming 3D Trajectory Design for UAV-Enabled Wireless Sensor Networks under Probabilistic LoS Channel
Article
Nov 2020
IEEE T VEH TECHNOL
Bin Duo
Qingqing Wu
Xiaojun Yuan
Rui Zhang
This paper investigates the anti-jamming three-dimensional (3D) trajectory design to safeguard the legitimate communications of unmanned aerial vehicle (UAV)-enabled wireless sensor networks (WSNs). Specifically, a UAV is dispatched to collect data over multiple ground sensors (GSs) in the presence of a malicious ground jammer. Under the practical probabilistic line-of-sight (LoS) channel model, we aim to maximize the minimum (average) expected rate among GSs over a finite flight period, by jointly optimizing the GS transmission scheduling, the UAV horizontal and vertical trajectories. To make the formulated non-convex problem tractable, we provide an achievable lower bound for the expected rate, based on which an efficient iterative algorithm is proposed to solve it suboptimally by exploiting the block coordinate descent and successive convex approximation techniques. Numerical results show the significant rate improvement of the proposed joint design and provide new insights into the anti-jamming 3D trajectory design under the probabilistic LoS model, as compared to the conventional two-dimensional (2D) UAV trajectory or under LoS channel models.
Joint Precoding Optimization for Secure SWIPT in UAV-Aided NOMA Networks
Article
Sep 2020
IEEE T COMMUN
Wei Wang
Jie Tang
Nan Zhao
Yi Qian
Combination of unmanned aerial vehicle (UAV) and non-orthogonal multiple access (NOMA) is deemed as an promising solution to achieving massive connectivity in future wireless networks. In this paper, a UAV-aided NOMA scheme is proposed to achieve simultaneous wireless information and power transfer (SWIPT) and guarantee the secure transmission for ground passive receivers (PRs), in which the nonlinear energy harvesting model is applied. Each time frame is divided into two phases. In the first phase, the received power at each PR is maximized to achieve rapid charging. In the second phase, SWIPT is performed via NOMA with the remaining energy at each PR, and artificial jamming is generated at UAV together with the NOMA information to guarantee the security. The throughput of PRs is maximized, with the highest received jamming power cancelled at each PR via successive interference cancellation (SIC). This disrupts the eavesdropping effectively by jamming without affecting the legitimate transmission. Due to the non-convexity of these two optimization problems, we first convert them to convex ones and then propose iterative algorithms to solve them. Simulation results are presented to show the effectiveness of the proposed scheme.
Hybrid Offline-Online Design for UAV-Enabled Data Harvesting in Probabilistic LoS Channels
Article
Mar 2020
IEEE T WIREL COMMUN
Changsheng You
Rui Zhang
This paper considers an unmanned aerial vehicle (UAV)-enabled wireless sensor network (WSN) in urban areas, where a UAV is deployed to collect data from distributed sensor nodes (SNs) within a given duration. To characterize the occasional building blockage between the UAV and SNs, we construct the
probabilistic
line-of-sight (LoS) channel model for a Manhattan-type city by using the combined simulation and data regression method, which is shown in the form of a
generalized logistic
function of the UAV-SN elevation angle. We assume that only the knowledge of SNs’ locations and the probabilistic LoS channel model is known
a priori
, while the UAV can obtain the
instantaneous
LoS/Non-LoS channel state information (CSI) with the SNs in
real time
along its flight. Our objective is to maximize the minimum (average) data collection rate from all the SNs for the UAV. To this end, we formulate a new rate maximization problem by jointly optimizing the UAV
three-dimensional
(3D) trajectory and transmission scheduling of SNs. Although the optimal solution is intractable due to the lack of complete UAV-SNs CSI, we propose in this paper a
novel
and
general
design method, called
hybrid offline-online
optimization, to obtain a suboptimal solution to it, by leveraging both the statistical and real-time CSI. Essentially, our proposed method
decouples
the joint design of UAV trajectory and communication scheduling into two phases: namely, an
offline
phase that determines the UAV path prior to its flight based on the probabilistic LoS channel model, followed by an
online
phase that adaptively adjusts the UAV flying speeds along the offline optimized path as well as communication scheduling based on the instantaneous UAV-SNs CSI and SNs’ individual amounts of data received accumulatively. Extensive simulation results are provided to show the significant rate performance improvement of our proposed design as compared to various benchmark schemes.
View
Show abstract
Trajectory and Communication Design for UAV-Relayed Wireless Networks
Article
Jul 2019
Xu Jiang
Zhilu Wu
Zhendong Yin
Zhutian Yang
In this paper, an unmanned aerial vehicle (UAV) is employed to relay data for multiple pairs of ground users in time-division manner. Our objective is to maximize the minimum average information rate of each communication pair by optimizing the time slot allocation, power allocation and UAV trajectory. This is a non-convex optimization problem, which is challenging to address. Firstly we approximately solve the subproblem of time slot allocation with fixed power and trajectory, as well as the subproblem of power and trajectory optimization with fixed time slot allocation. Then we propose an efficient iterative algorithm to approximate the optimal solution by solving the two subproblems alternately. Numerical results show the effectiveness of the proposed algorithm.
Placement and Power Allocation for NOMA-UAV Networks
Article
Aug 2019
Xiaonan Liu
Jingjing Wang
Nan Zhao
F. Richard Yu
Unmanned aerial vehicles (UAVs) can be used as flying base stations to provide ubiquitous connections for mobile devices in overcrowded areas. On the other hand, non-orthogonal multiple access (NOMA) is a promising technique to support massive connectivity. In this letter, the placement and power allocation (PA) are jointly optimized to improve the performance of the NOMA-UAV network. Since the formulated joint optimization problem is non-convex, the location of the UAV is first optimized, with the total path loss from the UAV to users minimized. Then, the PA for NOMA is optimized using the optimal location of the UAV to maximize the sum rate of the network. Simulation results are presented to show the effectiveness and efficiency of the proposed scheme for NOMA-UAV networks.
Joint Channel Assignment and Stochastic Energy Management for RF-Powered OFDMA WSNs
Article
Dec 2018
IEEE T VEH TECHNOL
Ju Ren
Sheng Yue
Deyu Zhang
Jiannong Cao
As an emerging energy replenishment technique, RF energy transfer has been considered as a promising solution to power the low-end WSNs. However, in RF-powered OFDMA WSNs, both the energy provisioning and data transmission are easily impacted by highly dynamic and unpredictable wireless channels, making channel assignment and energy management closely coupled. Furthermore, due to the lack of priori knowledge of stochastic channel conditions, network performance optimization becomes more challenging. In this paper, we investigate joint channel assignment and stochastic energy management to optimize the long-term network utility in RF-powered OFDMA WSNs, by jointly considering the stochasticity in RF energy harvesting rates and channel fading. We formulate the network utility optimization problem (NUOP) as a mixed-integer non-linear stochastic optimization problem. By leveraging Lyapunov optimization to decouple NUOP into two subproblems and address them separately, we propose an online algorithm, named JAMA, to adaptively adjust the sampling rates, data transmission power, transmission rate, and channel assignment according to the ever-changing channel conditions, while guarantee the network stability and sustainability. Theoretical analysis and extensive simulation results based on the experimental data of an RF-powered WSN testbed verify the effectiveness and efficiency of JAMA and evaluate the impacts of system parameters on network performance.
On Buffer-Constrained Throughput of a Wireless-Powered Communication System
Article
Sep 2018
IEEE J SEL AREA COMM
Zhidu Li
Yuming Jiang
Yuehong Gao
Dacheng Yang
In this paper, the buffer-constrained throughput performance of a multi-user wireless-powered communication (WPC) system is investigated, where energy harvesting follows a non-linear model. The investigation focuses on the buffer overflow performance of sending data in the downlink (DL) from the access point (AP) node to each user equipment (UE) node and that in the uplink (UL) from each UE node to the AP node, based on which, the throughput performance on both directions when a buffer constraint is enforced is studied. Specifically, the buffer overflow probability at each node is analyzed, based on which, the buffer-constrained throughput is studied. In addition, to ensure the throughput performance under the buffer constraint, the DL transmission power allocation policy and the required energy storage capacity at each UE are investigated. Also, the optimal channel time allocation policy is studied with the objective of maximizing the minimum bufferconstrained throughput guaranteed to each UE at the same time. To this aim, an optimization problem is first formulated and then a dichotomy-based time allocation algorithm combined with one-dimensional search is proposed to solve this problem. The analysis and results, explicitly relating the throughput to the buffer constraint in addition to WPC characteristics, shed new light on the design and performance analysis of wireless-powered communication systems.
Trajectory Design for Distributed Estimation in UAV Enabled Wireless Sensor Network
Article
Jul 2018
Cheng Zhan
Yong Zeng
Rui Zhang
In this paper, we study an unmanned aerial vehicle (UAV)-enabled wireless sensor network, where a UAV is dispatched to collect the sensed data from distributed sensor nodes (SNs) for estimating an unknown parameter. It is revealed that in order to minimize the mean square error (MSE) for the estimation, the UAV should collect the data from as many SNs as possible, based on which an optimization problem is formulated to design the UAV's trajectory subject to its practical mobility constraints. Although the problem is non-convex and NP-hard, we show that the optimal UAV trajectory consists of connected line segments only. With this simplification, an efficient suboptimal solution is proposed by leveraging the classic traveling salesman problem (TSP) method and applying convex optimization techniques. Simulation results show that the proposed trajectory design achieves significant performance gain in terms of the number of SNs whose data are successfully collected, as compared to other benchmark schemes. IEEE
UAV Trajectory Optimization for Data Offloading at the Edge of Multiple Cells
Article
Aug 2018
IEEE T VEH TECHNOL
Fen Cheng
Shun Zhang
Zan Li
Victor C. M. Leung
In future mobile networks, it is difficult for static base stations (BSs) to support the rapidly increasing data services, especially for cell-edge users. Unmanned aerial vehicle (UAV) is a promising method that can assist BSs to offload the data traffic, due to its high mobility and flexibility. In this paper, we focus on the UAV trajectory at the edges of three adjacent cells to offload traffic for BSs. In the proposed scheme, the sum rate of UAV served edge users is maximized subject to the rate requirements for all the users, by optimizing the UAV trajectory in each flying cycle. The optimization is a mixed-integer non-convex problem, which is difficult to solve. Thus, it is transformed into two convex problems, and an iterative algorithm is proposed to solve it by optimizing the UAV trajectory and edge user scheduling alternately. Simulation results are presented to show the effectiveness of the proposed scheme.
Xindi Wang
Chi-Tsun Cheng
Fu Xiao
Xinyu Liu
Unmanned aerial vehicles (UAVs) are usually dispatched as mobile sinks to assist data collection in large-scale wireless sensor networks (WSNs). However, when considering the limitations of UAV’s mobility and communication capabilities in a large-scale WSN, some sensor nodes may run out of storage space as they fail to offload their data to the UAV for an extended period of time. To minimize the ... [Show full abstract] data loss caused by the above issue, a joint user scheduling and trajectory planning data collection strategy is proposed in this letter, which is formulated as a non-convex optimization problem. The problem is further divided into two sub-problems and solved sequentially. Simulation results show that the proposed strategy is more effective in minimizing data loss rate than other strategies.
April 2022 · ACM Transactions on Sensor Networks
Xindi Wang
Xinyu Liu
Jianjian Wu
[...]
Ling Shen
The future sixth-generation (6G) communication system is promising to provide differentiated communication services for massive users worldwide. To achieve the above goals, wireless sensor networks (WSNs), regarded as the critical component of the 6G system, will be widely deployed in large-scale non-urban areas such as mountain villages, forests, and oceans. To ensure the high efficiency and ... [Show full abstract] stability of WSNs without the support of ground facilities, unmanned aerial vehicles (UAVs) are dispatched to provide assistance for WSNs. Nevertheless, considering the limitations of both the mobility and communication capability of UAVs, the diversified communication demands pose huge challenges for UAV-aided WSNs in the large-scale application scenarios, such as how to schedule the SNs served in each time slot, how to optimize their working parameters and how to plan the UAV trajectory. Therefore, a joint user scheduling, power configuration, and trajectory planning strategy is proposed in this article, which is formulated as an optimization problem suffering from non-convexity and complication. The successive optimization scheme is adopted here to efficiently solve the above problem, which divides the original problem into three sub-problems and solves them iteratively. The simulation results prove the effectiveness and efficiency of the proposed strategy.
July 2018 · IEEE Transactions on Vehicular Technology
Cheng Zhan
In this paper, we study an unmanned aerial vehicle (UAV)-enabled wireless sensor network, where a UAV is dispatched to collect the sensed data from distributed sensor nodes (SNs) for estimating an unknown parameter. It is revealed that in order to minimize the mean square error (MSE) for the estimation, the UAV should collect the data from as many SNs as possible, based on which an optimization ... [Show full abstract] problem is formulated to design the UAV's trajectory subject to its practical mobility constraints. Although the problem is non-convex and NP-hard, we show that the optimal UAV trajectory consists of connected line segments only. With this simplification, an efficient suboptimal solution is proposed by leveraging the classic traveling salesman problem (TSP) method and applying convex optimization techniques. Simulation results show that the proposed trajectory design achieves significant performance gain in terms of the number of SNs whose data are successfully collected, as compared to other benchmark schemes. IEEE
The benefits of using Unmanned Aerial Vehicles (UAVs) as mobile sinks for data collection have attracted great attention in Wireless Sensor Networks (WSNs). The problem that computes the optimal trajectories for UAVs to collect data from WSN is generally NP-Hard. However, the existing works focus on the optimal trajectories of UAVs while considering the data transmission based on either ... [Show full abstract] predefined path sets or paths with predefined hovering points, or they focus on seeking the optimal paths while ignoring the data transmission latency between UAVs and sensors. In this paper, we focus on the Transportation and Communication Latency Optimization (TCLO) problem which is to find the optimal trajectory of UAV in a continuous space to collect all data from sensors in a WSN, while minimizing the sum of travelling time and data transmission time without predefined paths or hovering points. To solve the TCLO problem, we first study a special case of the TCLO problem, which is called the TCLO-disjoint problem, in which the sensor neighborhoods are disjoint. An approximation algorithm is proposed for the TCLO-disjoint problem. Based on the TCLO-disjoint problem, we propose an approximation algorithm for the TCLO problem. The proposed algorithm is verified by extensive simulations, which shows its effectiveness to minimize the data collection latency of UAV in WSNs.
| https://www.researchgate.net/publication/349704208_Technical_Report_for_A_Joint_User_Scheduling_and_Trajectory_Planning_Data_Collection_Strategy_for_the_UAV-assisted_WSN |
Rail projects receive share of €6·2bn of Connecting Europe Facility grant funding | News | Railway Gazette International
EUROPE: Various rail enhancement schemes are among the 107 projects on the Trans-European Transport Network which have been allocated a total of €6·2bn under the latest EU Connecting Europe Facility grant provisions.
Rail projects receive share of €6·2bn of Connecting Europe Facility grant funding
<here is a image 2c8a17fa9f850919-8b7d36b1e6e1faa9>
EUROPE: Various rail enhancement schemes are among the 107 projects on the Trans-European Transport Network which have been allocated a total of €6·2bn under the latest EU Connecting Europe Facility grant provisions.
The projects ‘will take us closer to completing the Trans-European Network for Transport, the backbone of the EU’s economy’, Commissioner for Transport Adina-Ioana Vălean said when the chosen projects were announced on June 22.
Cross-border rail connections to be supported include the Brenner Base Tunnel between Italy and Austria,Rail Baltica, the Karlsruhe – Basel Ausbaustreckeand Emmerich –Oberhausen.
The funding will support the roll-out ofERTMSin Austria, Germany, France, Denmark, Czech Republic and Slovakia.
Rail projects selcted for funding under the 2022 CEF Transport call for proposals
Acronym Project Title Country Coordinator Recommended funding, € Project Summary
22-AT-TG-ETCS L2Austria ETCS Level 2 migration in Austria, ETCS Phase 3.1 AT OBB-Infrastruktur AG 49 707 000 The project concerns the deployment of ETCS Level 2, Baseline 3 on 1126.5km (double track equivalent) of existing Austrian main lines. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-CZ-TC-Bra-Kr-Spo Double-tracking of the line Branický most - Praha-Krč - Spořilov CZ SPRAVA ZELEZNIC STATNI ORGANIZACE 60 873 872 The project addresses an upgrade and double-tracking of the railway section Branický most – Praha-Krč – Spořilov. It is part of a global project covering the upgrade of the Prague railway node located on the Orient/East Med and Rhine – Danube core network corridors. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-CZ-TC-CD ETCS CEF2 II Vehicles for equipment with ETCS within CEF2 II CZ CESKE DRAHY AS 23 760 000 The project covers the retrofitment of 161 vehicles (161 OBUs) of nine different types with ERTMS/ETCS Level 2 Baseline 3. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic.
22-CZ-TC-CDCERTMS Delivery and implementation of the ETCS on-board units L2B3 into selected traction vehicles of ČD Cargo, a.s. CZ CD CARGO, AS 16 345 000 The project covers the retrofitting and fitment of 99 electrical locomotives of six different types with ERTMS on-board equipment Level 2 Baseline 3 set #2. The main benefit of the project will be the increased interoperability, efficiency and safety of rail traffic.
22-CZ-TC-Havirov Optimization of the Havířov – Havířov střed section CZ SPRAVA ZELEZNIC STATNI ORGANIZACE 91 607 501 The project addresses works for the upgrade of approximately 4 km long railway section Havířov – Havířov střed, including the Havířov railway station, located on the Rhine-Danube Core Network Corridor in Czechia. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-CZ-TC-Karlstejn - Beroun Optimization of the railway line Karlštejn – Beroun CZ SPRAVA ZELEZNIC STATNI ORGANIZACE 56 624 561 The project addresses an upgrade of the railway line Karlštejn – Beroun. It is part of the global project covering the upgrade of the entire railway section “Prague – Pilsen – Domažlice / Cheb – state border with Germany” which is located on the Rhine – Danube Core Network Corridor. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-CZ-TC-Masaryk Modernisation and completion of the railway station Masarykovo nádraží CZ SPRAVA ZELEZNIC STATNI ORGANIZACE 103 758 023 The project covers works for the upgrade of the railway infrastructure components of the Praha Masarykovo nádraží terminus railway station which is part of the Core Network Urban Node of Prague in Czechia. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-CZ-TC-METCS RETRO METRANS ETCS retrofitting CZ METRANS AS 4 940 000 The project covers the serial international retrofitment of 26 vehicles of type Bombardier Traxx F 140 MS DAPLCZSKH with ERTMS/ETCS Level 2, Baseline 3. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic.
22-CZ-TC-Praha-Smichov Upgrade of the Praha-Smíchov railway station CZ SPRAVA ZELEZNIC STATNI ORGANIZACE 137 083 934 The project addresses works for the upgrade of the railway infrastructure components of the Praha-Smichov railway station located on the Rhine – Danube Core Network Corridor in Czechia. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network in the EU.
22-CZ-TC-RMTF Reconstruction of a multimodal transhipment facility CZ VELLERIN, a. s. 2 795 989 The project addresses works for the reconstruction of a multimodal transhipment facility located in Obrnice, in the Ústí nad Labem region of the Czech Republic. It covers the upgrade of the existing paved handling area (12,000 m2) and the construction of a new paved handling area (25,000 m2). It includes as well the installation of an automatic weighing system for weighing vehicles entering and leaving the terminal and the construction of 2,000 m of fencing. The main benefit of the project will be the increased transhipment capacity of the rail-road terminal.
22-DE-TG-Angermuende- Stettin Planning and works cross-border section Angermünde (Germany) to Stettin (Poland) DE BUNDESMINISTERIUM FÜR DIGITALES UND VERKEHR 92 204 405 The project concerns studies and works upgrading the railway line section between Angermünde and the Germany/Poland border. The main benefit of the project will be better rail connection between Germany and Poland.
22-DE-TG-Emmerich- Oberh22 Realisation of construction phase 3 DE BUNDESMINISTERIUM FÜR DIGITALES UND VERKEHR 64 479 000 The project concerns the upgrade to a triple-track line of the cross-border railway section DE/NL border Emmerich-Oberhausen. It forms part of the global project covering upgrading the Emmerich – Oberhausen route (ABS 46/2) implemented in several construction phases. The main benefit of the project will be increasing capacity for rail freight and passengers traffic.
22-DE-TG-ETCS-PT-10-750 ETCS OBU B3 Prototyping of 10 vehicles for freight operations across Europe with a fleet of up to 750 locos DE DB CARGO AKTIENGESELLSCHAFT 7 200 000 The project concerns the retrofitting of ETCS OBU Baseline 3 on a fleet of 10 First in Class (FiC) prototype freight locomotives (8 international and 2 national). The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-DE-TG-ETCS-Serial-Retro-80 ETCS OBU B3 Serial Retrofit of vehicle type EG3100, BR187, DE6400 DE DB CARGO AKTIENGESELLSCHAFT 3 410 000 The project concerns the serial retrofitting of a fleet of 80 freight international locomotives with ETCS Level 2 Baseline 3, which will contribute to a smart and interoperable mobility on four Core Network Corridors. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-DE-TG-Karlsruhe- Basel22 ABS/NBS Karlsruhe - Basel DE BUNDESMINISTERIUM FÜR DIGITALES UND VERKEHR 178 250 000 The project concerns works for the extension and new construction of the sub-sections 1.0-1.2 (Karlsruhe–Rastatt-Süd) and 9.0, 9.2 and 9.3 (Müllheim–Basel) of the railway line between Karlsruhe and Basel. The main benefit of the project will be increasing capacity for rail freight and passengers traffic.
22-DK-TG-ITL-DK ERTMS Interlockings in Western Denmark DK BANEDANMARK 9 280 000 The project concerns the deployment of 5 digital interlocking modules on 270km of double track equivalent railway in Denmark. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-ES-TG-ATXONDO- ABADINO ATLANTIC CORRIDOR. TRACK BED WORKS AND SERVICES FOR FOLLOW-UP WORKS. SECTIO ATXONDO - ABADIÑO. PHASE 2 ES ADIF-ALTA VELOCIDAD 22 012 500 The project concerns the construction of the track bed for a High-Speed rail line in the section “Atxondo – Abadiño” (6.59 km of equivalent double track). The project will contribute to the completion of the High-Speed line Vitoria - Bilbao - San Sebastian.
22-ES-TG-CASTELLON- VANDELLOS MEDITERRANEAN CORRIDOR SECTION CASTELLÓN- VANDELLÓS. IMPLEMENTATION OF UIC GAUGE. TRACK ASSEMBLAGE AND ELECTRIFICATION WORKS ES ADIF-ALTA VELOCIDAD 27 990 000 The Project contains works for the implementation of standard UIC gauge along a 150 km (double track equivalent) rail section between Castellón and Vandellós. The main benefit of the project will be to contribute to the European gauge network deployment in Spain.
22-ES-TG-TmZ750 Upgrade of Zaragoza’s terminal rail facilities Upgrade of TmZ terminal rail facilities for 750 m trains and new North rail connection to become a through terminal and avoid bottlenecks in the accesses ES TERMINAL MARITIMA DE ZARAGOZA SL 1 805 491 The project aims at removing operational constrains in the TmZ through an extension of 3 tracks which would allow 3 trains of 750 m to be managed at same time including construction of a concrete slab for loading/unloading containers. Moreover, in the north of the terminal a connection with the General Interest Railway Network (RFIG) will be implemented. The main benefit of the project will be the optimisation of the intermodal and cross-border traffic between France-Spain.
22-EU-TC-RBGP Part VIII C Rail Baltica - 1435 mm standard gauge railway line development in Estonia, Latvia and Lithuania (Part VIII) EE, LV, LT RB RAIL AS 323 530 274 The project is the next step in the implementation of Rail Baltica. It contains works on the main line in EE, LV and LT; additional designs in LV, and land acquisition in the three Member States. The proposal is twinned with 22-EU-TG-RBGP Part VIIIG. The project will contribute to the timely completion of Rail Baltica.
22-EU-TG-BBT Brenner Base Tunnel – Realization of the cross-border railway link between Austria and Italy in the Scandinavian-Mediterranean Corridor AT, IT Galleria di Base del Brennero - Brenner Basistunnel BBT SE 700 000 000 The project refers to the continuation of civil works activities to achieve the Brenner Base Tunnel, meaning in particular the excavation of the main tunnels and multi-functional stations, the completion of the exploratory tunnel and the preparation and construction of the supporting technical infrastructure. It also includes the continuation of activities concerning the design and preparation and execution of tenders; obtaining the necessary authorisations; geognostic and exploratory surveys; monitoring and compensatory measures as well as the development of design activities, preparatory to the construction of the railway equipment for the tunnel. The project will contribute to the timely completion of the Brenner Base Tunnel.
22-EU-TG-DP-RAIL Digital Platform for Rail Freight AT, BE, DE, FR, LU, PL UNION INTERNATIONALE DES CHEMINS DE FER 3 560 000 This project consists in a study developing a TAF TSI compliant digital platform for data exchange between the actors involved in the freight transport chain. The main benefit of the project will be improved data harmonisation and exchange in rail freight.
22-EU-TG-PCZ 2022 PCZ 2022: Bridging the cross border missing link between FR & SP: Pau-Canfranc-Zaragoza ES, FR REGION NOUVELLE- AQUITAINE 9 094 197 The project concerns a study that is part of a Global Project aimed at the rehabilitation/reopening of the Pau – Canfranc – Zaragoza cross-border railway line between France and Spain. It includes studies necessary to be declared of public interest in France, studies to prepare the network to new traffic induced by the project, technical studies on the Somport International Railway Tunnel, and a detailed design study for improving connections to the PLAZA rail-road terminal in Zaragoza. The project will contribute to the reinforcement of the cross-border rail infrastructure between Spain and France.
22-EU-TG-PL-UA railway BCPs EU-UA Solidarity Lanes- optimisation and modernisation of transport flows in terms of infrastructure capacity, interoperability and efficiency of the BC services at the main PL/UA rail border crossings PL, UA CENTRUM UNIJNYCH PROJEKTOW TRANSPORTOWYCH 32 646 712 The project concerns studies and works related to Dorohusk (PL)/Yahodyn(UA) rail BCP (both the Feasibility Study Lublin/PL-Kovel/UA and short term urgent works) and Medyka(PL)/Mostyska I and Mostyska II (UA) rail BCP area (short term urgent works and fixed transhipment equipment purchase and installation). The main benefit of the project will be the increased capacity, interoperability and safety of rail passenger and freight traffic between the EU and UA as part of the Solidarity Lanes initiative.
22-EU-TG-PL-UA roads BCPs EU–Ukraine Solidarity Lanes. Optimisation and modernisation of transport flows in terms of infrastructure capacity, interoperability and efficiency of the services at the main PL/UA BCPs PL, UA CENTRUM UNIJNYCH PROJEKTOW TRANSPORTOWYCH 62 322 285 The project covers works and studies that will optimise and modernise transport flows in terms of infrastructure capacity, interoperability and efficiency of the road border crossings along the Polish (PL) / Ukrainian (UA) at 3 border crossing points (BCP): 1) Yagodyn / Dorohusk – Okopy along international route E373 (S12 on the PL side and M07 on the UA side), 2) Rava Ruska / Hrebenne along international route E372 (S17 on the PL side and M09 on the UA side) and 3) Krakovets / Korczowa along international route E40 (A4 on the PL side and M10 on the UA side). The main benefit of the project will be the increased capacity, interoperability and safety of road passenger and freight traffic between the Euroopean Union and Ukraine as part of the Solidarity Lanes initiative.
22-EU-TG-Rail BCP RO- UA EU-Ukraine Solidarity Lanes – improving the rail border crossing at Vicsani (RO) – Vadul Siret (UA) RO, UA COMPANIA NATIONALA DE CAI FERATE CFR SA 24 380 546 The project aims to optimise rail traffic across the Romanian-Ukrainian border on the TEN-T Core route connecting Romania and the Balkans towards western Ukraine. On the Romanian territory, it envisions the electrification of 30.313 km of single railway track between Dărmănești and Vicșani and ancillary track works as well as the modernisation of the bridge over the Suceava river in Dornești station. On the Ukrainian territory, the project includes the upgrade of tracks no. 14 (1 km) and no. 21 (0.3 km) in Vadul Siret station as well as upgrade of track no. 2 (1.5 km) at Hlyboka-Bukovynska station. The main benefit of the project will be the increased capacity, interoperability and safety of road passenger and freight traffic between the European Union and Ukraine as part of the Solidarity Lanes initiative.
22-EU-TG-Rail-IT-MoS Rail-IT-MoS DE, SE TRELLEBORGS HAMN AB 12 012 500 The project targets two core maritime ports of Rostock (Germany) and Trelleborg (Sweden) and includes the reconstruction of existing port rail infrastructure and expanding port capacities by additional handling, storage and transport areas in both ports. The project aims to increase rail/intermodal transport capacity, reduce port bottlenecks, relieve network congestion, improve the integration of rail and maritime operations, and optimise freight handling in the ports. The project will upgrade an important maritime link in the Baltic Sea.
22-EU-TG-RBGP Part VIII G Rail Baltica - 1435 mm standard gauge railway line development in Estonia, Latvia and Lithuania (Part VIII) EE, LV, LT RB RAIL AS 605 437 328 The project encompasses the next phase in the implementation of Rail Baltica. It encompasses works on the main line in EE, LV and LT; and studies necessary for the management and implementation of the Global Project. The proposal is twinned with 22-EU-TC-RBGP Part VIIIC. The project will contribute to the timely completion of Rail Baltica.
22-EU-TG-RE-AVIBUS- TELT-2 Lyon – Torino base tunnel access: Upgrading of the rail historic line Bussoleno – Avigliana FR, IT TUNNEL EURALPIN LYON TURIN SAS 44 500 000 The project refers to the upgrading of the cross-border link Lyon-Turin and contributes to the upgrading the capacity and performance of an existing/new line, including the removal of level- crossings. It addresses capacity increasing in nodes with the realisation of new technological installations for the management of the traffic on the Bussoleno–Avigliana section. It contributes to the upgrade/construction of electrification system by adaptation of the line power supply system through the construction of two new electrical substations in Avigliana and Borgone. The main benefit of the project will be the progress in the preparation of the Italian access routes to the Lyon-Turin rail tunnel.
22-EU-TG-RGT Upgrade of the Cross Border Railway Connection Ghent (BE) and Terneuzen (NL) - Integrated Preparatory Phase BE, NL NORTH SEA PORT NETHERLANDS N.V. 3 367 083 The project is part of a global project to improve the cross-border Rail section Gent (BE) – Terneuzen (NL). It aims to execute the legal procedures and additional studies which are required to reach the next development stage. The main benefit of the project will be to improve the rail interconnection between Belgium and the Netherlands.
22-EU-TG-SEINE- ESCAUT 2.2 SEINE-ESCAUT 2.2: Developing the largest inland waterway network in the heart of the EU BE, FR MINISTERE DE LA TRANSITION ECOLOGIQUE ET DE LA COHESION DES TERRITOIRES 506 295 314 The project forms part of a large-scale and long-term cross-border global project aiming to connect the Seine and Scheldt basins and further the Rhine and Maas, and create a high gauge cross-border 1100 km network of waterways. This global project is key to the North Sea – Mediterranean Core Network Corridor as reflected in its work plans, in the CEF regulation and in the implementing act C(2019)4531 which provides a roadmap for its implementation until 2030. The project will contribute to the timely completion of the Canal Seine-Nord Europe and of further sections of the Belgian waterways in the Seine-Scheldt network.
22-EU-TG-UA-SK-HU_rail_BCP EU-Ukraine SL–optimisation and modernisation of transport flows in terms of infrastructure capacity, interoperability and efficiency of the border crossing services at the common HU/SK/UA rail BCP HU, SK, UA Építési és Közlekedési Minisztérium 67 751 208 The project covers studies and works for upgrading the Hungarian/Slovakian/Ukrainian rail border crossings (BCP) and the relevant transhipment areas at Chop/Záhony (UA/HU), Chop/Čierna nad Tisou (UA/SK) and Batovo/Eperjeske (UA/HU). The main benefit of the project will be the increased capacity, interoperability and safety of rail freight traffic between the European Union and Ukraine as part of the Solidarity Lanes initiative.
22-FI-TG-AIRPORT LINE Airport Line FI Suomi-rata Oy 2 750 000 The project encompasses a study aiming to improve the integration of the rail and air networks on the Helsinki Airport Line; located at the intersection between the Scandinavian- Mediterranean Core Network Corridor (CNC) and the North-Sea Baltic CNC. The project will contribute to a better rail connection to this airport.
22-FI-TG-HERI2 Construction of the main railway section Helsinki-Riihimäki (2nd phase in 2023-2027) FI VAYLAVIRASTO 40 342 050 The project addresses works for upgrading the capacity and improving the performance of the existing railway line Helsinki-Riihimäki. The project will improve the rail traffic for passengers and freight.
22-FI-TG-Karelia Planning of the Karelian railway (Luumäki-Joutseno) FI VAYLAVIRASTO 2 250 000 The project concerns the planning of a double track line replacing the current single track on the Luumäki-Joutseno section of the Karelian railway as well as the planning of the Lauritsala rail yard. The project will contribute to the future development of the railway line.
22-FR-TG-AFSB-works-step1 Rail enhancements in the South of the urban node of Bordeaux on the French part of the Atlantic corridor (AFSB): works step 1 FR SNCF RESEAU 27 189 000 The project aims to prepare the upgrade of an existing 12 km conventional railway south of the Bordeaux Saint-Jean station. The project involves preparatory studies and works. The project is part of the Global project GPSO, involving the construction of two new high-speed lines (Bordeaux-Toulouse and Bordeaux-Dax), which are one of the missing links to complete the Atlantic Core Network Corridor. The project will prepare for the timely construction of a first section of this new high speed line.
22-FR-TG-AKIEM- ERTMS-4 Upgrade to ERTMS Baseline 3 of12 locomotives series for the improvement of rail interoperability on the TEN-T Corridors FR AKIEM SAS 9 345 000 The project covers deployment of ERTMS Level 2, Baseline 3 on 157 locomotives of 7 different types, which will run on the Core Network Corridors. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-FR-TG-CAT-DAX- BAY Interoperable and resilient overheadcontact system between Dax and Bayonne on the Atlantic Corridor: Studies and works FR SNCF RESEAU 27 313 225 The project aims to carry out detailed design studies and works to upgrade the existing line between Dax and Bayonne (20.2 km). The main benefits of the project will be to enhance the rail transport service for passenger and freight towards Spain.
22-FR-TG-GPSO LNstudies GPSO new high speed lines on the Atlantic corridor – studies FR SNCF RESEAU 32 500 000 The project involves detailed design studies for the construction of two new high-speed passenger railway lines on the sections Bordeaux – Toulouse and Bordeaux – Dax. The project is part of the Global project GPSO, involving the construction of two new high-speed lines (Bordeaux-Toulouse andBordeaux-Dax), which are one of the missing links to complete the Atlantic Core Network Corridor. The main benefits of the project will be to enhance the rail transport service for passenger and freight towards Spain.
22-FR-TG-HPMV NiceUrban Node Works for deployment of ERTMS Level 3 Hybrid on Nice urban Node - HPMV zone 1 FR SNCF RESEAU 32 580 000 The project concerns deployment of ERTMS Hybrid Level 3 (Baseline 3) on the 110 km double track equivalent from Théoule-sur-Mer and Grasse through to Ventimiglia in the area of the urban node of Nice. The project is the phase 1 of the deployment of ERTMS Hybrid Level 3 (Baseline 3) between Marseille and Ventimiglia. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic in EU.
22-FR-TG-LNMP-PH1- STUDIES New and non-climate vulnerable railway line on the Mediterranean Corridor – Preparation of the design- build contract for Phase 1 Montpellier - Béziers FR SNCF RESEAU 6 342 432 The project involves preparatory studies for the Montpellier-Perpignan New Line (LNMP) – Phase 1 (from Montpellier to Béziers). The project will prepare for the timely construction of a first section of this new high speed line.
22-FR-TG-MODERN MULT HUB BSJ Bordeaux - Modernisation of the multimodal passenger hub: detailed and final studies FR SNCF GARES & CONNEXIONS 1 153 000 The Project seeks to marshal all the deliverables and resources required for putting the implementation contract out to competitive bidding (detailed design studies and works) for the Montpellier Perpignan New Line (LNMP) Phase 1. The Project aims at preparing the ground for mitigating agricultural and environmental measures by finalising the programme, conducting first experimental environmental tests and planning ahead for first work on site, enabling the selected contractor for the LNMP Phase 1 to start work without delay from 2028, at the end of the detailed studies. The project will produce benefits for passengers by making the multimodal interchange accessible for all users including those with reduced mobility.
22-HR-TC-DSNOV Upgrade of existing and construction of second track on sections B and C of Dugo Selo – Novska railway line HR HZ INFRASTRUKTURA DOO ZA UPRAVLJANJE ODRZAVANJE I IZGRADNJU ZELJEZNICKE INFRASTRUKTURE 245 615 155 The project addresses the works for the upgrade of the 42 km rail section between Ivanic-Grad to Kutina on the M103 Dugo Selo – Novska conventional railway line from a single-track railway section into a double track section. It is located on the Croatian Mediterranean Core Network Corridor. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-HR-TC-SKRKRTI Preparation of designs for the new doubletrack railway line on section Skradnik-Krasica-Tijani HR HZ INFRASTRUKTURA DOO ZA UPRAVLJANJE ODRZAVANJE I IZGRADNJU ZELJEZNICKE INFRASTRUKTURE 4 930 000 The study project addresses the upgrade and construction of a 72km new double-track railway on the section Skradnik-Krasica-Tijani, which is located on the comprehensive rail network of the Mediterranean Corridor. It covers the completion of the preliminary design documentation and the obtaining of the location permit. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-HU-TC- DNYRAILWAY Modernisation of Debrecen (excl.) – Nyíregyháza (excl.) railway section HU Építési és Közlekedési Minisztérium 256 000 000 The project addresses the upgrade of the 46.9 km long double-track electrified railway line section Debrecen – Nyíregyháza (excluding the two station nodes) in Hungary. It is located on the cross-border link Budapest - Miskolc - Ukranian border. The project will contribute to the increased capacity, interoperability and safety of the rail network, including connectivity with Ukraine.
22-IE-TG-CONNECT Project Implementation Plan for enhanced Passenger Rail Connectivity IE IARNROD EIREANN 2 595 000 The project addresses studies for upgrading the Dublin – Cork rail line, including the Limerick branch, which is located on the North Sea – Mediterranean Corridor. The project will contribute to future works implementation and traffic flow increase in this important line.
22-IE-TG-FourNorth Four-tracking of North Coastal Line IE IARNROD EIREANN 1 290 000 The project addresses studies to double the track capacity on Dublin Connolly Station - Malahide rail section, which is located on the North Sea – Mediterranean corridor. The project will contribute to future works implementation and traffic flow increase in this important line.
22-IT-TG-MEGA2 Milan East Gate hub: final design IT COMUNE DI MILANO 5 745 000 The project consists of preparation of the final designs for the multimodal passenger hub - “Milan East Gate Hub”, which includes the Milan Segrate East Gate high speed rail station, the metro link between the said station and the Core Airport of Milan Linate, pedestrian and cycling connections to the rail station and airport. The benefits of the project include better accessibility of the Milan airport and improve the mobility of all transport users.
22-IT-TG-PFTE Rovereto Southern Access Route to the Brenner Base Tunnel: Preliminary design of the Rovereto By-pass as part of the TEN-T Scan–Med Core Corridor IT RETE FERROVIARIA ITALIANA 2 000 000 The project aims to carry out the preliminary design of the Rovereto Bypass, part of the global project Southern Access Route to the Brenner Base Tunnel, located on the section Fortezza- Verona. The project will contribute to the timely completion of the access route to the Brenner Base Tunnel on the Italian side.
22-IT-TG-PORTE Upgrading the multimodal logistic platform of Pordenone through the adaptation and improvement of railway facilities and terminal efficiency. IT INTERPORTO - CENTRO INGROSSO DI PORDENONE SPA 2 858 580 The project aims to upgrade the existing multimodal logistics platform of Pordenone by adapting the existing marshalling tracks for handling of 740m long trains, constructing a new marshalling yard and wagon recovery tracks, extending the terminal area, installing OCR (Optical Character Recognition) railway gate and power connections for green transshipment equipment. The main benefit of the project will be to facilitate multimodality.
22-IT-TG-UPaRRT UPgrading Parma Rail-Road Terminal IT Centro Padano Interscambio Merci S.p.A. 3 092 880 The project aims at upgrading the railroad terminal of Parma. In particular, it will upgrade 115,000 m2 of intermodal area by constructing a pavement for transshipment operations and accompanying utilities infrastructure (electricity, water disposal, lighting, fire protection). The main benefit of the project will be to facilitate multimodality.
22-LV-TG-LPXRORO Providing of safe berthing of Ro-Ro ferries in the port of Liepaja LV Liepaja Special Economic Zone Authority 6 927 015 The project aims to implement technical studies and construction works to rebuild an existing berth (No. 46) where Ro-Ro traffic is served in the port of Liepaja, Latvia. The main benefit of the project will be the improvement of safe, sustainable, and efficient maritime services.
22-NL-TG-EnergiehavenIJmond Preparatory Studies for basic port infrastructure for offshore wind industry:Energiehaven IJmond NL HAVENBEDRIJF AMSTERDAM N.V. 2 037 610 The project aims to develop preparatory studies for the realization of basic port infrastructure for the offshore wind industry on the port area of IJmuiden, in the Netherlands. The project will contribute to adapt the port infrastructure for the development of offshore wind farms, building synergies between transport and energy infrastructure.
22-NL-TG-PHS AMSCS Programme High Frequent Rail (PHS) Amsterdam Central Station NL PRORAIL BV 70 275 540 The Project concerns the capacity upgrade of rail infrastructure (construction of fly-over/dive-under, removal of tracks and switches, new tracks) and corresponding railway infrastructure components (extending and broadening platforms and stairs, upgrading passenger tunnels) at and around Amsterdam Central Station (NL) in order to handle increasing rail traffic flows, including international rail freight transport.
22-NL-TG-REBOVEKA Removing bottleneck on the cross-border rail section Venlo (NL)- Kaldenkirchen (DE) level-rossing Vierpaardjes NL GEMEENTE VENLO 9 045 338 The project aims to remove a complex level-crossing located on the comprehensive rail network at the Vierpaardjes in Venlo, by creating an underpass-for fast and slow road traffic. The project will contribute to the road safety and rail competitiveness.
22-NL-TG-Rhombus UPSIDE II Rhombus UPSIDE II: Upscaling inland Port infrastructure in Support of modal shift and regional Sustainable Development, part 2 NL Provincie Limburg 37 395 885 The project involves studies and works to construct inland waterway portside infrastructure in the Comprehensive IWW ports of Stein, Roermond and two sites in Maastricht, located in the border areas of Netherlands, Belgium and Germany. The main benefit of the project will be to reinforce the inland waterway system connecting the Netherlands, Belgium and Germany.
22-PL-TC-Access to the port Improving the infrastructure of the Port of Gdansk with analysis for implementation of the low-emission OPS system for the sustainable development of the TEN-T network PL Zarzad Morskiego Portu Gdansk S.A. 99 586 250 The project concerns the extension and modernisation of four quays, including their railway infrastructure, and a study for Onshore Power facilities (OPS) in the core port of Gdansk, located on the Baltic Adriatic corridor. The main benefits of the project will be better navigation conditions and enhanced transshipment capacity of the port.
22-PL-TC-OWENS Building the capacity of the Swinoujscie seaport to handle offshore wind energy needs PL Zarzad Morskich Portow Szczecin i Swinoujscie S.A. 65 899 761 The project covers the development of the maritime access to the future construction of an offshore wind farm (OWF) terminal in Świnoujście seaport, located on the Baltic Adriatic and North Sea-Baltic Core Network Corridors. The main benefit of the project will be the contribution to creating transport and energy infrastructures for the production of zero-emission electricity in the Baltic Sea basin, building synergies between energy and transport infrastructure.
22-PL-TC-Rzeszow - Medyka Works on E30 railway line, Rzeszów - Medyka (state border) section - design documentation PL PKP POLSKIE LINIE KOLEJOWE SPOLKA AKCYJNA 47 347 227 The project covers the preparation of design documentation for the subsequent construction works on the section Rzeszów - Medyka (state border). It is part of the Global Project “Design documentation and execution of construction works on the entire Medyka (state border to Ukraine) – Rzeszów – Kraków – Katowice section” of railway line E30 in Poland. The main benefit of the project is to improve the cross-border connection between Poland and Ukraine.
22-PL-TC-WAWLDZ Development of the design documentation for the construction of high-speed railways in the North Sea-Baltic Sea CNC at the Warsaw - Łódź Niciarniana section (excluding the STH Junction) PL CENTRALNY PORT KOMUNIKACYJNY SP ZOO 63 639 500 The project concerns the development of the design documentation consisting of complete building permit design, water permit, railway line location decision as well as the preparation & submission for the building permit application for 120 km for the subsequent upgrades to High Speed Rail (HSR) on the Warsaw Zachodnia (Warsaw West Station) – Lodz Niciarniana railway line excluding the Solidarity Transport Hub (STH) Junction. The main benefits are bridging the missing link Warszawa/Idzikowice – Poznan/Wroclaw, removing existing bottlenecks, reduce the travel time, increase rail interoperability and the capacity of the railway infrastructure.
22-PL-TC-Zabrzeg - Zebrzyd Works on primary passenger lines (E30 and E65) within the Silesian Province, stage I: E65 railway line, Zabrzeg - Zebrzydowice (state border) section PL PKP POLSKIE LINIE KOLEJOWE SPOLKA AKCYJNA 362 024 154 The project covers the modernisation of over 36 km of railway line E 65 on the Zabrzeg - Zebrzydowice (PL/CZ state border) section, to meet TEN-T core requirements. It covers construction/reconstruction of engineering structures, construction/modernization of stations/passenger stops and eliminations of level crossings. The main benefist of the project are improving the quality of the cross-border link, reducing travel time, enhancing safety and adapting stations to servicing 750 m trains.
22-PL-TG-Bialystok - Elk Works on the E75 railway line Białystok – Suwałki – Trakiszki (state border) section, Stage I Białystok - Ełk section (phase II) PL PKP POLSKIE LINIE KOLEJOWE SPOLKA AKCYJNA 285 000 000 The project aims to upgrade a section of the 96 km long railway line Bialystok-Elk, part of the Rail Baltica alignment in Poland. The project will contribute to the timely completion of the upgraded rail connection between Poland and Lithuania.
22-RO-TC-CT Port stage II Modernization of the railway infrastructure in Constanta Port - Stage II RO COMPANIA NATIONALA DE CAI FERATE CFR SA 106 764 800 The project aims to improve the local railway connections to the core port of Constanta, which includes modernization of the railway infrastructure and the related railway station, electrification, consolidation, construction works and introducing the centralized electronic signalization and telecommunication. The project will increase the connectivity between the port and rail transport and increase the efficiency of operations and traffic flows. It is also important in the context of Solidarity Lanes.
22-RO-TC-Giurgiu Stage II Modernization of the Railway Line Bucharest North - Jilava - Giurgiu North - Giurgiu North Border – Stage II RO COMPANIA NATIONALA DE CAI FERATE CFR SA 423 659 427 The project is part of the Global Project and covers its Phase II, namely works for the rehabilitation of the railway connection between Bucharest Progresu and Giurgiu North. The project will contribute to the cross-border connection between Romania and Bulgaria.
22-SE-TG-Green goods hub Enabling optimal and sustainable goods logistics and green cargo management in Södertälje by reinforcing the Port – The Gateway to the greater Stockholm Region. SE Södertälje kommun 1 002 495 The project addresses the studies and tender documentation which are the first step needed in order to develop the comprehensive inland port of Södertälje in the southern Stockholm region, located on the Scan-Med corridor. The project will contribute to improving inland waterway connectivity.
22-SI-TC-CEF 2022 LJ-Divaca Elimination of bottlenecks on railway line Ljubljana–Divača: upgrading of railway infrastructure on 3 stations, on 1 underpass and electric power sub-stations SI MINISTRSTVO ZA INFRASTRUKTURO 64 071 810 The project addresses the removal of relevant bottlenecks on the railway line Ljubljana-Divača, which is located on core rail network and belongs to the Mediterranean and Baltic-Adriatic Core Network Corridors (i.e. cross-border link Venezia – Trieste – Divača – Ljubljana). It covers the upgrade of railway stations Brezovica, Vnanje Gorice, Preserje, the construction of power sub- stations in Borovnica and Postojna, as well as the construction of pedestrian and cycling underpass in Postojna. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-SI-TG-Parking ARJA VAS Development of a modern certified parking ARJA VAS for improving security of the TEN-T core network SI #N/A 3 255 414 The project addresses the construction of a new safe and secure truck parking area (SSTPA) with 90 safe and secure parking spaces for Heavy Good Vehicles on the A1 motorway in Slovenia. It is located on the Mediterranean and Baltic-Adriatic Core Network Corridors. It will be in compliance with the “Silver” level EU Parking Standard. The main benefits of the project will be improved security of parked trucks and enhance road safety.
22-SK-TC-CREDNVM Complex Reconstruction and Electrification of track Devínska Nová Ves - State Border (Marchegg) SK ZELEZNICE SLOVENSKEJ REPUBLIKY 12 129 630 The project addresses works for the upgrade of the existing single-track railway section Devínska Nová Ves – state border SK/AT (Marchegg). It is part of the Global Project “Twin City Rail”, which aims to construct a double-track railway line between Bratislava and Vienna and is twinned with the proposal 22-SK-TC-22-SK-TC-DBTDNVMPPP “Double-tracking of the Devínska Nová Ves – state border SK/AT (Marchegg) line, pre-project and project preparation”. The main benefit of the project will be the increased capacity, interoperability and safety of the rail network.
22-SK-TC- ERTMS_ZSSK_CARGO Implementation of ERTMS / ETCS vehicle part on ZSSK CARGO series 131 and 363 locomotives SK ZELEZNICNA SPOLOCNOST CARGO SLOVAKIA AS 4 900 000 The project covers retrofitting of 12 freight locomotives of two types, including 2 prototypes, with ERTMS/ETCS Level 2, Baseline 3. The main benefit of the project will be the increased interoperability, efficiency and safety of the rail traffic.
22-SK-TC-Upgrade of CTT Dobra Upgrade of the Combined Transport Terminal Dobrá – I. Phase SK ZELEZNICNA SPOLOCNOST CARGO SLOVAKIA AS 2 193 753 The project addresses studies and works for the upgrade of an existing rail-road terminal in Dobra near the city of Košice in Slovakia, close to the Hungarian and the Ukrainian borders and is considered as an important nodal transport hub. The main benefit of the project will be the increased transhipment capacity of the rail-road terminal.
The 2022 CEF Transport call that closed on January 18 2023 attracted 353 applications seeking a total of €16·3bn. The 2023 calls for proposals will be launched towards the end of September.
The European Commission has reiterated its objective to complete the TEN-T core network by 2030 and the comprehensive network by 2050.
Speaking at the general assembly of the European supply industry association UNIFE in Madrid on June 15, Kristian Schmidt, Land Transport Director at the European Commission’s transport directorate DG Move, insisted that ‘commitments to minimum standards’ for the TEN-T core network must be maintained, including a minimum operating speed of 160 km/h and full deployment of ERTMS.
However, he reminded the industry that ‘the commission’s policy is not modal shift, it is the decarbonisation of transport’.
Topics
Centralny Port Komunikacyjny
ERTMS
Europe
Infrastructure
Policy
Rail Baltica
| https://www.railwaygazette.com/infrastructure/rail-projects-receive-share-of-62bn-of-connecting-europe-facility-grant-funding/64379.article |
Sensors | Free Full-Text | Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras
Flat-field correction (FFC) is commonly used in image signal processing (ISP) to improve the uniformity of image sensor pixels. Image sensor nonuniformity and lens system characteristics have been known to be temperature-dependent. Some machine vision applications, such as visual odometry and single-pixel airborne object tracking, are extremely sensitive to pixel-to-pixel sensitivity variations. Numerous cameras, especially in the fields of infrared imaging and staring cameras, use multiple calibration images to correct for nonuniformities. This paper characterizes the temperature and analog gain dependence of the dark signal nonuniformity (DSNU) and photoresponse nonuniformity (PRNU) of two contemporary global shutter CMOS image sensors for machine vision applications. An optimized hardware architecture is proposed to compensate for nonuniformities, with optional parametric lens shading correction (LSC). Three different performance configurations are outlined for different application areas, costs, and power requirements. For most commercial applications, the correction of LSC suffices. For both DSNU and PRNU, compensation with one or multiple calibration images, captured at different gain and temperature settings are considered. For more demanding applications, the effectiveness, external memory bandwidth, power consumption, implementation, and calibration complexity, as well as the camera manufacturability of different nonuniformity correction approaches were compared.
Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras
by Gabor Szedo Becker 1,* and Róbert Lovas 2
1
Doctoral School of Applied Informatics and Applied Mathematics, Óbuda University, Bécsi út 96/B, 1034 Budapest, Hungary
2
Institute for Computer Science and Control (SZTAKI), Eötvös Loránd Research Network (ELKH), Kende u. 13-17, 1111 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Sensors 2022 , 22 (24), 9733; https://doi.org/10.3390/s22249733
Received: 4 November 2022 / Revised: 28 November 2022 / Accepted: 8 December 2022 / Published: 12 December 2022
(This article belongs to the Topic Advanced Signal Processing and Data Analysis for Smart IoT Ecosystems )
Abstract
Flat-field correction (FFC) is commonly used in image signal processing (ISP) to improve the uniformity of image sensor pixels. Image sensor nonuniformity and lens system characteristics have been known to be temperature-dependent. Some machine vision applications, such as visual odometry and single-pixel airborne object tracking, are extremely sensitive to pixel-to-pixel sensitivity variations. Numerous cameras, especially in the fields of infrared imaging and staring cameras, use multiple calibration images to correct for nonuniformities. This paper characterizes the temperature and analog gain dependence of the dark signal nonuniformity (DSNU) and photoresponse nonuniformity (PRNU) of two contemporary global shutter CMOS image sensors for machine vision applications. An optimized hardware architecture is proposed to compensate for nonuniformities, with optional parametric lens shading correction (LSC). Three different performance configurations are outlined for different application areas, costs, and power requirements. For most commercial applications, the correction of LSC suffices. For both DSNU and PRNU, compensation with one or multiple calibration images, captured at different gain and temperature settings are considered. For more demanding applications, the effectiveness, external memory bandwidth, power consumption, implementation, and calibration complexity, as well as the camera manufacturability of different nonuniformity correction approaches were compared.
Keywords:
CMOS
;
image sensor
;
ISP
;
FPGA
;
ASIC
;
NUC
;
FFC
;
FPN
;
DSNU
;
PRNU
1. Introduction
Digital images captured by image sensors are contaminated with noise, which deteriorate performance and reduce sensitivity. Image noise can be characterized as temporal or lateral fixed-pattern noise (FPN). Temporal noise changes from frame to frame, while FPN is mostly constant, but may depend on temperature or sensor configuration.
1.1. A Linear Model of Spatial Nonuniformity
The mathematical framework for analysis was introduced by Mooney [
1
] and later simplified by Perry [
2
] for the linear model of FPN for infrared focal plane arrays. Though Schulz [
3
] expanded the nonuniformity correction (NUC) to multipoint analysis to account for the nonlinearities of IR FPNs, the linearity of the CMOS image sensor photoresponse allows a generalization of Mooney’s framework for CMOS imagers. The luminous flux received by a small surface element with
A
, exposed to irradiance
L
, with incident angle
Θ
is
P = L A Θ ,
(1)
Without considering the effect of temporal noise sources, such as electronic, thermal, and shot noise, the number of electrons present on the cathode of a reverse-biased photodiode illuminated by a narrow-band light source can be modeled by:
N = T i n t ( η P + D ) + Q R ,
(2)
where
T i n t
is the integration time,
η
is the quantum efficiency, assumed constant for the narrow spectrum of the illuminator,
D
is the dark current, and
Q R
is the residual charge present on the cathode after reset. CMOS image sensors use correlated double sampling (CDS) which effectively cancels out the
Q R
term [
3
]. For a pixel with area
A
, at position
x , y
in the pixel array, illuminated via a lens by a wideband illuminator, the number of electrons collected by the pixel can be expressed as
N x , y = T i n t τ x , y ∫ λ 1 λ 2 L x , y ( λ ) η x , y ( λ ) d λ A Ω x , y + D x , y ,
(3)
where
L x , y
,
η x , y
, and
D x , y
are the spectral radiance density, the quantum efficiency, and the residual dark offset specific for pixel
x , y
, respectively, while
Ω x , y = π cos 4 Θ x , y 4 F 2 + 1 ,
(4)
is the projected solid angle subtended by the exit pupil of the optical system, as viewed from the sensor pixel
x , y
, where
Θ x , y
is the off-axis angle of the pixel and
F
is the F-number of the lens. The transmittance of the optical system is assumed to be homogeneous in Mooney’s model; however, for many CMOS cameras, optical efficiency tends to drop towards the corner of the image due to the chief ray angle (CRA) mismatch between the last lens element and the microlens array focusing light onto the photodiodes. Hence, the optical efficacy,
τ x , y
, is dependent on pixel position and is an important source of fixed-pattern nonuniformity. With the introduction of a response coefficient,
R x , y = A τ x , y π cos 4 Θ x , y 4 F 2 + 1 ,
(5)
(
3
) can be simplified to
N x , y = T i n t R x , y ∫ λ 1 λ 2 L x , y ( λ ) η x , y ( λ ) d λ + D x , y ,
(6)
To analyze the impact of pixel-to-pixel variation of parameters, the parameters can be expressed as:
D x , y = 〈 D 〉 + d x , y ,
(7)
R x , y = 〈 R 〉 + r x , y ,
(8)
η x , y ( λ ) = 〈 η ( λ ) 〉 + κ x , y ( λ ) ,
(9)
where the bracketed variables denote the mean value of the corresponding parameter across the entire image, and the additive quantities capture the pixel-to-pixel variations. Namely,
d x , y , r x , y ,
and
κ x , y ( λ )
are the pixel-to-pixel variation in dark current, response coefficient, and quantum efficiency, respectively. When capturing an image with zero illumination,
L x , y ( λ ) = 0
, referred to as the dark image, (
6
) yields
N x , y = D x , y = 〈 D 〉 + d x , y ,
(10)
the time-invariant pixel-to-pixel nonuniformity
d x , y
, referred to as dark signal nonuniformity (DSNU), with variance
σ d
.
When looking at a uniform gray field, often referred to as a flat field (FF), with
L x , y ( λ ) = L
, (
6
) yields
N x , y = T i n t R x , y L ∫ λ 1 λ 2 ( λ ) η x , y ( λ ) d λ + D x , y ,
(11)
By substituting (
7
)–(
9
) into (
11
),
N x , y = T i n t ( 〈 R 〉 + r x , y ) L ∫ λ 1 λ 2 〈 η ( λ ) 〉 + κ x , y ( λ ) d λ + 〈 D 〉 + d x , y ,
(12)
which in turn can be separated to a spatially uniform part, the perfectly reproduced, constant, flat field:
N ( L ) = T i n t 〈 R 〉 L ∫ λ 1 λ 2 〈 η ( λ ) 〉 ( λ ) d λ + 〈 D 〉 ,
(13)
and another term constituting the fixed-pattern noise:
N x , y = T i n t L r x , y ∫ λ 1 λ 2 〈 η ( λ ) 〉 + κ x , y ( λ ) d λ + d x , y ,
(14)
the first term of which is referred to as the photoresponse nonuniformity (PRNU). The variance of the PRNU, following the derivation in [
2
], assuming
κ x , y ( λ )
,
d x , y
, and
r x , y
are statistically independent, can be expressed as:
σ n 2 = σ D 2 + σ R 2 〈 R 〉 2 ( N ( L ) − 〈 D 〉 ) + 〈 R 〉 L ∫ λ 1 λ 2 κ x , y ( λ ) d λ ,
(15)
1.2. FPN Noise Reduction in CMOS Sensors
Figure 1 shows the typical structure of a CMOS image sensor.
Figure 1. Typical CMOS image sensor block diagram.
A matrix of pixels can collect electrons generated by the photoelectric effect. A row of pinned photodiodes can be reset, exposed, and read out by corresponding row reset, row transfer, and select drivers. Multiple pixels of a row can be read out simultaneously via a set of programmable gain amplifiers (PGAs) and analog to digital converters (ADCs). Modern CMOS sensors use correlated double sampling (CDS, Nakamura [
4
]) or correlated multiple sampling (CMS) (Min-Woong [
5
]). Analog or digital hardware solutions eliminate dark charge
Q R
, by sampling and holding the output of a pixel after reset, then sampling the same output during readout. The column amplifier outputs the difference between the two samples, which effectively removes any common mode bias, such as reset noise. Differential delta sampling (DDS) aims to remove fixed-pattern noise introduced by small differences between the sample-and-hold (SH) capacitors, and biases of the programmable gain amplifiers using a crowbar operation (Kim [
6
]). Before CDS and DDS, column-wise readout via PGAs and ADCs and row-wise addressing gave the DSNU and PRNU a characteristic striated, row–column-oriented structure shown on the left-side image of
Figure 2
. The right-side image shows a magnified, contrast-enhanced sample enhanced for visibility.
Figure 2. FPN of the IMX265LLR-C at 60 °C and 12 dB of analog gain: ( a ) no zoom and ( b ) 8× zoom.
Another often-used technique to remove DSNU is to use the optically masked pixels surrounding the active pixel area. These pixels are affected by the same conditions (temperature, electronic noise, analog gain) as the active pixels, and their values could be digitally subtracted from the corresponding rows and columns, further reducing systemic, row–column-structured noise
1.3. Temperature Dependence
The temperature dependence of dark current in silicon photodiodes (Takayanagi [
7
]) can be expressed as:
I D ( T ) = A d g e n T 1.5 e − − E g 2 k T + B d i f f T 3 e − − E g k T ,
(16)
where
E g
is the activation energy,
k
is the Boltzmann constant, and
A d g e n
and
B d i f f
are technology dependent coefficients. The shape of the aggregate temperature dependence function has two exponential regions, one dominated by the diffusion current and one by the spontaneous generation current.
2. Motivation
This section provides an overview of the application areas benefiting from an improved uniformity of image sensors.
2.1. Image and Video Quality Improvements for Enhanced Viewer Experience
While this analysis focuses on large pixel, high-quality, low-noise, global shutter sensors, many consumer products use small, low-cost CMOS sensors. Smaller pixels often have a reduced full well capacity and in turn a smaller dynamic range. Video recorded from sensors contains temporal and fixed-pattern noise superimposed on the signal. The human visual system easily disregards the temporal, Gaussian noise, but discerns patterned FPN deeply buried in temporal noise. FPN is particularly disturbing when it is superimposed on human faces in video conferencing. As viewers track facial features, movements of the face relative to the image sensor causes an apparent shift of FPN artifacts over the subject, which most viewers notice and may find objectionable.
2.2. Astronomy and LIDAR
On the other end of the sensor price/quality spectrum, large, stabilized focal plane arrays are used to image celestial objects. High-end staring cameras typically track their targets and use extended exposure intervals or collect many exposures to form output images then register the image stacks. Image stacking may amplify DSNU if motion between constituent frames is negligible relative to the spatial frequencies of the DSNU. Scheimpflug Lidars using CMOS sensors (Mei [ 8 ]) also depend on FFC to improve SNR.
2.3. Visual Odometry
In machine vision camera applications, the consumer of video streams are algorithms, which may be less effective at canceling noise than the human visual system. Especially for high-frame-rate imaging tasks with short integration time, the relatively low signal-to-noise ratio calls for digital postprocessing of the images to reduce FPN. A prime example of this use case is disparity mapping for visual odometry. In this case, two image sensors, with different FPN profiles are looking at the scene. The processing algorithm infers depth or the z-axis distance from the sensor pair from the difference or disparity between the images. Disparity mapping attempts to find a correspondence between an image pair, and often sub-pixel differences in x–y plane disparities are amplified when estimating the z-axis depth.
The analysis of stereo image pairs collected using a low-cost sensor (EV76C661 [ 9 ]) showed that matching density improved from 10.2% to 13.1% with FFC enabled, a 28% improvement. Expected improvements in matching performance can be simulated without the actual image sensor in hand. If detailed FPN information is available, e.g., by performing the EMVA1288 [ 10 ] analysis of a sensor, then synthetic image pairs with ground-truth depth information, such as the Middlebury dataset (Scharstein [ 11 ]), can be analyzed with and without FPN ( Figure 3 ). Similar to lab results with actual image sensors, matching densities without lens shading, DSNU, and PRNU were 28% better for both the cone and teddy datasets ( Figure 4 ).
Figure 3. Cone dataset original ( left ) and with FPN ( right ).
Figure 4. Teddy dataset original ( left ) and with FPN ( right ).
2.4. Forensics
To extract DSNU and PRNU from live video or image frames using nonuniform illumination, different algorithmic solutions have been proposed, based on regularization (Li, [ 12 ]), or convolutional neural networks (Guan, [ 13 ]). Using a large number of frames, especially with large image areas with frequency content sufficiently different from the spectra of the DSNU and PRNU, such as images of the sky, allows the recovery of the DSNU and PRNU. The same techniques can be used to identify the source of a video, by matching FPN as a watermark, embedded in the sources. One application of FFC is to promote data privacy by reducing FPN to a level below the capabilities of forensic algorithms (Karaküçük [ 14 ]).
3. Materials and Methods
3.1. Image Capture Parameters
At least two exposures, one with no illumination, and one with a flat uniform illumination are necessary to capture the sensor-specific correction images. For low-noise, CMOS, visible light sensors with improved image sensor circuitry (7 transistor pixels, CDS, DDS), thermal, electrical, and shot noise can be several orders of magnitude larger than FPN. In order to cancel temporal noise and to measure DSNU and PRNU, thousands of images need to be captured and averaged. To analyze the temperature and analog gain level dependency of the DSNU and PRNU, the capture sequence was performed in a temperature-controlled environment, with different gain settings. Specifically, images were captured
For two 2nd generation, global shutter, monochrome, Sony Pregius machine vision sensor candidates, the IMX265LLR-C and the IMX273LLR-C;
Across the entire analog gain range supported by the two sensor candidates, at 0.0, 6.0, 12.0, 18.0 and 24.0 dB;
For the above datasets, for both sensors, for 5 gain settings, via the temperature range supported by the sensors, at 0.0, 15.0, 30.0, 45.0, and 60 Celsius degrees.
The dataset was collected with the Sony IMX265LLR-C, with the lens and lens housing removed. A smaller dataset, with two temperatures (10 °C and 50 °C) and two analog gain settings (2.0 dB and 24.0 dB), was collected for both the IMX265 and IMX273, with two different lens assemblies attached to the sensor PCBA. For each sensor, gain, and temperature setting, the mean of the collected image stack:
μ x , y ( p ¯ ) = 1 N ∑ 1 N F x . y ( p ¯ ) ,
(17)
and the standard deviation of the stack was computed as
σ x , y ( p ¯ ) = 1 N − 1 ∑ 1 N F x . y 2 ( p ¯ ) − N μ x , y 2 ( p ¯ ) ,
(18)
where
p ¯ = [ T , α , s I D , t ]
is a parameter vector of the capture temperature (
T
), analog gain (
α
), sensor ID (
s I D
), and exposure time (
t
).
F x , y 2 ( p ¯ )
and
μ x , y 2
designate the element-wise squaring of pixel values for FF frame
F x , y ( p ¯ )
and image stack mean frame
μ x , y ( p ¯ )
. To reduce temporal noise below 1 LSB,
N
= 4000 images had to be averaged for each parameter combination.
3.2. Instrumentation
In order to precisely control the temperature of the sensor, the sensor module was mounted on a 24 V 30 W flexible polyimide heating film, connected to a USB controllable power supply (Keysight E3634A). To control sensor temperature, a software-defined PID controller was employed, using the built-in thermometer function of the sensor.
Data collection took place in a temperature chamber (No Door α LST365W-PF), which could cool the sensor down to 0 °C. As a FF light source, an LED panel, Imaging Tech Innovation model ITLB-ST-V1-100K, was used. The thermoelectric heating/cooling plate and the sensor module were housed in a custom designed, 3D-printed enclosure, which attached the sensor assembly to a flexible, collaborative robot arm (Universal Robot UR5e), programmed to move the sensor assembly on a closed, circular trajectory ( Figure 5 ).
Figure 5. Sensor assembly on robot arm in temperature chamber.
The introduction of motion while the image stack was recorded was necessary to blur any nonuniformity attributable to the light source. This was essential for the dataset with properly focused lens assemblies attached to the sensor. While many other results published (Burggraaff [
15
]) were based on measurements with integrating spheres, experiments with the lens assembly attached and properly focused revealed both the low-frequency (shading), and the high-frequency (contamination) characteristics of our integrating sphere. Wang [
16
] also documented and addressed this issue. The specified uniformity of laboratory integrating spheres, typically in the 40 dB range [
17
], is insufficient for testing 12-bit sensors.
With lens shading corrected and the image normalized for viewing, the high-frequency content of the integrating sphere nonuniformity was revealed ( Figure 6 ). If the image sensor was repositioned in the viewport, the PRNU component remained fixed, but smudges and other artifacts were shifted.
Figure 6. Static integrating sphere’s image artifacts.
4. Related Work
As mentioned in the introduction, the linear model framework for FFC was introduced by Mooney [ 1 ] and Perry [ 2 ]. Generalized linear correction architectures similar to (19) were proposed in the seminal works of Seibert [ 18 ] and Snyder [ 19 ].
Most FFC approaches are based on static dark-frame and flat-field calibration images, but dynamic methods, using scene-based FFC have also been proposed [
20
]. While scene-based methods require no calibration prior to use, significant back-end image processing is necessary to discern non-striated nonuniformities to be suppressed from the dynamic scene content. Convolutional neural networks (CNN) can also be used to identify and suppress FPN [
13
]; however, this method also requires dedicated HW resources or CNN accelerators made available for the embedded ISP platform. With either method, ISP architects are trading static calibration time, invested during manufacturing, with initialization time spent after each power-on, while the system dynamically calibrates to discern sensor-specific FPN. It is worth mentioning that dynamic methods can automatically correct for FPN variations due to parameter and temperature changes.
Based on application area, cost, and performance requirements, many solutions were proposed for FFC implementation and calibration methods. As for the implementation of FFC in an FPGA, Vasiliev [ 21 ] describes an FPGA-based ISP for a VGA CMOS image sensor, including a column-based DSNU correction. For a basic FFC of the OmniVision OV5647 and Sony IMX219 sensor, Bowman et al. [ 22 ] proposed a simple apparatus to counter lens shading and establish color-correction coefficients.
To correct lens shading and sensor nonuniformity, many documented solutions propose static, single-reference solutions. This is suitable for applications such as microscopy (Zhaoning [ 23 ]), where at least temperature is expected to be relatively stable. The approach is also viable for IR FPAs, used by many consumer grade (Teledyne-FLIR [ 24 ]) and aerospace (Hercules [ 25 ]) IR cameras, which perform NUC periodically during operation using a cold-plate mechanical shutter (Orżanowski [ 26 ]). However, closing the shutter during use for a short period to capture FPN reference images may not be acceptable for defense or real-time process control applications. Another class of FFC solutions compensate for temperature but disregards the dependency of the DSNU and PRNU on analog gain (Yao, [ 27 ]).
5. Results
This section first introduces the proposed FFC architecture, suitable for an embedded implementation on FPGAs or ASIC ISPs, then reviews temperature and analog gain dependence of DSNU and PRNU measurements on the Sony IMX265 and IMX273 global shutter machine vision sensors. Fixed-pattern noise suppression results are presented for different FFC configurations.
5.1. Flat-Field Correction
In the pixel stream
N x , y
, as defined by (
12
), the signal is coupled with the DSNU term
d x , y
and PRNU term
r x , y
. In order to correct frames with the commonly used reference-based two-point calibration (TPC) method [
26
], the additive DSNU, and the multiplicative PRNU need to be removed by performing the following correction:
O x , y ( p ¯ ) = G g N x . y ( p ¯ ) − Z i n − G d ( p ¯ ) d x . y ( p ¯ ) g x . y ( C , T ) r x . y ( p ¯ ) + Z o u t ,
(19)
where
Z i n = 〈 D 〉
is the black level of the sensor input frame,
Z o u t
is the expected output black level,
G d ( p ¯ )
is a temperature, gain, and sensor
( p ¯ )
-dependent coefficient, which may need to be re-evaluated every time parameters, such as temperature or analog gain, change. During DSNU measurement, and consequently during regular use, the input black level,
Z i n
, is typically set in the sensor to several times the expected standard deviation of the DSNU to avoid clipping the measured FPN. Coefficients
G g
and
Z o u t
perform a linear transformation of the output pixel range, mapping values to the expected output range, 8–16 bits per pixel data.
Figure 7 shows a block diagram of a single-channel FFC module. Inputs to the module are the sensor input pixels i x , y = α ρ N x , y , where α is the analog gain applied, ρ is a charge-to-voltage coefficient, and [] denotes the quantization, clipping, and clamping of the sensor output. Internal to the FFC module is an optional, parametric lens shading correction (LSC) block, which can be configured with a 32 × 32 matrix C(T) of temperature-dependent coefficients.
Figure 7. Flat-field correction module block diagram.
Parameters
G d
,
G G
,
C ( T )
,
Z i n
, and
Z o u t
, which only change between frames, are provided by ISP FW. In the proposed FPGA implementation of an ISP for a stereo machine vision camera, the module maps efficiently to the DSP48 resources of novel Xilinx or Lattice FPGAs. Generic parameters controlling the instantiation of the DSNU, lens shading, and PRNU correction sections allow a balancing of FPGA logic resources with the performance requirement of the target application. For example, if a temperature-compensated lens shading correction is not a requirement, lens shading correction can be performed by the PRNU correction multiplier, if the frame buffer providing
r x , y
is initialized with the combined PRNU and lens shading correction image. All coefficients of the FFC hardware component need to be initialized before use, and coefficients
G d ( p ¯ ) , C ( T ) , d x , y
, and
r x , y
may need to be regularly updated to match sensor operating parameters. The initialization and subsequent parameter updates are carried out by firmware (FW), which in the proposed implementation are executed by an embedded processor collocated in the same multiprocessor system on a chip (MPSoC) FPGA as the ISP HW (
Figure 8
). Besides configuring FFC parameters, FW also configures the sensor(s), which includes programming the black level to the same
Z i n
value provided to the FFC module corresponding to the sensor.
Figure 8. Uniformity correction of stereo cameras.
Per-pixel DSNU and PRNU correction reference frames
d x , y
and
r x , y
are provided to the HW FFC modules from external memory (DDR). The video direct memory access (VDMA) modules in the system transfer video frames between the memory controller and other system components. The memory controller provides a shared access to external memory, by arbitrating and prioritizing requests. The VDMAs are also configured by the system processor, and cyclically write or read frames from predetermined memory address ranges. During initialization, one, or many DSNU and PRNU calibration images, pertinent to different temperature and analog gain settings, can be loaded to the DDR memory. During operation, FW programs exposure and analog gain settings into the image sensors for every frame (autoexposure) and periodically reads sensor temperatures. Based on temperature and gain settings, it may also reconfigure the VDMAs to select PRNU and DSNU images best matched to the operating conditions and update the parametric lens shading model coefficients (
C
) based on temperature.
The DDR memory bandwidth is a scarce resource, shared by the VDMA modules, the system processor, and other ISP modules and HW accelerators implemented in the MPSoC. As the high-speed components of the external memory interface subsystem are primary drivers of dissipation and power consumption, a secondary goal of an efficient FFC solution is to minimize the DDR memory bandwidth. Another design objective is to minimize manufacturing and calibration time. Capturing DSNU and PRNU images for large sets of gain–temperature combinations for each individual sensor can be prohibitively costly for mass manufacturing practical machine vision systems.
The subsequent analysis and summary focus on DSNU and PRNU reduction over the entire gain and temperature range served by the ISP, while simultaneously minimizing access to the DDR memory and the number of calibration images used.
5.2. DSNU Analysis
DSNU measurements without the lens holder and lens assembly were conducted with a cover over the sensor. DSNU measurements with the lens assembly attached were conducted with the lens cap covering the lens.
5.2.1. DSNU and Exposure Time
In the first dataset DSNU images for the IMX265LLR-C and IMX273LLR-C sensors were captured at 0.5 ms and 2 ms exposure times, while holding the temperature and gain constant. Table 1 demonstrates almost perfect correlation between frames captured with different exposure times, with an almost identical standard deviation (SD). The SD is expressed in LSBs of 12-bit sensor data.
Table 1. DSNU standard deviations and Pearson correlations.
The dark current (thermal noise) was attenuated, but not fully canceled by averaging. Note that the lower correlation values pertained to parameter sets with a low SD, which amplified the relative effects of quantization and residual temporal noise. Likely these sensors already contained advanced silicon processes and features to reduce dark current and to compensate for biases. These findings were consistent with the findings of Changmiao [ 28 ]. Based on the results, for the rest of the analysis, the DSNU was treated as invariant with respect to the exposure time.
5.2.2. Standard Deviation of Uncorrected DSNU
Figure 9 presents the SD of the uncorrected DSNU as a function of temperature and analog gain. Matching expectations and existing results, the magnitude of the DSNU scaled exponentially with both temperature and analog gain.
Figure 9. Standard deviation of uncorrected DSNU.
5.2.3. Single-Point Correction
As a first approximation a single prior, d ^ x , y , was used without adjusting the magnitude ( G d ) to cancel the DSNU across the entire temperature and analog gain range. Figure 10 presents the SD of the residual DSNU when corrected with a static reference image captured at 45 C and 18.0 dB. At these parameter values, the SD of the DSNU was 28.64 ( Table 2 ), about half of the worst-case SD.
Figure 10. Residual SD of DSNU with a single, static image.
Table 2. SD and Pearson correlation for DSNU correction with a single static reference.
As expected, due to the strong correlation between the DSNU across temperatures and gain ranges, the DSNU was almost perfectly canceled at parameter values close to reference image capture conditions. The nonzero residual noise was due to the fact that two sets of 2000 images were collected for each parameter setting, and one stack was corrected using the other as reference. This method also helped quantify leftover temporal noise in the data. The worst-case DSNU was reduced considerably, by 37%, but the
DSNU is significantly increased
in the range of the parameter space where the SD of the DSNU was lower than that of the reference image. Pearson’s correlation was chosen as a similarity metric between FPN captures due to its invariance to signal magnitude. Pearson’s correlation between a scaled reference frame and an actual dark input frame remained unaffected by scaling with (
G d
).
Equation ( 16 ) establishes the theoretical background for the exponential relation with temperature, while the definition, α = 20 l o g 10 A g (dB) of analog gain consequently results in α , used by the programmable gain amplifiers in the sensor to scale exponentially with the A g factor as shown in Figure 11 a.
Figure 11. Standard deviation of DSNU at 30 °C ( a ) and at a gain of 24.0 dB ( b ).
By fitting exponentials along the axes (
Figure 11
) and modeling DSNU as a product of an FPN template, with the magnitude approximated with a separable surface yielded:
d x , y ( T , α ) ≈ d ^ x , y D ( T , α )
(20)
D ( T , α ) = c 0 ( c 1 e c 2 α + c 3 ) ( c 4 e c 5 T + c 6 )
(21)
where
d ^ x , y
is a reference DSNU capture, normalized to
σ
= 1.0. For optimal results
d ^ x , y
should be captured at a temperature and gain setting maximizing correlation with DSNU images captured for the rest of the parameter space.
For the IMX265, c 0 , 1 , … , 6 = {0.0196, 3.1605, 0.1156, 0.2679, 1.547, 0.0449, 45.5775}.
Considering the high correlation of FPN patterns for different parameters ( T , α ) , FPN suppression could be significantly improved by scaling the reference DSNU image captured using the parametric approximation model of Equation ( 20 ).
Figure 12
presents the standard deviation of the residual DSNU after correction with a single reference that was scaled by
G d ( T , α ) = D ( T , α ) σ ( d ^ x , y ) ,
(22)
where
D ( T , α )
is the approximation introduced in Equation (
21
), and
σ ( d ^ x , y )
is the SD of the reference frame. This method reduced the DSNU across the entire temperature and gain parameter space. The best DSNU reduction performance, 91.39% (21.3 dB), coincided with the temperature and gain identical to the reference frame parameters, with the highest Pearson correlation between frame and reference. The worst reduction performance, 25.1% (2.51 dB), was measured at the parameter combination with the least Pearson correlation with the reference frame. Establishing
D ( T , α )
for each sensor instance may be prohibitively costly for mass manufacturing. While
D ( T , α )
is fairly uniform for the same batch of sensors, a more accurate method is to read out the optically blanked pixels (OBP) around the active region of the sensor image frame, then calculate the standard deviation of the OBP region. OBPs are affected by temperature and gain settings identical to regular pixels and provide an accurate value for in situ assessment of SD magnitude. This method can be considered a digital postprocessing step after the analog correction proposed by Zhu [
29
]. Reading out the OBP presents a small (~1%) overhead during regular operation, which is a trade-off to be considered with the manufacturing overhead of establishing
D ( T , α )
.
Figure 12. Standard deviation of DSNU corrected with a single, scaled image.
5.2.4. Multipoint Correction
Results from correction with a single reference frame have confirmed that the key to improved FPN reduction performance is to use reference frames better correlated with the FPN characteristic to the temperature and gain parameters of the image frames to be corrected. For this purpose, many IR thermal imaging sensors and staring cameras use multiple sets of FPN reference images and apply the one best suited to actual operating parameters.
5.2.5. Linear Interpolation between Multiple Reference Images
A straightforward way to improve correlation is to calibrate at multiple gain and temperature settings, then interpolate the reference frame used by FFC HW based on current temperature and gain settings
( T , α )
. Suppose
n ≥ 3
reference points, {
p 1 , p 2 , … , p n
}, in parameter space
p ¯
are selected for calibration, for which the corresponding DSNU reference images
d ^ i ∈ { d ^ 1 , d ^ 2 … d ^ n }
have been captured. To find the estimated
d ^
pertinent to
p = { a , T }
, we need to find
p A , p B
and
p C ,
the three closest neighbors to
p
, defining a triangle that preferably contains
p
. Operator
∥ p − p i ∥ = ( c ( α − α i ) 2 + ( T − T i ) 2
can be used to rank order all candidate reference points by proximity, where
α
and
T
are the analog gain and temperature for
p
,
α i
and
T i
are the analog gain and temperature for reference point
p i
, and
c
is a constant scalar. Note that the perfect distance metric would be the inverse of the correlation between the DSNU of the particular frame and the DSNU of the reference frame; however, the DSNU of the current frame is unknown. Based on
Table 2
, the analog gain only scales DSNU; therefore, the DSNU along the gain axis is highly correlated, suggesting a low value for
c
. The resulting reference frame to be used for FFC is interpolated using
d ^ = ∑ i ∈ { A , B , C } λ i d ^ i ,
(23)
where
λ i
are the barycentric coordinates of
p
, as defined by the triangle formed by
p A , p B
and
p C
in the analog gain and temperature parameter space
p ¯ = { a , T }
.
λ i
can be found by solving
P λ ¯ = p ¯ ′
(24)
1 1 1 a A a B a C T A T B T C λ A λ B λ C = 1 a T
(25)
for
λ ¯
, which yields
λ A λ B λ C = ( ( λ B − λ C ) ( T − T C ) + ( λ − λ C ) ( T C − T B ) ) / D ( ( λ C − λ A ) ( T − T C ) + ( λ − λ C ) ( T C − T A ) ) / D 1 − λ A − λ B
(26)
D = ( λ C − λ B ) ( T A − T C ) + ( λ A − λ C ) ( T B − T C )
(27)
The magnitude of D can be thought of as the oriented area of a parallelogram defined by the p → A B and p → A C vectors. If p A , p B and p C are on a line, then D = 0. The larger | D | is, the more orthogonal p → A B and p → A C are, thus the better for interpolating p ¯ . Another consideration besides having D ≠ 0 for selecting three candidates from the rank-ordered list of reference candidates is to have positive barycentric coordinates ( λ i > 0 ) , ∀ i ∈ { A , B , C } , which ensures d ^ is not extrapolated in Equation ( 23 ).
5.2.6. Single-Point Correction
The SD of the resulting blended reference
d ^
can be calculated during the evaluation of (
23
), or can be estimated using precomputed SDs of the constituent references:
σ ( d ^ ) ≈ ∑ i ∈ { A , B , C } λ i σ 2 ( d ^ i ) ,
(28)
Similar to the method introduced for a single reference, the estimated SD can be used to scale the interpolated reference frame
d ^
according to (
22
). To evaluate the linear interpolation method, four reference DSNU images were captured at the four corners of the parameter space, using both extremes of temperature and gain. This intuitive selection ensured that for any parameter combination
p
in parameter space
p ¯
, a set of three references could be selected such that
p
was inside the triangle defined by the references.
Figure 13
shows that interpolating the reference image produced very good results, significantly reducing the worst-case DSNU.
Figure 13. SD of DSNU corrected with linearly interpolated reference, using 4 reference captures.
5.2.7. Optimizing DSNU Reference Selection
In order to interpolate between references, at least three reference DSNU captures are needed. Intuitively, by each additional reference image captured, we can minimize the DSNU for the parameter combinations of the reference image, at the cost of additional calibration time, DDR memory allocation, and boot time. DSNU suppression quality can be also improved by optimizing the reference parameters for a given number of reference frames. Figure 14 presents the residual SD after correction with five reference images, captured at (0 °C, 0 dB), (60 °C, 0 dB), (0 °C, 24 dB), (30 °C, 24 dB), and (60 °C, 24 dB).
Figure 14. SD of DSNU corrected with linearly interpolated reference, using 5 reference captures.
Table 3 lists the Pearson correlation values between the actual frames and the interpolated references. Besides improved DSNU suppression measurements, notice the improvement in the correlation with respect to the correlation values in Table 2 .
Table 3. Residual SD, Pearson correlation, and DSNU reduction using interpolation and 5 references.
Every time the analog gain or measured die temperature deltas exceed a predefined threshold, the embedded processor controlling the ISP needs to recompute the interpolated reference image
d ^
. Selecting the three closest candidates around the current
p = { α , T }
from a set of
{ p 1 , p 2 … p n }
reference parameters is trivial. The majority of the FFC-related workload for the embedded ISP processor is to perform the actual interpolation on millions of pixels, which is dependent on the frame size, but invariant regarding the number of reference images,
n
. At startup, the embedded processor needs to load reference DSNU frames from the nonvolatile memory (NVME) to the system memory (DDR), which, depending on the NVME used may present a small penalty in terms of boot time, for each additional reference image. DDR memory or NVME’s size/cost is typically not a concern considering image sizes relative to current package capacities. In order to optimize the locations of reference captures
{ p 1 , p 2 … p n }
in parameter space
p ¯ = { α , T }
, we need to introduce the following quantities:
Let
ψ ϵ ¯ ( α ′ , T ′ )
denote the probability that during regular operation, the sensor temperature (
T
) and analog gain (
α
) are within a predefined range
| T − T ′ | < ϵ T
and
| α − α ′ | < ϵ a
, such that
∑ α m i n α m a x ∫ T m i n T m a x ψ ϵ ¯ ( α , T ) d T = 1.0
(29)
ψ ϵ ¯ is essentially the 2D probability density function based on discrete parameter α , which is a register setting, and continuous parameter T, derived from camera usage statistics.
Let ω ( α , T ) denote the weight or relative importance of the user application, e.g., disparity mapping, associated with parameter combination ( α , T ) . For high-gain scenarios, an increased temporal noise may reduce the importance of DSNU.
With these quantities, we can now select the optimum set of reference parameters,
p ¯
, defined by:
p ^ = arg min p ∈ p ¯ ∑ α m i n α m a x ∫ T m i n T m a x σ p ( α , T ) ω ( α , T ) ψ ϵ ¯ ( α , T ) d T ,
(30)
where
p = { p 1 , p 2 … p n }
is the set of
( α , T )
parameters at which reference images were captured.
σ p ( α , T )
is the SD of the residual DSNU on images corrected with reference set
p
. The argmin operation can be implemented with the simulated annealing (SA) by Kirkpatrick [
30
], starting with
p
chosen from a constellation of parameters distributed along the edges of the parameter space. This offline operation may be time-consuming even on a powerful computer, but it only has to be performed once per reference set
p
during system design, assuming
ω ( a , T )
and
ψ ϵ ¯ ( a , T )
are stable.
5.2.8. Correction with Logarithmic Interpolation
Since DSNU is an exponential function of both
α
and
T
, interpolating in logarithmic space intuitively may improve results:
d ^ ′ = exp ∑ i ∈ { A , B , C } λ i d ^ i ′ ,
(31)
where
d ^ i ′ = ln d ^ i
are the reference DSNU images stored in logarithmic format. Results unfortunately did not confirm this hypothesis, and with the same set of reference parameters, the resulting DSNU residuals were slightly higher than that of the linear interpolation.
5.3. PRNU Analysis
Noise patterns on the sensor output image depend on imaging conditions: illumination, exposure time, analog gain, temperature, and conducted, capacitive, and inductive electronic interference. The first set of experiments were designed to determine which imaging parameters affected the PRNU.
5.3.1. PRNU and Exposure Time
FF images were captured for multiple IMX265LLR-C and IMX273LLR-C sensor instances at 0.5 ms and 2 ms exposure times, while holding the temperature and gain constant. Measurements were performed with the lens assembly present over the sensor. Table 4 demonstrates the almost perfect correlation between FF image stacks captured with different exposure times.
Table 4. PRNU standard deviations and Pearson correlations.
For the IMX265, the SD displayed only a slight dependence on exposure time and temperature, a 0.1% increase at 0 °C, and a 2.1% increase at 60 °C, while the exposure time increased fourfold from 0.5 ms to 2.0 ms. These increases were under the residual noise floor after averaging the temporal noise over 2000 images. The IMX273 did not display any measurable dependence on exposure time. Based on these results, for the rest of this analysis, PRNU was treated as invariant with respect to the exposure time.
In comparison with
Table 1
, the SD of the PRNU was up to two orders of magnitude larger than that of the DSNU, and initially seemed a lot less dependent on analog gain or temperature. A second set of measurements were performed with a focus on temperature and gain dependence for the IMX265LLR-C, capturing the PRNU at analog gain levels {0, 6, 12, 18, and 24 dB} levels, at {0, 15, 30, 45, and 60} degrees Celsius temperatures. For each sensor, gain, and temperature combination, two sets of measurement data were recorded, based on N = 2000 frame captures in each set. Both sets contained mean images,
μ 1 ( T , α )
and
μ 2 ( T , α )
, which were generated by averaging the captured images, as well as standard deviation
σ 1 ( T , α )
and
σ 2 ( T , α )
images, by calculating the SD for each pixel across the stack of N images. The per-pixel SD allowed the estimation of the residual temporal noise present in the data.
5.3.2. PRNU and Exposure Time
Before continuing with the analysis of the noise on image stacks captured with the FF illumination, it was important to characterize noise sources. At higher illumination levels, temporal noise is dominated by shot noise, the collective effect of the quantum nature of light. The actual number of photons captured during the exposure period follows a Poisson distribution. If the mean number of photons captured is
ν
, then the SD of shot noise is
ν
. The maximum number of photons converted to electrons is limited by the full well capacity of the sensor,
ν m a x
, as well as the saturation level of the ADCs following the PGAs. Thus, to get to an expected digital output level, such as a 70% white level, with higher analog gains, fewer photons need to be captured. When using analog gain
α
, the SD of the shot noise associated with the photon flux is reduced by
α
at the photodiode, but this noise, superimposed on the signal, is then amplified by the PGA.
σ ( α ) = α ν α = α ν ,
(32)
Effectively, when comparing FF images captured with different analog gain settings resulting from similar output white levels, the SD is expected to scale with the square root of the gain applied. Figure 15 , plotting the measured standard deviations E [ σ 1 ( T , α ) ] on a lin–log scale, confirms this expectation. The 24.0 dB (maximum gain for the IMX265 and IMX273) applied a factor of 16 amplification, for which a 4× increase in shot noise was observed.
Figure 15. Shot noise as a function of analog gain.
Averaging over
N
images reduces the SD of shot noise by a factor of
N
. Based on SD measurements, the SD of temporal noise present in the image stack means
μ 1 ( α , T )
and
μ 2 ( α , T )
are expected to range from 11.2 LSBs (
T = 0
°C,
α = 0.0
dB) to 44.72 LSBs (
T = 60
°C,
α = 24.0
dB), due to averaging.
It is also worth noting that the distribution of per-pixel standard deviation
σ 1 ( α , T )
is not necessarily Gaussian (
Figure 16
). Per the central limit theorem, the effects of multiple, uncorrelated noise sources with different means and SDs (such as shot noise, thermal noise, and electronic noise) superimposed on pixel outputs would present as a single Gaussian even if the distributions of the individual noise sources were not Gaussian. Different sensitivities translate to different photon counts and in turn, different SD distributions of shot-noise. For a monochrome sensor, with no lens assembly attached,
Figure 16
is proof of a continuum of different sensitivities, which effectively is the definition of the PRNU present. To analyze noise variance on the pixel output, all temporal noise sources dependent on the illumination and gain, such as shot noise, were incorporated into
n s ( L , α )
and all other temporal noise sources, such as reset, electronic, thermal noise into
n T ( α , T )
. By factoring these into (
11
), with
N x , y ′ ( α , T )
as the output pixel value, assuming a uniform gray illumination (
L
), we obtained:
N x , y ′ ( α , T ) = T i n t R x , y L α + D x , y ( α , T ) + n s ( L , α ) + n T ( α , T )
(33)
Figure 16. Distribution of per-pixel SD at T = 30 °C, α = 0.0 dB.
For FF measurements, exposure time
T i n t
was set such that the expected output value remained constant (70% of the white value,
N m a x
) for the chosen illumination intensity
L
and analog gain
α
. Hence,
L T i n t α = 0.7 N m a x
was a constant factored into the PRNU,
r x , y = T i n t R x , y L α = 0.7 N m a x R x , y
. Since the DSNU for all analog gain and temperature combinations used in the PRNU analysis were recorded, captures could be corrected with the DSNU:
n x , y ( α , T ) = N x , y ′ ( α , T ) − D x , y ( α , T ) ,
(34)
n x , y ( α , T ) = r x , y + n s ( L , α ) + n T ( α , T ) ,
(35)
Assuming statistical independence between the noise sources, the noise variance on the output could be expressed as:
σ n 2 = σ r 2 + σ s 2 + σ T 2 = σ r 2 + σ t 2
(36)
The first noise term, σ r was pertinent to the fixed pattern PRNU, which we aimed to minimize. The suppression of the temporal noise term σ t was beyond the scope of this paper.
Figure 17 illustrates the SD of the temporal noise as a function of the temperature and analog gain used. As expected, thermal noise n T ( α , T ) increased with temperature, and shot noise n s ( L , α ) increased with analog gain α .
Figure 17. σ t ( α , T ) °C, α = 0.0 dB.
5.3.3. Analysis of Flat-Field Image Stacks
The SD of the FF image stack
( σ n )
and temporal noise
( σ t )
were directly observable. When the two sets of mean images,
μ 1 ( α , T )
and
μ 2 ( α , T )
, of the image stacks were combined:
s ( α , T ) = μ 1 ( α , T ) + μ 2 ( α , T ) 2
(37)
The SD of the per-pixel temporal noise was suppressed by
2 N ≈ 63.24
and
σ s 2 = σ r 2 + σ t 2 2 N
(38)
In the per-pixel
differences
of the two sets of mean images
d ( α , T ) = μ 1 ( α , T ) − μ 2 ( α , T ) 2
(39)
the FPN term was eliminated, and the difference image capturing the residual temporal noise after averaging was:
σ s 2 = σ t 2 2 N
(40)
5.3.4. Standard Deviation of Uncorrected PRNU
From measurements of
σ s ( α , T )
and
σ d ( α , T )
, the SD of the fixed-pattern component (PRNU) could be deduced:
σ r = σ s 2 − σ d 2
(41)
Figure 18 illustrates the dependence of the PRNU on the analog gain and temperature. It is also worth noting that the nonuniformity was only visible, though subtle, at very low gains where shot noise was at minimum. Above 0.5 dB gain, the FPN on the video was imperceptible as it was deeply buried in temporal noise.
Figure 18. SD of uncorrected PRNU, σ r ( α , T ) .
5.3.5. Single-Point Correction
Selecting a single correction image ( Figure 19 ) is the simplest way to calibrate nonuniformity and has demonstrated good results (Yao, [ 27 ]). For suppression of the visible PRNU artifacts, selecting a calibration frame in the middle of the temperature range and at analog gain α = 0.0 dB removed all visible artifacts.
Figure 19. Residual SD of PRNU, single-reference correction.
The analysis of the PRNU recorded at different temperatures and analog gains revealed a very high correlation across the entire temperature range. This augmented the findings of Figure 20 , suggesting that the PRNU was stable across the operating temperature range.
Figure 20. Projections and averages of σ r ( α , T ) .
5.3.6. Multipoint Correction
The results suggested that using multiple reference frames along the gain axis in the middle of the temperature range could minimize the SD over the entire parameter range ( Figure 21 ).
Figure 21. Residual SD of PRNU, multi-reference correction.
Even though a multipoint correction can reduce the worst-case PRNU by a factor of four, a practical implementation of this method requires capturing multiple PRNU reference images in a temperature-controlled environment. The large number of images to capture for each image stack and reference image may be prohibitively expensive in a production environment.
6. Discussion
Based on the initial design objectives (FPN suppression performance, design silicon footprint, DDR memory bandwidth, and calibration complexity), and the insights gained from the analysis of factors affecting the DSNU and PRNU performance, the following solutions are recommended for different performance tiers:
The most egregious nonuniformity problem is uncorrected lens shading. For consumer products with inexpensive CMOS sensors and optics, such as webcams, a minimal ISP solution can use population images, captured once per manufactured batch, for lens shading correction, and no correction for DSNU or PRNU. Objectionable to human observers, and detrimental to machine vision and processing algorithms, lens shading can be compensated using just the parametric LSC module in the proposed FFC solution. This performance tier does not require an external frame buffer, VDMAs, or FW initialization of the correction buffers ( d x , y and r x , y ).
For video applications where visible FPN is not acceptable, such as cell phones and DSLR cameras, the PRNU and DSNU has to be suppressed. This performance tier requires an external frame buffer, and VDMAs around the ISP block to provide d x , y and r x , y . If fixed -focus optics are used, and the temperature compensation of the lens is not a requirement, LSC can be performed by convolving the intensity correction with PRNU correction in r x , y . The results of Section 5.2.3 demonstrated that using a single, static image did not correct the DSNU sufficiently. As temperature and sensor gain change, this method may introduce more noise than originally present in the sensor image.
The top performance tier is suitable for high-end machine vision cameras, studio equipment, or computational photography where motion-compensated image stacks are registered to suppress temporal noise. For these demanding applications gain- and temperature-compensated DSNU, PRNU, and LSC are all utilized. Parametric LSC is suggested with module-specific, temperature-compensated lens shading parameters accounting for zoom and focus settings. For this tier, FW needs to either calculate D ( T , α ) or gather image statistics from the OBP region of the sensor and calculate σ ( T , α ) ( Section 5.2 ). Moreover, FW may dynamically adjust the frame buffer contents to interpolate between DSNU and PRNU frames stored in DDR memory. As demonstrated in Section 5.2.3 , DSNU correction can be significantly improved by using the global DNSU amplifier ( G d ) feature of the FFC. PRNU suppression can be improved by using gain-dependent calibration images ( r x , y ). For this performance tier, at initialization, multiple r x , y images need to be deposited into DDR memory by FW. During use, FW also needs to read out sensor temperature T, and based on the current analog gain setting α , update G d ( α , T ) and reprogram the VDMA read controller to point to the r x , y ( α ) best matched to operating conditions.
7. Future Work
More work is necessary to study the stability of DSNU and PRNU images over time. It is well understood that the aging of image sensors due to high temperature and exposure to cosmic rays may introduce defective pixels during use. Very likely the same processes affect DSNU and PRNU, for which nonuniformity correction images need to be recalibrated periodically. Removing and reattaching the lens assembly to record PRNU images without LSC is problematic and may require access to a clean room and AA equipment, as the removal of sealing compounds may damage or contaminate the sensor assembly. Therefore, for the long-term use of sensor modules, DSNU and PRNU calibration with the lens assembly attached is much preferred.
8. Summary
In the introduction, we reviewed sources of nonuniformity in imaging systems: DSNU, PRNU and lens shading. In the subsequent Results section, we analyzed the dependency of the DSNU and PRNU of two modern, global shutter machine vision sensors on exposure time, die temperature, and analog gain ( Figure 9 and Figure 18 ). In Section 5.1 , we also provided an FFC architecture for ISPs, optimized for FPGA or ASIC implementation supporting different FPN suppression performance and resource use trade-offs. Based on different use case scenarios, the proposed FFC and ISP architecture could be configured for different performance tiers. For all performance tiers, the proposed architecture introduced minimal latency as images were read out from attached image sensors. The noise suppression performance of four different algorithms were quantified to suppress DSNU ( Section 5.2 ), along with the analysis of the embedded software and calibration complexity of the different approaches. We provided methods ( Section 5.2.7 ) for optimizing the capture parameters of reference captures. The performance of PRNU suppression with single and multiple reference captures were analyzed in Section 5.3 .
Author Contributions
Conceptualization, methodology, software, validation, formal analysis, investigation, resources, original draft preparation: G.S.B.; Review and editing, supervision, project administration: R.L. All authors have read and agreed to the published version of the manuscript.
Funding
This research was partly supported in project no. TKP2021-NVA-01 by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NVA funding scheme.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the author upon reasonable request.
Acknowledgments
We would like to acknowledge Gábor Kertész, for his review of the manuscript and guidance on scientific content.
Conflicts of Interest
The author declares no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
ADC Analog-to-digital converter
ASIC Application-specific integrated circuit
CDS Correlated double sampling
CMOS Complementary metal–oxide semiconductor
CNN Convolutional neural network
DDS Differential delta sampling
DDR Double data rate random-access memory
DSNU Dark signal nonuniformity
FFC Flat-field correction
FPA Focal plane array
FPGA Field-programmable gate array
FPN Fixed-pattern noise
FW Firmware
ISP Image signal processor
IR Infrared
LSC Lens shading correction
LED Light-emitting diode
MPSoC Multiprocessor system on a chip
PGA Programmable gain amplifier
PRNU Photoresponse nonuniformity
RST Reset
SD Standard deviation
SEL Select
SH Sample and hold
SoC System on a chip
TEC Thermoelectric cooler
TX Transmit
VDMA Video direct memory access
References
Mooney, J.M.; Sheppard, F.D.; Ewing, W.S.; Ewing, J.E.; Silverman, J. Responsivity Nonuniformity Limited Performance of Infrared Staring Cameras. Opt. Eng. 1989 , 28 , 281151. [ Google Scholar ] [ CrossRef ]
Perry, D.L.; Dereniak, E.L. Linear theory of nonuniformity correction in infrared staring sensors. Opt. Eng. 1993 , 32 , 1854–1859. [ Google Scholar ] [ CrossRef ]
Schulz, M.; Caldwell, L. Nonuniformity correction and correctability of infrared focal plane arrays. Infrared Phys. Technol. 1995 , 36 , 763–777. [ Google Scholar ] [ CrossRef ]
Nakamura, J. Dark Current. In Image Sensors and Signal Processing for Digital Still Cameras , 1st ed.; Taylor and Francis: Boca Ranton, FL, USA, 2006; Chapter Basics of Image Sensors; pp. 68–71. ISBN 0849335450. [ Google Scholar ]
Seo, M.W.; Yasutomi, K.; Kagawa, K.; Kawahito, S. A Low Noise CMOS Image Sensor with Pixel Optimization and Noise Robust Column-parallel Readout Circuits for Low-light Levels. ITE Trans. Media Technol. Appl. 2015 , 3 , 258–262. [ Google Scholar ] [ CrossRef ][ Green Version ]
Kim, M.K.; Hong, S.K.; Kwon, O.K. A Fast Multiple Sampling Method for Low-Noise CMOS Image Sensors with Column-Parallel 12-bit SAR ADCs. Sensors 2016 , 16 , 27. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Takayanagi, I. Fixed Pattern Noise Suppression. In Image Sensors and Signal Processing for Digital Still Cameras , 1st ed.; Taylor and Francis: Boca Ranton, FL, USA, 2006; Chapter CMOS Image Sensors; pp. 147–161. ISBN 0849335450. [ Google Scholar ]
Mei, L.; Zhang, L.; Kong, Z.; Li, H. Noise modeling, evaluation and reduction for the atmospheric lidar technique employing an image sensor. Opt. Commun. 2018 , 426 , 463–470. [ Google Scholar ] [ CrossRef ]
Teledyne. EV76C661 1.3 Mpixel CMOS Image Sensor. 2019. Available online: https://imaging.teledyne-e2v.com/content/uploads/2019/02/DSC_EV76C661.pdf (accessed on 29 October 2022).
EMVA. European Machine Vision Association (EMVA) Standard 1288, Standard for Characterization of Image Sensors and Cameras. 2016. Available online: https://www.emva.org/wp-content/uploads/EMVA1288-3.1a.pdf (accessed on 29 October 2022).
Scharstein, D.; Szeliski, R. High-accuracy stereo depth maps using structured light. In Proceedings of the 2003 IEEE Computer Society Conference on Computer Vision and Pattern Recognition, Madison, WI, USA, 18–20 June 2003; Volume 1, pp. 195–202. [ Google Scholar ] [ CrossRef ]
Liu, L.; Zhang, T. Optics Temperature-Dependent Nonuniformity Correction Via ℓ 0 -Regularized Prior for Airborne Infrared Imaging Systems. IEEE Photonics J. 2016 , 8 , 1–10. [ Google Scholar ] [ CrossRef ]
Guan, J.; Lai, R.; Xiong, A.; Liu, Z.; Gu, L. Fixed pattern noise reduction for infrared images based on cascade residual attention CNN. Neurocomputing 2020 , 377 , 301–313. [ Google Scholar ] [ CrossRef ][ Green Version ]
Karaküçük, A.; Dirik, A.E. Adaptive photo-response non-uniformity noise removal against image source attribution. Digit. Investig. 2015 , 12 , 66–76. [ Google Scholar ] [ CrossRef ]
Burggraaff, O.; Schmidt, N.; Zamorano, J.; Pauly, K.; Pascual, S.; Tapia, C.; Spyrakos, E.; Snik, F. Standardized spectral and radiometric calibration of consumer cameras. Opt. Express 2019 , 27 , 19075–19101. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Wang, Y.; Wan, B.; Fu, G.; Su, Y. PRNU Estimation of Linear CMOS Image Sensors That Allows Nonuniform Illumination. IEEE Trans. Instrum. Meas. 2021 , 70 , 1–11. [ Google Scholar ] [ CrossRef ]
CAL3. Image Engineering “CAL3 V2 Data Sheet”. 2016. Available online: http://www.image-engineering.de/content/products/equipment/illumination_devices/cal3/downloads/CAL3_data_sheet.pdf (accessed on 29 October 2022).
Seibert, J.A.; Boone, J.M.; Lindfors, K.K. (Eds.) Flat-field correction technique for digital detectors. In Proceedings of Medical Imaging 1998: Physics of Medical Imaging ; Society of Photographic Instrumentation Engineers (SPIE): San Diego, CA, USA, 1998; Volume 3336, pp. 348–354. [ Google Scholar ] [ CrossRef ]
Snyder, D.L.; Angelisanti, D.L.; Smith, W.H.; Dai, G.M. Correction for nonuniform flat-field response in focal plane arrays. In Proceedings of SPIE 2827, Digital Image Recovery and Synthesis III ; Idell, P.S., Schulz, T.J., Eds.; Society of Photographic Instrumentation Engineers (SPIE): Denver, CO, USA, 1996; Volume 2827, pp. 60–67. [ Google Scholar ] [ CrossRef ]
Ratliff, B.M.; Hayat, M.M.; Tyo, J.S. Radiometrically accurate scene-based nonuniformity correction for array sensors. J. Opt. Soc. Am. A 2003 , 20 , 1890–1899. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Vasiliev, V.; Inochkin, F.; Kruglov, S.; Bronshtein, I. Real-time image processing inside a miniature camera using small-package FPGA. In Proceedings of the International Symposium on Consumer Technologies, St. Petersburg, Russia, 11–12 May 2018; pp. 5–8. [ Google Scholar ] [ CrossRef ]
Bowman, R.W.; Vodenicharski, B.; Collins, J.T.; Stirling, J. Flat-Field and Colour Correction for the Raspberry Pi Camera Module. J. Open Hardw. 2020 , 4 , 1–9. [ Google Scholar ] [ CrossRef ][ Green Version ]
Zhang, Z.; Wang, Y.; Piestun, R.; Huang, Z.-L. Characterizing and correcting camera noise in back-illuminated sCMOS cameras. Opt. Express 2021 , 29 , 6668–6690. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Teledyne-FLIR. 160 × 120 High-Resolution Micro Thermal Camera: Lepton 3 & 3.5. 2022. Available online: https://flir.netx.net/file/asset/15529/original/attachment (accessed on 29 October 2022).
Silicon and Devices. Hercules 1280 × 1024, 15 µm Pitch, Digital InSb MWIR. 2016. Available online: https://www.scd.co.il/wp-content/uploads/2019/04/HERCULES_brochure_v3_PRINT.pdf (accessed on 29 October 2022).
Orżanowski, T. Nonuniformity correction algorithm with efficient pixel offset estimation for infrared focal plane arrays. SpringerPlus 2016 , 5 , 1831. [ Google Scholar ] [ CrossRef ][ Green Version ]
Yao, P.; Tu, B.; Xu, S.; Yu, X.; Xu, Z.; Luo, D.; Hong, J. Non-uniformity calibration method of space-borne area CCD for directional polarimetric camera. Opt. Express 2021 , 29 , 3309–3326. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hu, C.; Bai, Y.; Tang, P. Denoising Algorithm for the Pixel-Response Non-uniformity Correction of a Scientific CMOS Under Low Light Conditions. Int. Arch. Photogramm. Remote Sens. Spat. Inf. Sci. 2016 , XLI-B3 , 749–753. [ Google Scholar ] [ CrossRef ][ Green Version ]
Zhu, Y.; Niu, Y.; Lu, W.; Huang, Z.; Zhang, Y.; Chen, Z. A 160 × 120 ROIC with Non-uniformity Calibration for Silicon Diode Uncooled IRFPA. In Proceedings of the 2019 IEEE International Conference on Electron Devices and Solid-State Circuits (EDSSC), Xi’an, China, 12–14 June 2019; pp. 1–3. [ Google Scholar ] [ CrossRef ]
Kirkpatrick, S.; Gelatt, C.D.; Vecchi, M.P. Optimization by Simulated Annealing. Science 1983 , 220 , 671–680. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Figure 1. Typical CMOS image sensor block diagram.
Figure 2. FPN of the IMX265LLR-C at 60 °C and 12 dB of analog gain: ( a ) no zoom and ( b ) 8× zoom.
Figure 3. Cone dataset original ( left ) and with FPN ( right ).
Figure 4. Teddy dataset original ( left ) and with FPN ( right ).
Figure 5. Sensor assembly on robot arm in temperature chamber.
Figure 6. Static integrating sphere’s image artifacts.
Figure 7. Flat-field correction module block diagram.
Figure 8. Uniformity correction of stereo cameras.
Figure 9. Standard deviation of uncorrected DSNU.
Figure 10. Residual SD of DSNU with a single, static image.
Figure 11. Standard deviation of DSNU at 30 °C ( a ) and at a gain of 24.0 dB ( b ).
Figure 12. Standard deviation of DSNU corrected with a single, scaled image.
Figure 13. SD of DSNU corrected with linearly interpolated reference, using 4 reference captures.
Figure 14. SD of DSNU corrected with linearly interpolated reference, using 5 reference captures.
Figure 15. Shot noise as a function of analog gain.
Figure 16. Distribution of per-pixel SD at T = 30 °C, α = 0.0 dB.
Figure 17. σ t ( α , T ) °C, α = 0.0 dB.
Figure 18. SD of uncorrected PRNU, σ r ( α , T ) .
Figure 19. Residual SD of PRNU, single-reference correction.
Figure 20. Projections and averages of σ r ( α , T ) .
Figure 21. Residual SD of PRNU, multi-reference correction.
Table 1. DSNU standard deviations and Pearson correlations.
Sensor Type Temperature (°C) Analog Gain (dB) Std. Dev. T int = 0.5 ms Std. Dev. T int = 2.0 ms Pearson Correlation IMX265 10 2.0 1.423 1.416 0.974 IMX265 10 24.0 26.164 26.047 0.997 IMX265 50 2.0 3.275 4.982 0.983 IMX265 50 24.0 60.294 60.428 0.997 IMX273 10 2.0 4.430 4.416 0.988 IMX273 10 24.0 52.864 52.880 0.995 IMX273 50 2.0 4.799 5.376 0.962 IMX273 50 24.0 64.950 65.802 0.982
Table 2. SD and Pearson correlation for DSNU correction with a single static reference.
Temperature (°C) Analog Gain (dB) T int (ms) Original Std. Dev. Residual Std. Dev. Pearson Correlation 0 0 0.53 3.16 26.44 0.726 0 24 0.02 47.17 31.43 0.761 15 0 0.51 3.23 25.99 0.840 15 24 0.02 48.82 27.94 0.867 30 0 0.49 3.43 25.49 0.929 30 24 0.01 50.99 26.01 0.939 45 0 0.46 3.76 24.98 0.977 45 6 0.23 7.34 21.39 0.991 45 12 0.10 14.44 14.36 0.995 45 18 0.05 28.64 2.80 0.995 45 24 0.01 57.63 29.28 0.995 60 0 0.45 4.64 24.44 0.920 60 6 0.21 8.69 20.75 0.948 60 12 0.10 17.71 13.62 0.939 60 18 0.04 34.43 12.23 0.941 60 24 0.01 68.42 42.62 0.940
Table 3. Residual SD, Pearson correlation, and DSNU reduction using interpolation and 5 references.
Temperature (°C) Analog Gain (dB) Frame SD Residual SD Pearson Correlation DSNU Reduction (%) DSNU Reduction (dB) 0 12 11.90 1.28 0.994 89.3 19.39 0 24 47.17 3.82 0.997 91.9 21.84 0 18 23.61 2.89 0.993 87.8 18.24 0 6 6.05 0.87 0.990 85.7 16.88 0 0 3.16 1.06 0.944 66.6 9.52 15 24 48.82 5.33 0.994 89.1 19.24 15 18 24.40 2.73 0.994 88.8 19.01 ⋮ ⋮ ⋮ ⋮ ⋮ ⋮ ⋮ 45 12 14.44 2.28 0.987 84.2 16.02 45 6 7.34 2.12 0.958 71.1 10.80 45 0 3.76 0.65 0.985 82.8 15.30 60 24 68.42 7.10 0.995 89.6 19.69 60 18 34.43 5.17 0.989 85.0 16.47 60 12 17.71 3.21 0.984 81.9 14.84 60 6 8.69 1.56 0.984 82.0 14.90 60 0 4.64 1.55 0.944 66.6 9.52
Table 4. PRNU standard deviations and Pearson correlations.
Sensor Type Temperature (°C) Analog Gain (dB) Std. Dev. T int = 0.5 ms Std. Dev. T int = 2.0 ms Pearson Correlation IMX265 0 2.0 175.69 176.00 0.999141 IMX265 20 2.0 174.47 176.33 0.999050 IMX265 60 2.0 171.03 174.16 0.998582 IMX273 35 0.2 182.69 183.31 0.996231 IMX273 35 12.0 180.74 183.32 0.995280 IMX273 60 0.2 177.80 181.75 0.999082 IMX273 60 12.0 154.77 155.31 0.996216
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).
Share and Cite
MDPI and ACS Style
Becker, G.S.; Lovas, R. Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras. Sensors 2022, 22, 9733.
https://doi.org/10.3390/s22249733
AMA Style
Becker GS, Lovas R. Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras. Sensors. 2022; 22(24):9733.
https://doi.org/10.3390/s22249733
Chicago/Turabian Style
Becker, Gabor Szedo, and Róbert Lovas. 2022. "Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras" Sensors22, no. 24: 9733.
https://doi.org/10.3390/s22249733
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here .
Article Metrics
Becker, G.S.; Lovas, R. Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras. Sensors 2022, 22, 9733.
https://doi.org/10.3390/s22249733
AMA Style
Becker GS, Lovas R. Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras. Sensors. 2022; 22(24):9733.
https://doi.org/10.3390/s22249733
Chicago/Turabian Style
Becker, Gabor Szedo, and Róbert Lovas. 2022. "Uniformity Correction of CMOS Image Sensor Modules for Machine Vision Cameras" Sensors22, no. 24: 9733.
https://doi.org/10.3390/s22249733
Sensors ,
EISSN 1424-8220,
Published by MDPI
Subscribe to receive issue release notifications and newsletters from MDPI journals
| https://www.mdpi.com/1424-8220/22/24/9733/html |
Pain: Perception and motor impulses arise in the brain independently of one another - Medizin Aspekte
Pain: Perception and motor impulses arise in the brain independently of one another
Led by Markus Ploner, Heisenberg Professor for Human Pain Research, scientists from the Department of Neurology of the university hospital TUM Klinikum rechts der Isar investigated in detail how a painful event is processed in the brain. For the first time they were able to show that the brain yields at least three different responses to a painful stimulus, and that these responses are simultaneous and independent of one another. The results may have fundamental repercussions for the understanding of pain and treatment of pain patients.
Pain embodies at least three factors: Perception of pain, an action such as withdrawing the hand from a hot stove, and a response of the autonomic nervous system which provides the necessary energy for the action. The autonomic nervous system controls essential functions such as heart rate, breathing, digestion and metabolism.
Combination of behavioral and EEG measurements
In their experiments, the researchers applied short pain stimuli of varying strengths to the back of the hand of healthy volunteers. The perception of pain was determined based on the participants evaluation of the stimulus on a rating scale. The team, led by Markus Ploner, investigated the action component based on the reaction time the subjects needed to withdraw their fingers in response to the stimulus. Moreover, to determine the response of the autonomic nervous system, the team measured the sweat production at the interior surface of the hand.
For the entire duration of the experiment, brain activity was measured using electroencephalography (EEG). This method provides highly precise information on when and how nerve cells react to pain stimuli.
Pain components arise independently of one another
Ploner and his team applied a statistical method known as mediation analysis to the data. The method has been well established in the social sciences for some time now; however, this was its first application to EEG data. The team was thus able to find out which brain responses serve the three pain components, and when exactly they take place.
The results of the evaluations surprised the researchers: „For the first time we were able to see that the brain responses to the pain components did not take place one after the other, but rather in part simultaneously. This means that the preparation for action and the provision of energy are not entirely dependent on the perception of pain; instead they are in part triggered independently of one another,“ explains Laura Tiemann, the study’s lead author.
Comprehensive pain therapy for chronic pain patients
Although at first rather abstract, these findings could be of great importance to patients suffering from chronic pain. Ploner recommends considering all three components of pain in comprehensive pain therapy: „For chronic pain patients, it is possible that not only the perception of pain, but also the preparation and performance of actions against pain and the provision of the energy to do so are changed. Our findings are thus a biological argument for holistic pain therapy approaches that take different pain components into account. Such approaches would include psychotherapy and drug therapy as well as physiotherapy,“ Ploner says. This kind of therapy, referred to as Multimodal Pain Therapy, is already being offered at the TUM Interdisciplinary Center for Pain Medicine.
original publication:Laura Tiemann, Vanessa D. Hohn, Son Ta Dinh, Elisabeth S. May, Moritz M. Nickel, Joachim Gross and Markus Ploner: Distinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli, Nature Communications, October 2018, DOI: 10.1038/s41467-018-06875-x (Open Access).https://www.nature.com/articles/s41467-018-06875-x
| https://medizin-aspekte.de/pain-perception-and-motor-impulses-arise-in-the-brain-independently-of-one-another-104966/ |
Indoor IPM Plan
Indoor Integrated Pest Management (IPM) Plan
48 Main Street
Southborough, MA 01772
IPM Coordinator
Ron Wood
Primary Contact
Diane Byrne, 508-485-0100, [email protected]
Fay School employs no lisc. on campus, an on-site certified and/or licensed pesticide applicator (certification/license #: ) who may be called on to manage all or some of the necessary INDOOR pest problems that may arise.
By signing the end of this indoor IPM plan, the IPM coordinator, Ron Wood, of this School and the Pest Management Professionals described above acknowledge, and agree to the terms of this INDOOR integrated pest management plan.
A .INTRODUCTION
In compliance with the Act Protecting Children and Families from Harmful Pesticides, Fay School on 4/28/2023 7:06:00 AM has prepared the following indoor IPM plan. By centralizing all of the information about this facility’s pest management practices the plan serves as a guide to direct this facility’s IPM coordinator, Ron Wood , about pest control and pesticide use.This plan describes the pest management practices for indoor areas of the Fay School and clearly states it’s pesticide use policies.A copy of the plan has been filed with the Massachusetts Department of Agricultural Resources (MDAR), and at least one printed copy must be kept on site and made available to the public upon request. ObjectivesThe objectives of the integrated pest management program conducted at the Fay School are listed below. Reduce children’s exposure to pesticides and pesticide residues whenever possible. Manage pests that may occur on facilities to prevent interference with the learning environment of the students. Provide the safest playing or athletic surfaces possible.In light of these objectives, the Fay School has selected the following as it’s IPM policy statement:
B.POLICY STATEMENT
Structural and landscape pests can pose significant problems for people and property. Pesticides can pose risks to people, property, and the environment. It is therefore the policy of this school to incorporate Integrated Pest Management (IPM) procedures for control of structural and landscape pests. The objective of this program is to provide necessary pest control while minimizing pesticide use.
C.IPM COMMITTEE
The tasks set before an IPM committee are to:
Develop an IPM plan. The IPM plan is in essence, a document that describes the organization and implementation of IPM on school grounds. Evaluate progress of the IPM program. Communicate about IPM - Facilitate communication within the school about IPM practices. Assist in development of contract specifications. Provide notification to parents about pesticide use.
The INDOOR committee members selected for the Fay School are listed below:1) Ron Wood (Indoor IPM Coordinator)2) Rob Gustavson3) Diane Byrne
D. COMMUNICATING IPM WITHIN THE FACILITY
The Pest Management Professional communicates with the IPM coordinator of the facility. The IPM coordinator then posts this information in a common viewing area dedicated to the subject of integrated pest management.
Staff/Faculty/Students communicate via email with the Facilities Department. The information is delivered to the IPM coordinator who assigns it to the correct individual/contractor as well as delivering it to the Administrative Assistant who maintains a log in the Physical Plant.
E. EDUCATION AND TRAINING OF FACILITY OCCUPANTS & STAFF
Meetings of the IPM Committee are held on a regular basis during the school year. The pest activity log is kept at the Facilities office. The log includes all reported pest problems and the action taken to correct them. Faculty and Staff E-mail any pest complaints to the Physical Plant, a log is kept at the Physical Plant office. All complaints are followed up with reminders of good housekeeping. Building and grounds maintenance workers are sent out to examine the pest problems and eliminate access by filling cracks, fixing doors and screening. The Students, Faculty and Staff have also received mailings containing pertinent information such as that mentioned above as well as where all written notifications will be posted. Any school wide mailing also include this information as required by the Children''s Protection Act of 2000.
Training content will cover pest-reporting and pest prevention strategies such as sanitation and prevention. This is covered during Facilities Department Community Meetings held regularly.
Training will be done for all Facilities staff during community meetings. All other staff members will be notified via email.
Training will be conducted by Sheryl Traylor in conjunction with Battleline Pest Management on a seasonal basis as situations arise.
All community members are notified via handbooks (Faculty, Staff and Student) to the rules and regulations of the school.
F. INDOOR MONITORING
The IPM committee will evaluate the plan annually.
When pests are present
, Fay School has chosen an
INDOOR monitoring schedule that consists of weekly inspections
.
When pests are absent
the
INDOOR monitoring schedule will consist of monthly inspections
.
The following technique will be used to monitor for pests: Reports from facility personnel (Maintenance Request Forms) would prompt the IPM coordinator to contact the facility''s Pest Management Professional who would then conduct a facility audit.
G. COURSE OF ACTION TAKEN FOR INDOOR PESTS
The following pests have historically and/or currently been a problem at Fay School: Wood Damaging Pests Head Lice Ants Termites Mosquitoes & Flies Rats & Mice Silverfish, Firebrats, & Booklice
The School's IPM approach to managing the indoor pests includes the following actions: SCHOOL PEST DESCRIPTION Silverfish,firebrats-in the past we have experienced these pests. In response we keep all associated areas clean of natural debris, keeping areas dry and free of mold, caulking all cracks and crevis.Ants- Carpenter ants are treated with a liquid chemical (by contractor) on the exterior of a building. Small ants are first treated with ant cups and chemicals (by contractor) if necessary.Flies- are dealt with by hanging fly tape and changing them regularly.Mice- are historically a problem, we use mechanical traps. For further treatment poison in an approved receptacle is installed. (by contractor). SCHOOL PEST LOCATION DETAILS Most problems with wasps and yellow jackets occur in the fall. Wasps are attracted to trash cans, food dispensers,and other sources of food. Ants found inside buildings, near trash and at slab on grade foundation. Roaches have not been observed in the past 6 years. Silverfish have been observed in main kitchen storage rooms. SCHOOL PEST ACTIVITY Due to our diligence to keep our "house" in order we have very few reports of pests.Carpenter ants are dealt with ASAP. (by contractor)Ants are dealt with by locating ant cups in the area. Mice are found mainly in our faculty housing units during the fall. We have had several reports this year and dealt with them through Bain Pest Control.All of our pest reports are kept on file in the Physical Plant Office. MONITORING/INSPECTION Fay School has been practicing an ongoing cycle of inspecting, monitoring, and evaluating the presence of pests. Once a pest has been identified and the source of its activity pinpointed, habitat modifications- primarily exclusion, repair and sanitation efforts- seem to greatly reduce the prevalence of the pests. If the above mentioned modifications do not appear to remedy the problem, then the pest management professional will be contacted. ELIMINATING ACCESS Fay has enacted the following strategies to reduce pest activity:1. Entryways(door-ways, overhead doors, windows, holes in exterior wall, and openings around pipes, electrical fixtures and ducts.- All doors are to be kept shut when not in use.- Weather stripping is used on all doors.- All cracks in walls or foundations are sealed.- Holes in screens are promptly repaired.- Vegetation, shrubs and mulch are kept away from structures.2. Classrooms and Offices(including laboratories, Theatre Arts Center (TAC), Gym Complex, and hallways)- House plants are kept healthy, if any infestations are reported they are manually removed.3. Kitchen and Dinning Areas (faculty room, grill area, vending machines, food storage rooms)- Vents, windows and floor drains are screened to prevent pest from using as pathway.- Pest are captured using mechanical traps.4. Maintenance Areas(boiler room, mechanical rooms, pipe opening and housekeeping closets)- Trash areas are kept clean. Plastic liners are used in cans. ELIMINATING SOURCES OF FOOD AND WATER Fay has enacted the following strategies to eliminate the pest’s food and water supplies: 1. Staff and students- Information has been distributed.- Water spills and/or leaks are reported and dried in a timely manner.- Areas around sinks and toilets are kept dry. - Cleaning is done daily, including vacuuming. - Trash is removed on a daily basis. - Storage areas are kept clean.2. Classrooms and Offices (including laboratories, Theatre Arts Center (TAC), Gym Complex, and hallways)- Food and beverage spills are immediately cleaned.- Areas are kept dry.- Food sources are sealed tightly.- Lockers and desk are cleaned frequently.- Carpeted areas are vacuumed daily.3. Kitchen and Dinning Areas (faculty room, grill area, vending machines, food storage rooms)- Food is stored in sealed containers.- Kitchen staff is instructed in good cleaning practices.4. Areas with extensive plumbing (bathrooms, sink areas, dish rooms, labs, pool)- Leaks are repaired immediately.- Floor drains, strainers and grates are cleaned weekly.- Areas are kept dry using ventilation.5. Maintenance Areas (boiler room, mechanical rooms, pipe opening and housekeeping closet)- Mops and buckets are kept clean. They are hung over floor drains whenever possible.- Trash areas are kept clean. Plastic liners are used in cans. ELIMINATION OF SHELTER AND HARBORAGE Fay School routinely inspects the exterior and interior of all of our buildings. We keep all mulch and vegetation away from the buildings. Fay routinely cleans all storage areas and inspects them for nest. We also employ the services of Bain Pest Control on a monthly basis to inspect and advise as to pest control treatment. NON-CHEMICAL CONTROLS In addition to the above methods of pest control Fay also uses live traps, ant cups, havahart traps to control pests. CHEMICAL CONTROLS PESTICIDE USE ATTESTATION: Pesticides are only applied by a certified and/or licensed applicator. Only pesticides allowed under the Children's and Families' Protection Act are used indoors.
H. RECORD KEEPING
In the case of Fay School, INDOOOR monitoring records will be maintained through the following technique: The use of forms which will be filled out by the person monitoring the facility
I. EVALUATING THE PROGRAM
The IPM committee will evaluate the plan annually .
J. IN THE EVENT OF A HEALTH EMERGENCY
During the creation of this IPM plan, Diane Byrne has assigned committee member Andrew Carlisle with the responsibility of applying for an emergency waiver.
K. LIST OF PESTICIDES TO BE USED INSIDE THE FACILITY
The following list includes all the pesticides that will be used inside the Fay School. This list includes all herbicides, fungicides, and insecticides that will be used in the event that chemical is required. Pesticide Name Active Ingredient EPA Registration # Target Pest Rationale for use Advion DC Ant Stations Indoxacarb 0.01% 100-1485 Various species of ants Indoor Plan Contrac All Weather Blox Bromadiolone 0.005% 12455-79 Mice & Rats Indoor/Outdoor Ditrac Tracking Powder Diphacinone 0.2% 12455-56 Mice and rats Indoor/Outdoor Intice Sweet Ant Gel Orthoboric Acid 5% 73079-1 Sweet feeding ants Indoor Contrac Pellets Bromadiolone0.005% 12455-69 Mice & Rats Indoor/Outdoor Cimexa Insecticide Dust Amorphous Silica Gel 92.1% 73079-12 Various insects Indoor Borid Dust Orthoboric Acid 99% 9444-129 Ants (excluding carpenter ants), roaches, silverfish Indoor/Outdoor Delta Dust Deltametherin .05% 432-772 Various crawling and flying insects Indoor Alpine Dust Diotomaceous Earth 95% 499-527 Roaches, Ants, excluding carpenter ants and silverfish Indoor/Outdoor Ecoexempt D Phenethyl Propionate 4.5% FIFRA 25B Various crawling and flying insects Indoor/Outdoor Ecovia CA Thyme Oil 20% FIFRA 25B Various crawling and flying insects Indoor/Outdoor Ecovia WD Thyme Oil 10% FIFRA 25B Various crawling and flying insects Indoor/Outdoor First Strike Difethalone 0.0025% 7173-258 Mice and rats Indoor/Outdoor Maxforce C-Ant Gel Fipronil .001% 432-1264 Various species of ants Indoor/Outdoor Maxforce Roach Gel Hydramethylnon 2.15% 432-1254 Various species of roaches Indoor/Outdoor Advion Ant Gel Indoxacarb 0.05% 100-1498 Various species of ants Indoor/Outdoor Maxforce Roach Bait Stations Hydramethylnon 2% 432-1251 Various species of roaches Indoor Advion Roach Gel Bait Indoxacarb 0.06% 352-652 Various species of roaches Indoor/Outdoor
Indoor IPM Plan originally submitted on: 5/2/2005 2:39:00 PM Plan updated by Ron Wood, 508-485-0100, [email protected] on: 4/28/2023 7:06:00 AM
| https://www.massnrc.org/data/ipm/Fay_School_in_1_2023_337.htm |
Materials | Free Full-Text | Impacts of Space Restriction on the Microstructure of Calcium Silicate Hydrate
The effect of hydration space on cement hydration is essential. After a few days, space restriction affects the hydration kinetics which dominate the expansion, shrinkage and creep of cement materials. The influence of space restriction on the hydration products of tricalcium silicate was studied in this paper. The microstructure, morphology and composition of calcium silicate hydrate (C-S-H) were explored from the perspective of a specific single micropore. A combination of Raman spectra, Fourier transform infrared spectra, scanning electron microscopy and energy dispersive X-ray spectroscopy were employed. The results show that space restriction affects the structure of the hydration products. The C-S-H formed in the micropores was mainly composed of Q3 silicate tetrahedra with a high degree of polymerization. The C-S-H formed under standard conditions with a water to cement ratio of 0.5 mostly existed as Q2 units. Space restriction during hydration is conducive to the formation of C-S-H with silica tetrahedra of a high polymerization degree, while the amount of water filling the micropore plays no obvious role on the polymeric structure of C-S-H during hydration.
Impacts of Space Restriction on the Microstructure of Calcium Silicate Hydrate
by Yue Zhou 1,2 , Zhongping Wang 1,2 , Zheyu Zhu 1,2 , Yuting Chen 1,2 , Linglin Xu 1,2,* and Kai Wu 1,2
2
Key Laboratory of Advanced Civil Engineering Materials, Tongji University, Ministry of Education, 4800 Cao’an Road, Shanghai 201804, China
*
Author to whom correspondence should be addressed.
Materials 2021 , 14 (13), 3645; https://doi.org/10.3390/ma14133645
Received: 24 May 2021 / Revised: 26 June 2021 / Accepted: 27 June 2021 / Published: 30 June 2021
(This article belongs to the Special Issue Corrosion, Properties and Characterization in Concrete )
Abstract
The effect of hydration space on cement hydration is essential. After a few days, space restriction affects the hydration kinetics which dominate the expansion, shrinkage and creep of cement materials. The influence of space restriction on the hydration products of tricalcium silicate was studied in this paper. The microstructure, morphology and composition of calcium silicate hydrate (C-S-H) were explored from the perspective of a specific single micropore. A combination of Raman spectra, Fourier transform infrared spectra, scanning electron microscopy and energy dispersive X-ray spectroscopy were employed. The results show that space restriction affects the structure of the hydration products. The C-S-H formed in the micropores was mainly composed of Q
3
silicate tetrahedra with a high degree of polymerization. The C-S-H formed under standard conditions with a water to cement ratio of 0.5 mostly existed as Q
2
units. Space restriction during hydration is conducive to the formation of C-S-H with silica tetrahedra of a high polymerization degree, while the amount of water filling the micropore plays no obvious role on the polymeric structure of C-S-H during hydration.
Keywords:
calcium silicate hydrate (C-S-H)
;
space restriction
;
cement
;
hydration
1. Introduction
As the dominating hydration product of Portland cement, calcium silicate hydrate (C-S-H) plays a key role in the performance of cementitious materials. C-S-H grows when the cement is mixed with water [ 1 ], and this hydration continues until the water is exhausted [ 2 ]. Its structure varies with factors during hydration, especially the water to binder ratio [ 3 , 4 ], temperature [ 5 , 6 , 7 , 8 ] and curing age [ 6 , 9 ]. The growth of C-S-H involves the competition between water and hydration space, which are also essential to the microstructure evolution. The importance of water to the structure of C-S-H is prominent, and the role of space on the structure of C-S-H has been paid more and more attention, especially for those studies on the kinetics and mechanisms of cement hydration.
As the main constituent of Portland cement, the hydration of alite (C 3 S) is essential and it can be divided into three periods [ 2 , 10 ]. Initially, C 3 S massively dissolves and amorphous nanoglobular C-S-H mainly forms in this period (Period I) [ 11 ]. There is sufficient space at this stage. Then the hydration switches to the main hydration period (Period II). The C-S-H explosively grows and the hydration rate experiences a stage of acceleration to deceleration [ 2 ]. The initial space is continuously filled with hydration products. Initially, C-S-H grows rapidly to a certain length on the cement grains as needle morphology [ 12 ]. When it has covered most of the grain surface, this stage is related to the deceleration stage [ 12 ]. Then the hydration comes to period III, the later stages [ 13 ]. The C-S-H around the grain surface forms a shell which controls the inner space and available water outside. The growth of inner C-S-H is accompanied by a lack of space and water. Meanwhile, the outer C-S-H further fill the space at this stage [ 14 ]. The space filling hypothesis is suggested to dominate the later hydration mechanism [ 2 ]. The C-S-H which forms in the later stage grows in a diminishing, restricted space. In general, those unhydrated phases undergo a state transition from sufficiency to a restriction of space.
The growth of C-S-H and available space are inseparable. Recent research has proposed that the initial space occupied by water is the space where the C-S-H can grow [ 2 ]. The 1 H nuclear magnetic resonance is used to divide the “water space” in the cement paste into three types: interlayer water between C-S-H layers, gel pores and capillary pores [ 15 , 16 ]. The growth of hydrates in the capillary space is related to the expansion of the hardened cement matrix, due to crystallization pressure [ 10 , 17 ]. The crystals grown in the pores and also the pore walls generate stress to prevent crystal growth. Eventually, the crystals exert pressure on the surrounding solid phase [ 17 ]. The pore space affects the shrinkage and creep of the cement paste at the late hydration stage [ 18 , 19 ]. Thus space is considered a key factor for the construction of the C-S-H microstructure model. The classical C-S-H model proposed by Jennings describes two types of C-S-H: low-density C-S-H (LD C-S-H) and high-density C-S-H (HD C-S-H) [ 20 , 21 ]. LD C-S-H forms in the early hydration stage when there is enough capillary space to accommodate C-S-H [ 22 ]. With the proceeding of hydration, the continuous filling by hydration products leads to more restriction in the space, which drives LD C-S-H to HD C-S-H [ 22 , 23 ]. This finding indicates that the space limitation is firmly related to the diversity of C-S-H. Nanoindentation results show that HD C-S-H exhibits higher stiffness [ 24 ]. The difference in performance actually reflects the change in the microstructure of C-S-H.
The microstructure of C-S-H is commonly expressed by the polymerization degree of silicate tetrahedra. The Q n classification is used to represent the Si-environments in silicate tetrahedra with different polymerization degrees, where n stands for the number of oxygen atoms shared between the tetrahedra and its adjacent tetrahedra [ 25 , 26 ]. Studies show that the silicate tetrahedra of C-S-H in cement are mainly dimers (Q 1 Si sites), with few trimer (Q 2 Si sites) [ 27 , 28 , 29 ]. The silicate tetrahedra in tobermorite and jennite, which are used as reference when constructing the C-S-H model, with repeating structure of “dreierkette” and the ratio of Q 2 and Q 3 units are much higher than those of Q 1 units [ 27 , 28 ]. Studies indicate that the polymerization degree of C-S-H increases with curing age [ 6 , 30 , 31 ], while the available space decreases over time, simultaneously. There are many mysteries between the formation of highly polymerized units and space restriction.
During the entire hydration, the “water space” is gradually filled by the growing hydrates and undergoes a process from micrometer to nanometer scale. Therefore, the influence of the space restriction on the structure of C-S-H is explored from the perspective of a single micropore in this paper.
2. Materials and Methods
2.1. Sample Preparation
The pure M3 tricalcium silicate (C
3
S) was prepared by calcination. Magnesium was used to stabilize C
3
S with polymorph M3. The amount of chemically pure calcium oxide (CaO) and silicon dioxide (SiO
2
) with a molar ratio of 3.0 was accurately weighed, and MgO was added in an amount of 2% of the total mass. The raw materials were uniformly mixed and put into a platinum crucible. Then the crucible was put into the furnace and calcinated at 1400 °C for 4 h. After that, the sample was cooled to room temperature and ground into powder. To obtain the pure M3 polymorph C
3
S, this treatment was repeated 3 times. The phase composition was analyzed by XRD (Rigaku International Corporation, Akishima, Tokyo, Japan) and the pattern is shown in
Figure 1
.
Figure 1. XRD patterns of C 3 S.
The experiment was based on a stainless steel sheet customized by Shanghai Guangyan Laser Technology Co. (Room 896, No.235 Changyang Road, Hongkou District, Shanghai, China), Ltd. (the size was 5 mm × 5 mm, and the thickness was 100 μm). A 4 × 5 pore array was made on the sheet by a 50 w optical fiber marking machine, as shown in Figure 2 . The diameter of the pores was 10 ± 5 μm, and these pores did not penetrate the sheet.
Figure 2. Schematic diagram of stainless steel sheet with pore array.
C
3
S particles were placed in micropores (Shanghai Guangyan Laser Technology Co, Shanghai, China) of the sheet with a tweezer under a microscope. These samples were treated by two methods. On the one hand, the sheet was covered by a drop of deionized water and was placed at 20 °C and 65% relative humidity (RH) for 24 h (hereafter called water condition). On the other hand, the sheet was placed in the curing room at 20 °C and 65% RH for 24 h without further addition of water (hereafter called 65% RH condition). Meanwhile, C
3
S was mixed with deionized water at a water to cement ratio of 0.5 and hydrated for 24 h under the same curing conditions, as the control. The hydration was terminated via the freeze-vacuum drying for 48 h.
2.2. Analytical Methods
Raman spectra were collected by the LabRAM HR Evolution Raman Spectrometer (HORIBA Jobin Yvon, Paris, France) from HORIBA Jobin Yvon, France. A solid-state laser with a wavelength of 532 nm was used as the light source and the acquisition time was 10 s. The spectra were obtained with a 100× magnification. A micro area in a single pore of the sheet was selected for testing. Five pores were randomly selected for testing.
Fourier transform infrared spectra (FT-IR) were recorded using the EQUINOX 55 Fourier transform infrared spectrometer (Bruker, Karlsruhe, Baden-Württemberg, Germany) from Bruker and the MIRacle ATR measurement accessory (PIKE Technologies, Madison, WI, USA) from PIKE Technologies, USA. The ATR sample cell was made of ZnSe crystal. The sheet was placed in the sample cell and all pores were tested simultaneously. Each spectrum was acquired with 128 scans and at a resolution of 4 cm
−1
.
The morphology of samples was obtained by the Gemini Sigma 300/VP scanning electron microscope (SEM) (Carl Zeiss, Oberkochen, Baden-Württemberg, Germany) from Carl Zeiss, Germany. The images were acquired employing an acceleration voltage of 30 kV under high vacuum conditions. The elemental analysis was collected by the X-Max
N
spectrometer (Oxford Instruments, Abingdon, Oxfordshire, UK) of Oxford Instruments (EDS) and combined with Aztec software (Version 3.2, Oxford Instruments, Abingdon, Oxfordshire, UK).
3. Results
3.1. Raman
Figure 3 shows the Raman spectra of the hydration products in different pores which were treated by the water conditions. Besides those shifts at 316, 469, 1449, 1510 and 2425 cm −1 from the sheet, there was a strong and sharp peak at 1084 cm −1 in all pores. This peak may be assigned to the symmetrical stretching of Q 3 silicate tetrahedra, or the symmetric stretching of the C-O group in CaCO 3 [ 27 , 32 ]. The shift at 280 cm −1 corresponded to the lattice vibration of the CaCO 3 [ 33 ]. The ν4 in-plane bending mode of CaCO 3 was observed at 712 cm −1 in some pores [ 34 ]. The shift at 1595 cm −1 was also attributed to CaCO 3 [ 35 ].
Figure 3. Raman spectra of hydration products in different pores (treated by water condition).
By contrast, with 65% RH ( Figure 4 ), the 828 and 894 cm −1 peaks were the characteristic of Raman shifts of C 3 S [ 36 , 37 ]. Apart from the signals of unhydrated C 3 S and the sheet, the 1084 cm −1 peak was prominent which was consistent with the results of Figure 3 . The broad band at 551 cm −1 was due to Si-O-Si stretching modes in Q 3 silicate tetrahedra [ 32 ]. The peak at 519 cm −1 resulted from the O-Si-O bending mode in the C-S-H [ 27 , 36 ].
Figure 4. Raman spectra of hydration products in different pores (treated by 65% RH condition).
Figure 5 is the Raman spectra of the control. Except for the peaks of unhydrated C 3 S (829 and 890 cm −1 ), the broad shoulder signal near 513 and 558 cm −1 were speculated to belong to the antisymmetric bending vibration of O-Si-O in unhydrated C 3 S [ 37 , 38 ]. The peak at 668 cm −1 was characteristic of Si-O-Si symmetrical bending vibration in Q 2 silicate chains of C-S-H. The broad and strong peak at 1114 cm −1 was assigned to the hydroxylated species (Si-OH), which was due to the decrease in the proton numbers which bridged on Si-O of Q 2 silicate tetrahedra [ 32 , 38 ]. The shift at 355 cm −1 was the characteristic band of Ca(OH) 2 [ 37 , 38 ]. The signals around 1504 and 2234 cm −1 also belonged to Ca(OH) 2 [ 39 ].
Figure 5. Raman spectra of hydration products (the control).
3.2. FT-IR
Figure 6 presents the FT-IR spectra of hydration products in the pores of the sheets. There were some characteristic peaks of unhydrated C 3 S in the hydrates of the 65% RH condition and the control. For instance, the 873 cm −1 band with shoulder bands at 921 and 835 cm −1 were related to the asymmetric stretching vibrations of Si-O bonds in unhydrated C 3 S [ 40 , 41 ]. Besides some peaks at 821, 873 and 920 cm −1 , the absorption at 522 cm −1 was also attributed to unhydrated C 3 S [ 40 ]. In addition, the proximity signal at 804 cm −1 in the curve of water condition was due to Si-O-Si symmetric stretching of SiO 2 [ 42 , 43 ].
Figure 6. FT-IR spectra of hydration products under different hydration conditions.
The hydration results of water condition were similar with those of 65% RH condition. The absorption bands centered at 624 and 628 cm −1 of the two sheets were attributed to Si-O-Si bending vibration in depolymerized structure [ 44 , 45 ]. The broad absorption bands at 1107 cm −1 and 1103 cm −1 were both Si-O stretching vibrations in Q 3 silicate tetrahedra [ 40 , 41 , 46 ]. However, the 968 cm −1 band observed in the control was the characteristic of Si-O stretching vibrations in Q 2 units of C-S-H gel [ 40 , 46 ].
The peaks related to Ca(OH) 2 and its carbonized products were found in all curves. The absorption at 871 cm −1 was the characteristic vibration mode of carbonate [ 41 , 46 ]. The bands at 1411, 1417 and 1483 cm −1 observed were characteristic of O-C=O symmetric stretching vibrations [ 47 ]. The peak at 1730 cm −1 was assigned to the C=O stretching vibrations which were related to the carbonation of Ca(OH) 2 [ 45 , 48 ] In addition, The O-H bending vibration signals of water molecules were observed at 1643 cm −1 [ 46 , 49 ].
3.3. SEM/EDS
Figure 7 exhibits the SEM images of hydration products under different conditions. It can be seen that the hydration conditions played a prominent role on the morphology of the hydrates. The hydration products in the pore which was treated by the water condition were flake-like, while those treated by the 65% RH condition were honeycomb-like. The morphology of hydration products of the control exhibited interlaced fibers.
Figure 7. SEM images of hydration products under different conditions after 24 h.
The elements in the representative areas in Figure 7 were scanned by EDS and shown in Table 1 . Besides the Ti contained in the sheet, the composition of different samples was similar, with calcium and oxygen in the majority. The calcium to silicon ratio (Ca/Si) of the hydration products hydrated by water condition was the highest, followed by that under normal conditions and treated by 65% RH condition.
Table 1. EDX analysis of hydration products under different conditions after 24 h (at.%).
4. Discussion
The Raman shifts, FT-IR bands and their distributions observed in the hydration products are summarized in Table 2 and Table 3 , respectively.
Table 2. Raman shifts and distribution of hydration products.
Table 3. FT-IR bands and distribution of hydration products.
Combining the results of Raman and FT-IR spectra, it was clear that the hydration products exhibited a high degree of polymerization dominated by Q
3
silicates for the hydration products in pores. By comparing the hydrates under the water condition and 65% RH condition, the amount of water filling the micropore played no obvious role on the polymeric structure. The difference was that there was still unhydrated C
3
S in the sample which was placed at the 65% RH condition.
SEM and EDS showed the morphology and their Ca/Si ratio of the hydration products in pores. A lower Ca/Si ratio was observed in the sample of the 65% RH condition than in that of the control. This is consistent with previous studies [
50
,
51
], which propose that the higher the polymerization degree, the lower the Ca/Si ratio. However, the hydrates under the water condition showed an unexpectedly higher Ca/Si ratio above 2. It lay in the fact that the C-S-H in this region was surrounded by Ca(OH)
2
[
52
]. It can be confirmed that the oxygen content of products with water condition was higher than those at the 65% RH condition in those testing areas. The flake-like hydration products in this region were similar to Ca(OH)
2
[
53
]. Although the results about the Ca/Si ratio of the products were inconsistent, it is certain that C-S-H gel formed in these micropores. The combinations of the Raman spectra, FT-IR spectra and SEM-EDS results demonstrated that the C-S-H grown in micropores had a high degree of polymerization.
The results of Raman and FT-IR spectra indicated that the C-S-H structure in control obviously grew as Q 2 silicate tetrahedra. This finding has been confirmed by many scholars [ 38 , 40 , 54 , 55 ]. However, the hydration products in the pores showed a higher degree of polymerization (Q 3 ), and there was almost no characteristic peak of Q 2 unit. This finding indicates that space restriction affects the structure of the hydration products and the cement which hydrated in the space restriction of micropores tended to form C-S-H with silica tetrahedra of high polymerization degree.
Recently, the space filling hypothesis was opposed by Zajac et al. [ 56 ]. They proposed that the slow hydration in the later stage was not due to the effect of restricted space on the further growth of C-S-H, but caused by the slow transport of dissolved ions through the hydrates layer from the dissolution point to the precipitation point [ 56 ], and the slow diffusion had an impact on the evolution of the microstructures, such as the fine structure of the inner C-S-H [ 56 ]. In this paper, the characterization of the surface hydrates by means of Raman, FT-IR spectra and SEM-EDS indicated that space restriction actually changed the structure of the external hydrates. The influence of space restriction on the growth of C-S-H cannot be ignored, but the relationship between the structure change and the slow diffusion of dissolved ions needs to be further explored. At present, no theory can exclusively dominate the later hydration mechanism. The later stage kinetics is considered to be a combination of multiple mechanisms, such as diffusion mechanism, C-S-H densification and space filling hypothesis [ 2 , 13 ], which requires more research in the future.
5. Conclusions
This paper studied the microstructure of C 3 S hydrates in the restricted space of micropores in a sheet, by means of Raman, FT-IR spectra and SEM-EDS. Results indicate that space restriction affected the structure of the hydration products, and that the microstructure of the C-S-H which formed in the micropores was mainly composed of Q 3 silicate tetrahedra with a high degree of polymerization. The amount of water filled in the micropore only affected the hydration degree, rather than the polymeric structure. The C-S-H which formed under conventional conditions mostly existed as a Q 2 unit. The space restriction of cement hydration is conducive to the formation of C-S-H with silicate tetrahedra of a high polymerization degree.
Acknowledgments
The authors acknowledge greatly the financial support from the fund of National Natural Science Fund of China (51772212), the fund of National Natural Science Fund of China (51978505) and Shanghai Rising Star Program (20QC1400600). Additionally, thanks are extended to the anonymous reviewers whose suggestions improved this manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
References
Allen, A.J.; Thomas, J.J.; Jennings, H.M. Composition and density of nanoscale calcium-silicate-hydrate in cement. Nat. Mater. 2007 , 6 , 311–316. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Scrivener, K.; Ouzia, A.; Juilland, P.; Mohamed, A.K. Advances in understanding cement hydration mechanisms. Cem. Concr. Res. 2019 , 124 , 105823. [ Google Scholar ] [ CrossRef ]
Sato, M.; Umemura, Y.; Koizumi, K. Effect of water-binder ratio on silicate structure and hydration of silicafume cement. Cem. Sci. Concr. Technol. 2011 , 65 , 456–463. [ Google Scholar ] [ CrossRef ][ Green Version ]
Tanaka, Y.; Saeki, T.; Sasaki, K.; Suda, Y. Fundamental study on density of C-S-H. Cem. Sci. Concr. Technol. 2009 , 63 , 70–76. [ Google Scholar ] [ CrossRef ][ Green Version ]
Gallucci, E.; Zhang, X.; Scrivener, K.L. Effect of temperature on the microstructure of calcium silicate hydrate (C-S-H). Cem. Concr. Res. 2013 , 53 , 185–195. [ Google Scholar ] [ CrossRef ]
Okada, Y.; Ishida, H.; Sasaki, K.; Young, J.; Mitsuda, T. Characterization of C-S-H from highly reactive β-dicalcium silicate prepared from hillebrandite. J. Am. Ceram. Soc. 1994 , 77 , 1313–1318. [ Google Scholar ] [ CrossRef ]
Martínez-Ramírez, S.; Frías, M. The effect of curing temperature on white cement hydration. Constr. Build. Mater. 2009 , 23 , 1344–1348. [ Google Scholar ] [ CrossRef ][ Green Version ]
Xu, L.; Tang, C.; Li, H.; Wu, K.; Zhang, Y.; Yang, Z. Hydration characteristics assessment of a binary calcium sulfoaluminate-anhydrite cement related with environment temperature. J. Therm. Anal. Calorim. 2021 . [ Google Scholar ] [ CrossRef ]
Narattha, C.; Chaipanich, A. Effect of curing time on the hydration and material properties of cold-bonded high-calcium fly ash–Portland cement lightweight aggregate. J. Therm. Anal. Calorim. 2020 . [ Google Scholar ] [ CrossRef ]
Wu, K.; Han, H.; Xu, L.; Gao, Y.; Yang, Z.; Jiang, Z.; De Schutter, G. The improvement of freezing–thawing resistance of concrete by cellulose/polyvinyl alcohol hydrogel. Constr. Build. Mater. 2021 , 291 , 123274. [ Google Scholar ] [ CrossRef ]
Schönlein, M.; Plank, J. A TEM study on the very early crystallization of C-S-H in the presence of polycarboxylate superplasticizers: Transformation from initial C-S-H globules to nanofoils. Cem. Concr. Res. 2018 , 106 , 33–39. [ Google Scholar ] [ CrossRef ]
Bazzoni, A. Study of Early Hydration Mechanisms of Cement by Means of Electron Microscopy. Ph.D. Thesis, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2014. [ Google Scholar ]
Ouzia, A.R.C.W.C. Modeling the Kinetics of the Main Peak and Later Age of Alite Hydration. Ph.D. Thesis, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2019. [ Google Scholar ]
Bullard, J.W.; Jennings, H.M.; Livingston, R.A.; Nonat, A.; Scherer, G.W.; Schweitzer, J.S.; Scrivener, K.L.; Thomas, J.J. Mechanisms of cement hydration. Cem. Concr. Res. 2011 , 41 , 1208–1223. [ Google Scholar ] [ CrossRef ]
Berodier, E.; Scrivener, K. Evolution of pore structure in blended systems. Cem. Concr. Res. 2015 , 73 , 25–35. [ Google Scholar ] [ CrossRef ][ Green Version ]
Xu, L.; Ou, Y.; Hecker, A.; Rößler, C.; Ludwig, H.M.; Yang, Z.; Wu, K. State of water in calcium sulfoaluminate cement paste modified by hydroxyethyl methyl cellulose ether. J. Build. Eng. 2021 , 102894. [ Google Scholar ] [ CrossRef ]
Scherer, G.W. Stress from crystallization of salt. Cem. Concr. Res. 2004 , 34 , 1613–1624. [ Google Scholar ] [ CrossRef ]
Wenzel, O.; Schwotzer, M.; Müller, E.; Chakravadhanula, V.S.K.; Scherer, T.; Gerdes, A. Investigating the pore structure of the calcium silicate hydrate phase. Mater. Charact. 2017 , 133 , 133–137. [ Google Scholar ] [ CrossRef ]
Li, H.; Xue, Z.; Liang, G.; Wu, K.; Dong, B.; Wang, W. Effect of C-S-Hs-PCE and sodium sulfate on the hydration kinetics and mechanical properties of cement paste. Constr. Build. Mater. 2021 , 266 , 121096. [ Google Scholar ] [ CrossRef ]
Jennings, H.M. A model for the microstructure of calcium silicate hydrate in cement paste. Cem. Concr. Res. 2000 , 30 , 101–116. [ Google Scholar ] [ CrossRef ]
Jennings, H.M. Refinements to colloid model of C-S-H in cement: CM-II. Cem. Concr. Res. 2008 , 38 , 275–289. [ Google Scholar ] [ CrossRef ]
S˘milauer, V.; Bittnar, Z.k. Microstructure-based micromechanical prediction of elastic properties in hydrating cement paste. Cem. Concr. Res. 2006 , 36 , 1708–1718. [ Google Scholar ] [ CrossRef ]
Königsberger, M.; Hellmich, C.; Pichler, B. Densification of C-S-H is mainly driven by available precipitation space, as quantified through an analytical cement hydration model based on NMR data. Cem. Concr. Res. 2016 , 88 , 170–183. [ Google Scholar ] [ CrossRef ]
Constantinides, G.; Ulm, F.-J. The effect of two types of C-S-H on the elasticity of cement-based materials: Results from nanoindentation and micromechanical modeling. Cem. Concr. Res. 2004 , 34 , 67–80. [ Google Scholar ] [ CrossRef ]
Farhadi, N.; Peyvandi, A.; Holmes, D.; Soroushian, P.; Balachandra, A.M. Effects of Graphite Nanoplatelets on the Structure of Cementitious Materials. Iran. J. Sci. Technol. Trans. Civ. Eng. 2019 , 43 , 403–411. [ Google Scholar ] [ CrossRef ]
Richardson, I.G. The nature of the hydration products in hardened cement pastes. Cem. Concr. Compos. 2000 , 22 , 97–113. [ Google Scholar ] [ CrossRef ]
Kirkpatrick, R.J.; Yarger, J.L.; McMillan, P.F.; Ping, Y.; Cong, X. Raman spectroscopy of C-S-H, tobermorite, and jennite. Adv. Cem. Based Mater. 1997 , 5 , 93–99. [ Google Scholar ] [ CrossRef ]
Cong, X.; Kirkpatrick, R.J. 29Si MAS NMR study of the structure of calcium silicate hydrate. Adv. Cem. Based Mater. 1996 , 3 , 144–156. [ Google Scholar ] [ CrossRef ]
Rodriguez, E.T.; Richardson, I.G.; Black, L.; Boehm-Courjault, E.; Nonat, A.; Skibsted, J. Composition, silicate anion structure and morphology of calcium silicate hydrates (C-S-H) synthesised by silica-lime reaction and by controlled hydration of tricalcium silicate (C3S). Adv. Appl. Ceram. 2015 , 114 , 362–371. [ Google Scholar ] [ CrossRef ][ Green Version ]
Thomas, J.J.; Jennings, H.M. A colloidal interpretation of chemical aging of the C-S-H gel and its effects on the properties of cement paste. Cem. Concr. Res. 2006 , 36 , 30–38. [ Google Scholar ] [ CrossRef ]
Jennings, H.M. Colloid model of C−S−H and implications to the problem of creep and shrinkage. Mater. Struct. 2004 , 37 , 59–70. [ Google Scholar ] [ CrossRef ]
Ortaboy, S.; Li, J.; Geng, G.; Myers, R.J.; Monteiro, P.J.M.; Maboudian, R.; Carraro, C. Effects of CO 2 and temperature on the structure and chemistry of C–(A–)S–H investigated by Raman spectroscopy. RSC Adv. 2017 , 7 , 48925–48933. [ Google Scholar ] [ CrossRef ][ Green Version ]
Potgieter-Vermaak, S.S.; Potgieter, J.H.; Belleil, M.; Deweerdt, F.; Grieken, R.V. The application of Raman spectrometry to the investigation of cement: Part II: A micro-Raman study of OPC, slag and fly ash. Cem. Concr. Res. 2006 , 36 , 663–670. [ Google Scholar ] [ CrossRef ]
Bai, Y.; Guo, X.-j.; Li, Y.-z.; Huang, T. Experimental and visual research on the microbial induced carbonate precipitation by Pseudomonas aeruginosa. Amb Express 2017 , 7 , 57. [ Google Scholar ] [ CrossRef ][ Green Version ]
Podborodnikov, I.; Shatskiy, A.; Arefiev, A.; Rashchenko, S.; Chanyshev, A.; Litasov, K. The system Na 2 CO 3 –CaCO 3 at 3 GPa. Phys. Chem. Miner. 2018 , 45 , 773–787. [ Google Scholar ] [ CrossRef ]
Liu, F.; Sun, Z.; Qi, C. Raman spectroscopy study on the hydration behaviors of Portland cement pastes during setting. J. Mater. Civ. Eng. 2014 , 27 , 04014233. [ Google Scholar ] [ CrossRef ]
Tarrida, M.; Madon, M.; Le Rolland, B.; Colombet, P. An in-situ Raman spectroscopy study of the hydration of tricalcium silicate. Adv. Cem. Based Mater. 1995 , 2 , 15–20. [ Google Scholar ] [ CrossRef ]
Garbev, K.; Stemmermann, P.; Black, L.; Breen, C.; Yarwood, J.; Gasharova, B. Structural features of C-S-H(I) and its carbonation in air — A Raman spectroscopic study. Part I: Fresh phases. J. Am. Ceram. Soc. 2007 , 90 , 900–907. [ Google Scholar ] [ CrossRef ]
Liu, F.J.; Sun, Z.H. Chemical mapping of cement pastes by using confocal Raman spectroscopy. Front. Struct. Civ. Eng. 2016 , 10 , 168–173. [ Google Scholar ] [ CrossRef ]
del Bosque, I.F.S.; Martinez-Ramirez, S.; Blanco-Varela, M.T. FTIR study of the effect of temperature and nanosilica on the nanostructure of C-S-H gel formed by hydrating tricalcium silicate. Constr. Build. Mater. 2014 , 52 , 314–323. [ Google Scholar ] [ CrossRef ][ Green Version ]
Choudhary, H.K.; Anupama, A.V.; Kumar, R.; Panzi, M.E.; Matteppanavar, S.; Sherikar, B.N.; Sahoo, B. Observation of phase transformations in cement during hydration. Constr. Build. Mater. 2015 , 101 , 122–129. [ Google Scholar ] [ CrossRef ]
Al-Maliki, F. Detection of Random Laser Action from Silica Xerogel Matrices Containing Rhodamine 610 Dye and Titanium Dioxide Nanoparticles. Adv. Mater. Phys. Chem. 2012 , 2 , 110–115. [ Google Scholar ] [ CrossRef ][ Green Version ]
Ramalla, I.; Gupta, R.; Bansal, K. Effect on superhydrophobic surfaces on electrical porcelain insulator, improved technique at polluted areas for longer life and reliability. Int. J. Eng. Technol. 2015 , 4 , 509–519. [ Google Scholar ] [ CrossRef ][ Green Version ]
Darmakkolla, S.R.; Tran, H.; Gupta, A.; Rananavare, S.B. A method to derivatize surface silanol groups to Si-alkyl groups in carbon-doped silicon oxides. RSC Adv. 2016 , 6 , 93219–93230. [ Google Scholar ] [ CrossRef ]
Grill, A.; Neumayer, D.A. Structure of low dielectric constant to extreme low dielectric constant SiCOH films: Fourier transform infrared spectroscopy characterization. J. Appl. Phys. 2003 , 94 , 6697–6707. [ Google Scholar ] [ CrossRef ]
Fernandez, L.; Alonso, C.; Hidalgo, A.; Andrade, C. The role of magnesium during the hydration of C 3 S and C-S-H formation. Scanning electron microscopy and mid-infrared studies. Adv. Cem. Res. 2005 , 17 , 9–21. [ Google Scholar ] [ CrossRef ]
Bonnier, F.; Blasco, H.; Wasselet, C.; Brachet, G.; Respaud, R.; Carvalho, L.F.C.S.; Bertrand, D.; Baker, M.J.; Byrne, H.J.; Chourpa, I. Ultra-filtration of human serum for improved quantitative analysis of low molecular weight biomarkers using ATR-IR spectroscopy. Analyst 2017 , 142 , 1285–1298. [ Google Scholar ] [ CrossRef ][ Green Version ]
Das, I.; Mishra, M.K.; Medda, S.K.; De, G. Durable superhydrophobic ZnO-SiO 2 films: A new approach to enhance the abrasion resistant property of trimethylsilyl functionalized SiO 2 nanoparticles on glass. RSC Adv. 2014 , 4 , 54989–54997. [ Google Scholar ] [ CrossRef ]
Kalkan, E.; Nadaroglu, H.; Celebi, N.; Tozsin, G. Removal of textile dye Reactive Black 5 from aqueous solution by adsorption on laccase-modified silica fume. Desalin. Water Treat. 2014 , 52 , 6122–6134. [ Google Scholar ] [ CrossRef ]
He, Y.; Zhao, X.; Lu, L.; Struble, L.J.; Hu, S. Effect of C/S ratio on morphology and structure of hydrothermally synthesized calcium silicate hydrate. J. Wuhan Univ. Technol. Mater. Sci. Ed. 2011 , 26 , 770–773. [ Google Scholar ] [ CrossRef ]
He, Y.; Lu, L.; Struble, L.J.; Rapp, J.L.; Mondal, P.; Hu, S. Effect of calcium–silicon ratio on microstructure and nanostructure of calcium silicate hydrate synthesized by reaction of fumed silica and calcium oxide at room temperature. Mater. Struct. 2014 , 47 , 311–322. [ Google Scholar ] [ CrossRef ]
Hu, Q.N.; Aboustait, M.; Kim, T.; Ley, M.T.; Hanan, J.C.; Bullard, J.; Winarski, R.; Rose, V. Direct three-dimensional observation of the microstructure and chemistry of C 3 S hydration. Cem. Concr. Res 2016 , 88 , 157–169. [ Google Scholar ] [ CrossRef ][ Green Version ]
García Carmona, J.; Gómez Morales, J.; Rodríguez Clemente, R. Rhombohedral–scalenohedral calcite transition produced by adjusting the solution electrical conductivity in the system Ca(OH) 2 –CO 2 –H 2 O. J. Colloid Interface Sci. 2003 , 261 , 434–440. [ Google Scholar ] [ CrossRef ]
Masmoudi, R.; Kupwade-Patil, K.; Bumajdad, A.; Buyukozturk, O. In situ Raman studies on cement paste prepared with natural pozzolanic volcanic ash and Ordinary Portland Cement. Constr. Build. Mater. 2017 , 148 , 444–454. [ Google Scholar ] [ CrossRef ]
Dariz, P.; Schmid, T. Ferruginous phases in 19th century lime and cement mortars: A Raman microspectroscopic study. Mater. Charact. 2017 , 129 , 9–17. [ Google Scholar ] [ CrossRef ]
Zajac, M.; Skocek, J.; Lothenbach, B.; Mohsen, B.H. Late hydration kinetics: Indications from thermodynamic analysis of pore solution data. Cem. Concr. Res. 2020 , 129 , 105975. [ Google Scholar ] [ CrossRef ]
Figure 1. XRD patterns of C 3 S.
Figure 2. Schematic diagram of stainless steel sheet with pore array.
Figure 3. Raman spectra of hydration products in different pores (treated by water condition).
Figure 4. Raman spectra of hydration products in different pores (treated by 65% RH condition).
Figure 5. Raman spectra of hydration products (the control).
Figure 6. FT-IR spectra of hydration products under different hydration conditions.
Figure 7. SEM images of hydration products under different conditions after 24 h.
Table 1. EDX analysis of hydration products under different conditions after 24 h (at.%).
Table 2. Raman shifts and distribution of hydration products.
Conditions Raman Shift (cm −1 ) C 3 S C-S-H CaCO 3 Ca(OH) 2 Stainless Steel Sheet water condition (pores) —— 1084 (Q 3 ) 280, 713, 1595, 1581 and 1084 —— 316, 469, 1449, 1510 and 2425 65% RH condition (pores) 830 and 889 519; 551 and 1084 (Q 3 ) 279 and 1084 —— 316, 471, 1417, 1511 and 2423 the control (w/c = 0.5) 513, 558, 829 and 890 668 (Q 2 ); and 1114 —— 355, 1504 and 2234 ——
Table 3. FT-IR bands and distribution of hydration products.
Conditions FT-IR Spectra (cm −1 ) C 3 S C-S-H CaCO 3 Water water condition (pores) 804 624; 1107 (Q 3 ) 871 and 1417 —— 65% RH condition (pores) 873, 921 and 835 628; 1103 (Q 3 ) 1411 and 1730 —— the control (w/c = 0.5) 522, 821, 873 and 920 968 (Q 2 ) 1417 and 1483 1643
| https://www.mdpi.com/1996-1944/14/13/3645 |
2 Chronicles 34 Bengel's Gnomon of the New Testament
Bengel's Gnomon of the New Testament
2 Chronicles 34:1
Josiah was eight years old when he began to reign, and he reigned in Jerusalem one and thirty years.
2 Chronicles 34:2
And he did that which was right in the sight of the LORD, and walked in the ways of David his father, and declined neither to the right hand, nor to the left.
2 Chronicles 34:3
For in the eighth year of his reign, while he was yet young, he began to seek after the God of David his father: and in the twelfth year he began to purge Judah and Jerusalem from the high places, and the groves, and the carved images, and the molten images.
2 Chronicles 34:4
And they brake down the altars of Baalim in his presence; and the images, that were on high above them, he cut down; and the groves, and the carved images, and the molten images, he brake in pieces, and made dust of them , and strowed it upon the graves of them that had sacrificed unto them.
2 Chronicles 34:5
And he burnt the bones of the priests upon their altars, and cleansed Judah and Jerusalem.
2 Chronicles 34:6
And so did he in the cities of Manasseh, and Ephraim, and Simeon, even unto Naphtali, with their mattocks round about.
2 Chronicles 34:7
And when he had broken down the altars and the groves, and had beaten the graven images into powder, and cut down all the idols throughout all the land of Israel, he returned to Jerusalem.
2 Chronicles 34:8
Now in the eighteenth year of his reign, when he had purged the land, and the house, he sent Shaphan the son of Azaliah, and Maaseiah the governor of the city, and Joah the son of Joahaz the recorder, to repair the house of the LORD his God.
2 Chronicles 34:9
And when they came to Hilkiah the high priest, they delivered the money that was brought into the house of God, which the Levites that kept the doors had gathered of the hand of Manasseh and Ephraim, and of all the remnant of Israel, and of all Judah and Benjamin; and they returned to Jerusalem.
2 Chronicles 34:10
And they put it in the hand of the workmen that had the oversight of the house of the LORD, and they gave it to the workmen that wrought in the house of the LORD, to repair and amend the house:
2 Chronicles 34:11
Even to the artificers and builders gave they it , to buy hewn stone, and timber for couplings, and to floor the houses which the kings of Judah had destroyed.
2 Chronicles 34:12
And the men did the work faithfully: and the overseers of them were Jahath and Obadiah, the Levites, of the sons of Merari; and Zechariah and Meshullam, of the sons of the Kohathites, to set it forward; and other of the Levites, all that could skill of instruments of musick.
2 Chronicles 34:13
Also they were over the bearers of burdens, and were overseers of all that wrought the work in any manner of service: and of the Levites there were scribes, and officers, and porters.
2 Chronicles 34:14
And when they brought out the money that was brought into the house of the LORD, Hilkiah the priest found a book of the law of the LORD given by Moses.
2 Chronicles 34:15
And Hilkiah answered and said to Shaphan the scribe, I have found the book of the law in the house of the LORD. And Hilkiah delivered the book to Shaphan.
2 Chronicles 34:16
And Shaphan carried the book to the king, and brought the king word back again, saying, All that was committed to thy servants, they do it .
2 Chronicles 34:17
And they have gathered together the money that was found in the house of the LORD, and have delivered it into the hand of the overseers, and to the hand of the workmen.
2 Chronicles 34:18
Then Shaphan the scribe told the king, saying, Hilkiah the priest hath given me a book. And Shaphan read it before the king.
2 Chronicles 34:19
And it came to pass, when the king had heard the words of the law, that he rent his clothes.
2 Chronicles 34:20
And the king commanded Hilkiah, and Ahikam the son of Shaphan, and Abdon the son of Micah, and Shaphan the scribe, and Asaiah a servant of the king's, saying,
2 Chronicles 34:21
Go, inquire of the LORD for me, and for them that are left in Israel and in Judah, concerning the words of the book that is found: for great is the wrath of the LORD that is poured out upon us, because our fathers have not kept the word of the LORD, to do after all that is written in this book.
2 Chronicles 34:22
And Hilkiah, and they that the king had appointed , went to Huldah the prophetess, the wife of Shallum the son of Tikvath, the son of Hasrah, keeper of the wardrobe; (now she dwelt in Jerusalem in the college:) and they spake to her to that effect .
2 Chronicles 34:23
And she answered them, Thus saith the LORD God of Israel, Tell ye the man that sent you to me,
2 Chronicles 34:24
Thus saith the LORD, Behold, I will bring evil upon this place, and upon the inhabitants thereof, even all the curses that are written in the book which they have read before the king of Judah:
2 Chronicles 34:25
Because they have forsaken me, and have burned incense unto other gods, that they might provoke me to anger with all the works of their hands; therefore my wrath shall be poured out upon this place, and shall not be quenched.
2 Chronicles 34:26
And as for the king of Judah, who sent you to inquire of the LORD, so shall ye say unto him, Thus saith the LORD God of Israel concerning the words which thou hast heard;
2 Chronicles 34:27
Because thine heart was tender, and thou didst humble thyself before God, when thou heardest his words against this place, and against the inhabitants thereof, and humbledst thyself before me, and didst rend thy clothes, and weep before me; I have even heard thee also, saith the LORD.
2 Chronicles 34:28
Behold, I will gather thee to thy fathers, and thou shalt be gathered to thy grave in peace, neither shall thine eyes see all the evil that I will bring upon this place, and upon the inhabitants of the same. So they brought the king word again.
2 Chronicles 34:29
Then the king sent and gathered together all the elders of Judah and Jerusalem.
2 Chronicles 34:30
And the king went up into the house of the LORD, and all the men of Judah, and the inhabitants of Jerusalem, and the priests, and the Levites, and all the people, great and small: and he read in their ears all the words of the book of the covenant that was found in the house of the LORD.
2 Chronicles 34:31
And the king stood in his place, and made a covenant before the LORD, to walk after the LORD, and to keep his commandments, and his testimonies, and his statutes, with all his heart, and with all his soul, to perform the words of the covenant which are written in this book.
2 Chronicles 34:32
And he caused all that were present in Jerusalem and Benjamin to stand to it . And the inhabitants of Jerusalem did according to the covenant of God, the God of their fathers.
2 Chronicles 34:33
And Josiah took away all the abominations out of all the countries that pertained to the children of Israel, and made all that were present in Israel to serve, even to serve the LORD their God. And all his days they departed not from following the LORD, the God of their fathers.
| https://www.biblehub.com/commentaries/bengel/2_chronicles/34.htm |
Metabolic Syndrome and Insulin Resistance | Anesthesiology | American Society of Anesthesiologists
Metabolic Syndrome and Insulin Resistance : Perioperative Considerations
Hema S. Bagry, M.D., D.N.B., F.R.C.A.
Hema S. Bagry, M.D., D.N.B., F.R.C.A.
* Research Fellow.
Sreekrishna Raghavendran, M.D., D.N.B., F.R.C.A.
Sreekrishna Raghavendran, M.D., D.N.B., F.R.C.A.
† Pediatric Anesthesia and Pain Fellow.
Franco Carli, M.D., M.Phil., F.R.C.A., F.R.C.P.C.
‡ Professor.
David S. Warner, M.D.
;
David S. Warner, M.D.
Mark A. Warner, M.D.
Mark A. Warner, M.D.
Anesthesiology March 2008, Vol. 108, 506–523.
https://doi.org/10.1097/ALN.0b013e3181649314
Metabolic syndrome represents a constellation of risk factors associated with increased incidence of cardiovascular disease and progression to diabetes mellitus. Insulin resistance, a state of decreased biologic response to physiologic concentrations of insulin, is a key component of this syndrome and seems to be the result of a primary defect at the skeletal muscle glucose transporter. Acute illness and the perioperative period are characterized by a state of insulin resistance that manifests as hyperglycemia and leads to various other metabolic and biochemical alterations that adversely affect end organ function. Hyperglycemia in acutely ill patients adversely affects outcome. Achieving euglycemia seems beneficial in certain clinical situations, but considerable disagreement exists regarding the target blood sugar levels, the duration of therapy, and the modality. Pharmacotherapy, exercise, and nutrition to improve insulin sensitivity seem promising but require further evaluation to confirm their efficacy for perioperative risk reduction. This review discusses the pathophysiology and the clinical implications of metabolic syndrome and insulin resistance in the acutely ill patient with an emphasis on perioperative modulation strategies.
Topics:
insulin
,
insulin resistance
,
metabolic syndrome x
,
diabetes mellitus
METABOLIC syndrome represents a cluster of related cardiovascular risk factors that include central obesity, insulin resistance, atherogenic lipid profile, and hypertension. Several definitions of metabolic syndrome exist that share the core components but differ in the criteria required to diagnose the syndrome. Among these, the World Health Organization definitions and the National Cholesterol Education Program Adult Treatment Panel III (table 1) are widely accepted.1,2
Table 1. Definitions of Metabolic Syndrome
Pathophysiology of Metabolic Syndrome
Central (Visceral) Obesity
Abnormal fat distribution plays a key role in the pathogenesis of metabolic syndrome. Obesity is associated with an increased risk of diabetes and cardiovascular disease. Furthermore, visceral fat by itself is a strong determinant of insulin sensitivity and B-cell function.3,4Waist circumference is found to be superior to the body mass index as a measure of visceral adiposity and is widely used to quantify central obesity in clinical practice.3Further, visceral adiposity as measured by waist circumference correlates better with the risk of diabetes or coronary vascular disease than total obesity as measured by body mass index.5,6Central obesity also shares a strong relation with other components of metabolic syndrome. The IDF definition draws attention to the fact that waist circumference may be population specific because differences have been observed between various ethnic groups and thus may warrant the use of different cutoff values while defining metabolic syndrome.3
Adipose tissue is an active endocrine organ that secretes numerous bioactive substances, including hormones, growth factors, and cytokines. Central (visceral) obesity represents dysfunctional adipose tissue whose dysregulated metabolism leads to increased free fatty acid (FFA) flux in the liver and muscle. This contributes to insulin resistance that further worsens the dyslipidemia.7Visceral fat also secretes proinflammatory cytokines interleukin 6 and tumor necrosis factor α. Together with the reduced secretion of adiponectin, it further aggravates insulin resistance.8
Insulin Resistance
Insulin resistance can be defined as “a state where there is a reduced biologic effect for any given concentration of insulin.”9It is a central feature of metabolic syndrome, showing a strong association with most components of the syndrome.3,10The prevalence of insulin resistance in the general population has seen a phenomenal increase in the past decade.7It may be seen during pregnancy or starvation but is more widely recognized in patients with type II diabetes mellitus. Transient insulin resistance may often develop with surgical and nonsurgical trauma and critical illness.11
Insulin resistance manifests as a broad clinical spectrum evolving progressively from hyperinsulinemia to glucose intolerance and eventually to frank diabetes. Therefore, the diagnosis of insulin resistance in the various definitions of metabolic syndrome has required the presence of one or more features from this spectrum. Genetic susceptibility, along with environmental factors such as lifestyle, diet, stress, and smoking, can trigger the development of insulin resistance.8The metabolic consequences, hyperinsulinemia, hyperglycemia, and lipid and lipoprotein dysregulation, act in synergy to potentiate and sustain the pathologic state of insulin resistance. With the evolution of insulin resistance, endothelial dysfunction, inflammation, and atherosclerosis worsen progressively.7,12
Atherogenic Dyslipidemia
The combination of increased triglycerides and reduced high-density lipoprotein (HDL) cholesterol together with increased apolipoprotein B and small–dense low-density lipoprotein (LDL) particles best describes the atherogenic lipid profile associated metabolic syndrome.3,7Alterations in the lipid and lipoprotein metabolism are closely linked with hepatic and peripheral insulin resistance. The small–dense LDL is highly atherogenic and therefore has become the main target for lipid lowering therapy.13
Hypertension
The mechanism of hypertension in metabolic syndrome is multifactorial and may be related, among other factors, to obesity and dietary thermogenesis.14Insulin-related alteration in renal sodium handling and salt sensitivity, central activation of the sympathetic nervous system, along with angiotensin II and endothelin 1–mediated vasoconstriction might also contribute.12
Thrombogenicity
Metabolic syndrome predisposes to a prothrombotic state as a result of elevated fibrinogen levels along with decreased fibrinolytic activity due to increased plasminogen activator inhibitor 1. Platelet function is also disturbed, leading to increased aggregation and thrombin generation.15
Inflammation and Endothelial Dysfunction
Metabolic syndrome is a proinflammatory state. Insulin resistance and the atherogenic dyslipidemia cause up-regulation of inflammatory adipokine tumor necrosis factor α, interleukin 6, and C-reactive protein and a decrease in adiponectin.7Overexpression of the inflammatory proteins further interferes with insulin signaling pathways, enhances lipid peroxidation, and increases FFA flux.
Systemic Effects of Metabolic Syndrome
Patients with metabolic syndrome are at a greater risk of developing coronary artery disease and major adverse vascular events (table 2).16–18A threefold increase in the risk of myocardial infarction (MI) or stroke with twice the mortality from such an event is reported in patients with metabolic syndrome as compared with those without the syndrome.19While the individual components of metabolic syndrome have been recognized as independent risk factors of coronary vascular disease, clustering of these adverse metabolic factors may further intensify the risk.3
Table 2. Clinical Outcomes of Metabolic Syndrome
Patients with metabolic syndrome have fivefold higher risk for developing diabetes. Insulin resistance and altered glucose metabolism, the key component of the syndrome, may be responsible for this increased risk.20
Metabolic syndrome and its individual components are risk factors for acute stroke in the elderly. Stroke patients with metabolic syndrome exhibited an atherogenic profile with higher concentrations of triglycerides and lower HDL cholesterol.21Patients, especially women, with metabolic syndrome and atherosclerotic disease were at an increased risk for ischemic stroke or transient ischemic attack even in the absence of diabetes. Further, hypertension and fasting hyperglycemia were stronger predictors of cerebrovascular events than other components of metabolic syndrome.22
The individual components of metabolic syndrome adversely affect the kidney initiating loss of renal function. The constellation of the syndrome acts in synergy, the risk increasing progressively with the number of components involved, to accelerate renal damage from microalbuminuria to eventual end-stage renal disease.23Metabolic syndrome has also been identified as an important risk factor for diabetes mellitus, chronic renal graft dysfunction, and graft loss after renal transplantation.24
Metabolic syndrome has been shown to be associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.25Nonalcoholic steatohepatitis is characterized by hepatocellular inflammation and necrosis along with elevated transaminases and may progress to cirrhosis.7Insulin resistance may be the main causative factor because improving insulin sensitivity has been shown to decrease hepatic fat and inflammation, improve metabolic profile, and resolve the histologic changes.7,26
A retrospective study of a large cohort of pregnant women showed that features of metabolic syndrome before pregnancy were linked to a higher risk of placental dysfunction, including fetal growth retardation and demise. The study also found that this risk increased progressively with the number of components of metabolic syndrome involved, with the odds ratio increasing from 3.1 for one feature to 7.7 when three or four components were affected.27Metabolic syndrome has also been linked with an increased risk of adverse vascular events and venous thrombosis.17,28
The pathophysiology of metabolic syndrome may have important implications for the surgical patient. Obesity, hypertension, and diabetes mellitus are well-recognized perioperative risk factors that contribute to morbidity and mortality.29,30It is possible that the clustering of these cardiometabolic risk factors may further potentiate surgical risk and impact outcome. The incidence and degree of insulin resistance may also be related to the clustering of features of metabolic syndrome.10In the context of perioperative or acutely ill patients, insulin resistance may be one of the only features that is easily amenable to modulation and that may lead to an improvement in outcome.
Pathophysiology and Molecular Mechanisms of Perioperative Insulin Resistance
Insulin is secreted mainly in response to plasma glucose.31With the onset of insulin resistance, normoglycemia is achieved by increasing the secretion of insulin from pancreatic β-cells resulting in hyperinsulinemia. This state of “prediabetes” manifests clinically as impaired fasting glucose and/or impaired glucose tolerance.7,32Further resistance to insulin results in a failure to achieve normoglycemia despite increased insulin secretion, resulting in diabetes mellitus. Eventually, a “burnout” of β cells results, followed by decreased insulin levels along with further failure of glucose homeostasis7,31(fig. 1). Hyperinsulinemia, glucose intolerance, hyperglycemia, and frank diabetes thus represent a clinical continuum of abnormal glucose homeostasis and insulin resistance. Features of this clinical continuum often coexist, and it may not always be possible to dissect the effects of hyperglycemia per sefrom the state of insulin resistance.
Fig. 1. Schematic representation of the temporal progression of insulin resistance. FPG = fasting plasma glucose; IFG = impaired fasting glucose, elevated fasting glucose levels but with normal response to oral glucose tolerance test (OGTT); IGT = impaired glucose tolerance, abnormal postprandial glucose excursion but with normal fasting glucose levels.
Fig. 1. Schematic representation of the temporal progression of insulin resistance. FPG = fasting plasma glucose; IFG = impaired fasting glucose, elevated fasting glucose levels but with normal response to oral glucose tolerance test (OGTT); IGT = impaired glucose tolerance, abnormal postprandial glucose excursion but with normal fasting glucose levels.
The stress of acute illness and surgery induces transient but reversible acceleration of the progression of insulin resistance.33The magnitude of insulin resistance and the metabolic response to surgical stress may be linked to the invasiveness of the surgery. Blood loss may also have a direct and independent correlation with postoperative insulin resistance.33Whether the body cavity operated on influences the magnitude of insulin resistance is not known and remains open to speculation. Stress response may also be related to the duration of the surgical trauma, because glucose utilization seems to be reduced after prolonged surgery.34Physical status and postsurgery rehabilitation may further influence the development of insulin resistance by affecting skeletal muscle glucose uptake. Nutrition may be another contributing factor. A diet inadequate in calories, besides causing negative nitrogen balance, has been shown to alter the metabolic environment and give rise to insulin resistance.31Although the biochemical manifestation of this transient state of insulin resistance is obvious, the underlying mechanisms remain poorly understood.
Several alterations in the skeletal muscle, adipose tissue, hormones, and cytokines are proposed to explain the pathogenesis of perioperative insulin resistance. It is now increasingly recognized that perioperative insulin resistance is predominantly an extrahepatic phenomenon, primarily affecting the skeletal muscle. It is characterized by a decrease in peripheral glucose uptake with an increase in endogenous glucose production.11,33Insulin facilitates glucose entry in insulin sensitive tissues such as muscle and adipose tissue by increasing the number of GLUT4 transporters.31These receptors are stored in intracellular vesicles, and insulin-mediated activation of phosphoinositol-3-kinase causes fusion of the vesicles with the cell membrane, thereby resulting in insertion of the transporter into the cell membrane and increasing glucose entry into the cell. A defect at this GLUT4 transporter prevents insulin-stimulated glucose uptake and subsequent glycogen synthesis in skeletal muscle. This is now considered the principal abnormality underlying insulin resistance.11,33,35,36Studies on muscle biopsies from patients undergoing hip replacement seem to corroborate the role of skeletal muscle GLUT4 transporter in the pathogenesis of peripheral insulin resistance.36Furthermore, with insulin resistance there is upregulation of insulin-independent GLUT1–3 transporters that are found in neurons, renal cells, erythrocytes, and immunocytes, exposing them to excess glucose load and glucotoxicity (fig. 2).11Skeletal muscles also contain a subpopulation of GLUT4 transporters that translocate to the cell membrane in response to exercise and enhances glucose uptake independent of insulin. Limitation of physical exercise results in down-regulation of these GLUT4 transporters, aggravating insulin resistance.31,37
Fig. 2. Physiology of glucose uptake and biochemical alterations contributing to perioperative insulin resistance. FFA = free fatty acid; GLUT1–4 = glucose transporters; IGF = insulin-like growth factor.
Fig. 2. Physiology of glucose uptake and biochemical alterations contributing to perioperative insulin resistance. FFA = free fatty acid; GLUT1–4 = glucose transporters; IGF = insulin-like growth factor.
Lipid and lipoprotein dysregulation are closely linked to the insulin-resistant state. Defects in FFA storage and metabolism result in increased FFA flux in primary insulin sensitive tissues like the liver and skeletal muscle. The FFAs and their metabolites decrease phosphoinositide-3-kinase activity that ultimately leads to failure of GLUT4 translocation and insulin signaling mechanisms. The resulting insulin-resistant state further enhances lipolysis, setting up a vicious cycle (fig. 3).7
View large Download slide
Fig. 3. Mechanisms of insulin resistance during the perioperative period. FFA = free fatty acid; GLUT = glucose transporter; PI-3 = phosphoinositide-3.
Fig. 3. Mechanisms of insulin resistance during the perioperative period. FFA = free fatty acid; GLUT = glucose transporter; PI-3 = phosphoinositide-3.
Insulin resistance and the inflammatory stress response seem to be interlinked. Plasma insulin levels and interleukin 6 follow a similar pattern during the perioperative period.38Whereas inflammatory cytokines such as interleukin 6 seem to inhibit insulin sensitivity by their effects on lipid peroxidation, and FFA flux, and GLUT4 expression, adipokines such as tumor necrosis factor α and resitin decrease insulin sensitivity by modulating lipid metabolism and GLUT4 activity.7,31,38
Insulin-like growth factors (IGFs) and their binding proteins may also play a role in the pathophysiology of perioperative insulin resistance. IGFs are polypeptides secreted by the liver that mediate the anabolic effects of growth hormone. Most IGF-1 in the plasma is bound to IGF-binding proteins 1–6. Free IGF-1 binds specifically to IGF receptors and weakly to insulin receptors, both of which are tyrosine kinases that enhance glucose uptake.31,33Levels of IGF-binding protein 1 are elevated in the perioperative period, whereas IGF-1 levels remain unchanged or even decrease, resulting in altered bioavailability of IGFs in the perioperative period.33The neuroendocrine system also contributes to the development of insulin resistance. Elevated circulating cortisol, growth hormone, and catecholamines seen during surgical stress exert an antiinsulin effect resulting in enhanced hepatic glucose output.39
Insulin Resistance and Hyperglycemia
There is mounting evidence attesting to the detrimental effects of hyperglycemia on outcomes in diverse clinical settings (table 3).40,41–48The impact of hyperglycemia on outcome in critically ill patients was first evaluated prospectively in the Leuven study by van den Berghe et al.40It was found that tight glycemic control (blood glucose <110 mg/dl or 6.1 mm) reduced morbidity and mortality among surgical intensive care patients irrespective of their diabetic status.40Among medical intensive care patients, van den Berghe et al.reported that intensive insulin therapy to achieve blood glucose levels of 80–110 mg/dl (4.4–6.1 mm) while reducing morbidity did not affect mortality. However, a reduction in mortality with intensive insulin therapy was observed in patients who required intensive care for more than 3 days.49An observational study involving critically ill patients showed that glycemic control and not insulin dosage seemed to explain mortality benefits of intensive insulin therapy.46Therefore, the primary benefits of intensive insulin therapy may be related to its glucose-decreasing effect and maintenance of normoglycemia.46,50
Table 3. Studies Investigating the Effects of Hyperglycemia on Perioperative Outcome
Hyperglycemia is a frequent metabolic disturbance observed in patients with MI. Stress-induced insulin resistance mediates decreased availability of glycolytic substrate, and increased fatty acid utilization may impair myocardial contractility and increase oxygen requirements, promoting arrhythmias and pump failure.51A meta-analysis reviewing the risk of in-hospital mortality after MI in patients with stress hyperglycemia found that nondiabetic patients with blood glucose in the range 6.1–8 mm (100–140 mg/dl) had 3.9-fold increased risk of death than patients who had blood glucose of 6.1 mm (100 mg/dl) or less. Admission hyperglycemia corresponded with the risk of in-hospital mortality, congestive cardiac failure, and cardiogenic shock after MI in both diabetic and nondiabetic patients, with more pronounced effects in the latter.52A prospective study involving nondiabetic patients with acute MI reported increasing mortality with fasting glucose levels of 6.1 mm (110 mg/dl) or greater. Fasting glucose was also found to be better at predicting short-term mortality after acute MI than admission glucose levels.53Patients without previous history of diabetes with admission hyperglycemia (fasting glucose >7 mm [>125 mg/dl] or random >11.1 mm [>200 mg/dl]) on general surgical and medical wards were found to have higher mortality and poorer outcome as compared with normoglycemic patients. Further, these patients had higher rates of intensive care unit admissions and greater risk of infection and acute neurologic events.54The American Diabetes Association and the American Association of Clinical Endocrinologists have subsequently issued guidelines recommending fasting glucose level less than 6.1 mm (110 mg/dl) in hospitalized patients irrespective of their clinical history.55
The insulin resistance and hyperglycemia frequently observed during cardiac surgery occurs as a result of release of inflammatory cytokines during cardiopulmonary bypass, use of heparin, release of stress hormones, and iatrogenic catecholamine use, among others. Hyperglycemia during cardiopulmonary bypass and after cardiac surgery has been associated with increased mortality among both diabetics and nondiabetics.48,56,57In a study involving diabetic patients undergoing coronary artery bypass graft, plasma glucose levels greater than 175 mg/dl (9.7 mm) were related to higher mortality principally from cardiac causes. Achieving glycemic control with continuous insulin infusion improved survival in these patients by reducing cardiac mortality.58Others have reported similar improvements in morbidity and mortality using insulin infusion to achieve tight glycemic control.40,59
The potential diabetogenicity of uremia and peritransplant therapy may be aggravated further by surgical stress. Glucose uptake into renal tubular cells is insulin independent, making them vulnerable to glucotoxicity related to hyperglycemia.11Perioperative hyperglycemia has been shown to be associated with acute rejection in known diabetics.60Thomas et al.,61however, reported that 71% of nondiabetic renal transplant recipients whose postoperative blood glucose levels were greater than 8 mm (144 mg/dl) developed acute rejection. Acute hyperglycemia due to insulin resistance may enhance ischemia–reperfusion injury and antigen presentation, escalating the inflammatory response that mediates graft rejection.61
Insulin resistance seems to play a central role in the pathophysiology of the glucose intolerance commonly observed in brain-dead donors. Detrimental effects include osmotic diuresis, electrolyte disturbances, and impairment of end-organ function. Insulin therapy to maintain blood glucose levels between 4.4 and 8.3 mm (80 and 150 mg/dl) and avoidance of hypotonic dextrose solutions have been recommended. Treatment of insulin resistance during the process of graft harvest and transplantation may improve the number and viability of the organs procured.62
Persistent hyperglycemia 48 h after thromboembolic stroke seems to increase mortality, whereas achieving euglycemia seems to improve outcome. Normoglycemia was reported to be an independent predictor of survival after stroke. This effect seemed to be independent of the method used for blood glucose control.63Hyperglycemia has also been reported to be associated with poor neurologic outcome after traumatic brain injury in both adults and children.47,64
Hyperglycemia has been shown to have detrimental effects on the immune system. Acute hyperglycemia impairs monocyte activation and oxidative burst as well as phagocytic capacity of macrophages.65,66It may also lead to glycosylation of immunoproteins.11Another effect observed is an exaggeration of injury-induced inflammatory response. These effects, in conjunction with the enhanced protein breakdown caused by insulin resistance, may predispose to systemic and surgical site infections, impair wound healing, and delay recovery.40,59,67Amelioration of hyperglycemia may partly account for the beneficial immunomodulating effects of insulin therapy.
Assessment of Insulin Resistance
Hyperinsulinemic euglycemic clamp remains the accepted standard for assessment of insulin resistance.68With this method, blood glucose is “clamped” at a predetermined level by titrating glucose infusion against a fixed rate of insulin infusion. The degree of insulin resistance is inversely related to the amount of glucose required to maintain the target concentration when steady state is achieved. The clamp technique provides a quantitative measure of insulin-mediated glucose disposal and also defines the site of insulin resistance.68In the insulin-resistant state, the insulin-mediated glucose disposal curve is typically shifted to the right, often with reduction in the maximal effect of insulin (fig. 4). This is reflected in clinical practice by increasing insulin requirements to achieve blood glucose control.9
Fig. 4. Representation of insulin dose–response curve. Arepresents normal state of insulin sensitivity. Bdepicts insulin response curve shifted to right, showing decremented response to insulin. Cdepicts decreased maximal response to insulin secretion. Band Crepresent progression of the insulin-resistant state.
Fig. 4. Representation of insulin dose–response curve. Arepresents normal state of insulin sensitivity. Bdepicts insulin response curve shifted to right, showing decremented response to insulin. Cdepicts decreased maximal response to insulin secretion. Band Crepresent progression of the insulin-resistant state.
Several other validated tests are available for the assessment of insulin resistance and are summarized intable 4. These are useful research tools and may provide valuable input for clinical management. Insulin resistance may be quantified by mathematical models, clamp techniques, insulin infusion tests, or by glucose tolerance tests.9,68Due consideration should be given to the method of assessment of insulin resistance when comparing different studies.
Table 4. Methods of Assessment of Insulin Resistance 9,68
Strategies for Metabolic Management
The complex cellular and molecular mechanisms underlying insulin resistance and metabolic syndrome may be further altered by the dynamics of surgical trauma and the associated stress response, analgesia, nutritional status, and bed rest, among other factors. Active modulation of the altered metabolic status may improve outcome after a surgical injury.
Insulin Therapy and Glucose Control
Insulin, endogenous and exogenous, has long been recognized as a metabolic hormone. Its primary effect is on glucose homeostasis, i.e., enhanced peripheral glucose uptake with inhibition of glycogenolysis and hepatic gluconeogenesis. It promotes protein anabolism while also inhibiting fatty acid breakdown. The nonmetabolic effects of insulin are increasingly being recognized. It is believed to have an antiinflammatory effect while enhancing phagocyte function and opsonic activity. It may maintain fibrinolytic activity, prevent platelet activation, and improve vascular reactivity and endothelial function. These effects may act in synergy with the metabolic effects to promote and maintain organ function.11However, it should be noted that persistent hyperinsulinemia might be associated with detrimental effects, such as such as coronary stenosis in transplanted hearts.16
Insulin therapy for the management of insulin resistance and the potential benefits of glycemic control among acutely ill subjects has been well studied (table 5).40,42,49Although data from heterogenous surgical populations are sparse, several authors have addressed the effect of insulin therapy in cardiac surgery.40,58,59,69Furthermore, in practice, the glycemic target, timing, and duration of therapy vary widely. A common method of insulin therapy in acutely ill patients is intravenous insulin infusion. Other methods used include glucose–insulin–potassium infusions, subcutaneous injections, dextrose infusions with insulin boluses, and insulin clamp techniques.
Table 5. Studies Investigating the Effects of Glycemic Control (Insulin Therapy) in the Critically Ill (Including MI and CABG)
The Leuven study by van den Berghe et al.40was a prospective, randomized controlled trial of surgical intensive care patients, more than two thirds of whom had had cardiac surgery. It showed that intensive insulin therapy to maintain glucose at or below 110 mg/dl (6.1 mm) was associated with a reduction in morbidity and mortality. Furthermore, there was reduced mortality from multiorgan failure irrespective of a history of diabetes, reduced duration of stay in intensive care, and lower requirement for mechanical ventilation and renal replacement therapy. Intensive insulin therapy was also associated with reduced episodes of septicemia and lower levels of inflammatory markers.40However, intensive insulin therapy to achieve blood glucose levels below 110 mg/dl (6.1 mm) was associated with increased mortality among medical intensive care patients who required intensive care for less than 3 days.49Lazar et al.59showed that tight glycemic control (defined as blood glucose ≤11.1 mm or 200 mg/dl) with glucose insulin potassium infusion improved perioperative outcome, increased survival, and decreased incidence of ischemic events and wound infection in diabetic patients undergoing coronary artery bypass graft.
Furnary et al.58conducted a large retrospective study involving more than 3,000 diabetic patients undergoing coronary artery bypass graft and found that patients receiving continuous insulin infusion achieved tighter blood glucose control as compared with patients managed with intermittent subcutaneous insulin injections. Furthermore, the perioperative mortality was significantly lower in the continuous insulin infusion group (2.5% vs.5.3%; P<0.0001). The decrease in mortality was primarily from a reduction in the incidence of cardiac related deaths. The authors proposed that continuous insulin infusion improves myocardial glycometabolic function by insulin-induced stimulation of pyruvate dehydrogenase activity and enhanced glycolysis that replenishes cytoplasmic adenosine triphosphate stores required for phosphorylation of extracellular glucose, stabilization of membrane function, and maintenance of cellular integrity. Enhanced glycolysis is also believed to inhibit lipolysis and mitochondrial β oxidation, preventing accumulation of toxic FFA metabolites.58
Pharmacologic Agents
The IDF currently recommends treatment of individual components of metabolic syndrome in patients where lifestyle modification alone is insufficient or the patient is at high risk of cardiovascular disease (table 6).3In clinical practice, many of the drugs used in the secondary intervention may have complementary effects and modulate more than one component of the syndrome.
Table 6. Classification of Pharmacologic Agents Used in the Therapy of Metabolic Syndrome
Insulin Secretagogues: Sulfonylureas and Glinides.
Sulfonylureas close adenosine triphosphate–sensitive potassium (K ATP) channels on the pancreatic β cells depolarizing the cell and consequently releasing insulin. K ATPchannels are tetradimeric molecules that exhibit adenosine triphosphatase activity. K ATPchannel isoforms that differ in the composition of the individual subunits are also found on the cell membranes of cardiomyocytes and vascular myocytes, among others, as well as the inner mitochondrial membrane (mito K ATPchannels). Sulfonylureas differ in their selectivity for the pancreatic and cardiovascular isoforms of K ATPchannels, with glibenclamide being one of the least selective (table 7).70–72Newer sulfonylureas, such as glimepiride, exhibit greater selectivity to the pancreatic K ATPchannels.73
Table 7. Selectivity of Sulfonylureas for Different Types of Adenosine Triphosphate–sensitive K +Channels70–72
The K ATPchannels in the cardiac sarcolemma and the mitochondria are now believed to play a central role in the phenomenon of ischemic preconditioning—a phenomenon whereby brief periods of ischemia and reperfusion before prolonged ischemia protects the myocardium from the consequent deleterious effects.74These K ATPchannels are also believed to mediate a similar phenomenon, called anesthetic preconditioning, whereby volatile anesthetics protect the myocardium against the effects of ischemia.75
The effects of sulfonylurea use on both animal and human myocardium have been extensively researched, and the compound most often studied is glyburide (also known as glibenclamide). An increase in vascular tone, decreased tolerance to ischemic injury mediated by an inhibition of ischemic preconditioning, and an antiarrhythmic effect, among others, have been reported.71However, the clinical significance of these effects is uncertain. Besides, the proposed subtype selectivity of sulfonylureas has also not been addressed. Sulfonylureas may also adversely affect anesthetic preconditioning. Glibenclamide has been shown to prevent isoflurane-induced anesthetic preconditioning during cardiac surgery in diabetic subjects. Further, preoperative use of insulin instead of glibenclamide seemed to restore the protective effect of anesthetic preconditioning.76Sulfonylureas may thus not be appropriate agents in an acute care setting considering the potentially harmful myocardial effects of sulfonylureas, their inability to achieve metabolic control due to stress-induced insulin resistance after an acute illness, and the potential benefits of tight glycemic control with insulin.41
The University Group Diabetes Program study, a placebo-controlled, multicenter, clinical trial, reported in 1970 an increased risk of cardiovascular mortality in patients with type II diabetes treated with tolbutamide.77The findings resulted in the termination of the tolbutamide arm of the study and the publication of a US Food and Drug Administration warning.71These findings have been criticized because a subsequent analysis showed that the excess cardiovascular mortality purportedly related to tolbutamide was in fact restricted to a group with poorly controlled diabetes.78The United Kingdom Prospective Diabetes Study (UKPDS), a large prospective study of newly diagnosed type II diabetics, restored confidence in sulfonylureas, showing no increase in cardiovascular mortality. They further reported that intensive glycemic control either with sulfonylureas or insulin reduced microvascular but not macrovascular disease among type II diabetics.79Apart from the side effects of weight gain and hypoglycemia, sulfonylureas do not influence other components of metabolic syndrome.73
Another class of insulin secretagogues introduced recently are the glinides. These molecules resemble the nonsulfonylurea portion of glibenclamide and have a similar mechanism of action. They differ from sulfonylureas in their poor protein binding and shorter duration of action. Their role in clinical management of diabetes is yet to be established.70,73
Biguanides.
Metformin, the only drug among the biguanide class in clinical use, decreases blood glucose levels by sensitizing target tissues to insulin, especially the liver, inhibiting hepatic glucose production and increasing peripheral glucose uptake. It has good oral bioavailability and negligible protein binding and is almost exclusively excreted unchanged by the kidneys.80It has modest effects on lipid metabolism, including decreasing triglycerides and LDL cholesterol, increasing HDL cholesterol, and promoting weight loss.80It may also improve endothelial dysfunction.73
The United Kingdom Prospective Diabetes Study (UKPDS 34) showed that addition of metformin to diet-controlled overweight type II diabetics significantly reduced microvascular and macrovascular disease. Metformin did not induce weight gain and was also associated with fewer episodes of hypoglycemia. The additional benefits observed with metformin monotherapy could not be accounted for by the improvement in glycemic control alone but were suggested to be due to decreases in plasminogen activator inhibitor 1 and enhanced fibrinolysis.81A population based retrospective study showed that metformin use either alone or in addition to sulfonylureas in newly treated diabetics reduced all-cause and cardiovascular mortality in comparison to sulfonylurea monotherapy.82Combinations of metformin with other oral hypoglycemic and insulin-sensitizing agents have also been shown to be safe and effective.80,83Adjuvant metformin therapy in type I diabetes improves insulin sensitivity, diabetic control, body composition, and patient well-being.84
A retrospective investigation of diabetic patients undergoing cardiac surgery reported that allowing metformin therapy until the night before surgery and early resumption postoperatively did not increase cardiac morbidity (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1–1.7), neurologic morbidity (OR, 0.9; 95% CI, 0.3–2.6), or in-hospital mortality (OR, 0.5; 95% CI, 0.1–2.0) as compared with other oral hypoglycemic agents. Metformin-treated patients, however, required a shorter course of tracheal intubation and had lower infection-related morbidity (OR, 0.2; 95% CI, 0.1–0.7) and overall morbidity (OR, 0.4; 95% CI, 0.2–0.8).85
Thiazolidinediones.
Thiazolidinediones are insulin-sensitizing agents that bind to the nuclear γ isoform of peroxisome proliferator–activated receptor (PPAR-γ). These receptors are primarily expressed in adipose tissues but also find expression in the skeletal myocytes, hepatocytes, and vascular endothelial and smooth muscle cells. PPAR-γ activation results in the transcription of several genes encoding various insulin-sensitive proteins, including lipoprotein lipase and GLUT4. They have a slow onset, requiring up to 12 weeks to reach maximum effect.73Thiazolidinediones enhance insulin sensitivity in adipose tissue, skeletal muscle, and the liver. They are highly protein bound and undergo extensive hepatic metabolism, in the case of pioglitazone to active metabolites.80
Thiazolidinediones also increase expression of genes that encode proteins that enhance adipogenesis in the subcutaneous adipose tissue. The net result is believed to be a redistribution of fat stores from the muscle and visceral adipose tissue resulting in a decreased visceral-to-subcutaneous adipose tissue ratio.80Thiazolidinediones differ in their effects on the lipid profile. Whereas pioglitazone alters the profile favorably by decreasing triglycerides, rosiglitazone was associated with an increase in LDL cholesterol and total plasma cholesterol. The mechanism of this differential alteration in lipid profile and its clinical significance are as yet unclear.86
Thiazolidinediones have favorable effects on markers of atherosclerosis.80They decrease thrombotic risk especially on atherosclerotic areas by inhibiting plasminogen activator inhibitor 1. Further, they decrease the serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and inerleukin-6 levels. While some of the antiatherogenic effects could be associated with improvement of glucose metabolism, thiazolidinediones seem to prevent progression of atherosclerosis independent of their effects on glucose metabolism. Nitric oxide, an important regulator of vascular endothelial function, is inactivated by superoxide (O 2 −) free radicals. PPAR-γ agonists are believed to promote endothelial function by suppression of NADPH oxidase, a major superoxide generating enzyme while inducing the superoxide scavenging cytosolic superoxide dismutase.87The antioxidant properties of PPAR-γ agonists may also restore the function of K ATPchannels that are impaired by high glucose concentrations.88
In animal models, thiazolidinediones seems to limit infarct size and attenuate postinfarct left ventricular remodeling and failure.89,90In comparison with other oral hypoglycemic agents, thiazolidinediones significantly reduces microalbuminuria. However, it remains unclear whether this is mediated primarily viaimprovement in glycemic control, insulin sensitivity, or endothelial dysfunction or is independent viaits the blood pressure–decreasing effect.91A prospective study to assess the ability of rosiglitazone to reduce the incidence of diabetes mellitus in subjects with impaired fasting glucose and/or impaired glucose tolerance reported an absolute risk reduction of 14.4% (number needed to treat = 7) at the end of a median follow-up period of 3 yr. That the study reported 70–80% increased likelihood of return to normoglycemia may suggest that thiazolidinediones treat dysglycemia as well as prevent diabetes.92
The PROactive study, a large European multicenter study involving 5,238 patients, showed no significant reduction in the composite primary endpoints with pioglitazone. However, the study found a significant reduction in the secondary endpoints of all-cause mortality, MI, or stroke. This improvement, observed in a group of high-risk patients, was in addition to that with their normal medical care, including antihyperglycemic, antiplatelet, antihypertensive, and lipid-lowering therapies. Glycemic control and lipid profile was better with pioglitazone compared with placebo, despite an increased use of metformin and insulin in the placebo group. They also had a better blood pressure profile at the end of the study than at the beginning.93However, considerable controversy surrounds the methodology and statistical analysis of the PROactive study. It is suggested that the results need to be confirmed and that they are seen as hypothesis-generating only.94
A meta-analysis of 22 trials that randomly assigned approximately 6,200 people to pioglitazone therapy for at least 24 weeks showed no evidence of benefit with respect to patient-oriented outcomes such as mortality, morbidity, adverse effects, cost, and health-related quality of life. Further, metabolic control (hemoglobin A 1c) was found to be no better when compared with other oral antidiabetic drugs. However, the analysis reported a higher incidence of edema with pioglitazone and concluded that the risk–benefit ratio was unclear until further results were available. It also highlighted the different prescribing indications by the US Food and Drug Administration and the European Medicines Agency.94Common side effects reported with thiazolidinediones include weight gain (up to 4 kg), fluid retention, and heart failure.86,92–94They are contraindicated in New York Heart Association class III or IV heart failure, and the American Heart Association recommends that patients and physicians be aware of the risk of heart failure associated with their use in type II diabetes patients.95
Statins.
Statins are inhibitors of β-hydroxy-β-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the synthesis of cholesterol. They interrupt cholesterol synthesis in the liver and activate hepatocyte LDL receptors and decrease LDL.
Statins have proved beneficial in primary and secondary prevention of adverse cardiovascular events.96,97Furthermore, intensive decreasing of LDL cholesterol with high-dose atorvastatin therapy (80 mg) has also been shown to significantly reduce adverse vascular events in high-risk patients with both coronary heart disease and metabolic syndrome.13They are recommended in the early treatment of patients with unstable angina and MI.98
Evidence suggests that statins, besides their effects on lipids, reduce endothelial dysfunction, inhibit inflammatory responses, stabilize atherosclerotic plaques, and modulate procoagulant activity and platelet function, the so-called pleiotropic effects.99Statins may reduce the risk of severe sepsis and infection-related mortality independent of their lipid-lowering effect.100The effect of withdrawal of chronic statin therapy during acute coronary syndromes has been studied prospectively. Statin therapy was associated with a reduced rate of nonfatal MI or death at the end of 30 days. Requirement for revascularization procedures was reduced, as was hospital stay. However, among patients whose chronic statin therapy was withdrawn after hospital admission, the incidence of death and nonfatal MI increased when compared not only with patients whose statin therapy was continued, but also with patients who did not receive any statin therapy at all.101It is hence suggested that statins should be continued uninterrupted in acute coronary syndrome and intensive care patients to maintain their beneficial pleiotropic effects.102
A large observational study based on administrative data found that preoperative lipid-lowering therapy primarily with statins reduced the odds of in-hospital mortality after major noncardiac surgery by 38%. The study also reported that the number needed to treat to prevent a postoperative death was 30 among patients with a higher cardiac risk.103A recent meta-analysis of perioperative statin therapy concluded that while statins may confer a survival benefit, their effect of postoperative cardiovascular morbidity was inconclusive. The paucity of prospective data and heterogeneity of retrospective data were also highlighted. The authors suggest that with current data preoperative statin therapy be restarted as early as possible postoperatively.104
Fibrates.
Fibrates are lipid-modulating drugs that act as ligands to the α isoform of PPAR nuclear receptors that activates the transcription genes encoding for proteins involved in lipoprotein metabolism. Fibrates induce synthesis of the major HDL apolipoproteins (apoA-I and apoA-II). By inducing lipoprotein lipase, fibrates stimulate lipolysis and decrease triglyceride synthesis and very-low-density lipoprotein secretion.105Gemfibrozil has been shown to reduce the risk of major cardiovascular events in middle-aged men with dyslipidemia.106But the FIELD study investigating the effects of fenofibrate on cardiovascular events in type II diabetes showed only a weak reduction in cardiovascular risk. However, it did show that fibrates were associated with less albuminuria progression and retinopathy and a significant reduction in incidence of nonfatal MI in low-risk patients.107Fibrates are associated with a 5.5-fold increase in the risk of rhabdomyolysis when compared with statin monotherapy. When combined with fibrates, statins further double this risk.108The IDF recommends fibrates as an option in the management of atherogenic dyslipidemia but highlights the risk of complications when combined with statins.3
Antihypertensive Therapy.
Intensive treatment of diastolic hypertension has been shown to reduce the incidence of adverse cardiovascular events, with diabetic patients deriving most benefit.109The IDF recommends that antihypertensive therapy be introduced early and at much lower blood pressure (≥130/≥80 mmHg) in diabetic patients as compared with nondiabetic patients (≥140/≥90 mmHg).3Tight blood pressure control with either angiotensin-converting enzyme inhibitors or β-blockers has been associated with reduced incidence of microvascular and macrovascular complications in diabetic patients.110
No particular agent has been identified as being preferable for hypertensive patients with metabolic syndrome. Instead, current data suggest that the benefits associated with antihypertensive therapy are largely due to their blood pressure–decreasing effect rather than the drug type.3,110However, it has recently been suggested that drugs that block the renin–angiotensin system may prevent or delay the development of diabetes and thus confer cardiovascular benefit.111–113
Exercise and Mobilization
Increased physical activity has been recommended in the primary management of metabolic syndrome because of its beneficial effects on the various components of the syndrome.2,3Exercise induces the insertion of glucose transporters that do not depend on insulin into the skeletal muscle membrane.31Immobilization may thus induce insulin resistance with reduction in skeletal muscle glucose uptake and glycogen synthesis. In diabetic patients, physical rehabilitation and exercise may improve insulin sensitivity and glucose control.2Early postoperative mobilization as part of an enhanced recovery protocol has been shown to be associated with minimal postoperative insulin resistance.114
Nutrition
Fasting represents an extreme state of nutritional stress, and its adverse effects include depletion of glycogen stores and breakdown of proteins and fat to provide energy. It also impairs mononuclear phagocytic system, increases bacterial translocation, and enhances oxidative stress injury.115,116Studies in experimental animal models have shown that feeding before acute injury preserves energy stores, maintains bacterial homeostasis in the gut, and aids endotoxin clearance.116Therefore, the issue of preoperative fasting must be addressed from a metabolic perspective. Preoperative intake of carbohydrate-rich beverage has been shown to maintain insulin sensitivity in surgical patients.117Improvement in insulin sensitivity with preoperative carbohydrate treatment may also decrease nitrogen losses and promotes protein synthesis.118However, the effects of preoperative carbohydrate loading on postoperative morbidity and mortality have not been evaluated.
Anesthesia and Analgesia
Volatile anesthetics protect the myocardium against the effects of ischemia, a phenomenon closely resembling ischemic preconditioning. This phenomenon, called anesthetic preconditioning, is also believed to be mediated by K ATPchannels in the myocardial sarcolemma and the mitochondrial membrane.75Hyperglycemia is believed to adversely affect preconditioning. High blood glucose concentrations have been shown to attenuate the protective effects of ischemic and anesthetic preconditioning in both diabetic and nondiabetic animal models.119,120In doses used for anesthesia, intravenous induction agents have no effect on circulating metabolite and hormone concentrations, except for etomidate, which has been shown to inhibit cortisol synthesis.121
In healthy volunteers, acute pain has been shown to induce insulin resistance and decrease nonoxidative glucose disposal.122Therefore, it seems logical that effective analgesia may potentially attenuate insulin resistance. High-dose opioids have been shown to attenuate the stress response to surgery, but this response lasts only till the high levels are maintained.123Epidural anesthesia has been shown to attenuate stress response, prevent intraoperative hyperglycemia, and reduce protein breakdown, which also lasts only for the duration of continuous blockade.124,125The effect of neuraxial blockade on sympathetic efferents to the liver, adrenals, and pancreas may mediate these effects. Decreased hepatic sympathetic efferent tone may reduce glucose output from the liver, whereas a reduced sympathetic stimulation of the adrenals attenuates release of catecholamines and cortisol, promoting peripheral glucose clearance.39Neuraxial blockade may also reduce hepatic perfusion and hence the supply of gluconeogenic precursors to the liver.125Furthermore, effective analgesia provided by neuraxial blockade may attenuate reduction in pain-mediated insulin resistance.123Children demonstrate similar responses to surgical stress that is attenuated by epidural blockade.126Continuous neural blockade has also been shown to improve insulin sensitivity after major joint surgery in subjects previously known to be insulin resistant.127Whether effective neuraxial blockade in patients with metabolic syndrome impacts perioperative morbidity or mortality is as yet unknown.
Conclusions
Metabolic syndrome, a rapidly growing global epidemic, is a cluster of cardiovascular risk factors that is associated with a heightened risk of morbidity and mortality. Lifestyle modification and pharmacotherapy targeting individual components of the syndrome have been recommended as primary and secondary prevention strategies. Insulin resistance and central obesity are increasingly recognized as being central to the pathogenesis of metabolic syndrome. Insulin resistance commonly manifests as hyperglycemia during acute illness and in the perioperative period. Management of insulin resistance to achieve glycemic control improves outcome. It is suggested that preoperative statins be continued uninterrupted or at least reinstated as soon as feasible to harness the benefits derived from its pleiotropic effects. Early postoperative mobilization and exercise have shown some promise, but their role must be defined clearly. Modulation of the other components of the syndrome in the acute phase of illness and in the perioperative period needs further evaluation. Perioperative physicians must identify patients at risk of insulin resistance and metabolic syndrome, and strategies aimed at modulating the altered metabolic milieu should be identified.
The authors thank Joel G. Ray, M.D., M.Sc., F.R.C.P.C. (Departments of Medicine, Obstetrics and Gynecology and Health Policy Management and Evaluation, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada), for kindly providing copies of his published studies.
References
1.
World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation. Geneva, World Health Organization, 1999
World Health Organization
Geneva
,
World Health Organization
2.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–97
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
3.
Alberti KGMM, Zimmet P, Shaw J: Metabolic syndrome: A new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006; 23:469–80
4.
Utzschneider KM, Carr DB, Hull RL, Kodama K, Shofer JB, Retzlaff BM, Knopp RH, Kahn SE: Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function. Diabetes 2004; 53:2867–72
5.
Ohlson LO, Larsson B, Svardsudd K, Welin L, Eriksson H, Wilhelmsen L, Bjorntorp P, Tibblin G: The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 1985; 34:1055–8
6.
Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson JE: Abdominal adiposity and coronary heart
disease
in women. JAMA 1998; 280:1843–8
7.
Avramoglu RK, Basciano H, Adeli K: Lipid and lipoprotein dysregulation in insulin resistant states. Clinica Chimica Acta 2006; 368:1–19
8.
Despres JP, Lemieux I: Abdominal obesity and metabolic syndrome. Nature 2006; 444:881–7
9.
Wallace TM, Matthews DR: The assessment of insulin resistance in man. Diabet Med 2002; 19:527–34
10.
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M: Prevalence of insulin resistance in metabolic disorders: The Bruneck Study. Diabetes 1998; 47:1643–9
11.
Langouche L, Van den Berghe G: Glucose metabolism and insulin therapy. Crit Care Clin 2006; 22:119–29
12.
Scott CL: Diagnosis, prevention and intervention for the metabolic syndrome. Am J Cardiol 2003; 92:35–42
13.
Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S, Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, Waters DD, Treating to New Targets Investigators: Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: Analysis of the Treating to New Targets study. Lancet 2006; 368:919–28
14.
Reaven GM, Lithell H, Landsberg L: Hypertension and associated metabolic abnormalities: The role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996; 334:374–81
15.
Grundy SM, Howard B, Smith S Jr, Eckel R, Redberg R, Bonow RO: Prevention Conference VI: Diabetes and Cardiovascular Disease. Executive summary: Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105:2231–9
16.
Valantine H, Rickenbacker P, Kemna M, Hunt S, Chen YD, Reaven G, Stinston EB: Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease. Circulation 2001; 103:2144–52
17.
Saely CH, Aczel S, Marte T, Langer P, Hoefle G, Drexel H: The metabolic syndrome, insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients. J Clin Endocrinol Metab 2005; 90:5698–703
18.
Hu R, Ma CS, Nie SP, Lu Q, Kang JP, Du X, Zhang Y, Gao YC, He LQ, Jia CQ, Liu XM, Dong JZ, Liu XH, Chen F, Zhou YJ, Lu SZ, Wu XS: Effect of metabolic syndrome on prognosis and clinical characteristics of revascularization in patients with coronary artery disease. Chin Med J (Engl) 2006; 119:1871–6
19.
Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24:683–9
20.
Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM: Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care 2004; 27:2676–81
21.
Milionis JH, Rizos E, Goudevenos J, Seferiadis K, Mikhailidis DP, Elisaf MS: Components of the metabolic syndrome and risk for first-ever acute ischemic nonembolic stroke in elderly subjects. Stroke 2005; 36:1372–6
22.
Koren-Morag N, Goldbourt U, Tanne D: Relation between the metabolic syndrome and ischemic stroke or transient ischemic attack: A prospective cohort study in patients with atherosclerotic cardiovascular disease. Stroke 2005; 36:1366–71
23.
Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004; 140:167–74
24.
Porrini E, Delgado P, Bigo C, Alvarez A, Cobo M, Checa MD, Hortal L, Fernandez A, Garcia JJ, Velazquez S, Hernandez D, Salido E, Torres A: Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis 2006; 48:134–42
25.
Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37:917–23
26.
Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K: A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. N Engl J Med 2006; 355:2297–307
27.
Ray JG, Vermeulen MJ, Schull MJ, McDonald S, Redelmeier DA: Metabolic syndrome and the risk of placental dysfunction. J Obstet Gynaecol Can 2005; 27:1095–101
28.
Ageno W, Prandoni P, Romualdi E, Ghirarduzzi A, Dentali F, Pesavento R, Crowther M, Venco A: The metabolic syndrome and the risk of venous thrombosis: A case-control study. J Thromb Haemostasis 2006; 4:1914–8
29.
Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, Fleisher LA, Froehlich JB, Gusberg RJ, Leppo JA, Ryan T, Schlant RC, Winters WL Jr, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC Jr, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: Executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002; 105:1257–67
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery)
30.
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH, American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism Obesity and Cardiovascular Disease: Pathophysiology, evaluation, and effect of weight loss: An update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006; 113:898–918
American Heart Association
Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism Obesity and Cardiovascular Disease
31.
Ganong WF: Review of Medical Physiology, 22nd edition. New York, Lange Medical Books/McGraw-Hill Medical Publishing Division, 2005, pp 333–55
New York
,
Lange Medical Books/McGraw-Hill Medical Publishing Division
32.
Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R, Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P, Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26:3160–7
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
33.
Thorell A, Nygren J, Ljungqvist O: Insulin resistance: A marker of surgical stress. Curr Opin Clin Nutr Metab Care 1999; 2:69–78
34.
Tsubo T, Kudo T, Matsuki A, Oyama T: Decreased glucose utilization during prolonged anesthesia and surgery. Can J Anaesth 1990; 37:645–9
35.
Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106:171–6
36.
Thorell A, Nygren J, Hirshman MF, Hayashi T, Nair KS, Horton ES, Goodyear LJ, Ljungqvist O: Surgery-induced insulin resistance in human patients: Relation to glucose transport and utilization. Am J Physiol 1999; 276:E754–61
37.
Stuart CA, Shangraw RE, Prince MJ, Peters EJ, Wolfe RR: Bed-rest-induced insulin resistance occurs primarily in muscle. Metabolism 1988; 37:802–6
38.
Thorell A, Loftenius A, Andersson B, Ljungqvist O: Postoperative insulin resistance and circulating concentrations of stress hormones and cytokines. Clin Nutr 1996; 15:75–79
39.
Desborough JP: The stress response to trauma and surgery. Br J Anaesth 2000; 85:109–17
40.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345:1359–67
41.
Malmberg K, Norhammar A, Wedel H, Ryden L: Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999; 99:2626–32
42.
Krinsley JS: Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004; 79:992–1000
43.
McGirt MJ, Woodworth GF, Brooke BS, Coon AL, Jain S, Buck D, Huang J, Clatterbuck RE, Tamargo RJ, Perler BA: Hyperglycemia independently increases the risk of perioperative stroke, myocardial infarction, and death after carotid endarterectomy. Neurosurgery 2006; 58:1066–73
44.
Malmstedt J, Wahlberg E, Jorneskog G, Swedenborg J: Influence of perioperative blood glucose levels on outcome after infrainguinal bypass surgery in patients with diabetes. Br J Surg 2006; 93:1360–7
45.
Pomposelli JJ, Baxter JK III, Babineau TJ, Pomfret EA, Driscoll DF, Forse RA, Bistrian BR: Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. J Parenter Enteral Nutr 1998; 22:77–81
46.
Finney SJ, Zekveld C, Elia A, Evans TW: Glucose control and mortality in critically ill patients. JAMA 2003; 290:2041–7
47.
Cochran A, Scaife ER, Hansen KW, Downey EC: Hyperglycemia and outcomes from pediatric traumatic brain injury. J Trauma 2003; 55:1035–8
48.
Doenst T, Wijeysundera D, Karkouti K, Zechner C, Maganti M, Rao V, Borger MA: Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2005; 130:1144–50
49.
van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R: Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449–61
50.
Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P: Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose
versus
glycemic control. Crit Care Med 2003; 31:359–66
51.
Taegtmeyer H, McNulty P, Young ME: Adaptation and maladaptation of the heart in diabetes: I. General concepts. Circulation 2002; 105:1727–33
52.
Capes SE, Hunt D, Malmberg K, Gerstein HC: Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: A systematic overview. Lancet 2000; 355:773–8
53.
Suleiman M, Hammerman H, Boulos M, Kapeliovich MR, Suleiman A, Agmon Y, Markiewicz W, Aronson D: Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: A prospective study. Circulation 2005; 111:754–60
54.
Umpierrez GE, Isaacs SD, Bazagan N, You X, Thaler LM, Kitabchi AE: Hyperglycemia: An independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87:978–82
55.
Garber AJ, Moghissi ES, Bransome ED Jr, Clark NG, Clement S, Cobin RH, Furnary AP, Hirsch IB, Levy P, Roberts R, Van den Berghe G, Zamudio V, American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control: American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 2004; 10:77–82
American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control
56.
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, Williams BA, Schrader LM, Rizza RA, McMahon MM: Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005; 80:862–6
57.
Ouattara A, Lecomte P, Le Manach Y, Landi M, Jacqueminet S, Platonov I, Bonnet N, Riou B, Coriat P: Poor intraoperative blood glucose control is associated with a worsened hospital outcome after cardiac surgery in diabetic patients. Anesthesiology 2005; 103:687–94
58.
Furnary AP, Gao G, Grunkemeier GL, Wu Y, Zerr KJ, Bookin SO, Floten HS, Starr A: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125:1007–21
59.
Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS: Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004; 109:1497–502
60.
Thomas MC, Mathew TH, Russ GR, Rao MM, Moran J: Early perioperative glycaemic control and allograft rejection in patients with diabetes mellitus: A pilot study. Transplantation 2001; 72:1321–4
61.
Thomas MC, Moran J, Mathew TH, Russ GR, Rao MM: Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes. BMC Nephrol 2000; 1:1
62.
Wood KE, Becker B, McCartney JG, D’Alessandro A, Coursin DB: Care of the potential organ donor. N Engl J Med 2004; 351:2703–9
63.
Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J: Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med 2006; 13:174–80
64.
Jeremitsky E, Omert LA, Dunham CM, Wilberger J, Rodriguez A: The impact of hyperglycemia on patients with severe brain injury. J Trauma 2005; 58:47–50
65.
Kwoun MO, Ling PR, Lydon E, Imrich A, Qu Z, Palombo J, Bistrian BR: Immunologic effects of acute hyperglycemia in nondiabetic rats. J Parenter Enteral Nutr 1997; 21:91–5
66.
Weekers F, Giulietti AP, Michalaki M, Coopmans W, Van Herck E, Mathieu C, Van den Berghe G: Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology 2003; 144:5329–38
67.
Latham R, Lancaster AD, Covington JF, Pirolo JS, Thomas CS: The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol 2001; 22:607–12
68.
Monzillo LU, Hamdy O: Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev 2003; 61:397–412
69.
Butterworth J, Wagenknecht LE, Legault C, Zaccaro DJ, Kon ND, Hammon JW Jr, Rogers AT, Troost BT, Stump DA, Furberg CD, Coker LH: Attempted control of hyperglycemia during cardiopulmonary bypass fails to improve neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2005; 130:1319
70.
Quast U, Stephan D, Bieger S, Russ U: The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium. Diabetes 2004; 53:S156–64
71.
Riveline JP, Danchin N, Ledru F, Varroud-Vial M, Charpentier G: Sulfonylureas and cardiovascular effects: From experimental data to clinical use. Available data in humans and clinical applications. Diabetes Metab 2003; 29:207–22
72.
Proks P, Reimann F, Green N, Gribble F, Ashcroft F: Sulfonylurea stimulation of insulin secretion. Diabetes 2002; 51 (suppl 3):S368–76
73.
Macfarlane DP, Paterson KR, Fisher M: Oral antidiabetic agents as cardiovascular drugs. Diabetes Obes Metab 2007; 9:23–30
74.
Gross GJ, Peart JN: KATP channels and myocardial preconditioning: An update. Am J Physiol Heart Circ Physiol 2003; 285:H921–30
75.
Riess ML, Stowe DF, Warltier DC: Cardiac pharmacological preconditioning with volatile anesthetics: From bench to bedside? Am J Physiol Heart Circ Physiol 2004; 286:H1603–7
76.
Forlani S, Tomai F, De Paulis R, Turani F, Colella DF, Nardi P, De Notaris S, Moscarelli M, Magliano G, Crea F, Chiariello L: Preoperative shift from glibenclamide to insulin is cardioprotective in diabetic patients undergoing coronary artery bypass surgery. J Cardiovasc Surg (Torino) 2004; 45:117–22
77.
Meinert CL, Knatterud GL, Prout TE, Klimt CR: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: II. Mortality results. Diabetes 1970; 19:789–830
78.
Kilo C, Miller JP, Williamson JR: The Achilles heel of the University Group Diabetes Program. JAMA 1980; 243:450–7
79.
Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Fighi V, Manley SE, Neil A, McElroy H, Wright D, Kohner E, Fox C, Hadden D: Intensive blood-glucose control with sulphonylureas or insulin compared with sulphonylureas or insulin compared with conventional treatment and risk of complications in type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–53
80.
Bailey CJ: Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab 2005; 7:675–91
81.
Turner RC, Holman RR, Stratton IM, Cull CA, Matthews DR, Manley SE, Frighi V, Wright D, Neil A, Kohner E, McElroy H, Fox C, Hadden D: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854–65
82.
Johnson JA, Majumdar SR, Simpson SH, Toth EL: Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002; 25:2244–8
83.
Derosa G, D’Angelo A, Ragonesi PD, Ciccarelli I, Piccinni MN, Pricolo F, Salvadeo SAT, Montagna L, Gravina A, Ferrari I, Paniga S, Cicero AFG: Metformin–pioglitazone and metformin–rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome. Clin Pharm Ther 2006; 31:375–83
84.
Moon RJ, Bascombe LA, Holt RIG: The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient wellbeing. Diabetes Obes Metab 2007; 9:143–5
85.
Duncan AI, Koch CG, Xu M, Manlapaz M, Batdorf B, Pitas G, Starr N: Recent metformin ingestion does not increase in-hospital morbidity or mortality after cardiac surgery. Anesth Analg 2007; 104:42–50
86.
Chiquette E, Ramirez G, DeFronzo R: A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004; 164:2097–210
87.
Hwang J, Kleinhenz DJ, Lassègue B, Griendling KK, Dikalov S, Hart CM: Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol 2005; 288:C899–905
88.
Kinoshita H, Azma T, Iranami H, Nakahata K, Kimoto Y, Dojo M, Yuge O, Hatano Y: Synthetic peroxisome proliferator-activated receptor-gamma agonists restore impaired vasorelaxation via ATP-sensitive K+ channels by high glucose. J Pharmacol Exp Ther 2006; 318:312–8
89.
Geng DF, Wu W, Jin DM, Wang JF, Wu YM: Effect of peroxisome proliferator-activated receptor gamma ligand: Rosiglitazone on left ventricular remodeling in rats with myocardial infarction. Int J Cardiol 2006; 113:86–91
90.
Shiomi T, Tsutsui H, Hayashidani S, Suematsu N, Ikeuchi M, Wen J, Ishibashi M, Kubota T, Egashira K, Takeshita A: Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002; 106:3126–32
91.
Bakris G, Viberti G, Weston WM, Heise M, Porter LE, Freed MI: Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens 2003; 17:7–12
92.
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomised controlled trial. Lancet 2006; 368:1096–105
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators
93.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, PROactive investigators: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005; 366:1279–89
PROactive investigators
94.
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH: Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; (4):CD006060
95.
Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R: Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27:256–63
96.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–22
97.
Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, Hague W, Beller E, Arulchelvam M, Baker J, Tonkin A, LIPID Study Group: Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: Results from the LIPID trial. Diabetes Care 2003; 26:2713–21
LIPID Study Group
98.
Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC Jr, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina): ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–2002: Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002; 106:1893–900
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina)
99.
Calabro P, Yeh ETH: The pleiotropic effects of statins. Curr Opin Cardiol 20:541–6
100.
Almog Y, Novack V, Eisinger M, Porath A, Novack L, Gilutz H: The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases. Crit Care Med 2007; 35:372–8
101.
Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD: Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002; 105:1446–52
102.
Cubeddu LX, Seamon MJ: Statin withdrawal: Clinical implications and molecular mechanisms. Pharmacotherapy 2006; 26:1288–96
103.
Lindenauer PK, Pekow P, Wang K, Gutierrez B, Benjamin EM: Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA 2004; 291:2092–9
104.
Hindler K, Shaw AD, Samuels J, Fulton S, Collard CD, Riedel B: Improved postoperative outcomes associated with preoperative statin therapy. Anesthesiology 2006; 105:1260–72
105.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088–93
106.
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V: Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317:1237–45
Helsinki Heart Study
107.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M, FIELD study investigators: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005; 366:1849–61
FIELD study investigators
108.
Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R: Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292:2585–90
109.
Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755–62
110.
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317:703–13
111.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355:253–9
112.
Niskanen L, Hedner T, Hansson L, Lanke J, Niklason A, CAPPP Study Group: Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: A subanalysis of the Captopril Prevention Project. Diabetes Care 2001; 24:2091–6
CAPPP Study Group
113.
Jandeleit-Dahm K, Cooper ME: Hypertension and diabetes: Role of the renin-angiotensin system. Endocrinol Metab Clin North Am 2006; 35:469–90
114.
Soop M, Carlson GL, Hopkinson J, Clarke S, Thorell A, Nygren J, Ljungqvist O: Randomized clinical trial of the effects of immediate enteral nutrition on metabolic responses to major colorectal surgery in an enhanced recovery protocol. Br J Surg 2004; 91:1138–45
115.
Nettelbladt CG, Katouli M, Volpe A, Bark T, Muratov V, Svenberg T, Mollby R, Ljungqvist O: Starvation increases the number of coliform bacteria in the caecum and induces bacterial adherence to caecal epithelium in rats. Eur J Surg 1997; 163:135–42
116.
van Hoorn DE, Boelens PG, van Middelaar-Voskuilen MC, Nijveldt RJ, Prins H, Bouritius H, Hofman Z, M’rabet L, van Leeuwen PA, van Norren K: Preoperative feeding preserves heart function and decreases oxidative injury in rats. Nutrition 2005; 21:859–66
117.
Nygren J, Soop M, Thorell A, Nair KS, Ljungqvist O: Preoperative oral carbohydrates and postoperative insulin resistance. Clin Nutr 1999; 18:117–20
118.
Crowe PJ, Dennison A, Royle GT: The effect of pre-operative carbohydrate glucose loading on postoperative nitrogen metabolism. Br J Surg 1984; 71:635–637
119.
Tanaka K, Kehl F, Gu W, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR: Isoflurane-induced preconditioning is attenuated by diabetes. Am J Physiol Heart Circ Physiol 2002; 282:H2018–23
120.
Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR: Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction. Anesthesiology 2002; 96:183–8
121.
Schricker T, Klubien K, Carli F: The independent effect of propofol anesthesia on whole body protein metabolism in humans. Anesthesiology 1999; 90:1636–42
122.
Greisen J, Juhl CB, Grofte T, Vilstrup H, Jensen T, Schmitz O: Acute pain induces insulin resistance in humans. Anesthesiology 2001; 95:578–84
123.
Schricker T, Carli F, Shreiber M, Wachter U, Geisser W, Lattermann R, Georgieff M: Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after, lower abdominal surgery. Anesth Analg 2000; 90:450–5
124.
Carli F, Emery PW: Intra-operative epidural blockade with local anaesthetics and postoperative protein breakdown associated with hip surgery in elderly patients. Acta Anaesthesiol Scand 1990; 34:263–66
125.
Lattermann R, Belohlavek G, Wittmann S, Fuchtmeier B, Gruber M: The anticatabolic effect of neuraxial blockade after hip surgery. Anesth Analg 2005; 101:1202–8
126.
Murat I, Walker J, Esteve C, Nahoul K, Saint-Maurice C: Effect of lumbar epidural anaesthesia on plasma cortisol levels in children. Can J Anaesth 1988; 35:20–4
127.
| https://pubs.asahq.org/anesthesiology/article/108/3/506/8275/Metabolic-Syndrome-and-Insulin?searchresult=1 |
Medication combined with behavior therapy works best for ADHD children, study finds | EurekAlert! Science News
A new study of treatments for children with attention deficit hyperactivity disorder (ADHD) has found that combining behavior modification therapy with medication is the most effective way to improve the behavior of many ADHD children.
Medication combined with behavior therapy works best for ADHD children, study finds
Research is first to test effectiveness of a new 'patch' for treating ADHD
BUFFALO, N.Y. -- A new study of treatments for children with attention deficit hyperactivity disorder (ADHD) has found that combining behavior modification therapy with medication is the most effective way to improve the behavior of many ADHD children.
In fact, when the two are combined, the study showed, the amount of medication required to achieve the same results as use of medication alone can be reduced by two-thirds.
"One of the major findings of the study is that when using behavior modification, you can get away with tiny, tiny doses of medication, much lower than previously thought," said ADHD researcher William E. Pelham, Jr., University at Buffalo Distinguished Professor in the Department of Psychology, UB College of Arts and Sciences and UB School of Medicine and Biomedical Sciences.
The study is the first to test the effectiveness of a new drug treatment, a methylphenidate (MPH) patch. Methylphenidate is the stimulant used in pill form by ADHD drugs Concerta and Ritalin.
The study is published in the May issue of Experimental and Clinical Psychopharmacology. It was funded by a grant from Noven Pharmaceuticals. Shire Pharmaceuticals Group, which purchased the rights to the MPH patch from Noven, will seek FDA approval for the MPH patch in 2006.
Twenty-seven children with ADHD, ages 6 to 12, participated in the study, conducted at the University at Buffalo's Summer Treatment Program for children with ADHD. Pelham and co-researchers assessed the effects of behavior modification, the MPH patch and a placebo on the children in classroom and organized play settings, and through use of parental behavior ratings.
The researchers found that when used alone, the MPH patch and behavior modification therapy were equally effective treatments. The MPH patch was effective in all doses tested, with few reports of side effects and good wear characteristics.
Combined treatment -- using a very low dose of the MPH patch with behavior modification -- was superior to either treatment alone, however.
"The patch used with behavior modification caused the greater amount of improvement in thebehavior of the children," says Pelham, who helped develop Concerta and who has conducted many other trials involving other stimulant drugs.
Significantly, the study also found that with combined treatment children required much lower doses of medication -- as much as 67 percent lower -- to achieve the same effects as high doses of medication used alone.
Lower dosages of medication lowers the risk of long-term drug side effects, which studies have shown to include loss of appetite and stunting of growth, Pelham points out. "Long-term side effects of ADHD drugs are almost always related to dosage," he says. "If you want to lower a child's dosages daily and throughout their lifetime, the best way to do that is to combine the medication with behavior modification."
According to Pelham, the MPH patch's dosage flexibility potentially makes it ideal for administering lower dosages of methylphenidate in combination with behavior modification. The MPH patch can be applied to a child for short periods during the course of the day. The most commonly used pill forms of methylphenidate, which last for 12 hours, do not offer such flexibility, Pelham says.
"The patch enables users to use less medication for short time periods, and that's good in my opinion," Pelham says. "I think parents are becoming more concerned about the safety of medications than they have been in the past."
The study is the first comparison study of medication and behavior modification to control for the presence and absence of behavior modification that is received by a child daily from parents, teachers, siblings or peers, according to Pelham. As such, the study is the first to accurately isolate the effects of medication and behavior modification treatments, Pelham says.
"There's so much behavior modification that goes on naturally in the world that unless you do a study where you guarantee that all of it is taken away you underestimate the effect of behavior modification because it's always there," Pelham says.
"This study shows that when you control for those outside factors, you get effects of behavior modification that are just as big as high doses of medication."
The study's results, Pelham says, should send a clear message to parents of children with ADHD. "You definitely should be using behavior modification," he says. "You'll be giving your children much lower doses of medication over their lifetimes if you combine behavior modification with medication."
###
The study's co-investigators were Lisa Burrows-MacLean, Elizabeth M. Gnagy, Gregory A. Fabiano, Erika K. Coles, Katy E. Tresco, Anil Chacko, Brian T. Wymbs, Amber L. Wienke, Kathryn S. Walker and Martin T. Hoffman from the UB Center for Children and Families.
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York.
Journal
Experimental and Clinical Psychopharmacology
Funder
Noven Pharmaceuticals
Keywords
Original Source
http://www. buffalo. edu/ news/ fast-execute. cgi/ article-page. html?article= 72800009
| https://archive.eurekalert.org/pub_releases/2005-05/uab-mcw050505.php |
Sustainability | Free Full-Text | Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System
Nowadays, engineering students have to improve specific competencies to tackle the challenges of 21st-century-industry, referred to as Industry 4.0. Hence, this article describes the integration and implementation of Education 4.0 strategies with the new educational model of our university to respond to the needs of Industry 4.0 and society. The TEC21 Educational Model implemented at Tecnologico de Monterrey in Mexico aims to develop disciplinary and transversal competencies for creative and strategic problem-solving of present and future challenges. Education 4.0, as opposed to traditional education, seeks to provide solutions to these challenges through innovative pedagogies supported by emerging technologies. This article presents a case study of a Capstone project developed with undergraduate engineering students. The proposed structure integrates the TEC21 model and Education 4.0 through new strategies and laboratories, all linked to industry. The results of a multidisciplinary project focused on an electric vehicle racing team are presented, composed of Education 4.0 elements and competencies development in leadership, innovation, and entrepreneurship. The project was a collaboration between academia and the productive sector. The results verified the students’ success in acquiring the necessary competencies and skills to become technological leaders in today’s modern industry. One of the main contributions shown is a suitable education framework for bringing together the characteristics established by Education 4.0 and achieved by our educational experience based on Education 4.0.
Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System
María Soledad Ramírez-Montoya 2 and
Edgar Lopez-Caudana 1,*
1
School of Engineering and Sciences, Tecnologico de Monterrey, CDMX 14380, Mexico
2
School of Humanities and Education, Tecnologico de Monterrey, Monterrey 64849, Mexico
*
Author to whom correspondence should be addressed.
Sustainability 2021 , 13 (11), 5768; https://doi.org/10.3390/su13115768
Received: 17 March 2021 / Revised: 6 May 2021 / Accepted: 7 May 2021 / Published: 21 May 2021
(This article belongs to the Special Issue Education 4.0: Mobilizing for Sustainable Development )
Abstract
:
Nowadays, engineering students have to improve specific competencies to tackle the challenges of 21st-century-industry, referred to as Industry 4.0. Hence, this article describes the integration and implementation of Education 4.0 strategies with the new educational model of our university to respond to the needs of Industry 4.0 and society. The TEC21 Educational Model implemented at Tecnologico de Monterrey in Mexico aims to develop disciplinary and transversal competencies for creative and strategic problem-solving of present and future challenges. Education 4.0, as opposed to traditional education, seeks to provide solutions to these challenges through innovative pedagogies supported by emerging technologies. This article presents a case study of a Capstone project developed with undergraduate engineering students. The proposed structure integrates the TEC21 model and Education 4.0 through new strategies and laboratories, all linked to industry. The results of a multidisciplinary project focused on an electric vehicle racing team are presented, composed of Education 4.0 elements and competencies development in leadership, innovation, and entrepreneurship. The project was a collaboration between academia and the productive sector. The results verified the students’ success in acquiring the necessary competencies and skills to become technological leaders in today’s modern industry. One of the main contributions shown is a suitable education framework for bringing together the characteristics established by Education 4.0 and achieved by our educational experience based on Education 4.0.
Keywords:
Education 4.0
;
educational innovation
;
higher education
;
skills
;
competencies
;
TEC21 Educational Model
;
electric automotive team
1. Introduction
The training of professionals in higher education institutions faces complex challenges in teaching scientific and technological advances and the requirements of creating new solutions to real problems of society. This training is also subject to the need to connect the academic sectors with the governmental, industrial, and social sectors. Changes in educational processes, associated with industry, have also been found along the way, ranging from education (1.0), around the industrial revolution of the 18th century, where the teacher was the center of education because he was in charge of determining and disseminating the essential information needed by students, to processes (2.0) with the imprint of educational technologies, with the first electronic devices used in education, such as printers, calculators and computers, to an education (3.0), within the framework of the third industrial revolution at the end of the 20th century, where automation and the use of resources such as multimedia, virtual tools and laboratories were enhanced, to an education (4.0), which is framed in the fourth industrial revolution, with processes are accompanied by pedagogical technologies and procedures and procedures, and the role of the teacher is that of mentor, referent and collaborator in relation to digital transformations and virtualization processes [
1
]. Because of this, several universities are changing their processes and models to respond to these requirements.
This article presents the case of a Mexican multicampus institution that has radically modified its educational model to focus on training students in disciplinary and transversal competencies. The focus is on describing the integration of this work’s Education 4.0 strategies with the new educational model of our university to respond to the needs of Industry 4.0. The article begins with a theoretical framework related to Education 4.0 in the framework of university education, then presents a contextual framework of the TEC21 educational model where the case of this article is integrated. The instrumental case method is presented through a project called escudería due to the worked-on characteristics. The “CCM Borregos Team” on the Tecnologico de Monterrey, campus in Mexico City, collaborates in a new multidisciplinary project. This team participates in the national “Electraton” competition to design an electric vehicle that satisfies established regulations. Currently, the team has shown a loss of interest in improving or innovating, which results in failures in the championship, thus, collapsing the commercial relations with the sponsors. The results are presented and discussed in light of the TEC21 model and the characteristics of Education 4.0. Finally, the conclusions report with characteristics established by Education 4.0 and achieved by our educational experience.
1.1. Conceptual Framework of Education 4.0 in University Education
The evolution of education begins with Education 1.0, in which the knowledge is transferred from teacher to students directly. Education 2.0 is a connection between society’s needs, so the required knowledge is integrated into the courses. However, creativity is not included. Education 3.0 integrates technological components, so the interactive learning methodology is stimulated. This innovation era promotes exceptional features of parallelism, connectivism, and visualization [ 2 ]. On the other hand, Education 4.0 is based on some trends [ 3 ]:
∎
The learning process has to offer in anyplace and anytime.
∎
The education has to be tailored according to the students’ needs and preferences.
∎
Students decide the best method for learning.
∎
The students have to be involved in short and long term projects.
∎
Hands-on learning is a fundament element in the learning experience.
∎
Making decisions and using logical interpretation using the acquired knowledge is essential.
∎
Self-learning is mandatory during application projects.
∎
Achievement of competencies by its graduates.
∎
Innovation in current learning tools.
∎
Use of the digital tools and emerging ICTs.
∎
Projects in living laboratories to produce real learning scenarios.
In the formation of university education, within the framework of Education 4.0, it is relevant to link students with real problems and developed competencies that encourage problem-solving. Reference [
4
] defined Education 4.0 as the current period in which higher education institutions apply new learning methods, innovative didactic and management tools, and intelligent and sustainable infrastructures complemented by emerging technologies that improve knowledge generation and information transfer processes. Reference [
5
] postulate for a 4.0 education based on the concept of learning by doing. Students are encouraged to learn and discover different things in a singular way from experimentation. Among the skills most in demand by new learners (and employers) are digital literacy, critical thinking, and problem-solving [
6
]. In the same sense, reference [
7
] analyzed the advances and transformations that education has undergone for the formation of digital competencies and how to face the demands of today’s society, finding that, in different international and national contexts, they are transforming their technological developments and their academic and labor competitiveness, enhancing the competencies as well as the mechanisms of participation of schools and companies, complying with the sustainable development goals.
In Education 4.0, the role of the teacher requires roles aimed at transformation and change. In [ 8 ], transactional, transformational, democratic, autocratic, bureaucratic, and charismatic leadership styles positively and significantly affect the teacher’s performance. In the era of Education 4.0, this type of teacher’s leadership could be a reference for future research in different places [ 9 ]. In addition, the teachers could be shown the agents of change and are requested to contribute more to the educational revolution [ 10 ]. At present, Education 4.0 has been developed and implemented. Thus, the profile of professor 4.0 was described [ 11 ] as a specialized professional with competencies for innovation, complex problem solving, entrepreneurship, collaboration, international perspective, leadership, and connection with the needs of society. Also, reference [ 12 ] indicates that academics should support new learning and ideas, formal learning, and external/interface learning.
The use of technology in training environments can be a positive driver or an area of opportunity to promote practices within the framework of Education 4.0. [ 13 ] mentioned that barriers continue to prevent wider adoption of Education 4.0 learning technologies, even though these technologies are available in the mainstream consumer market.
Reference [
14
] presents a historical moment in which postmodernity enters. It has not been able to adapt to information and communication technologies (ICT), the rapid technological innovation, the changes and trends in the industry, the collaborative economy, or the rise of distance careers. On the other hand, reference [
15
] provides a review of Education 4.0 across a select range of the UK and international higher education providers, highlighting the importance of personal digital assistants, online and lifelong learning in delivering world-class learning and teaching. Besides, in [
16
], the education sector has to cope with changes in the global economic landscape, as industries are highly technology-driven, and venturing into unconventional learning modalities is needed to maintain efficient and effective development of emerging and future skill needs, thereby increasing its productivity and innovation rates.
Specifically, in engineering education, it is required to develop transformation and change competencies that lead them to postulate for new solutions in the framework of an Education 4.0. Reference [ 17 ] mentions that the emergence of Industry 4.0 has inspired education to transform and change its delivery lens towards Education 4.0. Besides, in [ 18 ], the challenges in education and lifelong learning process engineers and the industry are explained to safeguard employability and competitiveness. Also, reference [ 19 ] enunciates the demand of Industry 4.0 for creative researchers able to adapt to the changing world and to think innovatively and raises the question of educational technologies used to prepare these specialists. Reference [ 20 ] emphasizes that teaching and learning approaches, innovation, and value-added experiences of students through technology are part of the concept of Higher Education 4.0. Reference [ 21 ] postulates for new recommender systems that represent an essential aspect of Education 4.0, especially for engineering education that is taking advantage of new technologies; or as the use of innovative platforms such as Teachers’ Research Exchange in the era of digital transformation and the emerging context of Education 4.0 [ 22 ]; as well as bringing open and shared learning platforms, so that schools and teachers can be supported to access, collaborate and undertake research, in the emerging context of Education 4.0 [ 23 ].
Likewise, several universities have allocated resources for the design and development of laboratories, whose function is to promote creativity and innovation, the fundamental pillars of “Education 4.0”. An example of this is the “Living Laboratory”, defined as an active-learning laboratory for activities that resolve real and semi-real problems and challenges [
24
,
25
]. Today, the strategy of using living labs and collaborating with industry represents an excellent opportunity for universities to address sustainability challenges while providing students with relevant and real information. In other words, living labs offer a challenging, collaborative, and iterative space for the co-production of knowledge. We could say that this strategy aims to provide a framework for students and teachers in an educational environment to apply theoretical knowledge to real-world situations. The generation of living lab projects produces knowledge-enhancing scenarios, without a doubt [
26
]. Education 4.0 also envisions preparing new professionals who are highly competitive and responsive to current and future needs and challenges. Industry must innovate and promote entrepreneurship to find feasible solutions to the new scenarios’ many challenges, many with high social content. Besides, academic institutions and their students must contemplate the challenges and opportunities present in Industry 4.0, such as cloud computing, the Internet of Things, multi-agent systems, cyber-physical systems, and artificial intelligence and their key points [
27
].
Moreover, industrial trends point to a future with more electric cars, robotics, and artificial intelligence. In Mexico, the lagging of universities in providing graduates with the knowledge, skills, abilities, and technology for this new industry directly relates to the limitations and obsolescence of their current professional curricula. Few have modified their curricula to eliminate or reduce the gap, so the academic communities do not learn the new skills, capacities, and technologies to solve the industry’s current and future problems. What is needed is “Education 4.0”, which provides new teaching and learning methods using innovative facilities with emerging technologies. Its function is to prepare students to face the future problems of industry [
28
], seeking to graduate a new generation of highly competitive professionals capable of applying the proper physical and digital resources to provide innovative solutions to current and future societal challenges.
1.2. The Contextual Framework of the TEC21 Educational Model
The Tecnologico de Monterrey has been characterized for being at the forefront in terms of educational models and avant-garde when it comes to educational innovations. The new educational model of the Tecnologico de Monterrey is committed to a more practically challenged education, combining theory with the adoption of skills. The rector stated that this new model “will begin in all degree courses and semesters in 2019, although for four years, it is already being implemented partially”, today, the current and invigorating model of Tecnologico de Monterrey, has established a panorama of educational vision in Mexico [
29
]. These connect with Education 4.0, as they offer students attractive projects with challenges that develop new skills, competencies, and knowledge. Tecnologico de Monterrey implemented the “TEC21 Educational Model” on its 26 campuses. It aims to improve its students’ competitiveness in different professional fields through comprehensive training and active-learning activities performed collaboratively with partners in the productive sector to develop entrepreneurship, leadership, and innovation competencies. The specific spaces designed for the collaborative and multidisciplinary work among students include the libraries, the Learning Commons, the InnovAction Gym, Labs, and various Active Learning classrooms [
30
].
Challenge-based learning is the key strategy of the TEC21 model and is transversal in the courses and training instances. The purpose of the courses’ challenges is to address industry needs and develop complete product and service solutions, which can be placed and distributed in the industries’ solutions portfolios. In this way, the industry can refine the product to an utterly digital-based model proposition. This model must consider the right incentives and find the proper distribution channels. Academic institutions must consider these and many other challenges to train their students. Immersing students in real challenges having the characteristics of Education 4.0 is fundamental in achieving better results [
31
].
Developing competencies for work and lifelong learning is what is projected in the TEC21 Educational Model. This model has two categories of competencies: disciplinary and transversal (
Figure 1
[
32
]. Disciplinary competencies emphasize the knowledge, attitudes, values, and skills necessary for professional practice; these are required in laboratory procedures in manufacturing, statistical analyses of experiments, and designing software for functional prototypes. Transversal competencies are helpful throughout the life of the graduate in all professional sectors. They directly impact the quality of professional practice and include communicating effectively in various situations, showing initiative, creativity, and integrity, and having a good work attitude.
The objective of the undergraduate Mechanical Engineering program at Tecnologico de Monterrey [
33
] is to prepare professionals competent in the design and innovation of electromechanical systems. They must have skills to select appropriate materials for product manufacturing; select, design, and integrate conventional and advanced manufacturing processes; formulate maintenance schemes; conduct failure analyses; integrate mechanical energy transformation systems; and integrate manufacturing and project management in productive, innovative processes. Throughout their academic programs, students take courses such as Engineering Modeling Using Dynamic Systems, Design of Products Subjected to Static Charges, Design of Mechanisms, or Analysis and Prevention of Faults, which directly address the aspects above. However, this challenge model is where many of the TEC21 objectives converge.
This article outlines the academic and non-academic competencies that are intended to be developed among undergraduate engineering students, presented in an Education 4.0 case study; this exercise illustrates active learning strategies and laboratories designed to collaborate with a company. The case is a multidisciplinary, sustainable project focused on a competitive team designing an electric vehicle suspension system. The project incorporates Education 4.0 elements and competencies. Finally, the results presented show the contributions of innovation and competency formation in undergraduate students.
2. Methods
The proposed methodology focuses on an instrumental case study. Instrumental cases are defined by [ 34 ] as complex and particular entities, where the situation under study is an instrument to achieve something different from the case itself. The instrumental case study, in this study, is presented with the opportunity to know the results of the development of competencies in undergraduate students through a laboratory where they worked with projects linked to industry.
From its inception, this project was carried out in facilities on the Mexico City Campus of Tecnologico de Monterrey, specifically in the Mechanical Engineering Laboratory, which was transformed into a “Living Laboratory”. In this laboratory, the students/members could research, create prototypes, validate them, and refine solution proposals for multiple, changing real-life problems [
35
]. The first stage focused mainly on creating an electric vehicle competitively to obtain the highest mechanical-electrical efficiency and, therefore, excellence during the tests of the national “Electraton” championship. As the project progressed and showed improvements, a channel of trust was to be generated with the current sponsoring companies, fostering the expansion of relations with these companies, with the possibility of their becoming training partners, who would acquire new specialized technologies. The aim is to achieve remarkable improvements by implementing innovations in each area of the project. University teams compete in the only electric car championship in Mexico, where they must manage materials and economic resources and develop academic skills and competencies [
36
].
This project is exclusively designed and deployed by the students/members of the Mexico City Tecnologico de Monterrey “Borregos” team. The project team is multidisciplinary. In addition to academic engineering disciplines, its range of studies includes academic disciplines such as Economics, Marketing, Industrial Design, and Logistics, which the Industrial Engineer contemplates. Figure 2 illustrates how the team (“Scuderia”) project aligns with the TEC21 Educational Model.
Figure 3 shows the current organizational chart of the Borregos team organization and the distribution of tasks and responsibilities within the project.
The TEC21 Educational Model uses an adequate schedule for such purposes, considering subjects that last 5, 10, or 15 weeks depending on the semester; some weeks are reserved for developing projects relevant to the student’s profile. As students advance in their academic programs, the semesters serve up more challenging projects for practice activities.
However, specific changes in the internal structure of the Borregos Team had to be contemplated to align the established objectives of the new project with the TEC21 Model.
Figure 4
shows the new organizational chart for this project. Compared to the first organization, the second distributes the project’s system components better under the respective department managers, who collaborated with the teachers and student members. Each system had its financial and technical coordinator to expedite the procedures for purchasing materials and resources by area, avoiding confusion with other departments. The leaders define the main functions and objectives of their departments, which were all interconnected. They specified the first design guidelines and the manufacturing processes, contemplating the members in their custody to obtain a better work distribution. These managers focused on being leaders of their departments’ systems, ensuring that each collaborating team member achieved continuous improvement within the project, which entailed having more responsibility. In turn, those in charge of the various systems had to cooperate and communicate to achieve the best possible project performance (see
Figure 4
).
The general project manager responded to the university authorities and the organizers or judges associated with the project competencies. He or she carried out the project’s general administration issues and performance reports. The general project managers were the team’s formal representatives to the training partners and were required to be in charge of one of the project’s systems. This scheme was designed to improve cooperation among team system members and speed up processes that previously had noticeable time delays.
There were design and test engineers and other members from other areas who collaborated to develop a whole system comprised of several elements not limited to engineering disciplines in each project department. In these systems, several modules of the new TEC21 educational model could be applied, including Main Structure (Frame Analysis), Transmission System (Power), Database (test and system design), Electrical System (Sensor, Electric Motor), Suspension System, and Braking System. All of these systems were interdependent. An example of this is presented in Figure 5 .
The suspension system provides better vehicle performance by keeping the tires at the optimum angle to the track through various situations, such as braking, cornering, and accelerating [ 37 ]. Tires, shock absorbers, rockers, suspension arms, and uprights comprise the suspension system.
Its relationship with the other systems, as shown in Figure 5 , may damage or benefit its behavior depending on the load distribution in the vehicle, the balance of the braking system, the movement caused by a change of direction, and resistance to speed changes by the transmission system. In designing each system, the student/member could implement their theoretical knowledge acquired through the TEC21 learning modules to develop new skills and technical expertise in each vehicle system.
3. Results
Suspension System of an “Electraton” and “Formula SAE” Competition
As background related to the case study, there are precedents of a Tec university project on the Mexico City campus where research and tests were carried out in laboratories with physical prototypes. The objective was to improve the performance of an electric vehicle’s front suspension system. The traditional suspension system is a set of passive elements intended to minimize road disturbances and improve the vehicle’s dynamic performances. It must be designed for the suspension to react optimally during driving, affecting the vehicle’s center-of-mass movement as little as possible [ 37 ].
Various design techniques can be implemented to minimize the dynamic effects that the vehicle may suffer. Several of these techniques can be found in the literature, but the methods’ verification is only theoretical. First, we take the example of the design of a suspension for the “Electraton” competition. In this championship contest, the suspension is of the utmost importance when developing the electric vehicle because of its dimensions. The regulations stipulate two limits for total length and width [ 38 ]. Figure 6 shows the minimum dimensions.
Similarly, the regulations have a section that mentions that the suspension system should be independent, contemplating a McPherson-type or double wishbone design (see Figure 7 ).
In either case, it must include a spring and shock absorber having a direct connection to the car’s main structure. The suspension system should provide an optimum height of at least 2″ (50.8 mm) from the ground in both front and rear suspension systems [
38
]. Knowing the stipulated measures and components, we proceeded to design such a system; the main goal was to establish the center of mass. It enabled us to know the static loads that the vehicle would have and, consequently, the efforts required to generate the suspension. The equations used to establish the center of mass:
M
m
=
1
+
m
2
.....
(1)
This equation shows us the sum of the different masses that are part of the vehicle.
We can also establish the distribution of each mass or component within a specific limit previously set by the regulations. We determined the longitudinal and height distribution of the vehicle with the following equations:
l
(3)
Equations (2) and (3) represent the longitudinal position and the resulting height of the center of mass (see Figure 8 ).
By obtaining the total weight and estimating each component’s position in the vehicle, we could find the center of mass’s distance and height. This allowed us to define the vehicle’s weight distribution percentages, obtaining Wf and Wr, representing the weights in the front and rear sections.
The total mass of the vehicle of 225 kg, multiplied by the gravity constant “g” (9.81 m/s 2 ), the total vehicle weight (W) is 2207.25 N.
With these weights defined, we could proceed to find a more suitable wheelbase (L) (the length of the front axle to the rear axle) to allow an optimal distribution of weight for the vehicle through the equation:
=
W
⋅
lm
L
(4)
The wheelbase (L) obtained was 1353.14815 mm.
Table 1 shows the total of the measurements made, while center of mass and vehicle weight distribution are showed on Table 2 and Table 3 , respectively.
These parameters allowed us to determine the load transfer of the vehicle during a race. In this case, we used an extreme situation for the front suspension during a hard cornering braking. Figure 9 synthesizes this idea.
Table 4 , Table 5 and Table 6 , show main aspects of braking and load transfer for vehicle.
These loads were a preamble for static analysis of the components of the suspension system. Still, because a vehicle is a highly dynamic object, new complications arise when the vehicle passes over bumps and curbs. The “shock” loads are transmitted through the suspension to the main structure. The actual magnitude of these loads is difficult to determine. However, the design procedures indicated that applying a dynamic factor of “3” directly to the total weight of the vehicle [
37
], together with the respective aerodynamic coefficients, was more than enough to simulate the vehicle dynamics behavior. We call these new charges “Design Loads”. In
Table 7
,
Table 8
and
Table 9
, it can see the main aspects of dynamic tests for vehicle.
These results provided an overview of the vehicle behavior in static and dynamic situations. We could use these data to determine:
Loads that affect the action of the suspension arms, whether lower or higher.
Behavior with other related systems.
Appropriate geometry or corresponding reinforcement for the suspension system, covering variables like camber, caster, instant-center, and roll-center.
Kinematic analysis for the suspension system mechanism.
Analysis of deformation in reinforcements corresponding to the suspension arms, theoretically, through simulations (FEM) and practice.
Properties such as stiffness and the damping coefficient required in the suspension system.
Motion ratio for push-and-pull-rod mechanisms.
With these design parameters already established, we could draw this system’s general schemes to actual scale, creating a complete system visualization ( Figure 10 ).
With this scheme presented in 2D complete and not showing visible obstructions or inconsistencies, we could make the system’s corresponding CAD drawings. Figure 11 , Figure 12 and Figure 13 illustrate this idea.
After these CAD drawings, we proceeded to perform a finite element model (FEM) analysis, through which each piece is submitted to its corresponding studies, contemplating its movement restrictions and the load characteristics to which it would be subjected. It is essential to bear in mind that even if these are simulations, they must comply with a specific mandatory safety factor contemplated in the design materials subject to different loads, as shown in Figure 14 .
Once the FEM simulations and their analyses with the corresponding safety factor were completed, we carried out the vehicle’s general assembly to evaluate the calculations previously made ( Figure 15 ).
With the simulations, design, and final assembly already established, each component’s prototype machining processes could begin, reviewing compliance with the appropriate tolerances for optimal practical functionality to avoid unnecessary waste of raw material. Figure 16 shows this process.
The prototype’s functionality was satisfactory, so the different processes of the system manufacturing were carried out, such as Manual and CNC lathe, Manual and CNC milling, Welding, and 3D Printing.
Once the physical components are machined, they must be subjected to different resistance tests. For this testing, metric gauges are essential because they provide data on micro deformations at the points where the highest possible stresses can occur (
Figure 17
and
Figure 18
). We could carry out the system’s final assembly with the tests satisfactorily performed for each interconnected system. The member (s) involved in this system must follow a series of crucial steps for the assembly, avoiding damaging any other vehicle system. Cooperation among the different vehicle systems teams is critical to obtain the best vehicle behavior during the competition.
In this case, the design of the suspension was for a national competition. Still, engineering complexity increases in the opportunity to participate in an international competition, the Formula Student (FSAE). In this competition, there are more restrictions regarding the suspension system, as discussed below:
The technical requirements specified in Article 6 of the general rules of the chassis (T6.1) and the general guidelines for the FSAE suspension system are:
T6.1.1. The vehicle must be equipped with an operating suspension system, with shock absorbers, front, and rear, having wheel travel of at least 15 mm to 50.8 mm during the boat, and bounce with the driver inside the cabin. Judges reserve the right to disqualify cars that do not present a serious attempt at an operational suspension system or demonstrate improper handling for a cross-car circuit [ 36 ].
T6.1.2. All suspension mounting points must be visible on technical inspection, either by direct vision or by removing any cover [ 36 ]. Below is a table that shows some of the requirements to consider in the design of a suspension.
With the design parameters mentioned in the previous specifications, it is possible to perform each of the steps mentioned in the case of “Electraton” for the suspension design in this competition, including:
Theoretical analyses of the center-of-mass, optimal track measurements, and vehicle load distributions.
Load transfer during different braking, acceleration, and cornering situations.
The geometry of camber, caster, instant center, and roll center.
Kinematic analysis of the suspension system.
Analysis of deformation in reinforcements corresponding to the suspension arms, theoretically, through simulations (FEM) and practice.
Properties such as stiffness and damping coefficient required in the suspension system.
Motion ratio for push or pull-rod systems, if used.
With these analyses and operations carried out, it is possible to obtain the components’ real-scale schematizations. Then, each element is subjected to static and dynamic tests, much stricter than those mentioned previously in the Electraton competition. In the FSAE competition tests, interdisciplinary and disciplinary competencies acquire more value since the vehicle’s data and general information are contemplated in engineering and economics, marketing, and administration. The competition judges evaluate verbal and body communication skills, teamwork, and work under pressure. The FSAE Tests include [
36
]: Static events (Presentation, Cost, and Design) and Dynamic Events (Acceleration, Skid Pad, Autocross, Efficiency, and Endurance).
Once all of the tests on the suspension system components are submitted, the 2D scheme must be performed ( Figure 19 ).
If the scheme does not present problems in assembly, location, and design tolerances, we proceed to 3D modeling (CAD) of the suspension system’s components ( Figure 20 ).
These models must withstand the movement restrictions, and the characteristics of the loads analyzed using FEM simulations; locating the most significant stress points is possible through these simulations. FEM analysis results are illustrated in Figure 21 .
With the FEM analyses completed, it is possible to perform the general assembly of the vehicle. Figure 22 shows the final assembly.
4. Discussion
In the analysis of the case presented, we used direct interpretation from the instrumental case-study perspective. Reference [
34
] states that direct interpretation is used to locate meanings in the situation with emic themes (essential data for the actors themselves). In his research, reference [
41
] reported the use of matrices to locate categories of analysis. With these considerations, our research analyses put into perspective the case study of the EV team as an instrument to illustrate the connection of Education 4.0 and the TEC21 Educational Model, as revealed in the study’s findings.
Table 10
lists the categories connected to the case study.
4.1. Relationship—TEC21 Model—Education 4.0—EV Case Study
Table 11 lists relationships between educative model and developed aspects.
4.2. Relationship—TEC21 Model—Education 4.0—Capstone Project
As mentioned earlier, the study’s specified project conforms to the TEC21 Educational Model. Sometimes, the academic programs’ challenges do not arouse students’ interest because they only manifest or reflect theoretical knowledge without actual practice or testing. This project’s advantage lies in its relating to the different TEC21 learning modules and proposing solutions to the challenges set out in each course. The students acquire knowledge and skills by making functional prototypes subject to constant improvements, simulating the skills and knowledge that the students pursue in search of excellence during their professional careers.
Also, this project presents excellent academic flexibility since one of its advantages is the vast area of opportunity to focus on professional skills and passions according to the interests of the students, in this case, aligning their knowledge acquired in the modules to specific vehicle systems. The students can explore, decide, and specialize during their training process, complementing it with a concentration. Participating in research collaborations with their teachers in each academic area and the project training partners from industry, the students acquire specific tools or certifications in the curriculum beneficial to them as they integrate into working life [
32
].
The competition judges evaluate verbal and non-verbal communication skills, teamwork, and work under high pressure. The FSAE Tests include [
36
]: static events that include the presentation of the designed vehicle, the cost required to develop the vehicle, and the design elements. Usually, the team has to look for funding opportunities that help to improve the vehicle’s design. However, the low cost of designing the vehicle is encouraged. Hence, creativity for solving design problems is promoted. Dynamic events regarding the dynamic performance of the vehicle are done. Those events include acceleration, skidpad, autocross, efficiency, and endurance.
As a result of this project, some students were connected to companies such as Tesla, in which they did an internship since those companies find in those students the skills and competencies they are searching for. (
https://tec.mx/es/noticias/ciudad-de-mexico/educacion/piden-en-tesla-talento-del-tec
, accessed on 5 April 2021) and (
https://tec.mx/es/noticias/ciudad-de-mexico/institucion/abre-tesla-sus-puertas-dos-alumnos-del-tec-ciudad-de-mexico
, accessed on 5 April 2021). It is essential to mention that those skills and companies allow students to become technological leaders
5. Conclusions
The training of professionals with a creative vision involves placing students in the realm of real problems. This article highlights the formation of students’ competencies, supported by an educational model that aims to develop innovation and problem-solving skills, to make them agents of change. The students who worked on their projects developed competencies through theoretical analyses, creative designs, simulations, and acceleration and validation of the team’s prototype. The students came up with good transmission designs due to acquiring avant-garde knowledge and concrete competencies linked to real problems. This educational experience can support students in facing new challenges, which is the aim of the TEC21 Educational Model, putting students into practice with different challenges to provide creative solutions. Through constant experimentation and experiential learning, they can scale mastery levels of the model’s established competencies.
This case study focused on improving the suspension systems by adequately managing the data presented during specific driving situations, such as braking, cornering, or accelerating. Contemplating the longitudinal mass distribution, the geometry of specific structural components, composite materials, damping systems, and manufacturing processes using research modules, digital technology, and design software improved vehicle performance. The performance of these activities led to the efficient acquisition of skills and competencies in the students involved. The TEC21 Educational Model favored the students’ development and involvement in constructing the automotive systems, proving it to be a suitable methodology that could work in similar projects.
Education 4.0 emphasizes problem-solving training, mediated by emerging technologies and innovative strategies. This project developed in the student/members the core elements of the TEC21 Educational Model, such as leadership, innovation, and entrepreneurship. It linked academia with the productive sector; the students inspired and influenced the people in their environment to work together for a common goal. This boosted their entrepreneurial spirit; they passionately proposed and implemented innovative solutions that transformed their reality, identifying the areas of opportunity and analyzing the risks and uncertainties in the project. If necessary, in case of failure, they could proceed to a rapid recovery. This experience ensures that, in the future, these same students will be able to promote the creation of high-impact companies.
This case study only considered the suspension system, which, as already mentioned, depends on other systems. By expanding and monitoring the design processes and acquiring data, as in this case study, there can be a design platform based on training, active learning experiences, and acquired self-knowledge through the TEC21 educational learning modules. With these advances, the communication among various project areas would reinforce research into innovative components or solutions that improve the vehicle performance without putting the other automotive systems at risk. These innovations would be designed, simulated, and manufactured in the laboratory where the project is developed, encouraging cooperation with training partners to create new products using new emerging technologies in the global market. With these innovations, the possibility of participating in international competitions is feasible. Participating in such competitions (competitive or commercial) offers project development and long-term monitoring, which would position Tecnologico de Monterrey, Mexico City Campus, as a center for innovation and use of emerging technologies in sustainable electric motoring.
Future research can be strengthened by a mixed methodology, exploring the previous levels of competency mastery and the final levels quantitatively while also supplementing qualitative analyses that enrich the data. We invite further research studies on educational innovation that provide empirical evidence of new strategies, processes, and products.
Future Development Proposals
When a multidisciplinary project is carried out, the open innovation laboratory allows joining all the required elements such as universities, industries, and governmental institutions like a unified team. The design structure that provides the open innovation laboratory results in a completely open design topology that grasps all the elements together. All of them can be active during the design process and integrates new ideas. As a result, when the students work on designing an electric vehicle under the open innovation laboratory, the vehicle becomes a living lab that makes available new engineering challenges aligned whit Education 4.0 to achieve advanced engineering skills.
This project has several opportunities for innovation and development in different systems in the short, medium, or long terms. The suspension system is covered in the case study; however, there are still components or methods to improve it. Other systems such as the transmission, braking system, fundamental structure, or even electronic improvements can benefit this study. Figure 23 shows several aspects for future scenarios.
Open innovation for these developments is an excellent way to link higher education institutions and industry, which would result in open designs by teams and the development of innovation, leadership, and entrepreneurship skills through co-construction spaces, such as living laboratories. Of substantial importance is to use metrics to measure undergraduates’ skills and competencies to contribute to Education 4.0 and Industry 4.0. The goal is to train undergraduates to be professionals committed to innovation and the desire to impact societal well-being using sustainability methodologies.
Author Contributions
Conceptualization, P.P. and A.M.; methodology, P.P., H.A.L. and M.S.R.-M.; software, H.A.L.; validation, H.A.L., P.P. and A.M.; formal analysis, E.L.-C. and M.S.R.-M.; investigation, H.A.L.; resources, P.P. and A.M.; data curation, P.P.; writing—original draft preparation, P.P.; writing—review and editing, M.S.R.-M. and E.L.-C.; visualization, E.L.-C.; supervision, P.P.; project administration, P.P.; funding acquisition, A.M. All authors have read and agreed to the published version of the manuscript.
Funding
The authors would like to acknowledge the financial support of Writing Lab, Institute for the Future of Learning, Tecnologico de Monterrey, Mexico, in the production of this work.
Acknowledgments
The authors would like to acknowledge the technical support of Writing Lab, Institute for the Future of Learning, Tecnologico de Monterrey, Mexico, in the production of this work.
Conflicts of Interest
The authors declare no conflict of interest.
References
Miranda, J.; Molina, A. Designing Hybrid Learning Programs in Higher Education by Applying Education 4.0: The Innovation Challenge Bootcamp as Case Study. In Proceedings of the 2020 IEEE Learning With MOOCS (LWMOOCS), Antigua Guatemala, Guatemala, 29 September–2 October 2020; pp. 31–36. [ Google Scholar ]
Puncreobutr, V. Education 4.0: New challenge of learning. St. Ther. J. Humanit. Soc. Sci. 2016 , 2 , 92–97. [ Google Scholar ]
Evans, J.; Jones, R.; Karvonen, A.; Millard, L.; Wendler, J. Living labs and co-production: University campuses as platforms for sustainability science. Curr. Opin. Environ. Sustain. 2015 , 16 , 1–6. [ Google Scholar ] [ CrossRef ]
Miranda, J.; Lopez, C.S.; Navarro, S.; Bustamante, M.R.; Molina, J.M.; Molina, A. Open Innovation Laboratories as Enabling Resources to Reach the Vision of Education 4.0. In Proceedings of the 2019 IEEE International Conference on Engineering, Technology and Innovation (ICE/ITMC), Valbonne Sophia-Antipolis, France, 17–19 June 2019; pp. 1–7. [ Google Scholar ]
Almeida, F.; Simoes, J. The Role of Serious Games, Gamification and Industry 4.0 Tools in the Education 4.0 Paradigm. Contemp. Educ. Technol. 2019 , 10 , 120–136. [ Google Scholar ] [ CrossRef ]
Peredrienko, T.; Belkina, O.; Yaroslavova, E. New Language Learning Environment: Employers’—Learners’ Expectations and the Role of Teacher 4.0. Int. J. Instr. 2020 , 13 , 105–118. [ Google Scholar ] [ CrossRef ]
Bernate, J.A.; Guativa, J.A.V. Desafíos y tendencias del siglo XXI en la educación superior/ Challenges and trends of the 21st century in higher education. Rev. De Cienc. Soc. 2020 , 26 , 141–154. [ Google Scholar ]
Kadiyono, A.L.; Sulistiobudi, R.A.; Haris, I.; Wahab, M.K.A.; Ramdani, I.; Purwanto, A.; Sumartiningsih, S. Develop leadership style model for indonesian teachers performance in Education 4.0 era. Syst. Rev. Pharm. 2020 , 363–373. [ Google Scholar ] [ CrossRef ]
Indrawan, I.; Evanirosa; Ali, R.; Indra, R.; Hanif, M.; Sumartiningsih, S. Develop model of transactional, transformational, democratic and authocratic leadership style for indonesian school performance in Education 4.0 era. Syst. Rev. Pharm. 2020 , 409–419. [ Google Scholar ] [ CrossRef ]
Sudaryono; Lutfiani, N.; Suseno; Aini, Q. Empirical study of research performance leading to education 4.0 using the ilearning method. Int. J. Adv. Trends Comp. Sc. Eng. 2019 , 8 , 264–268. [ Google Scholar ]
Ramírez-Montoya, M.; Loaiza-Aguirre, M.; Zúñiga-Ojeda, A.; Portuguez-Castro, M. Characterization of the Teaching Profile within the Framework of Education 4.0. Future Internet 2021 , 13 , 91. [ Google Scholar ] [ CrossRef ]
Ishak, R.; Mansor, M. The Relationship between Knowledge Management and Organizational Learning with Academic Staff Readiness for Education 4.0. Eurasian J. Educ. Res. 2020 , 20 , 169–184. [ Google Scholar ] [ CrossRef ]
Adnan, A.H.M.; Shak, M.S.Y.; Karim, R.A.; Tahir, M.H.M.; Shah, D.S.M. 360-Degree Videos, VR Experiences and the Application of Education 4.0 Technologies in Malaysia for Exposure and Immersion. Adv. Sci. Technol. Eng. Syst. J. 2020 , 5 , 373–381. [ Google Scholar ] [ CrossRef ][ Green Version ]
Alvarez-Cedillo, J.; Aguilar-Fernandez, M.; Sandoval-Gomez, R.J.; Alvarez-Sanchez, T. Actions to be taken in Mexico towards education 4.0 and society 5.0. Int. J. Eval. Res. Educ. 2019 , 8 , 693–698. [ Google Scholar ]
Bonfield, C.A.; Salter, M.; Longmuir, A.; Benson, M.; Adachi, C. Transformation or evolution?: Education 4.0, teaching and learning in the digital age. High. Educ. Pedagog. 2020 , 5 , 223–246. [ Google Scholar ] [ CrossRef ]
Anito, J.C., Jr.; Morales, M.P.E. The Pedagogical Model of Philippine STEAM Education: Drawing Implications for the Reengineering of Philippine STEAM Learning Ecosystem. Univers. J. Educ. Res. 2019 , 7 , 2662–2669. [ Google Scholar ] [ CrossRef ]
Koul, S.; Nayar, B. The holistic learning educational ecosystem: A classroom 4.0 perspective. High. Educ. Q. 2021 , 75 , 98–112. [ Google Scholar ] [ CrossRef ]
Wilk, M.; Rommel, S.; Liauw, M.A.; Schinke, B.; Zanthoff, H. Bildung 4.0: Herausforderungen für die Aus- und Fortbildung. Chem. Ing. Tech. 2020 , 92 , 983–992. [ Google Scholar ] [ CrossRef ]
Volchenkova, K.N. Flipped Classroom for Doctoral Students: Evaluating the Effectivness. Vyss. Obraz. V Ross. High. Educ. Russ. 2019 , 28 , 94–103. [ Google Scholar ] [ CrossRef ]
Goh, P.S.-C.; Abdul-Wahab, N. Paradigms to Drive Higher Education 4.0. Int. J. Learn. Teach. Educ. Res. 2020 , 19 , 159–171. [ Google Scholar ] [ CrossRef ]
Mogoş, R.; Bodea, C. Recommender systems for engineering education. Rev. Roum. Sci. Tech. Ser. Electrotech. Energetique 2019 , 64 , 435–442. [ Google Scholar ]
Alakrash, H.; Razak, N.A.; Krish, P. Social network sites in learning english; an invstigation on attitudes, digital literacy and usage. Linguist. Antverp. 2021 , 2021 , 26–43. [ Google Scholar ]
Connolly, C.; Hall, T.; Ryan, M.; McMahon, J.; McGann, M.; Egan, A. A fusion of research-informed teaching and teaching-informed research: Designing a scalable online ecosystem for new partnerships in educational research. Australas. J. Educ. Technol. 2020 , 37 , 82–95. [ Google Scholar ] [ CrossRef ]
Puerari, E.; De Koning, J.I.J.C.; Von Wirth, T.; Karré, P.M.; Mulder, I.J.; Loorbach, D.A. Co-Creation Dynamics in Urban Living Labs. Sustainability 2018 , 10 , 1893. [ Google Scholar ] [ CrossRef ][ Green Version ]
Voytenko, Y.; McCormick, K.; Evans, J.; Schliwa, G. Urban living labs for sustainability and low carbon cities in Europe: Towards a research agenda. J. Clean. Prod. 2016 , 123 , 45–54. [ Google Scholar ] [ CrossRef ][ Green Version ]
Selamat, A.; Alias, R.A.; Hikmi, S.N.; Puteh, M.; Tapsi, S.M. Higher Education 4.0: Current status and readiness in meeting the fourth industrial revolution challenges. Redes. High. Educ. Ind. 2017 , 4 , 23–24. [ Google Scholar ]
Fitsilis, P.; Tsoutsa, P.; Gerogiannis, V. Industry 4.0: Required personnel competencies. Industry 2018 , 3 , 130–133. [ Google Scholar ]
Miranda, J.; Chavarría-Barrientos, D.; Macías, M.; Molina, M.; Ponce, P.; Molina, A.; Wright, P.K. Experiences in interactive collaborative learning using an open innovation laboratory: The design methodologies course as case study. In Proceedings of the 2017 International Conference on Engineering, Technology and Innovation (ICE/ITMC), Madeira, Portugal, 27–29 June 2017; pp. 1235–1242. [ Google Scholar ]
Tecnológico de Monterrey. Historia del Modelo Educativo del Tec de Monterrey. 2019. Available online: https://tec.mx/es/nosotros/nuestra-historia (accessed on 26 March 2021).
Ponce, P.; Polasko, K.; Molina, A. Open innovation laboratory in electrical energy education based on the knowledge economy. Int. J. Electr. Eng. Educ. 2019 , 0020720919829711. [ Google Scholar ] [ CrossRef ]
Miranda, J.; Rosas-Fernandez, J.B.; Molina, A. Achieving Innovation and Entrepreneurship by Applying Education 4.0 and Open Innovation. In Proceedings of the 2020 IEEE International Conference on Engineering, Technology and Innovation (ICE/ITMC), Cardiff, UK, 15–17 June 2020; pp. 1–6. [ Google Scholar ]
Tecnológico de Monterrey. Modelo TEC21. 2019. Available online: https://tec.mx/es/noticias/nacional/educacion/el-tec-transforma-su-modelo-educativo-sera-mas-flexible-y-vivencial (accessed on 26 March 2021).
Tecnológico de Monterrey. BSc Mechanical Engineering. 2020. Available online: https://tec.mx/es/innovacion-y-transformacion/ingeniero-mecanico (accessed on 18 February 2021).
Stake, R.E. Multiple Case Study Analysis ; Guilford Press: New York, NY, USA, 2013. [ Google Scholar ]
Frantzeskaki, N.; Broto, V.C.; Coenen, L.; Loorbach, D. The dynamics and opportunities of sustainability transitions in cities. In Urban Sustainability Transitions ; Routledge: England, UK, 2017. [ Google Scholar ]
Tecnológico de Monterrey. Formula SAE. 2019. Available online: https://www.fsaeonline.com/…/gen/DownloadDocument.aspx (accessed on 28 October 2019).
Seward, D. Race Car Design ; Metzler, J.B., Ed.; Springer: Berlin/Heidelberg, Germany, 2014. [ Google Scholar ]
Tecnológico de Monterrey. Reglamento de Campeonato 2016. 2019. Available online: https://www.electraton.com/wp-content/uploads/2017/10/REGLAMENTO-2016.pdf (accessed on 1 October 2019).
MacPherson and Pseudo MacPherson Suspension. Available online: http://www.car-engineer.com/mac-pherson-and-pseudo-mac-pherson-suspension/ (accessed on 3 December 2019).
Double Wishbone Suspension. Available online: https://www.wikiwand.com/en/Double_wishbone_suspension (accessed on 3 December 2019).
Yin, R.K. Case Study Research , 4th ed.; Sage: Thousand Oaks, CA, USA, 2009. [ Google Scholar ]
Figure 1. TEC21 Model.
Figure 1. TEC21 Model.
Figure 2. Relationship between the TEC21 Model and the team project.
Figure 2. Relationship between the TEC21 Model and the team project.
Figure 3. Organization Chart of the “Borregos Team”.
Figure 3. Organization Chart of the “Borregos Team”.
Figure 4. New Organization Chart.
Figure 4. New Organization Chart.
Figure 5. Suspension System.
Figure 6. Minimum Dimensions of the “Electraton”.
Figure 6. Minimum Dimensions of the “Electraton”.
Figure 7. MacPherson and Doble Wishbone Suspensions, adapted from [ 39 , 40 ].
Figure 7. MacPherson and Doble Wishbone Suspensions, adapted from [ 39 , 40 ].
Figure 8. Mass distribution throughout the vehicle, adapted from [ 37 ].
Figure 8. Mass distribution throughout the vehicle, adapted from [ 37 ].
Figure 9. Longitudinal load transfer and lateral load transfer [ 37 ].
Figure 9. Longitudinal load transfer and lateral load transfer [ 37 ].
Figure 10. 2D Scheme of Suspension System.
Figure 10. 2D Scheme of Suspension System.
Figure 11. Lower arm suspension CAD.
Figure 12. Upper arm suspension CAD.
Figure 12. Upper arm suspension CAD.
Figure 13. Suspension rocker CAD.
Figure 13. Suspension rocker CAD.
Figure 14. Lower arm and suspension rocker FEM analyses.
Figure 14. Lower arm and suspension rocker FEM analyses.
Figure 15. Final assembly CAD.
Figure 15. Final assembly CAD.
Figure 16. Rocker 3D print process.
Figure 16. Rocker 3D print process.
Figure 17. Extensive metric gauges and compression test.
Figure 17. Extensive metric gauges and compression test.
Figure 18. Final assembly.
Figure 18. Final assembly.
Figure 19. 2D Schematic.
Figure 19. 2D Schematic.
Figure 20. FSAE lower and upper arm.
Figure 20. FSAE lower and upper arm.
Figure 21. FEM analysis.
Figure 21. FEM analysis.
Figure 22. Final CAD assembly.
Figure 22. Final CAD assembly.
Figure 23. Short, Medium, and Long Term Developments.
Figure 23. Short, Medium, and Long Term Developments.
Table 1. Final Distribution.
Table 1. Final Distribution.
Item Mass (Kg) Horiz. Distance from x (mm) Vert. Distance, Ground (mm) Front-wheel assembly 25 0 203.2 Pedal box 5 0 152.4 Steering gear 5 75 120 Engine 32 1150 250 Pilot 70 800 280 Controls 3 200 200 Battery 5 920 152.4 Body 15 870 260 Structural weight 0 0 0 Fuel tank 25 1020 200 Exhauts 5 1250 160 Drive shaft + Differential 25 1350 203.2 Front wing 5 −300 90 Rear wing 5 1450 350 225 TOTAL
Table 2. Center of Mass Position.
Table 2. Center of Mass Position.
Combined Mass (Mm) 225 Kg Horizontal distance (lm) 811.8888889 mm Vertical distance (hm) 232.817778 mm
Table 3. Front and rear vehicle weight distribution.
Table 3. Front and rear vehicle weight distribution.
Wf 882.9 N Wr 1324.35 N
Table 4. Braking and longitudinal load transfer.
Table 4. Braking and longitudinal load transfer.
Table 5. Longitudinal weight transfer in braking.
Table 5. Longitudinal weight transfer in braking.
FB 3310.875 N hm 232.8177 mm L 1353.6571 mm ΔWx (longitudinal weight transfer) 569.6571 mm WF(FB) Front brake load 1452.55 N WF(FB) Rear brake load 754.69 N
Table 6. Cornering and total lateral load transfer.
Table 6. Cornering and total lateral load transfer.
W (Vehicle weight) 2207.25 N µ (Coefficient of friction) 1.5 T (Track definition) 1200 mm Fco (Maximum cornering force) 3310.875 N ΔWy (Total lateral weight transfer) 642.3588 N
Table 7. Dynamic vertical loads.
Table 7. Dynamic vertical loads.
W (Vehicle wight) 2207.25 N Dynamic factor 3 DownForce factor 0.3 Security factor 1.3 Design vertical load 7482.578 N
Table 8. Dynamic braking force.
Table 8. Dynamic braking force.
FB (Dynamic) 8979.093 N ΔWx (Longitudinal dynamic weight transfer)) 2544.91 N Front-wheel loads 4537.941 N Rear-wheel loads 2944.636 N
Table 9. Maximum cornering.
Table 9. Maximum cornering.
Design vertical load 7482.578 N Fcor (Maximum cornering force) 8979.093 N ΔWy (Lateral dynamic weight transfer) 1742.077 N
Table 10. Suspension Solutions, Formal Design Requirements.
Table 10. Suspension Solutions, Formal Design Requirements.
Parameter Description Requirement of Units Size(Wheelbase) 62 inch—1.57 m Production Cost USD 2000 (Subject to change) Tire Adjustment Capacity Camber and Track Shock absorber mounting location Multiple Locations Minimum Chassis Height 1 inch/25.4 mm Suspension Movement No more than 2 inch—50.8 mm Security Factor 1.5 Manufacturing Method CNC/Welding Assembly Method Standard Tool
Table 11. Emic topics associated with the TEC21 Model, Education 4.0, and the EV Case Study.
Table 11. Emic topics associated with the TEC21 Model, Education 4.0, and the EV Case Study.
TEC21 Educational Model Education 4.0 Scudería Case Emic Topics Disciplinary competencies (emphasize the knowledge, attitudes, values, and skills necessary for professional practice) Competitive professionals capable of applying innovative solutions to current and future societal challenges. Achievement of exit competencies in learners. Static Equilibrium Analysis, Engineering Modeling—Dynamic Systems, Fundamentals of Materials Engineering, Analysis and Prevention of Failures, Manufacturing Engineering, Control Systems Engineering Avant-guard disciplinary knowledge to train competent professionals Transversal competencies (training experiences in entrepreneurship, leadership, innovation, linking academia and the productive sector) Develop attractive projects for students through the implementation of challenges to develop new skills, competencies, and knowledge Analysis and resolution of different situations that arise in the project use technologies to adapt and innovate in an environment of constant change, such as Industry 4.0. Competencies: Self-knowledge and management, reasoning to face complexity, communication, digital transformation. Transversal knowledge linked to problems to train competent professionals committed to society Challenging experiences (flexibility, problematic, search for creative solutions) New teaching and learning methods using innovative facilities with emerging technologies, whose function is to prepare students to face the future problems of the industry The project team consisted of academic Engineering disciplines, Economics, Marketing, Industrial design, Logistics: branches contemplated by the Industrial Engineer, obtaining new skills and technical expertise to develop each system comprising the vehicle. Challenging situations to encourage creativity and new possibilities Innovative spaces (multidisciplinary and collaborative work among students, using the libraries, the Learning Commons, the InnovAction Gym, labs, and various Active Learning classrooms). Innovation in current learning tools in universities uses current digital tools or ICTs that have been generated; real learning scenarios through projects and living laboratories developed for such purposes. Mechanical Engineering Laboratory, transformed into a “Living Laboratory”, where students/members can research, create prototypes, validate them, and refine solutions in multiple and changing real-life contexts. New spaces and emerging technologies for learning and creative collaboration. Liaison with the public and private sectors A new generation of highly competitive professionals capable of applying suitable physical and digital resources to propose innovative solutions to current and future societal challenges New solutions and innovations aligned with the latest industry trends. Open innovation for co-creation to impact government, social, business, and academic sectors
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
AMA Style
López HA, Ponce P, Molina A, Ramírez-Montoya MS, Lopez-Caudana E. Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System. Sustainability. 2021; 13(11):5768.
https://doi.org/10.3390/su13115768
Chicago/Turabian Style
López, Hugo A, Pedro Ponce, Arturo Molina, María Soledad Ramírez-Montoya, and Edgar Lopez-Caudana. 2021. "Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System" Sustainability13, no. 11: 5768.
https://doi.org/10.3390/su13115768
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here .
Article Metrics
MDPI and ACS Style
López, H.A.; Ponce, P.; Molina, A.; Ramírez-Montoya, M.S.; Lopez-Caudana, E. Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System. Sustainability 2021, 13, 5768.
https://doi.org/10.3390/su13115768
AMA Style
López HA, Ponce P, Molina A, Ramírez-Montoya MS, Lopez-Caudana E. Design Framework Based on TEC21 Educational Model and Education 4.0 Implemented in a Capstone Project: A Case Study of an Electric Vehicle Suspension System. Sustainability. 2021; 13(11):5768.
https://doi.org/10.3390/su13115768
Chicago/Turabian Style
| https://www.mdpi.com/2071-1050/13/11/5768/xml |
Development of Haptic Systems | Request PDF
Request PDF | Development of Haptic Systems | This chapter deals with the general design processes for the development of task-specific haptic systems. Based on known mechatronic development... | Find, read and cite all the research you need on ResearchGate
Development of Haptic Systems
September 2014
DOI: 10.1007/978-1-4471-6518-7_4
In book: Engineering Haptic Devices (pp.125-141)
Authors:
Christian Hatzfeld
Technische Universität Darmstadt
Thorsten Alexander Kern
Technische Universität Hamburg
Abstract
This chapter deals with the general design processes for the development of task-specific haptic systems. Based on known mechatronic development processes such as the V-model, a specialized variant for haptic systems is presented that incorporates a strong focus on the intended interaction and the resulting impacts on the development process. Based on this model, a recommended order of technical decisions in the design process is derived. General design goals of haptic systems are introduced in this chapter as well. These include stability, haptic quality, and usability that have to be incorporated in several stages of the design process. A brief introduction to different forms of technical descriptions for electromechanical systems, control structures, and kinematics is also included in this chapter to provide a common basis for the second part of the book.
Experimentelle Analyse der menschlichen Kraftwahrnehmung als ingenieurtechnische Entwurfsgrundlage für haptische Systeme
Thesis
Full-text available
Jan 2013
Christian Hatzfeld
Subject of this work is to determine the characteristics of human force perceptionand the application of the results on the design methodology of haptic systems. It is
motivated by the insufficient development basis for the design of haptic systems, especially for minimal invasive surgery and invasive cardiac diagnostics. It contributes
to project WE2308/7-1 funded by Deutsche Forschungsgemeinschaft (DFG).
The work includes an analysis of the state of art and actual research of haptic perception
with a focus on the development of haptic systems. In addition to the biological
basis of mechanoreceptors and the representation of perceptual characteristics in
psychophysics, the interactive character of haptics and the ergonomic aspects of that
interaction are addressed. Typical applications haptic systems and the associated development process are the basis for the derivation of the research focus of this work.
It includes the determination of absolute and differential perception threshold for
vibrotactile forces as well as the quantitative analysis of external factors influencing
the perception threshold. The novel approach of this work is the definition of the test
stimuli as a force over time in comparison to the definition as a kinematic quantity,
which is the current state of the art for determining haptic perception parameters.
To determine force perception characteristics a test bench is designed. It consists of
a controlled electrodynamic force source and sensors for determining displacement
and velocity. Forces up to 5N at frequencies up to 1000 Hz with a minimal displacement
of 200μm at all frequencies can be rendered by the source. The dynamic
effects of the setup are modeled on the basis of concentrated network elements,
based on this model, the dynamic effects are analyzed and compensated for the
measurement. The analysis of the inherent error of the measuring setup calculates
a maximum error of 5% that occurs at the minimal mechanical impedance of the
user. To measure perception thresholds, classic and adaptive psychometric procedures
are analyzed. This is done by a Monte Carlo simulation of three Adaptive Staircase
Methods with different progression rules (2down-1up, 1up-3down, and KE S T E Napproximation), the ML-Test method by Harvey et al., the PEST method by
Taylor and Creelman and the \Psi method by Kontsevich and Tyler. 2- and
3-Alternative-Forced-Choice paradigms (xAFC) and a yes/no paradigm are examined.
The review is based on the indicators of accuracy, efficiency and robustness of the
methods obtained from the simulation. A 1up-2down-Staircase Method with a 3AFC
paradigm is chosen for the experiment. With the measuring setup and the selected measurement procedures, absolute perception thresholds for vibrotactile forces on the fingertip are calculated. 9 frequencies in the range of 5. . . 1000 Hz are investigated. The lowest perception threshold is measured with a force amplitude of 0.5mN at a frequency of 160 Hz. Furthermore differential perception thresholds for three different reference stimuli - near the absolute threshold, 0.25N and 0.5N - are measured. The calculated values are between 5. . . 20 dB for larger reference stimuli , but increase to 18. . . 41 dB when the reference stimulus approaches the absolute threshold. All experiments are conducted with at least 25 test subjects.
To investigate the quantitative dependency of perception on external parameters, a
factorial experiment design is implemented. The statistical analysis of the results
confirmes a highly significant effect of frequency on the absolute and differential
perception threshold. Furthermore, age, fingertip size and fine motor activity of the
subjects are found to be significant in different extents. The experiments proof the
mechanical impedance as coupling parameter between the perception of forces and
kinematic quantities for the first time empirically.
From the results of the experiments, recommendations for the design of haptic
systems are derived and the design of a force sensor for a minimally invasive device
is presented as an example. With the the mechanical impedance as a proven coupling
parameter between the perception of forces and deflections, the concept of haptic
transparency can be expanded to an optimization criterion with respect to properties
of haptic perception.
Electrical Transducers
Chapter
Full-text available
Jan 2011
Arno Lenk
Rüdiger G. Ballas
Roland Werthschützky
Günther Pfeifer
Depending on whether electrical or magnetic quantities are associated with mechanical quantities, in Chap. 7 it has been demonstrated
that electromechanical interactions can be described by two basic types of transducers namely the electrical and magnetic
transducer. The electrostatic and piezoelectric transducer belong to the group of electrical transducers.
With the electrostatic transducer, the electromechanical coupling is provided between moving electrodes – plates or diaphragms
– of a capacitor comprising an isotropic dielectric. With the piezoelectric transducer, the coupling is provided within an
anisotropic dielectric of a solid.
Electromechanical Systems in Microtechnology and Mechatronics – Electrical, Mechanical and Acoustic Networks, their Interactions and Applications
Book
Full-text available
Jan 2011
Arno Lenk
Rüdiger G. Ballas
Roland Werthschützky
Günther Pfeifer
Electromechanical systems consisting of electrical, mechanical and acoustic subsystems
are of special importance in various technical fields, e.g. precision device engineering,
sensor and actuator technology, electroacoustics and medical engineering. Based on
a circuit-oriented representation, providing readers with a descriptive engineering
design method for these systems is the goal of this textbook. It offers an easy and fast
introduction to mechanical, acoustic, fluid, thermal and hydraulic problems through the
application of circuit-oriented basic knowledge. The network description methodology,
presented in detail, is extended to finite network elements and combined with the finite
element method (FEM): the combination of the advantages of both description methods
results in novel approaches, especially in the higher frequency range. The book offers
numerous current examples of both the design of sensors and actuators and that of direct
coupled sensor-actuator systems. The appendix provides more extensive fundamentals
for signal description, as well as a compilation of important material characteristics. The
textbook is suitable both for graduate students and for engineers working in the fields
of electrical engineering, information technology, mechatronics, microtechnology, and
mechanical and medical engineering.
The W-Model – Using Systems Engineering for Adaptronics
Article
Full-text available
Dec 2013
Roland Nattermann
Reiner Anderl
Active systems are characterized by a steadily increasing degree of structural integration of electronic components into mechanical structures. To enable a systematic development process supporting continuous improvement the so-called W-model as a new process model for the development of active system is proposed. The W-model takes into account the mutual cross- domain dependencies in adaptronic development.Following the principles of systems engineering, a system model based on the requirements is defined in the early phases of product development. The system model contains requirements, functions, components and the corresponding properties and parameters as well as their interdependencies. The resulting dependency-network is used during the discipline-specific detailed development for a control of the development process. Therefore integrated system simulations can be derived from the system model in which discipline-specific solutions are integrated and evaluated. Through interdisciplinary virtual validation and verification of partial and cross-disciplinary results during the development process, errors and inconsistencies are identified and can be corrected directly.Due to the continuous use of the system model in all development phases knowledge about dependencies between system elements, can be transferred into all disciplines.
Equivalent circuit representation of electromechanical transducers: II. Distributed-parameter systems
Article
Full-text available
Jan 1999
H.A.C. Tilmans
Distributed-parameter electromechanical transducers are examined theoretically with special regard to their dynamic electromechanical behaviour and equivalent circuits used to represent them. The circuits are developed starting from basic electromechanical transduction principles and the electrical and mechanical equations of equilibrium. Within the limits of the assumptions on boundary conditions, the theory presented is exact with no restrictions other than linearity. The link with lumped-parameter transducers, that were the subject of a previous publication will be indicated. Elementary electrostatic, electromagnetic, electrodynamic and piezoelectric transducers are used to illustrate the basic theory. Exemplary devices include a capacitive force (displacement) sensor, several types of a mechanical resonator, electromechanical filters, a piezoelectric thickness monitor and a piezoelectric acceleration sensor.
Equivalent circuit representation of electromechanical transducers: I. Lumped-parameter systems
Article
Full-text available
Jan 1999
H.A.C. Tilmans
Lumped-parameter electromechanical transducers are examined theoretically with special regard to their dynamic electromechanical behaviour and equivalent circuits used to represent them. The circuits are developed starting from basic electromechanical transduction principles and the electrical and mechanical equations of equilibrium. Within the limits of the assumptions on boundary conditions, the theory presented is exact with no restrictions other than linearity. Elementary electrostatic, electromagnetic, and electrodynamic transducers are used to illustrate the basic theory. Exemplary devices include electro-acoustic receivers (e.g., a microphone) and actuators (e.g., a loudspeaker), electromechanical filters, vibration sensors, devices employing feedback, and force and displacement sensors. This paper forms part I of a set of two papers. Part II extends the theory and deals with distributed-parameter systems.
The Handbook of Human-Machine Interaction A Human-Centered Design Approach
Book
Full-text available
Apr 2011
Guy André Boy
The Handbook of Human-Machine Interaction features 20 original chapters and a conclusion focusing on human-machine interaction (HMI) from analysis, design and evaluation perspectives. It offers a comprehensive range of principles, methods, techniques and tools to provide the reader with a clear knowledge of the current academic and industry practice and debate that define the field. The text considers physical, cognitive, social and emotional aspects and is illustrated by key application domains such as aerospace, automotive, medicine and defence. Above all, this volume is designed as a research guide that will both inform readers on the basics of human-machine interaction from academic and industrial perspectives and also provide a view ahead at the means through which human-centered designers, including engineers and human factors specialists, will attempt to design and develop human-machine systems.
Entwicklung interaktiver Systeme
Book
Jan 1999
Bernhard Preim
Mechatronic systems design. Methods, models, concepts
Article
Klaus Janschek
Mechatronic systems design. Methods, models, concepts. Translated by Kristof Richmond
Book
Jan 2012
Klaus Janschek
In this textbook, fundamental methods for model-based design of mechatronic systems are presented in a systematic, comprehensive form. The method framework presented here comprises domain-neutral methods for modeling and performance analysis: multi-domain modeling (energy/port/signal-based), simulation (ODE/DAE/hybrid systems), robust control methods, stochastic dynamic analysis, and quantitative evaluation of designs using system budgets. The model framework is composed of analytical dynamic models for important physical and technical domains of realization of mechatronic functions, such as multibody dynamics, digital information processing and electromechanical transducers. Building on the modeling concept of a technology-independent generic mechatronic transducer, concrete formulations for electrostatic, piezoelectric, electromagnetic, and electrodynamic transducers are presented. More than 50 fully worked out design examples clearly illustrate these methods and concepts and enable independent study of the material.
Numerical Solution of Mechatronic Sensors and Actuators
Book
Jan 2007
Manfred Kaltenbacher
The second edition of this book fully preserves the character of the first edition to combine the detailed physical modeling of mechatronic systems and their precise numerical simulation using the Finite Element (FE) method. Most of the text and general appearance of the previous edition were retained, while the coverage was extended and the presentation improved. In this second edition, the author enhances and improves many discussions on principles and methods. For example, he included a discussion of a priori estimates as well as a new section discussing locking effects as occurring in the numerical computation of thin mechanical structures. He also deepens the discussion of the physics of sound generation and propagation as well as includes the case of flow induced sound. A large part of the book describes the application of the developed numerical calculation schemes to industrial problems, e.g.: analysis and optimization of electrodynamic loudspeakers. In these parts, new computational methods are included, and last but not least, this new edition contains a new chapter on computational aeroacoustics to study the complex phenomenon of flow induced noise.
Application of Psychophysical Techniques to Haptic Research
Article
Jul 2013
Lynette A. Jones
Hong Z Tan
Various psychophysical methods have been used to study human haptic perception, although the selection of a particular method is often based on convention, rather than an analysis of which technique is optimal for the question being addressed. In this review, classical psychophysical techniques used to measure sensory thresholds are described as well as more modern methods such as adaptive procedures and those associated with signal detection theory. Details are provided as to how these techniques should be implemented to measure absolute and difference thresholds and factors that influence subjects' responses are noted. In addition to the methods used to measure sensory thresholds, the techniques available for measuring the perception of suprathreshold stimuli are presented. These scaling methods are reviewed in the context of the various stimulus and response biases that influence how subjects respond to stimuli. The importance of understanding the factors that influence perceptual processing is highlighted throughout the review with reference to experimental studies of haptic perception.
Geometric Fundamentals of Robotics
Book
Jan 2005
Jonathan Selig
Modeling and Control of Robot Manipu-lators
Book
Jan 1996
Lorenzo Sciavicco
Bruno Siciliano
Modelling and Control of Robot Manipulators
Article
Nov 2000
Lorenzo Sciavicco
Bruno Siciliano
This book is the second edition of a textbook published in 1996 by McGraw Hill and originates from a graduate level course given by the authors at the University of Naples. The topics include kinematics, statics and dynamics of robot manipulators together with trajectory planning and active control. There are only minor additions the first edition, which are mainly the use of quaternion to describe the orientation of the end effector and a short description of a closed chain architecture for a manipulator (parallelogram arm). The book is largely devoted to serial manipulators, with special developments about active control including adaptative control, robust controls and stability analysis. Another strength of this book is the great number of problems proposed at the end of each chapter, together with a list of references related to it. The fundamental features covered by the text are illustrated on simple examples of serial manipulators (two-link planar arm, parallelogram arm) including analytical results and numerical tests. The book has nine chapters followed by three appendices. The first appendix is devoted to linear algebra, the second recalls some fundamental aspects of rigid body mechanics and the third gives some basic principles of feedback control of linear systems. Chapter one is an introduction to the study of robot manipulators, giving an interesting classification of their architectures, the corresponding workspace and describes the tasks for which they are used. After some standard examples of industrial manipulators, bibliographical reference texts are proposed, including textbooks on modelling and control of robots, general books on robotics, specialized texts, scientific robotic reviews and some international conferences on robotics. Chapters two, three and four are devoted to mechanical modelling of robot manipulators. The fundamental basics of kinematics are given in chapter two, including the representation of finite rotations by Euler angles or unit quaternions, homogeneous transformations, Denavit-Hartenberg parameters and workspace. The direct and inverse kinematical problems are solved in analytical form for some typical manipulator structures. The differential kinematics of robots are presented in chapter three, with an introduction to the geometric and analytic Jacobian matrices, kinematic singularities and redundancy. The inverse kinematic problem is presented, with special attention to the case of redundant robots where the solution is obtained by a linear optimization problem leading to the introduction of the pseudo-inverse Jacobian matrix and to the solution of several objectives such as avoidance of collision with an obstacle or moving away from singularities. Several inverse kinematics algorithms are given wih an interesting application to a three-link planar arm. Finally, a property of kineto-statics duality is deduced from the principle of virtual work applied to an equilibrium configuration of the robot. Chapter four is a standard presentation of the derivation of the dynamical model by Lagrange formulation and then by the Newton-Euler method. In the Lagrange formulation method, the linearity with respect to inertial parameters is shown and a detailed formulation of the dynamical model is obtained for a two-link Cartesian arm, a two-link planar arm and a parallelogram arm. The problem of dynamic parameter identification is also briefly presented from a numerical point of view. The recursive algorithm constructed from the Newton-Euler formulation is presented and illustrated by considering a two-link planar arm. Finally, the operational space dynamic model is introduced. In chapter five, paths and trajectory planning in joints and in operational spaces are presented; several classical methods of interpolation are described. Chapter six is an extensive study of active control of manipulators. Several methods are presented, involving classical independent joint control, non-linear centralized control, robust control and adaptative control. Both joint-space control and operational-space control are studied together with stability analysis by using Liapounoff functions. An interesting application to the two-link planar arm already used shows the comparison between various control schemes. Chapter seven deals with interaction control of serial manipulators with the working environment. Several strategies involving compliance control, impedance control, force control and hybrid control are presented. Chapter eight describes the actuators and the sensors used in robotics. Several types of servomotors (electric and hydraulic) are presented, together with the model giving their input/output relationship. Several kinds of sensors are also described including encoders, tachometers, force and vision sensors. The last chapter gives a short presentation of the functional architecture of a robot's control system, including characteristics of the programing environment and the hardware architecture. In conclusion, the book provides a good insight about simulation and control of robot manipulators, with a detailed study of the various control strategies and several interesting and pedagogical applications. This book is an excellent review of the standard knowledge needed not only for graduate students but also for researchers interested in robot manipulators. M Pascal
Kinematics
Chapter
Jan 2008
Kenneth J. Waldron
James Schmiedeler
Kinematics pertains to the motion of bodies in arobotic mechanism without regard to the forces/torques that cause the motion.
Since robotic mechanisms are by their very essence designed for motion, kinematics is the most fundamental aspect of robot
design, analysis, control, and simulation. The robotics community has focused on efficiently applying different representations
of position and orientation and their derivatives with respect to time to solve foundational kinematics problems.
This chapter will present the most useful representations of the position and orientation of abody in space, the kinematics
of the joints most commonly found in robotic mechanisms, and aconvenient convention for representing the geometry of robotic
mechanisms. These representational tools will be applied to compute the workspace, the forward and inverse kinematics, the forward and inverse instantaneous kinematics, and the static wrench transmission of arobotic mechanism. For brevity, the focus will be on algorithms applicable to open-chain mechanisms.
The goal of this chapter is to provide the reader with general tools in tabulated form and abroader overview of algorithms
that can be applied together to solve kinematics problems pertaining to aparticular robotic mechanism.
View
Engineering Design â A systematic approach
Chapter
Jan 1995
G. Pahl Beitz
Development of NASA-TLX (Task Load Index): Results of empirical and theoretical research
Chapter
Dec 1988
Sandra G. Hart
L. E. Stavenland
The results of a multi-year research program to identify the factors associated with variations in subjective workload within and between different types of tasks are reviewed. Subjective evaluations of 10 workload-related factors were obtained from 16 different experiments. The experimental tasks included simple cognitive and manual control tasks, complex laboratory and supervisory control tasks, and aircraft simulation. Task-, behavior-, and subject-related correlates of subjective workload experiences varied as a function of difficulty manipulations within experiments, different sources of workload between experiments, and individual differences in workload definition. A multi-dimensional rating scale is proposed in which information about the magnitude and sources of six workload-related factors are combined to derive a sensitive and reliable estimate of workload.
Kombinierte Simulation-eine weitere Methode zur Optimierung elektromechanischer Systeme. Dissertation
E Starke
Numerical simulation of mechatronic sensors and actuators. In: Broad overview about finite element methods and the application to sensors and actuators
M Kaltenbacher
Recommended publications
Chapter
Full-text available
Development of Haptic Systems
November 2022
Thorsten Alexander Kern
Christian Hatzfeld
This chapter deals with the general design processes for the development of task-specific haptic systems. Based on known mechatronic development processes like the V-model, a specialized variant for haptic systems is presented, that incorporates a strong focus on the intended interaction and the resulting impacts on the development process. Based on this model, a recommended order of technical ... [Show full abstract] decisions in the design process is derived. General design goals of haptic systems are introduced in this chapter as well. These include stability, haptic quality and usability that have to be incorporated in several stages of the design process. A short introduction into different forms of technical descriptions for electromechanical systems, control structures and kinematics is also included in this chapter to provide a common basis for the second part of the book.
| https://www.researchgate.net/publication/300018330_Development_of_Haptic_Systems |
World War II Servicemen's Correspondence Collection, 1941-1945 | SDSUnbound
Jump to navigation
SDSUnbound
Scholarship. Research. Heritage.
Back to top
Main menu Browse
Contact
Search SDSU Repository
Select Collection
All SDSU collections World War II Servicemen's Correspondence Collection, 1941-1945 Annie L. Jobs Photograph Album, 1884-1887 Apprenticeship (Peer-led) Art Works Arturo Casares Papers Asa Sackman Diaries Associated Students Audiovisual Avenal State Prison Aztec Alumni News Black Manuscripts by Donna Barr Button and Pin Collection California Institution for Men California Institution for Women California New Deal Murals and Reliefs California Rehabilitation Center California State Prison, Los Angeles County Calipatria State Prison Career Papers Carmen Sandoval Fernandez Poster Collection Center for Regional Sustainability (CRS) Chicana and Chicano Community Citizens Interracial Committee City of El Centro City of La Mesa City of Lemon Grove City of National City City of San Diego City of Santee City of Tijuana Clarence “Beeb” Salzer Collection Collaborations and Partnerships Comic Arts Commencement Programs Community Multimedia Community Works Creating Community: African Americans in San Diego Curricula Department of Women's Studies Distance Learning Don Coryell Doug Moore Album: 1982 Pride and More Doug Moore Photographs El Palenque: Student Literary Magazine Evidence-Based Practice Reviews Facilitator Training Facilitator Training and Apprenticeship Curricula Gary Gulley Photograph Collection Gay Liberation Front General Catalogs Geological Sciences Senior Theses Graduate Bulletins Historical Ephemera In-person Learning Ironwood State Prison John Adams John Adams Papers John and Jane Adams Postcard Collection John and Jane Adams Trade Card Collection Jones Family Memorabilia Collection, 1962-2002 KPBS LASD Multimedia Lambda Archives Pride Banners Lambda Archives Pride T-shirt Collection Lambda Archives of San Diego Larry McCaffery Collection Lauren C. Post Papers Lionel Van Deerlin Photograph Collection Map Collection Selections Mark Freeman Normal News Weekly (1913-1917) Old Globe Theatre Photograph Collection Older Women's League (OWL) Oral Histories Collection Other Voices: Alternative Periodicals at San Diego State University Paper Lantern (1921-1925) Peoples Temple Collection (1972-1990) Personal Pride Photos from Christine Kehoe, 1970s to 1990s Prison Arts Collective Prison Arts Collective Artwork Prison Arts Collective Curricula Radical Ephemera and Underground Publications Religious Movements SDSU COVID-19 Memory Collection SDSU Course Catalogs and Bulletins SDSU Digital Humanities Collection SDSU Faculty and Staff Works SDSU Imperial Valley Bulletins SDSU Mission Valley SDSU Oaxaca Center for Mesoamerican Studies SDSU Research Foundation Grants SDSU Student Newspapers SDSU Student Symposium (S3) SDSU Student Works SDSU Syllabus Collection SDSU Theses and Dissertations Sage Project Reports San Diego Ballet San Diego Black Panther Collection San Diego History San Diego Normal School Blueprints San Diego Photograph Collection San Diego Pride Ephemera Collection San Diego Pride Guides San Diego Pride Photograph Collection San Diego Regional Water Quality Control Board San Diego State Summer Aztec (1971) San Diego State Yearbooks San Diego Symphony Orchestra Records San Diego Urban Sustainability Coalition (SDUSC) San Diego Zoo San Diego and Tijuana Pride 1977-2000 Santa Margarita Ecological Reserve School of Nursing Sheila Clark and Judy Reif at San Diego Pride Site Remediation Documents for High-Risk Dry Cleaners Teaching Resources The Aztec (1925-1927, 1938-1943, 1944-1960, 1961) The Aztec News Letter, 1942-1946 The Center at Pride, 1990s The Sage Project at SDSU The State College Aztec (1927-1938, 1943-1944) Thomas M. Davies, Jr. Papers and Lecture University Archives Collection University Archives Multimedia University Library University Works Urrutia de Vergara Family Papers, 1565-1769 Veterans Collection San Diego Veterans Oral Histories Veterans Oral History Program Walker Scott Department Store Women in Politics Women's Studies Department 50th Anniversary Oral Histories
Search box
Advanced Search
World War II Servicemen's Correspondence Collection, 1941-1945
You are here
Home ›› Browse Collections ›› University Works ››
Veterans Collection ›› World War II Servicemen's Correspondence Collection, 1941-1945
Collection Description
A collection of approximately 5,000 original letters sent by San Diego State students on active duty in the armed forces during World War II, or their families, to Professor Lauren Post who compiled and distributed the Aztec News Letter.
Immediately after Pearl Harbor and as the War progressed, Aztec students were soon scattered all over the globe, disconnected and separated from their college, their friends, their loved ones, and their former lives. In the spring of 1942, Dr. Post, professor of geography from 1937-69 and a veteran of World War I, decided to try a "news service experiment" intended to provide information about the locations of current and former Aztecs dispersed around the world. The Aztec News Letter thus became a crucial lifeline throughout the War for Aztec servicemen and women facing difficulty and danger wherever they were stationed. Lauded as one of the first of its kind in the nation, the Aztec News Letter premiered in May of 1942 and was released monthly until its 48th issue in March of 1946. By then, The Aztec News Letter circulated to more than 3,000 service and home front readers. The project and the letters that made it possible would forever characterize the Aztec spirit during wartime. Not only are the letters historically significant; they also offer a unique perspective about San Diego State during a global crisis.
Back to top Grid view List view Pages
« first ‹ previous … 12 13 14 15
16 17 18 19 20 … next › last »
Letter from Anthony A. Ghio, 1944-04 Letter from Anthony A. Ghio, 1944-06-07
Letter from Anthony A. Ghio, 1944-06-24
Letter from Anthony A. Ghio, 1944-09 Letter from Anthony A. Ghio, 1945-02 Letter from Anthony A. Ghio, 1945-08
Letter from Anthony A. Ghio, 1945-09 Letter from Anthony Long, 1942-07 Letter from Anthony Long, 1942-11
Letter from Archie B. Johnston, 1942 Letter from Archie B. Johnston, 1944
Letter from Archie B. Meihls, 1944-01
Pages
« first ‹ previous … 12 13 14 15
16 17 18 19 20 … next › last »
Bookmark
Bookmarks:
- Select bookmark list - My Default List
Limit by
Author
Abbey, Clem L. (8) + - Abbey, Ruby (1) + - Abbott, David Vincent (1) + - Abel, Ray L. (1) + - Ables, Charles N. (8) + - Ables, Mrs. charles N. (2) + - Ables, Thomas E. (1) + - Ackerman, Carl (1) + - Ackerman, Stephen W. (1) + - Adamson Thompson, Grace (1) + - Adamson, Nevin O. (1) + - Addleson, Herman H. (6) + - Addleson, Samuel (1) + - Ahler, H. james (2) + - Albrecht, Walter G. (1) + - Alcorn, Marvin D. (2) + - Alexander, Alex (3) + - Alexander, Charles S. (1) + - Alexander, George C. (1) + - Allard, Pat (1) + - Allen, Charles Daniel (4) + - Allen, Jack (1) + - Allen, Maybelle (1) + - Allen, Polly (1) + - Allison, Earl L. (9) + - Allphin, Richard L. (1) + - Allred, Phil A. (3) + - Alverson, Franklin G. (9) + - Amsden, Georgia C. (1) + - Anderson, Ervin Lee (2) + - Anderson, Jack C. (1) + - Anderson, Margaret Jean Widders (3) + - Anderson, Robert H. (11) + - Anketell, Robert H. (1) + - Anonymous Author (2) + - Armstrong, Charles B. (1) + - Arriola, Paul (2) + - Asberry, Owen F. (4) + - Askenaizer, Samuel David (1) + - Aubery, Melville W. (3) + - Ault, Armond A. (1) + - Ault, Laura Lou (1) + - Austin, Robert A. (1) + - Avoyer, Joseph (1) + - Ayars, Charles O. (1) + - Babick, John D. (6) + - Bachrach, Herbert R. (1) + - Bahl, Jack (9) + - Bailey, Jesse E. (2) + - Bailey, Mrs. ralph R. (1) + - Bailey, Ralph R. (4) + - Bainbridge, Moira V. (1) + - Baker, Harold B. (2) + - Baker, Mary J. (1) + - Baker, Mrs. h.E. (1) + - Baldwin, William E. (1) + - Ball, Orville P. (1) + - Ball, Richard S. (2) + - Ballam, Ted (3) + - Ballinger, Mrs. john (1) + - Ballou, James K. (1) + - Bankerd, Lincoln E. (1) + - Barbarick, Harding (1) + - Barbour, Willard C. (2) + - Barker, Alice (2) + - Barker, Edwin F., Jr. (2) + - Barker, Zachariah Allen (2) + - Barkley, Richard M. (1) + - Barley, Donald L. (1) + - Barnet, Harry N. (4) + - Barnhart, Donald S. (1) + - Barnhart, Kenneth E., Jr. (1) + - Barr, Mrs. e.S. (1) + - Barth, Pat Powers (1) + - Barth, Robert (7) + - Bascom, Marilyn (1) + - Basinger, Margaret (1) + - Bate, Mabel Rule (1) + - Bate, Richard L. (2) + - Batterton, R.V. (1) + - Bauder, Bob G. (4) + - Bauder, Leila Maude (4) + - Bauder, Louise M. (1) + - Bauder, Mrs. frank G. (1) + - Bean, Mrs. walter (1) + - Bean, Walter C. (3) + - Beck, James W. (1) + - Beck, John (1) + - Becker, Jack (2) + - Beckman, Bob (1) + - Bell, Audrey C. (1) + - Bell, Harlow (1) + - Bell, Jasper N. (1) + - Bell, Leonard T. (1) + - Benchley, Belle J. (2) + - Benner, Audree (4) + - Benner, Bob (1) + - Bennett, Dolores (1) + - Bennett, Edwin F. (3) + - Benson, Frederick A. (4) + - Benson, Jack (1) + - Berdel, Clair Vincent (1) + - Berg, Andrew H. (4) + - Berg, Donald M. (3) + - Berg, Jack (1) + - Berglund, Mrs. john (1) + - Bergman, George (4) + - Berliner, Jack W. (1) + - Berman, Ralph R. (4) + - Berman, Richard S. (1) + - Berman, Robert J. (1) + - Best, Shelby (3) + - Bethard, Mrs. f.D. (1) + - Bethard, William F. (2) + - Betts, Bert A., Jr. (1) + - Betts, Harry E. (3) + - Beyer, Carlton M. (1) + - Bickham, Mrs. noel O. (1) + - Bickham, Noel O. (4) + - Biery, Jack F. (2) + - Biery, Jean Franck (1) + - Bill (1) + - Billon, Jessie Winrow (1) + - Billon, John Peterson (6) + - Binder, H.A. (1) + - Binkley, John Burdette (3) + - Binkley, John P. (4) + - Binkley, Mrs. john P. (1) + - Binswanger, Max (2) + - Bishop, Mrs. a.L., Sr. (1) + - Black, Gay Dill (3) + - Black, Ralph J. (1) + - Blackburn, Charles A. (4) + - Blackstock, Mary Ann (1) + - Blanchard, Horace Jerry (4) + - Blethen, James H. (2) + - Blossom, Herbert H. (1) + - Blossom, Reba D. (1) + - Boaz, John K. (1) + - Boaz, Royce F. (2) + - Bock, Frances Marjorie Baecht (1) + - Bock, William Zentner (3) + - Bofinger, Andrew H. (1) + - | https://digitallibrary.sdsu.edu/islandora/object/sdsu:WWIIServiceLetters?f%5B0%5D=-mods_subject_geographic_ms%3A%22Austin%E2%80%93Bergstrom%5C%20International%5C%20Airport%5C%20%5C%28Texas%5C%29%22&f%5B1%5D=-mods_subject_hierarchicalGeographic_area_ms%3A%22Europe%5C%20%5C-%5C-%5C%20United%5C%20Kingdom%5C%20%5C-%5C-%5C%20England%5C%20%5C-%5C-%5C%20London%5C%20%5C-%5C-%5C%20Teddington%5C%20%5C-%5C-%5C%2092%5C%20Sandy%5C%20Lane%22&f%5B2%5D=-mods_originInfo_dateIssued_ms%3A%221943%5C-01%5C-28%22&page=15 |
Biology | Free Full-Text | Delivery of the 5-HT2A Receptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury
Traumatic spinal cord injury (SCI) interrupts spinobulbospinal micturition reflex pathways and results in urinary dysfunction. Over time, an involuntary bladder reflex is established due to the reorganization of spinal circuitry. Previous studies show that manipulation of serotonin 2A (5-HT2A) receptors affects recovered bladder function, but it remains unclear if this receptor regulates the activity of the external urethral sphincter (EUS) following SCI. To elucidate how central and peripheral serotonergic machinery acts on the lower urinary tract (LUT) system, we employed bladder cystometry and EUS electromyography recordings combined with intravenous or intrathecal pharmacological interventions of 5-HT2A receptors in female SCI rats. Three to four weeks after a T10 spinal transection, systemic and central blockage of 5-HT2A receptors with MDL only slightly influenced the micturition reflex. However, delivery of the 5-HT2A receptor agonist, DOI, increased EUS tonic activity and elicited bursting during voiding. Additionally, subcutaneous administration of DOI verified the enhancement of continence and voiding capability during spontaneous micturition in metabolic cage assays. Although spinal 5HT2A receptors may not be actively involved in the recovered micturition reflex, stimulating this receptor subtype enhances EUS function and the synergistic activity between the detrusor and sphincter to improve the micturition reflex in rats with SCI.
Line Spacing:
Column Width:
Background:
Delivery of the 5-HT 2A Receptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury
by Jaclyn H. DeFinis , Jeremy Weinberger and Shaoping Hou *
Marion Murray Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
Author to whom correspondence should be addressed.
Biology 2021 , 10 (1), 68; https://doi.org/10.3390/biology10010068
Received: 12 December 2020 / Revised: 10 January 2021 / Accepted: 15 January 2021 / Published: 19 January 2021
(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI) )
Simple Summary
2A
2A
2A
2A
Keywords:
micturition
external urethral sphincter
spinal cord injury
serotonin
electromyogram
1. Introduction
The lower urinary tract (LUT) has two main functions, the storage and periodic elimination of urine. These two processes are dependent upon coordinated activity between the smooth muscle of the bladder detrusor and the striated external urethral sphincter (EUS). In normal conditions, this synergy is accomplished through a complex neural control system involving multiple neurotransmitters and neuropeptides at the brain, spinal cord, and peripheral levels. Among the many neuromodulators of micturition, serotonin (5-hydroxytrpytamine, 5-HT) has gained significant attention over the years as numerous anatomical [ 1 , 2 , 3 ] and pharmacological investigations [ 4 , 5 ] provide important evidence of 5-HT in the central pathways controlling bladder function [ 6 ]. Supraspinal serotonergic pathways mainly originate from the caudal raphe nuclei within the brainstem [ 7 ] and distribute terminals to sensory, motor, and autonomic regions of the spinal cord [ 8 ]. Additionally, previous studies have demonstrated that 5-HT 2A receptors are expressed in the lower spinal cord [ 9 ], suggesting that these receptors have a modulatory role in pelvic visceral function.
Traumatic spinal cord injury (SCI) often interrupts spinobulbospinal micturition reflex pathways and results in LUT dysfunction. Following SCI, the bladder is initially areflexic but then partially recovers over time due to the reestablishment of an involuntary spinal micturition reflex pathway [ 10 ]. However, this partial recovery entails the emergence of detrusor-sphincter dyssynergia (DSD) and bladder hyperreflexia (or overactivity) which causes inefficient voiding and incontinence. Additionally, a large volume of residual urine remains in the bladder which increases the risk of infection and even life-threatening renal failure [ 11 ]. The most common treatments used to empty the bladder or treat overactivity are intermittent catheterization [ 12 ], antimuscarinic medications [ 13 ], and the neuromuscular blocker onabotulinumtoxin A (BTX-A) [ 14 , 15 ]. However, some treatment strategies have been met with serious health complications. Intermittent catheterization often leads to recurrent urinary tract infections and re-hospitalization, and antimuscarinic medications can have varying effects, such as tachycardia and impairment in cognition depending on what muscarinic receptor they are acting upon [ 11 , 16 ]. Additionally, patients who have undergone BTX-A injections have reported minor side effects, including urinary retention, urinary tract infection, and hematuria [ 17 ]. Therefore, limited effective treatment options are available to SCI individuals who suffer from lower urinary tract dysfunction.
18
19
20
2A
21
2A
22
2A
23
24
2A
7
25
2A
2. Materials and Methods
2.1. Animals
A total of 23 female adult Wistar rats (weigh 200–250 g, Charles River, Wilmington, MA, USA) were used. Animals were housed in sets of three per cage to provide social enrichment. Rats with a spinal cord transection (n = 7) were employed for metabolic cages. Some of these rats (n = 6, one suffered a leg injury after testing so it was excluded from subsequent experiments) were later used, together with other SCI rats (n = 6), for micturition reflex assays. Naïve rats (n = 10) were used to collect spinal cord tissue for molecular analyses. Institutional Animal Care and Use Committee and National Institute of Health guidelines on animal care were strictly followed to minimize the number of animals used and any potential suffering. Humane consideration for the well-being of animals was incorporated into the experimental design and conduct. All experimental procedures were reviewed by a local animal care committee to ensure compliance (Project identification code: 1045137).
2.2. Spinal Cord Surgery
Rats underwent a complete spinal cord transection at the 10th thoracic level (T10) to remove supraspinal control of micturition. Animals were anesthetized with 2% isoflurane and a partial laminectomy was performed at the T8 vertebrae to expose the dorsal spinal cord. The spinal cord was completely transected at T10 using a No. 11 blade. Lesion completeness was verified visually at the time of surgery. Overlying musculature and skin were then closed. Animals were administered Lactated Ringer’s solution (Baxter Healthcare, Deerfield, IL, USA), cefazolin (10 mg/kg), and buprenex (0.1 mg/kg; Reckitt Benckiser, Slough, United Kingdom) post-operatively. Bladders were manually expressed at least three times per day until sacrifice.
2.3. Metabolic Cages
2A
t
2.4. Bladder Cystometry and EUS Electromyography (EMG) Recordings
26
27
28
2.5. Drugs
2A
R
Table 1
Table 2
22
Table 1. Normalized parameters of bladder cystometry and EUS EMG activity in SCI rats ( i.v. administration).
Table 2. Normalized parameters of bladder cystometry and EUS EMG activity in SCI rats ( i.t. administration).
2.6. Fresh Tissue Harvesting and Protein Isolation
Anesthetized rats were perfused with HEPES buffer and approximately 0.5 cm spinal cord segments at T4/5 above the injury as well as L1/2 and L6/S1 below the injury, where neurons control the LUT, were extracted from naïve (n = 4) and SCI rats (n = 8). Sections were immediately frozen in dry ice and stored in −80 °C. Spinal cords were homogenized in 1 ml of RIPA buffer with Pierce™ protease and phosphatase inhibitors (1 tablet/10 mL RIPA buffer, Thermo Scientific, Waltham, MA, USA). The homogenized spinal cords were centrifuged at 4700 rpm for 90 s, and supernatants were obtained and stored at −80 °C. Following homogenization, standard protein concentrations were established with a Bradford protein assay, and plates were read on an Infinite ® 200 Pro microplate reader (Tecan, Männerdorf, Switzerland) at 595 nm using the i-control software package.
2.7. Western Blot
®
®
2A
t
p
2.8. RNA Extraction/Quantitative Real-Time PCR
2A
t
p
2.9. Statistical Analyses
Statistical analyses were performed in GraphPad Prism 8 (GraphPad Software, San Deigo, CA, USA). Significance throughout all experiments was set at p < 0.05. Data are represented as mean ± SEM. All groups (intact vs. SCI) and drugs (saline, MDL, DOI) were kept blind to the observer as to avoid biases during molecular and urodynamic analyses. Detailed analyses are listed separately under each experiment described above.
3. Results
3.1. 5-HT 2A Protein and Gene Expression Is Sustained in the Spinal Cord Following SCI
2A
p
t
Figure 1
2A
p
Figure 1
2A
Figure 1. Spinal 5-HT 2A receptor expression remains unchanged after SCI. ( A ), Western blots show that there is no difference between naïve and SCI rats in terms of protein expression levels of the 5-HT 2A receptor above (T4/5) and below the level of injury (L1/2, L6/S1) (Student’s t -test, all p > 0.05). ( B , C ), Quantitative PCR analysis reveals that mRNA levels of this receptor were not altered at any of the aforementioned segments in SCI rats (all p > 0.05). GAPDH served as a control.
3.2. I.v. Drug Delivery and its Effects on Bladder and EUS Reflexes
2A
Table 1
p
2A
p
p
p
p
Figure 2
Figure 2
2A
Figure 2. Intravenous (i.v.) administration of DOI to stimulate 5-HT 2A receptors improves the micturition reflex during bladder cystometry and sphincter EMG in SCI rats. ( A ), Stimulating 5-HT 2A receptors with the middle dose of DOI (20 µg/kg) prolongs the VI ( p < 0.05, Friedman’s test followed by Dunn’s) between voiding contractions (asterisks). The high dose of DOI (0.1 mg/kg) increases EUS tonic activity in the filling phase ( p < 0.01). Ensuing injection of MDL (0.1 mg/kg) eliminates the provoked effects. ( B ), Representative traces show no EUS bursting activity during voiding when saline is delivered. However, the middle dose of DOI triggers EUS bursting activity during voiding. Injection of MDL following the high dose of DOI masks the triggered bursting EUS activity during voiding.
3.3. I.t. Drug Delivery and Its Effects on Bladder and EUS Reflexes
2A
Table 2
2A
p
p
Figure 3
Figure 4
2A
Figure 3. Intrathecal (i.t.) administration of DOI to stimulate 5-HT 2A receptors affects the micturition reflex during bladder cystometry and sphincter EMG in SCI rats. ( A ), Representative tracers show that stimulating 5-HT 2A receptors with the middle (2 µg/kg) and high (10 µg/kg) doses of DOI prolongs the VI (both p < 0.05, Friedman’s test followed by Dunn’s) between voiding contractions (asterisks) and induces an increase in EUS tonic activity. ( B ), Importantly, the middle dose of DOI increases the duration of EUS bursting that consists of more regularly occurring active and silent periods along with bladder HFO, indicating an enhancement of detrusor-sphincter coordination during voiding.
Figure 4. Intrathecal (i.t.) administration of MDL abolishes DOI induced excitatory effects on the EUS reflex in SCI rats. A representative cystometry and EMG trace demonstrates that MDL, a 5-HT 2A receptor antagonist (10 µg/kg), shortens the VI ( p < 0.05, Friedman’s test followed by Dunn’s) ( A ) and masks bursting EUS activity ( B ), leading to the occurrence of detrusor-sphincter dyssynergia.
3.4. S.c. Delivery of DOI Improves Spontaneous Micturition Performance Following SCI
t
p
p
p
Figure 5
p
Figure 5. Stimulating 5-HT 2A receptors with DOI delivery improves spontaneous micturition function in SCI rats. Representative traces show volume-frequency patterns of urination in metabolic cage assays after 5-HT 2A receptor stimulation with DOI within a 6-h time period. Saline injections served as a control. In each “step-like” curve of these traces ( A ), the vertical lines represent the VV per void and the horizontal lines illustrate the VI. After s.c. injection of the 5-HT 2A receptor agonist DOI (60 µg/kg, 300 µL), ( B ) there was a significant increase in the VV per void and VI in comparison to saline controls (Paired t -test, all * p < 0.05).
4. Discussion
2A
2A
18
2A
2A
Serotonergic regulation of LUT function has been explored since the 1960s when dense supraspinal 5-HT innervation to autonomic nuclei was observed in the lower spinal cord [ 29 , 30 ], including the dorsal horn and Onuf’s nucleus which contains the motoneurons that control EUS function [ 7 , 31 ]. Although SCI interrupts descending neuronal pathways, previous studies have demonstrated the ability of the injured spinal cord to produce monoamines, such as serotonin, caudal to the level of injury [ 20 ]. Further, the expression of various serotonergic receptors within the lumbosacral cord has been examined [ 32 , 33 ] as well as an indication for their role in micturition function [ 34 , 35 , 36 , 37 , 38 ]. Accordingly, it is possible that these spinally located 5-HT receptors also serve to modulate pelvic visceral function after SCI. In line with this, our results have confirmed that neither the protein nor mRNA levels of 5-HT 2A receptors significantly decreased above or below the level of injury. However, previous studies reported that their expression is upregulated in motoneurons following SCI [ 39 ]. This contradiction could be due to the fact that our tissue samples were collected from spinal segments as opposed to specific populations of individual neurons. Nevertheless, spinal 5-HT 2A receptor expression is sustained in the cord of SCI rats.
2A
9
31
40
24
In the present study, DOI was able to elicit EUS bursting and bladder HFO. This indicates that stimulating spinal 5-HT 2A receptors, irrespective of delivery route, largely triggers its effects through central mechanisms that control the sphincter muscle. The EUS is continuously relaxed during voiding in humans whereas it is phasically relaxed in rats. Bursting EUS activity and bladder HFO occur during the expulsion phase in rats. SCI rats mainly show increased EUS tonic activity with little or no bursting and virtually no bladder HFO during voiding [ 41 ]. EUS bursting consists of both high frequency spikes that are deemed active periods (AP) and quiescent periods known as silent periods (SP), which alternate in such a way to allow for relaxation and contraction of the EUS, respectively, and are essential for efficient voiding [ 42 ]. HFO are thought to be generated by EUS bursting activity since these two patterns often occur synergistically [ 43 ]. Here we reported that stimulation of spinal 5-HT 2A receptors with DOI provoked EUS bursting. Subsequently, delivery of MDL to block these receptors eliminated the aforementioned effects, confirming mediation by spinal 5-HT 2A receptors. Similar to results from previous studies in which 5-HT 2A receptors exert excitatory control of the EUS in spinal cord intact rats [ 44 ], our results verified that activation of spinal 5-HT 2A receptors in SCI rats triggers EUS bursting which originates from simultaneous firing of Onuf’s motoneurons. Nevertheless, it has been assumed that propriospinal neurons in the L3/4 spinal cord contribute to the emergence of EUS bursting and bladder-EUS coordination [ 45 ]. If this is the case, DOI may indirectly affect Onuf’s motoneurons or does so via propriospinal neurons that express 5-HT 2A receptors.
Stimulation of spinal 5-HT 2A receptors with DOI increased EUS tonic activity in the filling phase during reflex assessments. Since EUS tonic activity reflects the capability of continence and DOI prolonged this activity between bladder contractions (e.g., prolonged VI), our data implies that DOI augments the ability to prevent leakage. This was also confirmed in spontaneous micturition assays by metabolic cages and s.c. administration of DOI in SCI rats. Because DOI did not affect the amplitude of bladder contractions, it is reasonable to conclude that the general impact of DOI on the micturition reflex is primarily caused by the agonist’s effects on motoneurons controlling the EUS rather than on parasympathetic preganglionic neurons regulating the bladder. In addition to its effects on the EUS, stimulation of 5-HT 2A receptors with DOI was able to significantly increase the voiding volume with both i.v. and i.t. delivery. This implies that the drug improved voiding efficiency by either (1) reducing the residual volume of urine that remains in the bladder following a contraction, (2) increasing bladder capacity, or (3) both. Based on previous reports, delivery of DOI peripherally or centrally increases the voiding volume while reducing the residual volume of urine [ 22 , 39 ]. Therefore, it seems likely that the increase in the voiding volume illustrated in the current experiments is due to improved voiding efficiency. It appears that DOI can produce similar effects in LUT performance when administered intravenously, intrathecally, and even subcutaneously. Thus, administration of DOI mainly stimulates centrally located 5-HT 2A receptors and contributes to detrusor-sphincter synergy to enhance voiding capability in SCI rats. Additionally, it is known that DOI also has an affinity for 5-HT 2C receptors [ 46 , 47 ]. Previous studies have shown that central 5-HT 2C receptors mainly inhibit the micturition reflex [ 4 ]. With this in mind, we administered MDL, which is a selective antagonist for 5-HT 2A receptors [ 48 ], directly following the high dose of DOI. This ultimately blocked changes that DOI induced on urinary function (e.g., EUS bursting and bladder HFO), and therefore, further supports the notion that DOI improves micturition performance via 5-HT 2A and not 2C receptors.
Urethane is currently the most widely used anesthetic to study micturition physiology. In fact, the majority of studies that examine the role of 5-HT receptors have been completed with the use of urethane or some other anesthetic [ 22 , 37 , 49 ]. The widespread use of this anesthetic is largely due to the fact that it spares the micturition reflex and is long-lasting [ 50 ]. Although urethane preserves vital parameters, such as bladder HFO and EUS bursting, it can interfere with the actions of glutamate and its analogs in the micturition pathway [ 51 ]. In addition, urethane was found to suppress sympathetic outflow to the bladder, and thus alter bladder capacity [ 52 ]. Notably, things become more complicated when applying anesthetics to SCI animals that already display several urinary complications (e.g., no bursting periods and emergence of non-voiding contractions) [ 53 ]. Therefore, the present study sought to avoid analgesic-related confounds by using awake rats for bladder cystometry and EUS EMG recordings.
54
55
2A
56
2A
57
5. Conclusions
Endogenous spinal 5-HT may not modulate recovered micturition function via 5-HT 2A receptors following SCI. Nonetheless, both systemic and central stimulation of these receptors with DOI can induce similar effects to increase EUS tonic activity in the filling phase and trigger bursting during voiding. It indicates that DOI enhances coordination of detrusor and sphincter activity to improve micturition function in SCI rats.
Author Contributions
S.H. and J.H.D. designed the experiments. J.H.D. and J.W. carried out the experiments and analyzed the data. J.H.D. and S.H. prepared the figures. J.H.D. and S.H. wrote the paper. All authors have read and agreed to the published version of the manuscript.
Funding
The support for this project was provided by NIH NINDS R01NS099076 to S. Hou and NIDDK F31DK123840-01 to J.H.D.
Institutional Review Board Statement
The study was conducted according to the guidelines of the National Institute of Health (NIH), and approved by the Institutional Animal Care and Use Committee (IACUC) of Drexel University College of Medicine (protocol code: 20550, date of approval: 09/07/2016).
Informed Consent Statement
Not applicable.
Data Availability Statement
Acknowledgments
The authors are grateful for Dong Wang and Yuan Qiao’s technical assistance. The support for this project was provided by NIH NINDS R01NS099076 to S. Hou and NIDDK F31DK123840-01 to J.H.D.
Conflicts of Interest
The authors declare no competing interests.
References
Nadelhaft, I.; Vera, P.L. Central nervous system neurons infected by pseudorabies virus injected into the rat urinary bladder following unilateral transection of the pelvic nerve. J. Comp. Neurol. 1995 , 359 , 443–456. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sugaya, K.; Roppolo, J.R.; Yoshimura, N.; Card, J.P.; de Groat, W.C. The central neural pathways involved in micturition in the neonatal rat as revealed by the injection of pseudorabies virus into the urinary bladder. Neurosci. Lett. 1997 , 223 , 197–200. [ Google Scholar ] [ CrossRef ]
Vizzard, M.A.; Erickson, V.L.; Card, J.P.; Roppolo, J.R.; de Groat, W.C. Transneuronal labeling of neurons in the adult rat brainstem and spinal cord after injection of pseudorabies virus into the urethra. J. Comp. Neurol. 1995 , 355 , 629–640. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mbaki, Y.; Ramage, A.G. Investigation of the role of 5-HT2 receptor subtypes in the control of the bladder and the urethra in the anaesthetized female rat. Br. J. Pharmacol. 2008 , 155 , 343–356. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Norouzi-Javidan, A.; Javanbakht, J.; Barati, F.; Fakhraei, N.; Mohammadi, F.; Dehpour, A.R. Effect of 5-HT7 receptor agonist, LP-211, on micturition following spinal cord injury in male rats. Am. J. Transl. Res. 2016 , 8 , 2525–2533. [ Google Scholar ] [ PubMed ]
De Groat, W.C. Influence of central serotonergic mechanisms on lower urinary tract function. Urology 2002 , 59 , 30–36. [ Google Scholar ] [ CrossRef ]
Bowker, R.M.; Westlund, K.N.; Coulter, J.D. Origins of serotonergic projections to the spinal cord in rat: An immunocytochemical-retrograde transport study. Brain Res. 1981 , 226 , 187–199. [ Google Scholar ] [ CrossRef ]
Ahn, J.; Saltos, T.M.; Tom, V.J.; Hou, S. Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats. Neurourol. Urodyn. 2018 , 37 , 2487–2494. [ Google Scholar ] [ CrossRef ]
Thor, K.B.; Nickolaus, S.; Helke, C.J. Autoradiographic localization of 5-hydroxytryptamine1A, 5-hydroxytryptamine1B and 5-hydroxytryptamine1C/2 binding sites in the rat spinal cord. Neuroscience 1993 , 55 , 235–252. [ Google Scholar ] [ CrossRef ]
de Groat, W.C.; Yoshimura, N. Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp. Neurol. 2012 , 235 , 123–132. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Taweel, W.A.; Seyam, R. Neurogenic bladder in spinal cord injury patients. Res. Rep. Urol. 2015 , 7 , 85–99. [ Google Scholar ] [ CrossRef ][ Green Version ]
Romo, P.G.B.; Smith, C.P.; Cox, A.; Averbeck, M.A.; Dowling, M.; Beckford, C.; Manohar, P.; Duran, S.; Cameron, A.P. Non-surgical urologic management of neurogenic bladder after spinal cord injury. World J. Urol. 2018 , 36 , 1555–1568. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Madersbacher, H.; Murtz, G.; Stohrer, M. Neurogenic detrusor overactivity in adults: A review on efficacy, tolerability and safety of oral antimuscarinics. Spinal Cord 2013 , 51 , 432–441. [ Google Scholar ] [ CrossRef ]
Al Taweel, W.; Alzyoud, K.M. The effect of spinal cord-injury level on the outcome of neurogenic bladder treatment using OnabotulinumtoxinA. Urol. Ann. 2015 , 7 , 320–324. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Schurch, B.; Schmid, D.M.; Stohrer, M. Treatment of neurogenic incontinence with botulinum toxin A. N. Engl. J. Med. 2000 , 342 , 665. [ Google Scholar ] [ CrossRef ]
Jamil, F. Towards a catheter free status in neurogenic bladder dysfunction: A review of bladder management options in spinal cord injury (SCI). Spinal Cord 2001 , 39 , 355–361. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Leu, R.; Stearns, G.L. Complications of Botox and their Management. Curr. Urol. Rep. 2018 , 19 , 90. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Magnusson, T. Effect of chronic transection on dopamine, noradrenaline and 5-hydroxytryptamine in the rat spinal cord. Naunyn Schmiedebergs Arch. Pharmacol. 1973 , 278 , 13–22. [ Google Scholar ] [ CrossRef ]
Newton, B.W.; Hamill, R.W. The morphology and distribution of rat serotoninergic intraspinal neurons: An immunohistochemical study. Brain Res. Bull. 1988 , 20 , 349–360. [ Google Scholar ] [ CrossRef ]
Wienecke, J.; Ren, L.Q.; Hultborn, H.; Chen, M.; Møller, M.; Zhang, Y.; Zhang, M. Spinal cord injury enables aromatic L-amino acid decarboxylase cells to synthesize monoamines. J. Neurosci. 2014 , 34 , 11984–12000. [ Google Scholar ] [ CrossRef ][ Green Version ]
Sawynok, J.; Reid, A. Spinal supersensitivity to 5-HT1, 5-HT2 and 5-HT3 receptor agonists following 5,7-dihydroxytryptamine. Eur. J. Pharmacol. 1994 , 264 , 249–257. [ Google Scholar ] [ CrossRef ]
Chen, J.; Gu, B.; Wu, G.; Tu, H.; Si, J.; Xu, Y.; Andersson, K.E. The effect of the 5-HT2A/2C receptor agonist DOI on micturition in rats with chronic spinal cord injury. J. Uro. 2013 , 189 , 1982–1988. [ Google Scholar ] [ CrossRef ] [ PubMed ]
D’Agostino, G.; Condino, A.M.; Franceschetti, G.P.; Tonini, M. Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor. J. Pharmacol. Exp. Ther. 2006 , 316 , 129–135. [ Google Scholar ] [ CrossRef ]
Ochodnicky, P.; Humphreys, S.; Eccles, R.; Poljakovic, M.; Wiklund, P.; Michel, M.C. Expression profiling of G-protein-coupled receptors in human urothelium and related cell lines. BJU Int. 2012 , 110 , 293–300. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Matsumoto-Miyai, K.; Yoshizumi, M.; Kawatani, M. Regulatory Effects of 5-Hydroxytryptamine Receptors on Voiding Function. Adv. Ther. 2015 , 32 , 3–15. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Yoshiyama, M.; Nezu, F.M.; Yokoyama, O.; de Groat, W.C.; Chancellor, M.B. Changes in micturition after spinal cord injury in conscious rats. Urology 1999 , 54 , 929–933. [ Google Scholar ] [ CrossRef ]
Kadekawa, K.; Nishijima, S.; Sugaya, K.; Miyazato, M.; Saito, S. Mechanisms by which the serotonergic system inhibits micturition in rats. Life Sci. 2009 , 85 , 592–596. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mitsui, T.; Shumsky, J.S.; Lepore, A.C.; Murray, M.; Fischer, I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J. Neurosci. 2005 , 25 , 9624–9636. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Dahlstroem, A.; Fuxe, K. Evidence for the Existence of Monoamine-Containing Neurons in the Central Nervous System. I. Demonstration of Monoamines in the Cell Bodies of Brain Stem Neurons. Acta Physiol. Scand. Suppl. 1964 , 232 , 1–55. [ Google Scholar ]
Dahlstroem, A.; Fuxe, K. Evidence for the Existence of Monoamine Neurons in the Central Nervous System. Ii. Experimentally Induced Changes in the Intraneuronal Amine Levels of Bulbospinal Neuron Systems. Acta Physiol. Scand. Suppl. 1965 , 247 , 1–36. [ Google Scholar ]
Xu, C.; Giuliano, F.; Sun, X.Q.; Brisorgueil, M.-J.; Leclerc, P.; Vergé, D.; Conrath, M. Serotonin 5-HT2A and 5-HT5A receptors are expressed by different motoneuron populations in rat Onuf’s nucleus. J. Comp. Neurol. 2007 , 502 , 620–634. [ Google Scholar ] [ CrossRef ]
Helton, L.; Thor, K.B.; Baez, M. 5-Hydroxytryptamine 2a , 5-Hydroxytryptamine 2B , 5-Hydroxytryptamine 2C receptor mRNA expression in the spinal cord of rat, cat, monkey, and human. Neuroreport 1994 , 5 , 2617–2620. [ Google Scholar ] [ CrossRef ]
Kong, X.Y.; Wienecke, J.; Hultborn, H.; Zhang, M. Robust upregulation of serotonin 2A receptors after chronic spinal transection of rats: An immunohistochemical study. Brain Res. 2010 , 1320 , 60–68. [ Google Scholar ] [ CrossRef ]
Chang, H.Y.; Cheng, C.L.; Chen, J.-J.J.; de Groat, W.C. Roles of glutamatergic and serotonergic mechanisms in reflex control of the external urethral sphincter in urethane-anesthetized female rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006 , 291 , R224–R234. [ Google Scholar ] [ CrossRef ][ Green Version ]
Chang, H.Y.; Cheng, C.L.; Chen, J.-J.J.; de Groat, W.C. Serotonergic drugs and spinal cord transections indicate that different spinal circuits are involved in external urethral sphincter activity in rats. Am. J. Physiol Renal Physiol 2007 , 292 , F1044–F1053. [ Google Scholar ] [ CrossRef ]
Cheng, C.L.; de Groat, W.C. Role of 5-HT1A receptors in control of lower urinary tract function in anesthetized rats. Am. J. Physiol. Renal. Physiol. 2010 , 298 , F771–F778. [ Google Scholar ] [ CrossRef ][ Green Version ]
Dolber, P.C.; Gu, B.; Zhang, X.; Fraser, M.O.; Thor, K.B.; Reiter, J.P. Activation of the external urethral sphincter central pattern generator by a 5-HT(1A) receptor agonist in rats with chronic spinal cord injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007 , 292 , R1699–R1706. [ Google Scholar ] [ CrossRef ]
Ramage, A.G. The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition. Br. J. Pharmacol. 2006 , 147 , S120–S131. [ Google Scholar ] [ CrossRef ]
Cao, N.; Ni, J.; Wang, X.; Tu, H.; Gu, B.; Si, J.; Wu, G.; Andersson, K.E. Chronic spinal cord injury causes upregulation of serotonin (5-HT)2A and 5-HT2C receptors in lumbosacral cord motoneurons. BJU Int. 2018 , 121 , 145–154. [ Google Scholar ] [ CrossRef ][ Green Version ]
Doly, S.; Madeira, A.; Fischer, J.; Brisorgueil, M.J.; Daval, G.; Bernard, R.; Vergé, D.; Conrath, M. The 5-HT2A receptor is widely distributed in the rat spinal cord and mainly localized at the plasma membrane of postsynaptic neurons. J. Comp. Neurol. 2004 , 472 , 496–511. [ Google Scholar ] [ CrossRef ]
Kruse, M.N.; Belton, A.L.; de Groat, W.C. Changes in bladder and external urethral sphincter function after spinal cord injury in the rat. Am. J. Physiol. 1993 , 264 , R1157–R1163. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kakizaki, H.; Fraser, M.O.; De Groat, W.C. Reflex pathways controlling urethral striated and smooth muscle function in the male rat. Am. J. Physiol. 1997 , 272 , R1647–R1656. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Maggi, C.A.; Giuliani, S.; Santicioli, P.; Meli, A. Analysis of factors involved in determining urinary bladder voiding cycle in urethan-anesthetized rats. Am. J. Physiol. 1986 , 251 , R250–R257. [ Google Scholar ] [ CrossRef ]
Danuser, H.; Thor, K.B. Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflexes in the anaesthetized cat. Br. J. Pharmacol. 1996 , 118 , 150–154. [ Google Scholar ] [ CrossRef ][ Green Version ]
Karnup, S.V.; de Groat, W.C. Propriospinal Neurons of L3-L4 Segments Involved in Control of the Rat External Urethral Sphincter. Neuroscience 2020 , 425 , 12–28. [ Google Scholar ] [ CrossRef ]
Hoyer, D. Molecular pharmacology and biology of 5-HT1C receptors. Trends Pharmacol. Sci. 1988 , 9 , 89–94. [ Google Scholar ] [ CrossRef ]
Lopez-Gimenez, J.F.; Vilaró, M.T.; Palacios, J.M.; Mengod, G. Multiple conformations of 5-HT2A and 5-HT 2C receptors in rat brain: An autoradiographic study with [125I](+/-)DOI. Exp. Brain Res. 2013 , 230 , 395–406. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Lopez-Gimenez, J.F.; Mengod, G.; Palacios, J.M.; Vilaró, M.T. Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedebergs Arch. Pharmacol. 1997 , 356 , 446–454. [ Google Scholar ] [ CrossRef ]
Wang, X.; Cao, N.; Ni, J.; Si, J.; Gu, B.; Karl-Erik, A. Effect of 5-HT2A receptor antagonist ketanserin on micturition in male rats. Neurosci. Lett. 2018 , 687 , 196–201. [ Google Scholar ] [ CrossRef ]
Brouillard, C.B.J.; Crook, J.J.; Lovick, T.A. Suppression of Urinary Voiding “on Demand” by High-Frequency Stimulation of the S1 Sacral Nerve Root in Anesthetized Rats. Neuromodulation 2019 , 22 , 703–708. [ Google Scholar ] [ CrossRef ][ Green Version ]
Morikawa, K.; Ichihashi, M.; Kakiuchi, M.; Yamauchi, T.; Kato, H.; Ito, Y.; Gomi, Y. Effects of various drugs on bladder function in conscious rats. Jpn. J. Pharmacol. 1989 , 50 , 369–376. [ Google Scholar ] [ CrossRef ]
Hou, S.; Rabchevsky, A.G. Autonomic consequences of spinal cord injury. Compr. Physiol. 2014 , 4 , 1419–1453. [ Google Scholar ] [ PubMed ]
Van Middendorp, J.J.; Goss, B.; Urquhart, S.; Atresh, S.; Williams, R.P.; Schuetz, M. Diagnosis and prognosis of traumatic spinal cord injury. Global. Spine J. 2011 , 1 , 1–8. [ Google Scholar ] [ CrossRef ][ Green Version ]
Wyndaele, M.; Wyndaele, J.J. Incidence, prevalence and epidemiology of spinal cord injury: What learns a worldwide literature survey? Spinal Cord 2006 , 44 , 523–529. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Abelson, B.; Sun, D.; Que, L.; Nebel, R.A.; Baker, D.; Popiel, P.; Amundsen, C.L.; Chai, T.; Close, C.; DiSanto, M.; et al. Sex differences in lower urinary tract biology and physiology. Biol. Sex. Differ. 2018 , 9 , 45. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Li, J.; Yang, L.; Pu, C.; Tang, Y.; Yun, H.; Han, P. The role of duloxetine in stress urinary incontinence: A systematic review and meta-analysis. Int. Urol. Nephrol. 2013 , 45 , 679–686. [ Google Scholar ] [ CrossRef ]
Figure 1. Spinal 5-HT 2A receptor expression remains unchanged after SCI. ( A ), Western blots show that there is no difference between naïve and SCI rats in terms of protein expression levels of the 5-HT 2A receptor above (T4/5) and below the level of injury (L1/2, L6/S1) (Student’s t -test, all p > 0.05). ( B , C ), Quantitative PCR analysis reveals that mRNA levels of this receptor were not altered at any of the aforementioned segments in SCI rats (all p > 0.05). GAPDH served as a control.
Figure 2. Intravenous (i.v.) administration of DOI to stimulate 5-HT 2A receptors improves the micturition reflex during bladder cystometry and sphincter EMG in SCI rats. ( A ), Stimulating 5-HT 2A receptors with the middle dose of DOI (20 µg/kg) prolongs the VI ( p < 0.05, Friedman’s test followed by Dunn’s) between voiding contractions (asterisks). The high dose of DOI (0.1 mg/kg) increases EUS tonic activity in the filling phase ( p < 0.01). Ensuing injection of MDL (0.1 mg/kg) eliminates the provoked effects. ( B ), Representative traces show no EUS bursting activity during voiding when saline is delivered. However, the middle dose of DOI triggers EUS bursting activity during voiding. Injection of MDL following the high dose of DOI masks the triggered bursting EUS activity during voiding.
Figure 3. Intrathecal (i.t.) administration of DOI to stimulate 5-HT 2A receptors affects the micturition reflex during bladder cystometry and sphincter EMG in SCI rats. ( A ), Representative tracers show that stimulating 5-HT 2A receptors with the middle (2 µg/kg) and high (10 µg/kg) doses of DOI prolongs the VI (both p < 0.05, Friedman’s test followed by Dunn’s) between voiding contractions (asterisks) and induces an increase in EUS tonic activity. ( B ), Importantly, the middle dose of DOI increases the duration of EUS bursting that consists of more regularly occurring active and silent periods along with bladder HFO, indicating an enhancement of detrusor-sphincter coordination during voiding.
Figure 4. Intrathecal (i.t.) administration of MDL abolishes DOI induced excitatory effects on the EUS reflex in SCI rats. A representative cystometry and EMG trace demonstrates that MDL, a 5-HT 2A receptor antagonist (10 µg/kg), shortens the VI ( p < 0.05, Friedman’s test followed by Dunn’s) ( A ) and masks bursting EUS activity ( B ), leading to the occurrence of detrusor-sphincter dyssynergia.
Figure 5. Stimulating 5-HT 2A receptors with DOI delivery improves spontaneous micturition function in SCI rats. Representative traces show volume-frequency patterns of urination in metabolic cage assays after 5-HT 2A receptor stimulation with DOI within a 6-h time period. Saline injections served as a control. In each “step-like” curve of these traces ( A ), the vertical lines represent the VV per void and the horizontal lines illustrate the VI. After s.c. injection of the 5-HT 2A receptor agonist DOI (60 µg/kg, 300 µL), ( B ) there was a significant increase in the VV per void and VI in comparison to saline controls (Paired t -test, all * p < 0.05).
Table 1. Normalized parameters of bladder cystometry and EUS EMG activity in SCI rats ( i.v. administration).
Drugs Doses (/kg) Bladder CMG EUS EMG VV VA CD VI # NVCs RMS MA MDL (n = 6) ( 5HT 2A receptor antagonist ) Saline 1.11 ± 0.10 0.96 ± 0.05 1.00 ± 0.05 1.31 ± 0.31 0.95 ± 0.06 0.82 ± 0.12 0.95 ± 0.09 20 µg 1.01 ± 0.19 0.93 ± 0.05 1.07 ± 0.14 1.25 ± 0.70 0.87 ± 0.02 0.71 ± 0.09 1.00 ± 0.15 0.1 mg 0.97 ± 0.06 0.98 ± 0.06 1.22 ± 0.11 * 1.56 ± 0.86 0.96 ± 0.09 0.81 ± 0.10 1.15 ± 0.10 0.5 mg 1.04 ± 0.04 0.95 ± 0.06 1.10 ± 0.07 0.88 ± 0.79 1.11 ± 0.16 1.00 ± 0.37 1.09 ± 0.14 DOI (n = 6) ( 5HT 2A receptor agonist ) Saline 1.11 ± 0.10 0.96 ± 0.05 1.00 ± 0.05 1.31 ± 0.31 0.95 ± 0.06 0.82 ± 0.12 0.95 ± 0.09 5.0 µg 1.08 ± 0.04 0.98 ± 0.04 1.34 ± 0.11 1.00 ± 0.84 1.03 ± 0.14 0.69 ± 0.97 1.23 ± 0.15 20 µg 1.06 ± 0.08 1.12 ± 0.04 1.73 ± 0.17 * 2.19 ± 1.59 1.13 ± 0.13 0.84 ± 0.21 1.32 ± 0.12 * 0.1 mg 1.00 ± 0.08 1.01 ± 0.04 1.51 ± 0.30 1.31 ± 0.80 1.53 ± 0.24 * 1.64 ± 0.55 1.24 ± 0.17
* p < 0.05; VA, voiding amplitude of intravesical pressure, CD, contraction duration, VI, voiding interval, VV, voiding volume, NVCs, non-voiding contractions, RMS, root mean square, MA, maximum amplitude of tonic activity; # non-normalized data.
Table 2. Normalized parameters of bladder cystometry and EUS EMG activity in SCI rats ( i.t. administration).
Drugs Doses (/kg) Bladder CMG EUS EMG VV VA CD VI # NVCs RMS MA MDL (n = 6) ( 5HT 2A receptor antagonist ) Saline 1.23 ± 0.11 1.01 ± 0.01 1.12 ± 0.11 0.29 ± 0.15 0.97 ± 0.19 0.92 ± 0.07 0.81 ± 0.03 2 µg 1.13 ± 0.10 0.97 ± 0.01 1.12 ± 0.11 0.20 ± 0.13 1.09 ± 0.06 0.95 ± 0.08 0.78 ± 0.03 10 µg 1.22 ± 0.18 1.08 ± 0.09 1.34 ± 0.20 0.29 ± 0.15 0.98 ± 0.05 0.74 ± 0.11 1.07 ± 0.09 50 µg 0.81 ± 0.08 0.83 ± 0.05 1.19 ± 0.15 0.58 ± 0.26 1.11 ± 0.05 1.46 ± 0.30 0.95 ± 0.09 DOI (n = 6) ( 5HT 2A receptor agonist ) Saline 0.94 ± 0.03 1.09 ± 0.04 1.24 ± 0.14 1.08 ± 0.60 1.01 ± 0.03 1.17 ± 0.20 0.95 ± 0.10 0.5 µg 1.03 ± 0.09 1.14 ± 0.05 1.42 ± 0.46 0.79 ± 0.64 1.01 ± 0.03 1.05 ± 0.09 0.88 ± 0.12 2 µg 1.21 ± 0.13 1.13 ± 0.08 3.27 ± 1.04 * 2.70 ± 1.77 1.14 ± 0.17 1.12 ± 0.28 1.14 ± 0.18 10 µg 1.12 ± 0.11 1.09 ± 0.05 3.98 ± 1.58 * 3.33 ± 2.41 1.46 ± 0.21 1.96 ± 0.31 1.33 ± 0.18 *
* p < 0.05; VA, voiding amplitude of intravesical pressure, CD, contraction duration, VI, voiding interval, VV, voiding volume, NVCs, non-voiding contractions, RMS, root mean square, MA, maximum amplitude of tonic activity; # non-normalized data.
MDPI and ACS Style
DeFinis, J.H.; Weinberger, J.; Hou, S. Delivery of the 5-HT 2AReceptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury. Biology 2021, 10, 68.
https://doi.org/10.3390/biology10010068
AMA Style
DeFinis JH, Weinberger J, Hou S. Delivery of the 5-HT 2AReceptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury. Biology. 2021; 10(1):68.
https://doi.org/10.3390/biology10010068
Chicago/Turabian Style
DeFinis, Jaclyn H., Jeremy Weinberger, and Shaoping Hou. 2021. "Delivery of the 5-HT 2AReceptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury" Biology10, no. 1: 68.
https://doi.org/10.3390/biology10010068
| https://www.mdpi.com/2079-7737/10/1/68/htm#B55-biology-10-00068 |
BOILING WATER REACTOR, BWR
BOILING WATER REACTOR, BWR
Dix, Gary E. DOI: 10.1615/AtoZ.b.boiling_water_reactor_bwr
A Boiling Water Reactor (BWR) circulates water past nuclear fuel in a large pressure vessel at 6.9 MPa. The nuclear fuelis configured as cylindrical pellets contained within long metallic tubes, referred to as fuel rods. The fuel rods are combined in various arrangements within flow channels to create fuel assemblies. Several hundred such fuel assemblies are connected in parallel between inlet and outlet plena. These parallel fuel assemblies are referred to as the coreof a BWR. During passage of water along the nuclear fuel, significant boiling and vapor formation occur — typically producing 10% to 20% vapor flow that exits into the outlet plenum. The resultant vapor is separated and directed to steam turbines for electrical generation. The remaining liquid is circulated back, along with condensate liquid returning from the turbines, to the inlet plenum. Key components of a jet-pump BWR steam supply system are illustrated inFigure 1.
Figure 1. Typical jet pump BWR steam supply system.
Normal operation of a BWR depends upon accurate prediction of several key thermal hydraulic parameters in the fuel assemblies. In particular, vapor void fractions, transition boiling limits and fuel assembly pressure drops must be accurately predicted to support BWR design and operation. Prediction methods must address the range of two-phase flow regimes from subcooled liquid at the fuel assembly inlet to annular flow at the outlet. (SeeForced Convective Boiling.)
The surrounding channels on BWR fuel assemblies effectively isolate flows within each fuel assembly. This allows the necessary two-phase flow characteristics to be evaluated by reproducing realistic thermal hydraulic conditions in isolated fuel assembly simulation tests. Such simulations require large experimental facilities that can reproduce the power and flows of full-scale BWR fuel assemblies, using electrically heated fuel rod simulators. Data from such full-scale experiments are used to provide very accurate empirical relationships for the two-phase flow parameters required for BWR design analyses.
The vaporVoid Fractionis the fraction of the flow area that is occupied by vapor. This is directly related to the average velocity of the vapor. In a BWR, the circulating water serves both as cooling medium and neutronic moderator for the nuclear fuel. This produces close coupling between power generation and two-phase flow conditions in the fuel assemblies. The primary coupling parameter is the density of the steam-water mixture surrounding the nuclear fuel. Predicting the two-phase density requires accurate prediction of the void fraction.
Fuel assemblyPressure Dropis one of the most important parameters determining conditions in the BWR core. Fuel assembly power and flows can differ significantly due to mechanical and nuclear design differences, as well as locations within the core. To assure appropriate flow distribution to all of the fuel assemblies, it is important to have accurate predictions of pressure drops over the entire range of fuel assembly operating conditions. (SeePressure Drop, Two-Phase.)
Boiling transitionrefers to conditions where typical boiling heat transfer starts to deteriorate. This has also been referred to as critical heat flux(seeBurnout). The boiling transition limit for BWR operation is usually associated with deterioration of the liquid film flowing on a fuel rod under annular flow conditions. The fuel rods of a BWR fuel assembly utilize zirconium alloy, which minimizes parasitic capture of neutrons, for the outer metallic tubes. This material has good corrosion resistance for temperatures existing under typical boiling conditions. However, if boiling transition conditions are exceeded, the deteriorated heat transfer causes higher temperatures in the fuel. If such conditions persist for an extended period of time, the increased corrosion rate of the metallic tubes can cause fuel failures. Therefore, accurate predictions of boiling transition limits are very important for reliable BWR operation.
The elimination of crossflows between BWR fuel assemblies allows for both realistic experimental simulations of fuel assembly thermal hydraulics and simplified analyses methods. BWR analyses methods typically utilize either one dimensional representations of fuel assemblies or subchannel representations. One-dimensional analyses utilize correlations based on cross-sectional averaged flow quantities, with empirical parameters to account for radial variations where necessary. Nuclear coupling based upon one-dimensional values is usually sufficiently accurate for typical BWR fuel assemblies. Representative solution techniques and correlations are discussed by Collier (1980) and Lahey (1993). Subchannel analyses icorporate more detailed mechanistic descriptions of two-phase flow phenomena to predict crossflows and local parameters within fuel assemblies. Subchannel methods are summarized by Shiralkar (1992).
One-dimensional void fraction predictions are often based on theDrift Fluxconcept of Zuber (1965). Average vapor velocity is characterized by the average of local vapor drift velocities and the volumetric flux adjusted by a distribution parameter. The distribution parameter incorporates radial phase and velocity distribution effects. These parameters are determined from experimental void fraction data. While the original drift flux work anticipated discrete values of these parameters for various flow regimes, considerable success has been achieved by Dix (1971) and Chexal (1991) with continuous correlation relations which implicitly reflect the effects of flow regimes. These correlations are usually assumed to be insensitive to power distribution changes across the fuel assemblies. It has been confirmed by recent data from Yagi (1992) which demonstrated that average void fraction results were unchanged even when large variations were imposed in local void fractions within a typical BWR fuel assembly.
One-dimensional pressure drop predictions typically use average values for void fraction and flow quality in combination with standard two-phase flow formulations and correlations. Single-phase pressure drop data associated with wall friction and local losses are necessary to provide the reference bases for each specific fuel assembly design.
Boiling transition limits reflect local liquid film disruptions on individual fuel rods. Those limits are dependent upon both local film flow characteristics and local power distributions across fuel assemblies. Mechanical spacers, which maintain fuel rod spacing along their axial lengths, have important effects on boiling transition limits. Detrimental thinning of the fuel rod liquid films can be caused just upstream of the spacers, while favorable deposition of droplets into the liquid films can be caused just downstream of the spacers. The detrimental upstream effects are usually sufficient to cause initial boiling transitions to occur just upstream of spacers. However, the favorable downstream effects usually dominate, such that boiling transition improves with closer axial pitch of the spacers. Boiling transition limits can vary by 10% due to mechanical features of the spacers.
Predictions of boiling transition are often based on one dimensional averaged parameters, such as critical quality and boiling length, with empirical treatments of local effects. Such correlations can provide very accurate predictions but require extensive calibration with full scale test results for each specific fuel assembly design and radial power distribution range. This extensive testing requirement is one of the major motivations for more general subchannel analysesmethods.
Subchannel analyses methods are based upon radial solution meshes within the fuel assemblies. Subchannel methods divide fuel assemblies into a number of interacting flow regions for analyses. The models then track liquid films, core vapor and core entrained droplets as separate fields for each of the subchannel regions. The goals for subchannel methods are to provide predictions which are mechanistically-based and less dependent upon full-scale calibration experiments, particularly for the development of new fuel designs.
Since BWR boiling transition limits are related to the deterioration of annular liquid films flowing on fuel rod surfaces, the subchannel methods incorporate mechanisms to predict and track the net liquid flows in those films, as well as criteria for the minimum film flows corresponding to film disruption and boiling transition. Key aspects for these film predictions are liquid evaporation, entrainment of liquid from the film to the vapor/droplet core and deposition of droplets from the core onto the surface films. Flow distributions among the subchannel regions usually require empirical mechanisms such as ‘void drift’ to achieve the overall flow distributions observed in BWR fuel assembly experiments.
The effects of fuel rod spacers are very important in determining boiling transition limits of BWR fuel assemblies, as previously discussed. Current subchannel methods incorporate various modeling assumptions to describe these spacer effects, including empirical parameters which must be calibrated with full scale boiling transition data for the specific spacer to be analyzed. General modeling of these spacer effects in subchannel analyses will require a further level of detail and mechanistic understanding which is not yet available.
Current subchannel modeling methods provide excellent predictions of boiling transition for limited variations from their calibration bases. Void fraction distributions are also predicted quite well by these methods, except for highly heterogeneous conditions across fuel assemblies. In general, subchannel methods are appropriate tools for BWR analyses, but further developments are necessary to significantly reduce dependence on full-scale testing for final design applications.
Stability analyses
Parallel flow channels and close coupling between neutronic power and two-phase flow conditions can cause instability conditions in a BWR. Accurate predictions and avoidance of potentially unstable conditions are important for reliable BWR operation. Two types of instability can occur. Density wave oscillations can be driven by the two-phase hydraulics in individual fuel assemblies, with only minor effects from neutronic coupling. Alternatively, core-wide neutronic coupling can cause instabilities in many or all of the fuel assemblies. The fuel assemblies can all have oscillations in-phase, or local regions can oscillate. Accurate predictions of these oscillation conditions require coupled solutions of neutronics and two-phase flow equations. The same basic one-dimensional formulations for two-phase flow parameters are also applied in stability predictions. Both frequency domain and time domain solution techniques are used successfully for these analyses, as discussed by Lahey (1993). (SeeInstability, Two-phase.)
Loss of coolant analyses
One of the most challenging and well-researched areas of BWR analyses is the prediction of safety system and fuel cooling responses to a wide range of accidents that might result in the loss of coolant water from the core. Postulated breakage of pipes connected to the pressure vessel are the primary bases for these accident evaluations. BWR designs include emergency systems to distribute coolant above the core, as well as systems to refill the pressure vessel and reflood the core if it does become uncovered during an accident. Modern BWR designs also include recirculation pumps within the pressure vessel (rotary or jet pumps) to minimize the size of potential breaks to pressure vessel connections.
Predictions of fuel cooling under these postulated loss of coolant accident (LOCA)conditions require detailed system simulation methods to analyze the transient two-phase fluid conditions adjacent to the fuel as the postulated accident proceeds. Accurate predictions require modeling of flow and heat transfer of flow and heat transfer with surface temperatures well aboveLeidenfrost conditions. Elements include falling liquid films, reflooding from below and countercurrent flows of the two phases. Modeling requirements for accurate BWR/LOCA predictions are summarized by Andersen (1985).
Large scale experiments have demonstrated that condensation of vapor by subcooled liquid and three-dimensional distribution effects are important aspects determining the progression of emergency coolant to the fuel. A significant effect for BWR/LOCA is the accumulation and drainage of coolant water in the plenum region above the core. Countercurrent flow limitation (CCFL)conditions at the top of fuel assemblies cause accumulation of emergency coolant water in a pool above the core. Some fuel assemblies then experience downward flow of subcooled liquid, while others experience counter-current flows. The results of this complex pattern are rapid reflooding and cooling of BWR core. These effects and other LOCA studies are summarized by Dix (1983). (See alsoFlooding and Flow Reversal.)
Passive safety features
The Simplified Boiling Water Reactor (SBWR)is a new reactor design which incorporates passive safety features rather than active safety systems used previously. This design includes a gravity drain pool inside the containment to provide liquid to the core in case of a LOCA. Heat exchangers submerged in large water pools outside the containment absorb energy from within the reactor containment and transport it to the atmosphere. The latter energy transport occurs without any activation in case of a LOCA. The water pools have sufficient capacity to transport decay heat for several days and can be replenished from outside the containment.
REFERENCES
Andersen, J. G. M., Chu, K. H., Cheung, Y. K., and Shaung, J. C. (1985) BWR Full Integral Simulation Test (FIST) Program, TRAC-BWR Model Development Volume 2 — Models, GEAP-30875-2,NUREG/CR-4127-2, EPRI NP-3987-2.
Chexal, B., Lellouche, G., Horowitz, J., Healzer, J., and Oh, S. (1991) The Chexal-Lellouche Void Fraction Correlation for Generalized Applications, NSAC Report-139.
Collier, J. G. (1980) Convective Boiling and Condensation, McGraw Hill.
Dix, G. E. (1971) Vapor Void Fractions for Forced Convection with Subcooled Boiling at Low Flow Rates, General Electric NEDO-10491 (PhD Thesis, University of California Berkeley).
Dix, G. E. (1983) BWR Loss of Coolant Technology Review, Proceedings ANS Symposium Thermal Hydraulics of Nuclear Reactors, Volume 1.
Lahey, R. T. and Moody, F. J. (1993) The Thermal Hydraulics of a Boiling Water Reactor, ANS Monograph.
Shiralkar, B. S. (1992) Recent Trends in Subchannel Analysis, Proceedings of the International Seminar on Subchannel Analysis, Tokyo.
Yagi, M., Mitsutake, T., Morooka, S., and Inoue, A. (1992) Void Fraction in BWR Fuel Assembly and Evaluation of Subchannel Code, Proceedings of the International Seminar on Subchannel Analysis, Tokyo.
Zuber, N. and Findlay, J. (1965) Average Volumetric Concentration in Two-Phase Flow Systems, Transactions of ASME, Volume 87, Series C.
Les références
Andersen, J. G. M., Chu, K. H., Cheung, Y. K., and Shaung, J. C. (1985) BWR Full Integral Simulation Test (FIST) Program , TRAC-BWR Model Development Volume 2 — Models, GEAP-30875-2,NUREG/CR-4127-2, EPRI NP-3987-2.
Chexal, B., Lellouche, G., Horowitz, J., Healzer, J., and Oh, S. (1991) The Chexal-Lellouche Void Fraction Correlation for Generalized Applications , NSAC Report-139.
Collier, J. G. (1980) Convective Boiling and Condensation , McGraw Hill.
Dix, G. E. (1971) Vapor Void Fractions for Forced Convection with Subcooled Boiling at Low Flow Rates , General Electric NEDO-10491 (PhD Thesis, University of California Berkeley).
Dix, G. E. (1983) BWR Loss of Coolant Technology Review , Proceedings ANS Symposium Thermal Hydraulics of Nuclear Reactors, Volume 1.
Lahey, R. T. and Moody, F. J. (1993) The Thermal Hydraulics of a Boiling Water Reactor , ANS Monograph.
Shiralkar, B. S. (1992) Recent Trends in Subchannel Analysis , Proceedings of the International Seminar on Subchannel Analysis, Tokyo.
Yagi, M., Mitsutake, T., Morooka, S., and Inoue, A. (1992) Void Fraction in BWR Fuel Assembly and Evaluation of Subchannel Code , Proceedings of the International Seminar on Subchannel Analysis, Tokyo.
Zuber, N. and Findlay, J. (1965) Average Volumetric Concentration in Two-Phase Flow Systems , Transactions of ASME, Volume 87, Series C.
| https://www.thermopedia.com/fr/content/592/ |
Nobel laureate James Watson puts forth novel hypothesis on curing late-stage cancers -- ScienceDaily
In a new paper he regards " among my most important work since the double helix," Nobelist James Watson sets forth a novel hypothesis regarding the role of oxidants and antioxidants in cancers that are currently incurable, notably in late-stage metastatic cancers.
Nobel laureate James Watson puts forth novel hypothesis on curing late-stage cancers
Summary:
In a new paper he regards "among my most important work since the double helix," Nobelist James Watson sets forth a novel hypothesis regarding the role of oxidants and antioxidants in cancers that are currently incurable, notably in late-stage metastatic cancers.
"Although mortality from many cancers has been steadily falling, particularly those of the blood [i.e., leukemias], the more important statistic may be that so many epithelial cancers (carcinomas) and effectively all mesenchymal cancers (sarcomas) remain largely incurable."
With these words as preface, Nobel laureate James D. Watson, Ph.D., in a newly published paper that he regards "among my most important work since the double helix," sets forth a novel hypothesis regarding the role of oxidants and antioxidants in cancers that are currently incurable, notably in late-stage metastatic cancers.
At the heart of his thesis are the group of molecules that scientists call reactive oxygen species, or ROS. Noting their fundamental two-sidedness, Watson calls ROS "a positive force for life" because of their role in apoptosis -- an internal program that highly stressed cells use to commit suicide. It's one of the key mechanisms that have arisen through eons of evolution to weed out biological dysfunction that poses a threat to the survival of organisms. On the other hand, ROS are also well understood -- indeed are notorious -- "for their ability to irreversibly damage key proteins and nucleic acid molecules [e.g., DNA and RNA]."
When they're not needed to curb wayward or out of control cells, which is to say under normal circumstances, ROS are constantly being neutralized by anti-oxidative proteins. We are often urged to eat foods rich in antioxidants such as blueberries; but, if Watson is correct about the role of ROS and antioxidants in late-stage cancer, as he writes in his new paper, "blueberries best be eaten because they taste good, not because their consumption will lead to less cancer."
Understanding why this might be so -- why antioxidants can in late-stage cancers actually promote cancer progression -- is central to Watson's paper, which appears online January 9 in Open Biology, a journal of Great Britain's Royal Society.
He proposes that the cell-killing ability of currently used anti-cancer therapies -- toxic chemotherapeutic agents such as Taxol as well as radiation treatment -- is mainly due to the action of ROS to induce apoptosis, or programmed cell death. This would explain "why cancers that become resistant to chemotherapeutic control become equally resistant to radiotherapy." The common feature would be their common dependence upon a ROS-mediated cell-killing mechanism.
Watson, who is Chancellor Emeritus of Cold Spring Harbor Laboratory, then takes up the case of cancer cells largely driven by mutant proteins such as RAS and MYC. These, he notes, are often hardest to get to respond to treatment. He suggests this could be due to their high levels of ROS-destroying antioxidants. He cites recent research showing up-regulation of a gene transcription factor called Nrf2 when cells proliferate as well as when oncogenes such as RAS, MYC and RAF are active. Nrf2 controls the synthesis of antioxidants, and "this makes sense because we want antioxidants present when DNA functions to make more of itself," Watson writes.
In calling for "a much faster timetable for developing anti-metastatic drugs," the Nobel laureate wants those reading his new paper to consider a proposition he considers grossly underexplored: "Unless we can find ways of reducing antioxidant levels, late-stage cancer 10 years from now will be as incurable as it is today."
Story Source:
Materials provided byCold Spring Harbor Laboratory. Note: Content may be edited for style and length.
Cite This Page:
MLA
APA
Chicago
Cold Spring Harbor Laboratory. "Nobel laureate James Watson puts forth novel hypothesis on curing late-stage cancers." ScienceDaily. ScienceDaily, 8 January 2013. <www.sciencedaily.com/releases/2013/01/130108201639.htm>.
Cold Spring Harbor Laboratory. (2013, January 8). Nobel laureate James Watson puts forth novel hypothesis on curing late-stage cancers. ScienceDaily. Retrieved July 7, 2023 from www.sciencedaily.com/releases/2013/01/130108201639.htm
Cold Spring Harbor Laboratory. "Nobel laureate James Watson puts forth novel hypothesis on curing late-stage cancers." ScienceDaily. www.sciencedaily.com/releases/2013/01/130108201639.htm (accessed July 7, 2023).
| https://www.sciencedaily.com/releases/2013/01/130108201639.htm |
A Supported Palladium Phosphide Catalyst for the Wacker‐Tsuji‐Oxidation of Styrene | Request PDF
Request PDF | A Supported Palladium Phosphide Catalyst for the Wacker‐Tsuji‐Oxidation of Styrene | The substitution of pure metal particles by metal phosphides in catalysis represents a promising opportunity to lower the required metal quantity... | Find, read and cite all the research you need on ResearchGate
Article
A Supported Palladium Phosphide Catalyst for the Wacker‐Tsuji‐Oxidation of Styrene
February 2023
ChemPlusChem88(2)
DOI: 10.1002/cplu.202200431
License
CC BY-NC 4.0
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Arjun Neyyathala
Arjun Neyyathala
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Franziska Flecken
Franziska Flecken
<here is a image f0b5a06f37f1f5f0-d27ff18c7ef9544e>
Schirin Hanf
Karlsruhe Institute of Technology
Abstract
The substitution of pure metal particles by metal phosphides in catalysis represents a promising opportunity to lower the required metal quantity in the context of a sustainable use of metal resources. Herein we show the synthesis of palladium phosphide, Pd3P, supported on silica, which is tested as catalyst for the Wacker‐Tsuji‐oxidation of styrene to acetophenone. The synthesized catalyst is characterized by PXRD, SEM‐EDX, FTIR, ICP‐AES and XPS measurements. Four different reaction systems are investigated in this study including different co‐catalysts and reaction media. Conversions of styrene up to 95% with a selectivity of 73% towards acetophenone are observed using Pd3P/SiO2 as catalyst, CuCl2 as co‐catalyst and O2 as oxidant. An enhanced selectivity up to 100% towards acetophenone is obtained in other reaction systems. The use of Pd3P/SiO2 leads to an optimized selectivity and conversion in the oxidation reaction in comparison with the purely Pd‐based system Pd/SiO2. These results give an insight on how the incorporation of phosphorus has a great effect on the performance of heterogeneous catalysts.
<here is a image 175d1bd4b7439d95-754927124da715c1>
Fast and Selective Aqueous-Phase Oxidation of Styrene to Acetophenone Using a Mesoporous Janus-Type Palladium Catalyst (Special Issue "Composite Porous Materials in Catalysis")
Article
Full-text available
Oct 2021
MOLECULES
<here is a image 9874136a3a1efeba-0667340de01d8176> Majid Vafaeezadeh
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ranja Saynisch
Andrea Lösch
<here is a image 677849bd02a252d7-9c7dd94fcd69f30a> Werner R Thiel
Article
Full-text available
Mar 2021
MOLECULES
Marta A. Andrade
Luísa M. D. R. S. Martins
Article
Full-text available
Mar 2021
Preeti S. Shinde
Pradnya S. Suryawanshi
Kanchan K. Patil
<here is a image b7f2346c513bb226-df6fd7726bc55aae> Sushilkumar A. Jadhav
Article
Full-text available
May 2020
<here is a image f0b5a06f37f1f5f0-d27ff18c7ef9544e> Schirin Hanf
<here is a image dbf6e5dd2b54690e-cc3cba4479e9ea0e> Roger Gläser
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Luis Alvarado
<here is a image 8a166152ac4406cb-e03a87a1db4ff70f> Stephan Schunk
Article
Full-text available
Feb 2020
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Adam H Clark
Jerick Imbao
<here is a image 351e0943b0a4224e-231d49376275c36e> Jeroen A van Bokhoven
<here is a image da81e87bb6f6ad43-16b0af4668dce461> Maarten Nachtegaal
The heterogenization of Wacker catalysts using chloride-free systems can potentially be a good alternative for the commercial homogeneous Wacker oxidation of ethylene, which utilizes excessive aqueous chloride solvents. However, the mechanism of the heterogeneous system has not been clarified, preventing the rational design of better catalysts. Here, we report a transient X-ray absorption spectroscopic (XAS) investigation of the heterogeneous Wacker oxidation over Pd-Cu/zeolite Y coupled with kinetic studies and chemometric analysis. Insight is obtained by operando quickXAS allowing the quantitative determination of rates and thereby revealing a rapid redox reaction involving copper. Our work demonstrates that copper is not only the site of oxygen activation, but is also involved in the formation of undesired carbon dioxide. Without detecting the presence of Cu(0) and Pd(I), our results suggest that two one-electron transfers to two Cu(II) ions to reoxidize Pd(0) is at work in this heterogeneous Wacker catalyst. Unlike the homogeneous Wacker process, understanding of the mechanism of the heterogeneous system remains superficial. Here, the authors investigate the mechanism of heterogeneous Wacker oxidation over Pd-Cu/zeolite Y through the synergistic combination of kinetic, spectroscopic and chemometric studies.
Optimization of a heterogeneous Pd–Cu/zeolite Y Wacker catalyst for ethylene oxidation
Jan 2020
Jerick Imbao
<here is a image 351e0943b0a4224e-231d49376275c36e> Jeroen A van Bokhoven
<here is a image da81e87bb6f6ad43-16b0af4668dce461> Maarten Nachtegaal
A heterogeneous catalyst based on palladium- and copper-exchanged zeolite Y is optimized for stable Wacker oxidation.
Pd-P nanoparticles as active catalyst for the hydrogenation of acetylenic compounds
Sep 2019
J NANOPART RES
Fedor K. Schmidt
L. B. Belykh
<here is a image b00728bd544319f8-3ba64371f971ac7e> Nikita Skripov
T. P. Sterenchuk
Pd-P nanoparticles were obtained by low-temperature reduction of Pd(acac)2 with hydrogen in the presence of elemental phosphorus. Using the EDX analysis, XRD, and HRTEM, the composition, size, and morphology of the particles were determined for different P:Pd ratios. The results of testing Pd-P nanoparticles showed that they are 8–9 times higher in activity in the hydrogenation of mono- and di-substituted acetylenic compounds than Pd-black and phase-pure Pd3P phosphide, while maintaining high selectivity to alkenes at 95–98% conversion of alkynes. Colloidal solutions of Pd-P nanoparticles can act as long-lived supported catalysts (TON = 27,444 mol PA·(mol Pd total)⁻¹). The effect of the P:Pd ratio on the change in the rates of hydrogenation of alkyne (r1) and the resulting alkene (r2) under the action of Pd-P nanoparticles has been found and experimentally substantiated. Electron-deficient small clusters of palladium contained along with palladium phosphides in the Pd-P nanoparticles are responsible for the decrease in the ratio r1:r2 in the ratio range P:Pd = 1–1.5.
Graphical abstract
A hydrofluoric acid-free method to dissolve and quantify silica nanoparticles in aqueous and solid matrices
May 2019
David Bossert
Dominic A. Urban
<here is a image eddf98bebbe8f4be-0feda298504e13a1> Mattia Maceroni
<here is a image 28a3d1680dd27b3d-76cb591d405a3617> Fabienne Schwab
As the commercial use of synthetic amorphous silica nanomaterials (SiO2-NPs) increases, their effects on the environment and human health have still not been explored in detail. An often-insurmountable obstacle for SiO2-NP fate and hazard research is the challenging analytics of solid particulate silica species, which involves toxic and corrosive hydrofluoric acid (HF). We therefore developed and validated a set of simple hydrofluoric acid-free sample preparation methods for the quantification of amorphous SiO2 micro- and nanoparticles. To circumvent HF, we dissolved the SiO2-NPs by base-catalyzed hydrolysis at room temperature or under microwave irradiation using potassium hydroxide, replacing the stabilizing fluoride ions with OH−, and exploiting the stability of the orthosilicic acid monomer under a strongly basic pH. Inductively coupled plasma – optical emission spectroscopy (ICP-OES) or a colorimetric assay served to quantify silicon. The lowest KOH: SiO2 molar ratio to effectively dissolve and quantify SiO2-NPs was 1.2 for colloidal Stöber SiO2-NPs at a pH >12. Fumed SiO2-NPs (Aerosil®) or food grade SiO2 (E551) containing SiO2-NPs were degradable at higher KOH: SiO2 ratios >8000. Thus, hydrofluoric acid-free SiO2-NP digestion protocols based on KOH present an effective (recoveries of >84%), less hazardous, and easy to implement alternative to current methods.
Preparation and Catalytic Performance of Metal-Rich Pd Phosphides for the Solvent-Free Selective Hydrogenation of Chloronitrobenzene
Feb 2019
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Chun-Shan Lu
Qianwen Zhu
<here is a image 3e4835d662b9ddf8-e71a9b71d436ed92> Xuejie Zhang
Xiaonian Li
A facile synthesis method of palladium phosphide supported on the activated carbon was developed. The effects of Pd precursors for phosphatization, phosphatization temperature, and the ratio of hypophosphite/Pd on the generation of palladium phosphide were investigated, and a generation mechanism of the Pd3P crystal structure is proposed. The results demonstrate that only PdO, rather than Pd or PdCl2, can transform into Pd phosphide without damage to the activated carbon. The penetration of P into the Pd particle can dramatically improve the dispersion of Pd species particles on the activated carbon. The generation of Pd phosphide greatly depends on the phosphatization temperature and the ratio of hypophosphite/Pd. An intact Pd3P crystal structure was obtained when the ratio of hypophosphite/Pd reached 32 and the phosphatization temperature was above 400 °C. The Pd3P supported on the activated carbon exhibited superior catalytic performance in terms of the hydrogenation of halonitrobenzenes to haloanilines because it had few L acids and B acids sites and could not generate deficient-electron active hydrogen atoms as electrophiles.
Platinum Group Metal Phosphides as Efficient Catalysts in Hydroprocessing and Syngas-Related Catalysis
Mar 2018
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Luis Alvarado
<here is a image 598423ccdfb276f6-615cb3e38991ca52> Chiara Boscagli
<here is a image 8a166152ac4406cb-e03a87a1db4ff70f> Stephan Schunk
Platinum group metal phosphides are reviewed as catalytic materials for hydroprocessing and syngas-related catalysis. Starting from synthetic procedures leading to highly disperse nano-particular compounds, their properties in the applications are discussed and compared with relevant benchmarks, if available. Regarding their mode of action, two confronting mechanistic scenarios are presented: (i) a cooperative scenario in which catalytic sites of different functionalities are active in hydroprocessing and (ii) single site catalysis, which appears to be the relevant mode of action in syngas-related catalysis and which occurs over “frustrated” active sites.
Acetic acid mediated leaching of metals from lead-free solders
Dec 2017
<here is a image e77a919339c96d90-77a9edbdd1213be0> Umesh Jadhav
C. Su
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Mital Jadhav-Chakankar
H. Hocheng
The replacement of lead (Pb)-bearing solders by several Pb-free solders is a subject of intense research in these days due to the toxic effects of Pb on the environment. However, the Pb-free solders contain metals such as silver (Ag), copper (Cu), and zinc (Zn). The increasing use of these Pb-free solders again increases the risk of release of Ag, Cu, and Zn metals into the environment. The Pb-free solders can, therefore, be used as a secondary source for the metals which will not only help in environmental protection but also for the resource recovery. This study reports a process to leach metals from hazardous soldering materials by acetic acid. Acetic acid was found more effective for metal recovery from the tin–copper (Sn–Cu) solder than tin–copper–silver (Sn–Cu–Ag) solder. Various process parameters were optimized for recovery of metals from Sn–Cu solder. It required 30 h for 100% recovery of Cu and Sn, respectively. The metal recovery increased gradually with an increase in acid concentration approaching complete recovery at an acid concentration of 80%. Effect of shaking speed and temperature on the recovery of metals from Sn–Cu solder was studied. The metal recovery decreased with an increase in solder weight. The present study reveals an effective process to recycle the Pb-free solders. The low concentration of acetic acid was also found significant for metal leaching from solder. The research provides basic knowledge for recovery of metals from Pb-free solders.
A ligand-free Pd(OAc)2 catalyst for the Wacker oxidation of styrene derivatives using hydrogen peroxide as the oxidant
Nov 2016
Xiaomeng Xia
Xi Gao
Junhui Xu
<here is a image 7c27d79046bcee1c-e1ba1199c46f3fe5> Xinhua Peng
A feasible palladium-catalyzed Wacker oxidation system has been developed, which is characterized by not adding ligand and using hydrogen peroxide as the sole oxidant. Compared with the traditional Wacker system, the newly developed method offers a cost-efficient and environment-friendly choice without using copper species, and can be applied to more complex substrates.
Influence of phosphorus concentration on the state of the surface layer of Pd–P hydrogenation catalysts
Sep 2016
T. P. Sterenchuk
L. B. Belykh
<here is a image b00728bd544319f8-3ba64371f971ac7e> Nikita Skripov
F. K. Schmidt
Phase composition and surface layer state of the Pd–P hydrogenation catalyst formed at various P/Pd ratios from Pd(acac)2 and white phosphorus in a hydrogen atmosphere were determined. Palladium on the catalyst surface is mainly in two chemical states: as Pd(0) clusters and as palladium phosphides. As the P/Pd ratio increases, the fraction and size of palladium clusters decrease, and also the phase composition of formed palladium phosphides changes: Pd3P0.8 → Pd5P2 → PdP2. The causes of the modifying action of phosphorus on the properties of palladium catalysts for hydrogenation of unsaturated compounds were considered.
The state of palladium in the nanosized hydrogenation catalysts modified with elemental phosphorus
<here is a image b00728bd544319f8-3ba64371f971ac7e> Nikita Skripov
<here is a image 52d0841a3b19e8ab-4e0074b9e8da7b87> Vladlen Akimov
L. B. Belykh
F. K. Schmidt
The size, nature, and surface state of nanoparticles formed by reduction of Pd(acac)2 with hydrogen in the presence of P4 have been elucidated by means of X-ray photoelectron spectroscopy, X-ray powder diffraction analysis, and transmission electron microscopy. The nanoparticles (average diameter of 5.6 nm) consist of Pd6P and palladium nanoclusters (at initial ratio P/Pd = 0.3). Dimethylammonium dihydro- and hydrophosphates are found in the surface layer of the catalyst nanoparticles. The nanoparticles are stabilized by ammonium salts formed via dimethylformamide hydrolysis.
Synthesis and Hydrodesulfurization Properties of Noble Metal Phosphides: Ruthenium and Palladium
Full-text available
<here is a image 01737c4dff0cba32-43680c25ecb025c4> Mica Smith
Richard H. Bowker
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Bo Carrillo
<here is a image 2c0143ff5348513a-654bc898de65f25b> Mark E. Bussell
Silica-supported ruthenium and palladium phosphide catalysts (Ru2P, RuP, Pd3P, Pd5P2) were investigated for the hydrodesulfurization (HDS) of dibenzothiophene (DBT). The Ru and Pd phosphide catalysts were prepared by temperature-programmed reduction of hypophosphite-based precursors consisting of uncalcined or calcined Ru/SiO2 or Pd/SiO2 impregnated with ammonium hyposphosphite (NH4H2PO2). The Ru2P/SiO2 and RuP/SiO2 catalysts prepared from uncalcined precursors had smaller average crystallite sizes, higher CO chemisorption capacities, and higher HDS activities than the catalysts prepared from the calcined precursors, while the effect of preparation method on catalytic properties was less clear for the Pd3P/SiO2 and Pd5P2/SiO2 catalysts. Following HDS testing at 673 K, X-ray diffraction analysis revealed that the Pd5P2/SiO2 catalysts decomposed to give Pd3P on the silica support, while the other phosphides exhibited good stability during the testing period. At temperatures at which high DBT conversion was observed (>598 K), the Ru and Pd phosphide catalysts were less active than sulfided Ru/SiO2 and Pd/SiO2 catalysts prepared from the uncalcined metal precursors.
Single-Atom Catalysts: A New Frontier in Heterogeneous Catalysis
Full-text available
ACCOUNTS CHEM RES
<here is a image a1cb5ed0e29be62f-1d6b27283882b039> Botao Qiao
<here is a image fd3a886a92b59a72-dca2186a261d3d18> Zhang Tao
Supported metal nanostructures are the most widely used type of heterogeneous catalyst in industrial processes. The size of metal particles is a key factor in determining the performance of such catalysts. In particular, because low-coordinated metal atoms often function as the catalytically active sites, the specific activity per metal atom usually increases with decreasing size of the metal particles. However, the surface free energy of metals increases significantly with decreasing particle size, promoting aggregation of small clusters. Using an appropriate support material that strongly interacts with the metal species prevents this aggregation, creating stable, finely dispersed metal clusters with a high catalytic activity, an approach industry has used for a long time. Nevertheless, practical supported metal catalysts are inhomogeneous and usually consist of a mixture of sizes from nanoparticles to subnanometer clusters. Such heterogeneity not only reduces the metal atom efficiency but also frequently leads to undesired side reactions. It also makes it extremely difficult, if not impossible, to uniquely identify and control the active sites of interest.
From materials discovery to system optimization by integrating combinatorial electrochemistry and data science
Helge S. Stein
Alexey Sanin
Fuzhan Rahmanian
Lisa Schroeder
Insight generation from electrochemical experiments augmented by data science requires broad, systematic, and well-defined parameter variations which build upon automation, data management, and flexible instrumentation interfaces. Combinatorial electrochemical synthesis of interfaces and interphases with liquid electrolytes by automated high-throughput robots offers the required high reproducibility. However, automation of electrochemistry is not enough as data needs to be collected in ways that make it machine readable and interpretable. Once established this integration allows scientists and algorithms to transfer knowledge and insights from interfaces and interphases to systems like batteries. Herein we present an overview of recent innovative methods of combinatorial electrochemistry and synthesis which have been integrated into our platform for accelerated electrochemical storage research (PLACES/R), targeting the entire battery research value chain.
Metal Phosphides and Sulfides in Heterogeneous Catalysis: Electronic and Geometric Effects
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> D. Q. Li
<here is a image 0f04d10ab22831b9-81b4523d60851f60> Yanan Liu
Alan J. McCue
Highly efficient photocatalytic Suzuki coupling reaction by Pd3P/CdS catalyst under visible-light irradiation
CHINESE CHEM LETT
Huai-Qing Yang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Qian-Qian Chen
<here is a image 0f9c103aff1ec7c2-2a909f08752a9a1f> Fulai Liu
<here is a image 120c656b1a5e31ac-3a8919a83e7e12e5> Yong Chen
Monodispersed palladium phosphide (Pd3P) (5.2 ± 0.5 nm) was firstly applied to photocatalytic Suzuki coupling reaction under visible light irradiation with CdS nanoflake as a photosensitizer. This heterogeneous system exhibited high yields to corresponding products and excellent stability in alcohol solvent at room temperature.
Palladium Phosphide as a Stable and Efficient Electrocatalyst for Overall Water Splitting
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Fang Luo
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Quan Zhang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Xinxin Yu
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Hansong Cheng
Efficient bifunctional electrocatalyst toward hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is highly desirable to substitute platinum and iridium oxide for water splitting. Herein, we report a novel palladium phosphide electrocatalyst supported on carbon black (PdP2@CB) for efficient water splitting in both alkaline and neutral electrolytes. Significantly lower overpotentials are required for PdP2@CB (27.5 mV in 0.5 M H2SO4; 35.4 mV in 1 M KOH; 84.6 mV in 1 M PBS) to achieve the HER electrocatalytic current density of 10 mA cm‐2 compared to commercial Pt/CB (30.1 mV in 0.5 M H2SO4; 46.6 mV in 1 M KOH; 122.7 mV in 1 M PBS). Moreover, undetectable loss in HER activity is recorded after 5000 potential sweeps in all pH values for PdP2@CB electrocatalyst indicating an exceptional durability. Additionally, only 270 mV and 277 mV overpotentials are required to reach current density of 10 mA cm‐2 for PdP2@CB to catalyze OER in 1 M KOH and 1 M PBS electrolytes, which exhibits better OER activity compared to the benchmark IrO2 electrocatalyst demanding 301 mV and 313 mV to drive current density of 10 mA cm‐2. 1.59 V and 1.72 V are needed for PdP2@CB to achieve stable water splitting catalytic current density of 10 mA cm‐2 in 1 M PBS and 50 mA cm‐2 in 1 M KOH for 10 h, respectively. This study presents a particularly efficient and stable bifunctional electrocatalyst for water splitting in neutral electrolyte.
Palladium Phosphide as a Stable and Efficient Electrocatalyst for Overall Water Splitting
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Fang Luo
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Quan Zhang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Xinxin Yu
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Hansong Cheng
Efficient bifunctional electrocatalyst toward hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is highly desirable to substitute platinum and iridium oxide for water splitting. Herein, we report a novel palladium phosphide electrocatalyst supported on carbon black (PdP2@CB) for efficient water splitting in both alkaline and neutral electrolytes. Significantly lower overpotentials are required for PdP2@CB (27.5 mV in 0.5 M H2SO4; 35.4 mV in 1 M KOH; 84.6 mV in 1 M PBS) to achieve the HER electrocatalytic current density of 10 mA cm‐2 compared to commercial Pt/CB (30.1 mV in 0.5 M H2SO4; 46.6 mV in 1 M KOH; 122.7 mV in 1 M PBS). Moreover, undetectable loss in HER activity is recorded after 5000 potential sweeps in all pH values for PdP2@CB electrocatalyst indicating an exceptional durability. Additionally, only 270 mV and 277 mV overpotentials are required to reach current density of 10 mA cm‐2 for PdP2@CB to catalyze OER in 1 M KOH and 1 M PBS electrolytes, which exhibits better OER activity compared to the benchmark IrO2 electrocatalyst demanding 301 mV and 313 mV to drive current density of 10 mA cm‐2. 1.59 V and 1.72 V are needed for PdP2@CB to achieve stable water splitting catalytic current density of 10 mA cm‐2 in 1 M PBS and 50 mA cm‐2 in 1 M KOH for 10 h, respectively. This study presents a particularly efficient and stable bifunctional electrocatalyst for water splitting in neutral electrolyte.
Synthesis of palladium phosphides for aqueous phase hydrodechlorination: Kinetic study and deactivation resistance
<here is a image 0136e0419ff369f9-016675146c59c2cf> Zhijie Wu
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Tao Pan
Yan Chai
Minghui Zhang
We report the synthesis of noble metal phosphides by a temperature-programmed reduction method for aqueous phase hydrodechlorination (HDC) of 4-chlorophenol (4-CP). Pd3P0.95/SiO2, Rh2P/SiO2 and PtP2/SiO2 catalysts were prepared and showed higher 4-CP HDC rates than their corresponding noble metal catalysts. Pd3P0.95/SiO2 sample exhibited a higher HDC rate than the other phosphide catalysts and Pd/SiO2 catalysts. The XPS spectra show the surface interaction reactions of the Pd and P species that occur via the electron transfer from Pd to P. Pd3P0.95/SiO2 was synthesized with different phosphide particle size (1.1–13.5 nm based on hydrogen chemisorptions) via changing the metal loading from 1 to 10 wt%. The 4-CP HDC reaction is sensitive to the size of the Pd and Pd3P0.95 particles, and the optimum sizes for Pd/SiO2 and Pd3P0.95/SiO2 were ∼8 and ∼5 nm, respectively. The effects of the initial 4-CP and Cl− ion concentration and the S to Pdsurf (surface active Pd metal sites determined by hydrogen chemisorptions) ratio on the 4-CP HDC activity were examined for both catalysts. The Langmuir-Hinshelwood kinetic model that was developed considering the surface reaction as the rate-determining step suggests P has an enhancing effect on sorption in the 4-CP HDC reaction and an inhibiting effect on chloride sorption for Pd3P0.95/SiO2. Moreover, Pd3P0.95/SiO2 possesses better sulfide resistance than Pd/SiO2 because P can prevent the conversion of Pd metallic sites into inactive Pd4S compounds with a sulfide treatment. As a result, Pd3P0.95/SiO2 shows better HDC stability than those of Pd/SiO2 catalysts.
Palladium phosphide nanoparticles as highly selective catalysts for the selective hydrogenation of acetylene
Pd3P and PdP2 phases of ca. 4 nm particle diameter were prepared on a TiO2 support by an impregnation route. Data from the hydrogenation of acetylene under both non-competitive and competitive conditions showed that PdP2/TiO2 exhibits enhanced selectivity and stability relative to Pd3P. Furthermore, the selectivity produced over PdP2 (84% ethylene selectivity @ 100% acetylene conversion) compares favorably with recently reported materials. XPS and CO-IR measurements reveal that the incorporation of P helps to break up contiguous Pd sites. This in turn is thought to affect the adsorption and desorption of reactants/products and thus improves selectivity. This work reveals that the incorporation of P into Pd materials could be regarded as a promising approach to develop new and improved Pd-based catalyst by creating a means to control the nature of the active sites.
The First Structure Determination of Nanosized Colloidal Particles of Pd3 P by High-Resolution Electron Microscopy
ANGEW CHEM INT EDIT
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Anna Carlsson
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Takeo Oku
<here is a image 4cd0df4e3c71dcf6-b3ed90972fb74422> Jan-Olov Bovin
Thomas Kubicki
The exact three-dimensional structure of a nanosized colloidal particle of Pd3 P was determined directly from high-resolution transmission electron microscopy (HRTEM) images that were recorded in several crystallographic directions. An HRTEM image recorded along [011] is shown on the right. The cores of the particles were excluded from the analysis because of severe multiple diffraction.
Wacker Oxidation of Terminal Alkenes Over ZrO2‐Supported Pd Nanoparticles Under Acid‐ and Cocatalyst‐Free Conditions
Taishin Hashiguchi
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Makoto Tokunaga
Highly efficient Wacker oxidation of aromatic or aliphatic terminal alkenes into methyl ketones and benzofurans is developed by using reusable Pd0 nanoparticles (NPs) supported on ZrO2 under acid- and cocatalyst-free conditions. Molecular oxygen or air can be utilized as the terminal oxidant, which results in the formation of H2O as the only theoretical byproduct. The activation of the Pd NPs by O2 plays an important role in promoting this reaction. Interestingly, PdO supported on ZrO2 showed no activity. Additionally, the Pd particle size significantly affects the catalytic activity, with an apparent optimal diameter of 4–12 nm. In addition to the heterogeneous catalyst forms, the Pd NPs can be generated from a Pd0 complex during the reaction, and these particles are even recyclable.
Isolated Single-Atom Pd Sites in Intermetallic Nanostructures: High Catalytic Selectivity for Semihydrogenation of Alkynes
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Quanchen Feng
<here is a image aafc4dfea8b5cac2-edd2865f4cccb783> Shu Zhao
<here is a image 0fff917ad7710b16-e0bb5ff88862f60d> Yu Wang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Yadong Li
Improving the catalytic selectivity of Pd catalysts is of key importance for various industrial processes and remains a challenge so far. Given the unique properties of single-atom catalysts, isolating contiguous Pd atoms into single-Pd-site with another metal to form intermetallic structures is an effective way to endow Pd with high catalytic selectivity and to stabilize the single site with the intermetallic structures. Based on density functional theory modeling, we demonstrate that (110) surface of Pm-3m PdIn with single-atom Pd sites shows high selectivity for semi-hydrogenation of acetylene, whereas (111) surface of P4/mmm Pd3In with Pd trimer sites shows low selectivity. This idea has been further validated by experimental results that intermetallic PdIn nanocrystals mainly exposing (110) surface exhibit much higher selectivity for acetylene hydrogenation than Pd3In nanocrystals mainly exposing (111) surface (92% vs. 21% ethylene selectivity at 90 °C). This work provides insight for rational design of bimetallic metal catalysts with specific catalytic properties.
Catalysis by Supported Metal Single Atoms
<here is a image 6583d4e0eb18ab08-91c96c188f880e99> Jingyue Liu
The recent explosive growth in research on catalysis by supported metal single atoms proves the scientific interest in this new frontier of heterogeneous catalysis. A supported single-atom catalyst (SAC) contains only isolated individual atoms dispersed on, or coordinated with, the surface atoms of an appropriate support. SACs not only maximize the atom efficiency of expensive metals but also provide an alternative strategy to tune the activity and selectivity of a catalytic reaction. When metal single atoms are strongly anchored onto high-surface-area supports SACs offer a great potential to significantly transform the field of heterogeneous catalysis that is critical to many important technologies. In this Perspective Review, I discuss the most recent advances in preparing, characterizing, and catalytically testing SACs with a focus on correlating the structural perspective of the anchored single metal atoms to the observed catalytic performances. The grand challenge to successfully developing practical SACs is to find appropriate approaches to strongly anchor the metal single atoms and to keep them stable during the desired catalytic reactions. I will highlight the recent advances to overcoming this barrier to develop SACs for a variety of catalytic transformations of molecules.
Structurally Characterized Transition-Metal Phosphine Complexes of Relevance to Catalytic Reactions
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nancy L Jones
A catalytic reaction that occurs under homogeneous conditions can be probed by spectroscopic and kinetic methods, but hardly by crystallographic techniques. Why then include in a book concerned with homogeneous catalysis a chapter on the structures of isolable transition-metal phosphine complexes? There are several answers. One is that such structures provide details, albeit indirectly, on the substrate-metal interaction that occurs in such a reaction. How this interaction is affected by the nature of the metal and its ligands can be probed macroscopically by kinetic measurements; it can also be probed at the molecular level in a qualitative way by spectroscopic methods. But if one seeks metrical details about the interaction, then one must turn to diffraction studies on stable, isolable analogues of the original system. Of course, one must employ spectroscopic methods to establish that the analogue is indeed a good model for the temporal species in the catalytic reaction. A second answer is that such structural information is an aid to the formulation of reaction schemes, some of which are based on minimal data. In such schemes there frequently are proposed intermediates of new or unusual structures. Known structures may serve as a basis for such speculation. Sometimes, of course, a scheme may precede the isolation and characterization of a new structural type. In such instances the ensuing characterization of a useful analogue supports the credibility (or perhaps minimizes the incredibility) of the scheme.
Ligand electronic effects in homogeneous catalysis using transition metal complexes of phosphine ligands
<here is a image 6908bd25c99b778d-b3078eefa9954acf> Jamie John Russell Frew
This report provides a discussion on the relative importance of electronic and steric effects in catalysis. More specificially, electronic effects that arise from phosphorus based supporting ligands in palladium catalysed cross-coupling and rhodium catalysed hydroformylation are reviewed and analysed. The report identifies certain trends that emerge from the literature data, and also points out that these effects can sometimes be subtle, or an indirect effect on the catalytic reaction rather than changing the rate of any of the key steps in the catalytic cycle directly.
A Facile Molecular Precursor Route to Metal Phosphide Nanoparticles and Their Evaluation as Hydrodeoxygenation Catalysts
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Frederick G. Baddour
<here is a image 966f122a3506e434-70a1a36e5aeeefa7> Joshua Schaidle
Metal phosphides have been identified as a promising class of materials for the catalytic upgrading of bio-oils, which are renewable and potentially inexpensive sources for liquid fuels. Herein, we report the facile synthesis of a series of solid, phase-pure metal phosphide nanoparticles (NPs) (Ni2P, Rh2P, and Pd3P) utilizing commercially available, air-stable metal-phosphine complexes in a one-pot reaction. This single-source molecular precursor route provides an alternative method to access metal phosphide NPs with controlled phases and without the formation of metal NP intermediates that can lead to hollow particles. The formation of the Ni2P NPs was shown to proceed through an amorphous Ni-P intermediate, leading to the desired NP morphology and metal-rich phase. This low-temperature, rapid route to well-defined metal NPs is expected to have broad applicability to a variety of readily available or easily synthesized metal-phosphine complexes with high decomposition temperatures. Hydrodeoxygenation of acetic acid, an abundant bio-oil component, was performed to investigate H2 activation and deoxygenation pathways under conditions that are relevant to ex situ catalytic fast pyrolysis (high temperatures, low pressures, and near-stoichiometric H2 concentrations). The catalytic performance of the silica-supported metal phosphide NPs was compared to the analogous incipient wetness (IW) metal and metal phosphide catalysts over the range 200-500°C. Decarbonylation was the primary pathway for H2 incorporation in the presence of all of the catalysts except NP-Pd3P, which exhibited minimal productive activity, and IW-Ni, which evolved H2. The highly controlled NP-Ni2P and NP-Rh2P catalysts, which were stable under these conditions, behaved comparably to the IW-metal phosphides, with a slight shift to higher product onset temperatures, likely due to the presence of surface ligands. Most importantly, the NP-Ni2P catalyst exhibited H2 activation and incorporation, in contrast to IW-Ni, indicating that the behavior of the metal phosphide is significantly different from that of the parent metal, and more closely resembles that of noble metal catalysts.
Tsuji–Wacker Oxidation of Terminal Olefins using a Palladium–Carbon Nanotube Nanohybrid
CHEMCATCHEM
<here is a image 122b08903940b9bd-05bbd8a96ba1f259> Simon Donck
<here is a image 848dfcbf42003800-b823f747ee075de8> Edmond Gravel
<here is a image 7114a760c7758a87-95ad69645ae9156a> Nimesh Shah
<here is a image c01ec5eff1926c06-745417c84afd5f8a> Irishi N. N. Namboothiri
Palladium nanoparticles supported on carbon nanotubes were used in the Tsuji–Wacker oxidation. The palladium‐based nanohybrid was found to be very active in combination with cuprous chloride for the selective oxidation of terminal olefins into methyl ketones. The co‐catalytic system operates under very mild and sustainable conditions (room temperature, atmospheric pressure, low catalyst loading), as opposed to previously reported catalysts, and can be recycled without any loss in activity. Give it a whack: Palladium nanoparticles supported on carbon nanotubes are used in combination with cuprous chloride for the selective Tsuji–Wacker oxidation of terminal olefins into methyl ketones. The co‐catalytic system operates under very mild and sustainable conditions and can be recycled without any loss in activity.
ChemInform Abstract: Deactivation of Solid Catalysts in Liquid Media: The Case of Leaching of Active Sites in Biomass Conversion Reactions
This review is aimed to be a brief tutorial covering the deactivation of solid catalysts in liquid phase, with specific focus on the leaching case, which can be especially helpful to researchers not familiarized with catalytic processes in liquid phase. Leaching refers to the loss of active species from the solid that are transferred into the liquid medium, causing eventually a deactivation of the catalyst. Intriguingly, not many published studies deal with leaching, since this is a specific phenomenon in liquid phase and heterogeneous catalysis occurs traditionally in gaseous phase. However, as a consequence of the development of new processes for biorefieneries, an increasing number of reactions deal with liquid media, and thus, the stability and reusability of solid catalyst in this situation represents a huge challenge that requires specific attention. Leaching of active phases is particularly problematic because of its irreversibility and it can be one of the main causes of catalyst deactivation in liquid media, threatening the sustainability of the process. This tutorial review presents a survey of the main aspects concerning the deactivation due to leaching of active species from the solid catalyst: mechanisms, detection methods, impact of these factors on the global activity and finally, some procedures to try to minimize the leaching or to cope with it. A decision flowchart is presented to help in the study of the catalyst stability and reusability. Interesting biomass conversion reactions have been chosen as examples to illustrate the importance of these aspects.
Highly selective Wacker oxidation of terminal olefins using magnetically recyclable Pd–Fe3O4 heterodimer nanocrystals
A new highly selective and environment-friendly Wacker oxidation process employing superparamagnetic Pd-Fe3O4 heterodimer nanocrystals in EtOH-H2O under 1 atm O2 has been developed. Consistently high yields of the desired Wacker product and excellent reaction selectivity were observed in almost all of the reactions examined. This operationally simple oxidation protocol allows recycling of the Pd-Fe3O4 catalyst after the reaction through the use of an external magnet.
Benzaldehyde synthesis via styrene oxidation by O2 over TiO2 and TiO2/SiO2
Styrene was oxidized by molecular oxygen over TiO2 and TiO2/SiO2 for the formation of benzaldehyde. In the absence of catalyst at 100 °C and 10 atm O2, polystyrene is the major product. Over the catalysts, the oxidation of styrene is enhanced with benzaldehyde and formaldehyde being the major whereas phenylacetaldehyde, acetophenone, styrene oxide, benzoic acid, and polymer being the minor products. The polymerization of styrene was initiated by the radicals formed in the oxidation reaction. The addition of radical inhibitor nitrobenzene and/or the employment of a catalyst of high specific surface area can promote the termination of the radicals, and hence improve the selectivity of benzaldehyde.
ChemInform Abstract: Metal Phosphides: Preparation, Characterization and Catalytic Reactivity
The preparation, characterization, and catalytic activity of supported metal phosphides are reviewed. Reduction of metal compounds together with phosphate is a convenient method to prepare metal phosphides, but requires high temperature. Reduction with phosphite, hypophosphite, or phosphine and the plasma reduction of phosphate can be carried out at lower temperatures, which leads to smaller metal phosphide particles and more active catalysts. Organometallic routes allow the separate synthesis of metal phosphide nanoparticles, which have to be added to the support in a second step. LEED, STM, XPS, and DFT studies have shown that the surfaces of Ni2P reconstruct to P-rich surfaces. The investigation of metal phosphides as catalysts for hydrotreating reactions continues to be a topic of considerable research with recent advances realized in using bimetallic and noble metal phosphides to achieve high activities and tailored selectivities. Finally, hydrodeoxygenation catalysis over metal phosphides is a growing area of research given the need to develop catalysts for upgrading biomass to transportation fuels.
Graphical Abstract
Structural features of some phases related to cementite
Investigations during the last few years have shown that a number of ; phases, especially borides, of the seventh and eighth group metals are ; isomorphous with cementite or crystallize in structures closely related to that ; of cementite. In this paper the recently obtained structural data are summarized ; and discussed. The influence of the radius ratio on trends in interatomic ; distances and lattice parameters is particularly considered. On basis of the ; presented data some general remarks on complicated'' interstitial phases are ; also made. (auth);
The Crystal Structure of Pd3P
: An X-ray investigation of the Pd-P system was initiated. Preliminary results indicated the apparent existence of at least 4 intermediate phases in the range of 0 to 25 at-%P. The existence of a phase near the composition Pd3P was confirmed. The homogeneity range determined from alloys quenched from 740 C extended from about Pd3P.75 to Pd3P1. The crystal structure was determined by examination of single-crystals selected from an alloy with the approximate composition PdeP.95. The following structural data for PdeP.95 were obtained: a equal to 5.947, b equal to 7.451, c equal to 5.170, and U eqaul to 229.1 angstroms.
Heteropolyanions as Redox Components in Heterogeneous Wacker Oxidation Catalysts
Heteropolyanions (HPAs) of the Keggin type have been successfully applied as redox components in heterogeneous Wacker catalysts. The catalysts consist of a silica support covered with a layer of HPA of the series H3+nPVnMo12−nO40 on which a submonolayer of palladium sulfate is deposited. The initial butanone yield in the oxidation of 1-butene at 343 K is approximately 0.10 g butanone per gram of catalyst per hour. The steady-state activity is, however, a factor of 10 lower due to the slow reoxidation of reduced HPA. The rate of reoxidation and hence the steady-state activity increases with increasing number (n) of vanadium atoms per Keggin unit and when the protons of the HPA are replaced by Cu2+ or by Ni2+. Even higher activity is obtained with palladium salts of heteropolyacids. In these palladium salts the palladium reaction centre and the redox component are combined in one complex. The butanone selectivity of the catalysts with n > 0 is high, viz. >95%, and increases with increasing values of n to more than 98%. The butanone selectivity also increases when the protons are exchanged for metal cations, such as Cu2+, Ni2+, Pd2+, or Cs+. The stability of the Keggin units under reaction conditions is high. Under Wacker oxidation conditions the HPAs are partly reduced, but DRIFT and ESR spectroscopy and TPR analysis of used catalysts show that the Keggin structure remains intact. Reoxidation of the reduced HPAs is, however, slow under reaction conditions.
Heterogeneously catalyzed vapor-phase oxidation of ethylene to acetaldehyde
A heterogeneous catalyst system has been developed for the vapor-phase oxidation of ethylene to acetaldehyde. The catalyst consists of palladium-doped vanadium pentoxide and, usually, a third component such as Ti, Ru, Pt, or Ir. Mechanistic studies, especially by ESR spectroscopy, have established a redox mechanism with the palladium ions playing a central role. The catalyst system operates under mild conditions (110–175 °C and 1–30 atm) with good efficiency and high space-time yields.
Highly active and selective catalysts of hydrogenation based on palladium bis-acetylacetonate and phenylphosphine
Catalytic properties of the hydrogenation system based on palladium bis-acetylacetonate and phenylphosphine have been studied. Promoting effect of phenylphosphine with low ratio P/Pd has been found. Interaction between phenylphosphine and Pd(acac)2 in hydrogen atmosphere leads to the formation of Pd6P and associates of palladium polynuclear complexes with organophosphorous ligand, on which Pd(0) clusters are immobilized.
Modified Wacker TBHP oxidation of 1-dodecene
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> José Aguado
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Michael Paul Bravo
A higher 1-olefin (1-dodecene) was oxidized to 2-dodecanone and other ketones in a modified Wacker system featured by omitting the use of copper chloride and employing tert-butylhydroperoxide (TBHP) as oxidant. Acetonitrile was the solvent of choice due to its higher selectivity towards 2-dodecanone, the reaction occurring mostly in the interface. A maximum in conversion and selectivity was measured for a ratio [CH3CN]/[1-dodecene]=10. The temperature abatement enhances the 2-dodecanone selectivity (61% at 40°C) because of the lower extent of the competing isomerization reactions. An optimum in 2-dodecanone selectivity was found for a [TBHP]/[1-dodecene] ratio=7. The use of H2O2 as oxidant led towards slower oxidation rates than TBHP. Other palladium salts (PdSO4 and Pd(CH3COO)2) and several R–CN solvents (propionitrile, benzonitrile, isobutyronitrile) yielded lower performances than palladium chloride and acetonitrile, respectively. On the contrary, β-cyclodextrin, a phase transfer catalyst, improved the selectivity towards 2-dodecanone.
The performance of titania-supported Wacker catalysts in the oxidation of 1-butene
The kinetics of 1-butene oxidation over titania-supported catalysts has been investigated. The reaction rate shows a first-order dependence on 1-butene and water coverage at low partial pressures. At higher partial pressures of water in the feed the reaction rate first strongly increases and then levels off, when the water coverage exceeds a monolayer, probably due to partial dissolution of PdSO4. The concentration of dioxygen in the feed has a slight positive influence on the activity up to 15 kPa. Heterogeneous Wacker catalysts consist of a palladium salt deposited on a vanadium pentoxide layer on a support material such as titania. The composition of the catalyst appears to be of major influence on its performance. For palladium acetate-based catalysts the activity shows a first order in the palladium coverage. The activity of the catalysts decreases with increasing vanadium oxide coverage. Temperature programmed reduction (TPR) shows that the reduction temperature of the vanadium oxide overlayer increases with increasing coverage. The easiness of reducibility of the titania-supported catalysts in comparison to the alumina-based ones is directly related to the one order of magnitude higher activity of the tinania-based catalysts. On oxidizing 1-butene to butanone, the activity of titania-supported catalysts decreases by approximately 60% during the first 100 h of operation. After this initial deactivation, the activity and selectivity of the catalyst remains stable for more than 700 h. TPR and high resolution electron microscopy (HREM) show that this deactivation is mainly caused by a slight sintering of the vanadium oxide layer.
Palladium-copper-exchanged Y type zeolites: A true heterogeneous Wacker catalyst
Evidence is presented that faujasite-type zeolites with specific Si : Al framework ratios exchanged with Pd(NH3)42+ and Cu2+, catalyse the oxidation of ethylene into acetaldehyde, in exactly the same way as the homogeneous Wacker system [PdII and CuII in concentrated chloride solution]; the active centre is found to be a partially ammoniated PdII ion, most probably PdII(NH3)2, which itself belongs to an electron transfer chain consisting of the alkene reagent, the faujasite encaged PdII/Pd0 and CuII/CuI redox couples and dioxygen.
Kinetics and mechanism of the gas-phase oxidation of 1-butene to butanone over a new heterogenized surface vanadate Wacker catalyst
A study has been made of the kinetics and mechanism of the oxidation of 1-butene to methyl ethyl ketone (MEK) over a new heterogeneous vana- date monolayer Wacker catalyst, in the temperature range of 363 to 408 K and at 0.11 MPa total pressure. The kinetics of reaction with respect to the dependency of the reaction rate on the partial pressures of 1-butene and of water, as well as on the surface Pd and NaCl concentrations, is logically related to the kinetics of the homogeneous Wacker process. At 10% con- version, the main product (MEK) is formed with 80 - 95% selectivity. The formation of byproducts, including crotonaldehyde, acetone, acrolein, acetaldehyde and acetic acid, has been studied and a reaction scheme developed. From an XPS/AES analysis of spent catalysts, it follows that deactivation is probably caused by a gradual decrease of the chlorine surface concentration. Compensation for the loss of chlorine by adding HCl to the deactivated catalyst leads to a partly regenerated catalyst. Replacing the PdCl2/NaCl sub-monolayer by PdSO4/H2SO4 leads to a stable catalyst.
Mesoporous Matrix Encapsulation for the Synthesis of Monodisperse Pd5P2 Nanoparticle Hydrodesulfurization Catalysts
ACS APPL MATER INTER
The synthesis of monodisperse 5-10 nm Pd5P2 catalytic particles by encapsulation in a mesoporous silica network, along with preliminary data on hydrodesulfurization (HDS) activity, is reported. Precursor Pd-P amorphous nanoparticles are prepared by solution-phase reaction of palladium (II) acetylacetonate with trioctylphosphine at temperatures up to 300 ºC. Direct crystallization of Pd5P2 in solution by increasing the temperature to 360 ºC leads to sintering, but particle size can be maintained during the transformation by encapsulation of the amorphous Pd-P particles in a mesoporous silica shell, followed by treatment of the solid at 500 ºC under a reducing atmosphere, yielding Pd5P2@mSiO2. The resultant materials exhibit high BET surface areas (> 1000 m2/g) and an average pore size of 3.7 nm. Access to the catalyst surface is demonstrated by dibenzodithiophene (DBT) HDS testing. Pd5P2@mSiO2 shows a consistent increase in HDS activity as a function of temperature, with DBT conversion approaching 60% at 402 °C. The ability to control particle size, phase, and sintering is expected to enable the fundamental catalytic attributes that underscore activity in Pd5P2 to be assessed.
Palladium-catalyzed oxidation of terminal olefins to methyl ketones by hydrogen peroxide
Endständige Olefine (I) reagieren mit Wasserstoffperoxid in Gegenwart von Pd-Katalysatoren zu den Methylketonen (II).
Catalytic properties of metal phosphides. I. Qualitative assay of catalytic properties
Preparation of transition metal phosphides supported on alumina was effected by deposition of metal complexes or organometallic compounds on alumina followed by hydrogen reduction and then reaction with phosphine at ∼200°. A variety of catalytic reactions was utilized to probe the surface chemistry of these phosphides. In the H2-1-butene reaction, phosphorus introduction onto the metal surface changed the reaction course from hydrogenation to isomerization. With ruthenium phosphide surfaces, there was a relatively selective interaction of acetylene and hydrogen to give ethylene. Yet under these same conditions ethylene and hydrogen reacted quite exothermally to give ethane. Acetylene and acetylene plus hydrogen appear to give a surface template of considerable stability; this template then appears to direct the chemical reaction. The acetylene-hydrogen produced template may be primarily σ-bonded vinyl groups which pyrolyze to acetylene and hydrogen (and ethane). Acetylene reacts with the metal phosphide surface in a complex fashion as indicated by the flash pyrolysis products from acetylene treated phosphide. These products include methane, ethane, acetylene, monovinylacetylene, butenes, pentenes, and benzene. The presence of benzene in high concentration in the acetylene reaction suggests multicenter surface sites while the lack of activity of the phosphides for butene hydrogenation indicates that the size and extent of surface metal clusters are quite small.
Mechanism of the Wacker Oxidation of Alkenes over Cu-Pd-Exchanged Y Zeolites
The catalytic potential of CuPd zeolites with faujasite topology in the Wacker oxidation of 1-alkenes with dioxygen is reported and compared with that of a homogeneous PdCl2-CuCl2 salt solution. The influence of water, oxygen, and alkene partial pressure on the rate of oxidation and the use of different alkenes and perdeuterated ethene as substrate allowed to establish similarities between the heterogeneous and homogenous system as well as specific zeolite effects. In situ IR and ESR spectroscopy of a working catalyst allowed to propose an active site consisting of a trinuclear Cu-O-Pd-O-Cu cationic complex and a catalytic cycle for the Wacker oxidation in which the reoxidation of Cu+ by dioxygen or of Pd0 by zeolite Cu2+ is rate determining. Diagnostic probing of the phenomena with CO in IR and ESR confirmed this picture.
Katalytische Umsetzungen von Olefinen an Platinmetall‐Verbindungen Das Consortium‐Verfahren zur Herstellung von Acetaldehyd
Es wird über einen neuen Weg der katalytischen Oxydation von Olefinen mit Platinmetall-Verbindungen berichtet. Mit Sauerstoff und Oxydationsüberträgern gelingt eine kontinuierliche, selektive Umsetzung zu Carbonyl-Verbindungen, die offensichtlich über Edelmetall-Olefin-Komplexe abläuft. Die Oxydation ist auch bei anderen ungesättigten Verbindungen möglich und eröffnet neue präparative Möglichkeiten. Die Methode ist Grundlage aussichtsreicher technischer Verfahren für die Herstellung von Carbonyl-Verbindungen aus niederen Olefinen, insbesondere von Acetaldehyd aus Äthylen.
Formation and Properties of Hydrogenation Catalysts Based on Palladium Complexes with Primary Phosphines
The formation and catalytic properties of hydrogenation catalysts based on palladium(II) complexes with primary phosphines were studied. With the use of IR and UV spectroscopy, XRD analysis and GLC, it was found that the interaction of bis(acetylacetonato)palladium(II) or palladium(II) acetate with primary phosphines in an inert atmosphere resulted in the formation of polynuclear palladium complex associates mainly containing μ3-PR and a coordinated phosphine. Polynuclear palladium complexes and the palladium phosphide Pd6P, which is formed from these complexes in an atmosphere of hydrogen, serve as supports for Pd(0) clusters. The effects of the ratio between initial components and the nature of the acido ligand at the palladium atom on the optimum conditions of catalyst formation were considered.
| https://www.researchgate.net/publication/367657897_Supported_Palladium_Phosphide_Catalyst_for_the_Wacker-Tsuji-Oxidation_of_Styrene |
Kanganwal Branch Post Office, Sangrur 20, Punjab
Kanganwal Post Office, Sangrur
Kanganwal post office is located at Kanganwal, Sangrur of Punjab state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Kanganwal PO is148020. This Postoffice falls under Sangrur postal division of the Punjab postal circle. The related head P.O. for this branch office is Sangrur head post office and the related sub-post office (S.O.) for this branch office is Sandhaur post office.
Kanganwal dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Kanganwal.
Types of Post Offices
Post offices are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Kanganwal P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Kanganwal Post Office & Its Pin Code
Branch Office Information
Kanganwal Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Kanganwal Post Office Recruitment
Location Map
Contact Details
About India Post
Kanganwal Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Kanganwal Post Office has the Postal Index Number or Pin Code 148020. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Kanganwal PO Pincode 148 020
The first digit of 148020 Pin Code '1' represents the region, to which this Post Office of Kanganwal belongs to. The first two digits of the Pin Code '14' represent the sub region, i.e, Punjab. The first 3 digits '148' represent the post-office revenue district, i.e, Sangrur. The last 3 digits, i.e, '020' represent the Kanganwal Delivery Branch Office.
Branch Office Information
The Kanganwal Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Sangrur, which falls under Chandigarh Hq region. The circle name for this PO is Punjab and it falls under Sangrur Taluka and Sangrur District. The state in which this Dakghar is situated or located is Punjab. The related head postoffice is Sangrur post office and the related sub post office is Sandhaur post-office. The phone number of Kanganwal post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Sangrur Postal Region Chandigarh Hq Postal Circle Punjab Town / City / Tehsil / Taluka / Mandal Sangrur District Sangrur State Punjab Related Sub PO Sandhaur Sub Office Related Head PO Sangrur Head Post Office
Kanganwal Post Office Services
Traditionally the primary function of Kanganwal post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Kanganwal P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Kanganwal and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Kanganwal Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Kanganwal can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Kanganwal peoples and nearby living people. The premium services provided by Kanganwal Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Kanganwal customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Kanganwal Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Kanganwal postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Kanganwal postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Kanganwal people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Kanganwal post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Kanganwal customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Kanganwal customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Kanganwal postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Kanganwal can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Kanganwal area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Kanganwal postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Kanganwal postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/-and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Disclaimer: All the information in this website is published for general information purpose only. Some schemes and other postal services may not be available in Kanganwal Post Office. Kindly verify for all India post saving schemes and other postal services with official resources.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 09:00 AM or 10:00 AM and the closing time is 06:00 PM or 07:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Kanganwal Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Kanganwal people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Kanganwal Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Kanganwal postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Kanganwal Post Office Recruitment
For latest Kanganwal post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Kanganwal Branch Post Office is located in Kanganwal, Sangrur.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc. services in Kanganwal Post Office, can be resolved at Kanganwal Branch Post Office. You can send letters to "Postmaster, Kanganwal Branch Post Office, Kanganwal, Sangrur, Punjab, India, Pincode: 148 020". The official website of the Berhampur University Sub Office is www.indiapost.gov.in.
Kanganwal Branch Office
Address: Kanganwal Branch Post Office, Kanganwal, Sangrur, Punjab, India
Pin Code: 148020
Website: www.indiapost.gov.in
About India Post
India Post is a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the India with over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Kanganwal Post Office Summary
Dak Ghar Name Kanganwal Branch Post Office Pincode 148020 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Sangrur Postal Region Chandigarh Hq Postal Circle Punjab Location Kanganwal District Sangrur State Punjab Country India Related Sub Office Sandhaur Sub Office Related Head Office Sangrur Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
Kothala Post Office
| https://www.postoffices.co.in/punjab-pb/kanganwal-sangrur-20/amp/ |
(PDF) Wood Debris Risk Analysis and Protection Scenarios of Lourdes City Using Iberwood Model
PDF | Large wood (LW) accumulations can cause several damages, especially if the recruited wood is transported during floods down to urban areas, like... | Find, read and cite all the research you need on ResearchGate
Wood Debris Risk Analysis and Protection Scenarios of Lourdes City Using Iberwood Model
Conference: SimHydro 2021: Models for complex and global water issues -Practices and expectations
Cédric Perrin
Abstract and Figures
Large wood (LW) accumulations can cause several damages, especially if the recruited wood is transported during floods down to urban areas, like Lourdes (France). One of the most serious problems concerning bridges and weirs all around the world, is the formation of LW accumulations, that might be responsible for the structure's failure. However, the transport and deposition of LW during floods are very complex processes, which make predictions of these accumulations' locations and potential impacts very challenging. Thus, reducing the LW-related risks is difficult. Thereby, we are conducting a study to assess the LW-related hazards by applying a numerical model of the Gave-de-Pau River. The software called Iber-Wood is a hydrodynamic model based on the 2D Saint Venant equations coupled to a wood dynamics module that simulates wood transport explicitly. It allows analyzing LW accumulations' formation, depending on several input parameters. The aim of this study was to simulate wood transport during floods, in order to identify the potential risks created by the formation of LW accumulations in Lourdes' city center. The paper first proposes a framework to calibrate the parameters of LW-supply (flux and size of logs) based on the typical dataset available in France. It then presents a preliminary study of the 2D hydrodynamic model showing its potential to identify preferential storage areas and bridges prone to the formation of LW accumulations. The calibration phase of the model is not finished but we can yet highlight some recommendations on LW-transport modelling from this early stage results.
: Aerial pictures exemplifying the large wood source areas: bank erosion that occurred during the flood as the difference between the blue strip (channel bed in 2010) and the black dotted lines (channel bed in 2013). Green points are automatically detected trees and black dots are false detection removed after manual control (road light poles in this case). …
: Volume of large wood per hectare of forest from the IFN database, subsampled on plots located close from rivers or from wetlands (Database IFN 2013-2018, https://inventaire-forestier.ign.fr/, whole France). More than half of the sites have forest densities in the range of 150-450 m³/ha. …
: Tree diameter estimation: A) tree height versus diameter for 605 000 + deciduous and 222 000 + evergreen trees from the IFN database, linear fits of Eq. (1) in black continuous lines and range Eq. (1)*0.5 or Eq. (1)*2 in dashed lines and B) residual from these fits showing that 90% of trees have diameter in the range of [0.5-2]*predicted diameter …
: Estimation of large wood size: (A) distribution of reduction factor from the dataset of Rickly et al. [12]. The black continuous line is for all logs with D>0.1 m, light grey lines are the same data but clustered by catchments. The dotted line is for logs with D<0.1 m; B) statistical distribution of tree height detected on LiDAR data and LW length computed as the produce of tree height times reduction factor after Monte Carlo analysis. Light grey lines are LW length when using the light grey lines of panel A rather than the black line. LW size typically varies from 1 m to 20 m, most pieces being shorter than 10 m. C) statistical distribution of LW diameter computed by Monte Carlo analysis using tree height detected on LiDAR data, Eq. (1a) and randomly sampling the residual in Fig. 4B data. 99% of pieces have diameter < 0.8 m. …
+4
: Maps with location Lourdes, France (left panel) and of the main structures considered in the model (right panel) …
LARGE WOOD TRANSPORT-RELATED FLOO D RISKS ANALYSIS OF
LOURDES CITY USING IBER-WOOD MODEL
Margaux Quiniou
ISL, 15 rue du Maréchal Harispe 64500 Saint- Jean - de-Luz - FRANCE
[email protected]
Guillaume Piton
Univ. Grenoble Alpes, INRAE, UR ETNA , 2 rue de la Papeterie, 38 402 St-Martin- d’Hères – F RANCE
[email protected]
Virginia Ruiz Villanueva
University of Lausanne, Faculty of Geosciences and the Environment, Institute of Earth Surface Dyna mics
(IDYST), Geopolis, UNIL-Mouline, CH-1015 Lausan ne, SWITZERL AND
[email protected]
Cédric Perrin and Jeremy Savatier
ISL, 15 rue du Maréchal Harispe 64500 Saint- Jean - de-Luz - FRANCE
[email protected], [email protected]
Ernest Bladé
Institut Flumen. Universitat Politècnica de C atalunya. C/ Jordi Girona 1-3 08034 Barcelona, SPAIN
[email protected].
KEY WORDS
Streamwood, flood modelling, bridge clogging, Gave- de-Pau
ABSTRACT
Large wood (LW) accumulations can cause several damages, especially if the recruited wood is transported
during flo ods d own to urban area s, like Lou rdes (F rance). One of the most serious problems concerning bridges and
weirs all around the world, is the formation of LW a ccumulations, that mig ht be responsible for the structure’s fa ilure.
However, the transport and deposition of LW during floods are very complex processes, which make predictions of
these accu mulation s’ locations and potential impacts very ch allenging . Th us, reducing the LW-related risks is d ifficult.
Thereby, we a re cond ucting a study to assess the LW-related hazards by applying a n umerical model of the Gave - de -
Pau River. The software called Iber-Wood is a hydrodyn amic model based on the 2D Sa int Venant equations coupled to
a wo od dynamics module that simulates woo d transport explicitly. It allows analyzing LW accumulations’ formation,
depending on several input parameters. The aim of this study was to simulate wood transport during floods, in order to
identify the potential risk s created by the formation of L W accumulations in Lourdes’ city center. The paper first
proposes a framework to ca librate the p arameters of LW -supply (flux and size of l ogs) based on the typical dataset
available in France. It then presents a prelim inary study of the 2D hyd rodynamic model showing its potential to identify
preferential storage areas an d bridges prone to the formation of LW accu mulations. The calibration ph ase of the model
is not finished but we can yet highlight some recommendatio ns on LW- tr ansport modelling from this early stag e results.
1 INTRODUCTION
It is part of the natural regime of r ivers to convey water, inorganic sediments as well as large wood (LW -
wood pieces longer t han 1 m and thicker than 0.1 m) and other organic matter during h igh magnitude floods
[2 3]. In mountainous catchments and piedmont rivers, large quantities of LW might be transpo rted, and
therefore, this phenomenon must be considered i n flood scenarios [2]. Moreover, streamwood accumulations
can cause several damages when LW is recruited by the flow and transported down t o urban areas. These
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
accumulations exert additional f orces to bridge structures and may l ead to local scouring, erosion, and, most
important ly in our case, usually reduce the hydraulic capacities of bridges and weirs, thus aggravating f lood
level in the vicinity.
However, until recently, LW effects on flooding were often neglected if not completely ignored [9]. Many
scientific works were recently undertaken to assess and predict the supply, transport and deposition of LW in
rivers [16]. Among various tools, numerical models of fluid mechanics were adapted to compute the
transport of LW , for example the software 2D Iber-Wood, considering the wood effects on hydrodynamics
[13]. Such approaches were subsequently used to study , among other t opics, factors controlling the
obstruction of bridges by large wood [19], the increase in flood risk associated to LW clogging [14], but also
large wood mobility in braided and single thread rivers [17] or LW dynamics under unsteady conditions [18].
Iber- Wo od has bee n so far widely applied in scientific projects, and it is continuously enhanced to better
reproduce LW dynamics, but its application t o practical studies is growing. However, users will eventually
need guidelines or examples of application in engineering case studies, regarding simulation input
param et ers, for example defining LW supply or input boundary con ditions.
The Gave-de-Pau River flow s from the Pyrenees mountain massif t hr ough the Lourdes city centre w ith a
catchment area of 1070 km². With many pilgrims visiting the city every year, Lourdes tourism economy is
very important and flood risks are high. The river experienced a large flood event in June 2013. The peak
discharge of 756 m 3 /s had a return period of about 100 years. The hydrological station of Lourdes city centre
recorded the flood hydrograph (total volume ≈ 5 3 000 000 m 3 ). In the valleys upstream from Lourdes city,
major geomorphic changes occurred along a dozen of kil ometres, hectares of floodplains were eroded, the
ponding area formed by old mining activity and called “ l ac -des-Gav es ” was filled by sediment, and a
hydroelectricity dam was affected. Yassine performed an in-depth analysis of the event [2 4] . At Lourdes city
centre, LW blocked several bridges logs were deposited on streets bordering the river . The bas in agency
(PLVG) is looking for a solution to prevent an eventual increase of the flood risk due to transport of LW.
Availabi li ty of hydrological data, from the detailed analysis of Yassine regarding the upstream processes and
the willingness of the PLVG to engage research on solutions lead us to focus on this case study applying
Iber-Wood.
This paper explains in detail how the key parameters of the model were selected, especially the LW-
related input boundary conditions. The method used here is replicable to other similar sites. Different types
of results are shown in this preliminary reconstruction of the clogging of bridge s in the city of L ourdes
during the June 2013 flood . The calibration of the model is not yet finished, and only preliminary results are
provided here. It nonetheless enabled to draw recommendations on how to approach LW modelling and what
can be expected from this type of model.
2 MATERIAL AND METHODS
2.1 Iber-Wood in a nutshell
Iber is a hydrodynamic model solving the shallow-water equations (SWE) on irregular meshes in a classical
Eulerian approach [1]. Based on the last generation of f inite volume numerical schemes, Iber is m ade for the
simulation of free surface flow, morphodynamics, transport processes and habitat in rivers. The software is
freely available (see https://www.iberaula.es/).
In Iber-Wood, Ruiz-Villanueva et al. coupled the hydrodynamics with a Lagrangian description of logs (i.e.,
wood pieces) in order to study large wood movement [13]. Logs are described as doubled cylinders figuring
the trunk and the root wa d. Newton equations of movement are solved at each time step on each log
accounting for log weight, buoyancy, friction on the channel bed, bouncing with other logs as well as the
drag force exerted by the flow on the logs. The model is fully coupled in t he sense that an additional friction
and the associ ated energy dissipation are added to the SWE due to t he wood. An accumulation of logs
against a bridge thus create an additional head loss due to friction. Note that the model being a 2D depth-
averaged model, the obstruction effect of logs, an intrinsically 3D process varying with the log elevation
position, is not taken into account.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
2.2 Iber-Wood parameters
Table 1 shows the main parameters used in the module of wood transport by t he software Iber-Wood. The
following sections explain how we estima ted each of these parameters.
LW Parameters
Unit
Type
Value
Log discharge
Log/minute
Times series
4- 20
Log length
m
Range
4-22
Log diameter
m
Range
0.1-0.8
Rootwad diameter
m
Range
Not used in this study
Rootwad length
m
Range
No t used in this study
Log density
-
Range
460 - 650
Drag coefficient
-
Scalar
1.2 (default)
Friction coefficient
-
Scalar
0.25 (default)
Restitution coefficient
-
Scalar
1.0 (default)
Table 1 : Parameters used in Iber-Wood to describe large wood
2.3 Setting model parameters for large wood modelling
2.3.1 Estimation of large wood supply volume
The sources of LW supply are very disparate, while being a key parameter to streamwood
accumulations’ studies, along with i ts quantification. Being extremely site - and event-specific, estimating
LW volume supply is one of the most difficult parameters to establish. A study to assess the LW volume
supply combining different types of data was first undertaken based on the guide edited by the WoodFlow
project [11]. The goal was to estimate the range of LW vol ume possibly supplied t o the G ave-de-Pau at
Lourdes city and to compare these volumes with th e historical data.
First of all, we collected all available data from the field including the mass of LW extracted from the
river during past events. The local experts and managers were interviewed, in order to determine the LW
transport regime during floods. Field observations showed that a large quantity of LW is usually supplied
during floods in Lourdes and trapped at bridges, causing significant damages on these structures and on the
downtown hotel’s fronts. During the flood on June 18 th 2013, an estimated mass of 430 tons was extracted at
the bridges (i.e., 660-935 m³ assuming a wood density of 460-650 kg/m³). Note that this mass is only t he
mass of LW that w as actually trapped and thus t he actual total supply was higher than th is estimate.
GIS based analysis enabled to extract parameters to be used in e mpirical f ormulas presented in the
re port of the WoodFlow project [11] . The main parameters considered are either catchment-specific
(c atchment area, channel length, wooded r iverbanks length) or event-specific (f lood volume, peak discharge ,
total transported sediment load). Figure 1 shows the main results produced by these methods, applied to the
Gave-de-Pau watershed. These empirical formulas for quantile 50% provided a similar order of magnitude
than the data collected in the field, meaning that the re cruitment o f LW for this eve nt was around the
“average”. Much larger supply was estimated by quantile 90% and the envelope values. The lower estimate
of quantile 10% (50-250 m³) is also useful to define other potential fl ood scenarios to model assuming an
optimistic case.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
Figure 1 : Volume of LW supply at Lourdes city center estimated by various empirical equations (parameter
used in the equation is written below) providing quantiles 10%, 50%, 90% and enveloppe values [11] and
comparison with the volume actually extracted on b ridges
To refine the results, a procedure of spatial delineation of source areas was implemented [9]. Yassine
[2 4] digitalized the active channel on aerial pictures taken before t he flood in 2010, and after the flood in
2013. It highlighted that bank erosion occurred along multiple small patches (e.g. Figure 2). The channel bed
polygons were crossed with the national forest map (IGN BD Forêt ® V2) demonstrating that 16 ha of forest
were located with in the extend of the 2013’s active cha nnel , while only 6 ha were located in the channel
polygon of 2010. We concluded that the forest area eroded during the flood ranged between 10 and 16 ha .
The next step was to estimate the characteristics of the trees (height, diameter, specie) located on this area
and the forest density, i.e., standing trees volume per unit area (m³/ha).
Figure 2 : Aerial p ictures exemplifying the large wood source areas: bank erosion that occurred during the flo od as the
difference b etween the blue strip (channel bed in 2010) and the black d otted lines (channel bed in 2013). Gree n points
are automatically detec ted trees and black dots are false detection removed after manual contro l (road light poles in this
case) .
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
The French National Forest Inventory (IFN, available at https://inventaire-forestier.ign. fr ) provides data
measured on 72,000 + forest plots on the period 2005-2018 fo r a total number of 827,000 + trees. For each plot,
the IFN database provides the number, height, perimeter, specie of every living and dead trees, as well as
plot-scale features, as e.g., proximity of wetland or stream, and terrain morphology. All these data were used
along with the formula called ‘EMERGE’ to estimate the total tree LW volume based on its diameter, height
and specie [3]. It enabled to compute in each plot the fores t density (m³/ha). Figure 3 shows the forest density
from the 2,680 plots located less than 50 m from wetlands or rivers. Fo rest density varies on several orders of
magnitude, with quantiles 25% and 75% are 148 ≈ 150 and 433 ≈ 450 m³/ha, respectively. Multiplying these
densities by the forested eroded area resulted in a total volume of wood recruited to t he river in the range
1500-4500 m³ (source area = 10 ha) to 2400-7200 m ³ (source area = 16 ha).
Overall, using three different m ethods, we estimate that the volume of LW supplied during the flood of June
18 th 2013 is probably in the range 1000 – 3000 m 3 with an envelope range of 660 – 7200 m³.
Figure 3 : Volume of large wood per hectare of forest from the IFN database, subsampled on plots located close from
rivers o r from wetlands ( Database IFN 2013-2018, https://inventaire -forestier.ign.fr/ , whole France). More than half of
th e sites have forest densities in the range of 150-450 m³/ha.
2.3.2 Estimation of large wood size (length and diam eter)
LiDAR data were also used to analyse forest features such as the number of tr ees and the tree height [10] .
The digital canopy model (DCM) was computed as the difference between the digital surface m odel and the
digital terrain model. It provided a continuous raster map with a one-meter resolution of vegetation height
and other high points (structures, electric network). LiDAR data was unfortunately available only for post-
flood conditions. It was c onsequently impossible t o analyse the number and height of the trees that were
actually recruited by the flood in June 2013 (unfortunately, because it would probably be the most relevant
method to estimate the actual volume of LW recruited by the flood). We analysed the forest located in a 50
m wide buffer strip along the channel prior to the flood (thin dotted line on Figure 2). 17,845 trees were
automatically detected using the lidaRtRee R package [10] in the 83.2 ha area. A full checking made obvious
that about five hundred artificial high points were detected as trees. These 3% of the points sample were
manually removed from the sample that finally incl uded 17,356 trees.
In addition to plot scale analysis, tree-scale analyses were performed on the IFN database analysis. Over
the whole dataset, a simple relationship between tree diameter D [m] and tree height h tot [m] was calibrated
to late r predict diameters from LiDAR data. Figure 4A shows that French trees have typically a height up to
50 m and a diameter up to 1.5 m. The obtained b est proportional fits were:
for deciduous species (1a)
for evergreen species (1b)
We are fully aware that more sophisticated formulations are in use in forestry science. Simplicity was
favored here to maximize its potential reuse. Analysis of residuals show ed that more than 90% of trees had a
diameter in the range 0.5-2 times the predicted va lue using Eq. (1) as shown in Figure 4B.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
Figure 4 : Tree diameter estimation: A) tree height versu s diameter for 605 000 + d eciduous and 222 000 + evergreen
trees from the IFN database, linear fit s of Eq. (1) in black continuous lines and range Eq. (1)*0.5 o r Eq. (1)*2 in dashed
lines and B) residual from these fits showing th at 90% of trees have diameter in the range of [0 .5-2]*predicted diameter
To estimate LW length, two parameters were taken into account: the actual height of the trees recruited
and a reduction factor that is the ratio between the l ength of the LW and the length of standing living trees.
The reduction factor captures the breaking of standing trees when they fall into the river and during their
transport [11]. Rickli et al. measured hundreds of LW after the 2005 flood in Swi tzerland and used allometric
equations to estimate their initial length [12]. The associated reduction factor was provided in the WoodFlow
guidelines [11]. The authors kindly shared the data with us, which are plotted as cumulative distribution
functions in Figure 4A (grey lines for each catchment, black line for whole dataset). In most catchments, LW
breaking was high, since 75% of trees were typically reduced in length by a factor <0.3. However, a few
pieces remained long and showed a reduction ratio up to 0.75. Pieces of sma ll diameter endure slightly
higher reduction ratio, i.e., stayed relatively longe r than larger pieces.
Using the statistical distribution of the 17,356 trees detected on the LiDAR da ta of the Gave-de-Pau, it
was possible to compute the probable statistical distribution of the LW length by a Monte Carlo analysis:
10,000 random values of reduction factor (Figure 5a) and tree height (Figure 5b dashed line) were sampled
and multiplied to compute the LW length distribution (Figure 5b dotted-dashed line). The distribution shows
that LW length varied in the range 0-22 m but 95% of pieces were usually shorter than 10 m (99% shor ter
than 13 m). LW length is a critical parameter on bridge blockage, thus, sensitivity tests will be performed
using maximum length of 10 m, 15 m and 20 m. The minimum size modelled will be 4 m, i.e., 1/3 of the
minimum bridge opening. Below this value, blockage is unlikely and modelling was considered useless.
The same exercise was performed to assess the variability of LW diameter (Figure 5C): 10,000 random
estimations were performed using the living tree height (Fig. 5B), Eq. (1a) and a residual t erm to compute
the variation around the trend of Eq. (1a). This term was randomly sampled in the distribution of Fig. 4B.
This analysis showed that in the deciduous riparian forest of the Gave the Pau, tree dia meters typically varied
in the range 0-1.5 m, though 95% of t rees had D<0.6 m and 99% of trees had D<0.8 m. The latt er value was
used in the model along with a minimum diame ter of 0.1 m.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
Figure 5 : Estimation of large wood size: (A) distribution of reduction factor from the d ataset of Rickly et al. [12]. The
black co ntinuous line is for all logs with D>0.1 m, light g rey lines are the same data but clustered by catchments. The
do tted line is for logs with D<0.1 m; B) statistical distribution of tree h eight detec ted on Li DAR d ata and LW length
computed as the produce of tree heigh t times reduction factor after Mon te Carlo analysis. Light grey lines are LW
length when using the ligh t grey lines of panel A rather than the black line. LW size typically varies from 1 m to 20 m,
mo st pieces being shorter than 10 m. C) statistical d istribution of LW diameter computed by Mo nte Carlo analysis using
tree heig ht detected on Li DAR d ata, Eq. (1a) and randomly sampling the residual in Fig. 4B data. 99% o f pieces have
diameter < 0.8 m.
2.3.3 Es tim ation of large wood densi ty
Lacking field data, the range 460-650 kg/m 3 was used. Fresh wood can be denser [9].
2.3.4 Estimation of the LW discharge time ser ies
The time-series of LW di scharge is extremely poorly known. Witnesses merely confirmed that the
transport regime was uncongested (i.e., logs transported one by one, no large clusters ac cording to
terminology by [15]). Studies of past events have shown that the LW discharge is very uneven [5, 24]. The
WoodFlow guidelines and other articles such as Macvicar et al. [8], Ruiz-Villanueva et al. [15] and
Gh affarian et al. [5] report that, in general, most LW is transported during the ris ing l imb of hydrographs.
Frequent low magnitude floods along with the regular dead wood removal management being done within
the catchment, are assumed to make negligible the quantity of LW initially deposited in the channel bed. As
a result, we hypothesized that only marginal LW transport occurred before a threshold discharge
approximated by the bankfull discharge (time return of 5-20 years, i.e., 290-400 m 3 /s ) and that LW supply
and transport occurred before the peak flow, i.e., in 9-14 h depending of the threshold discharge. Without
available observations, w e had to rely on these assumptions. A se nsitivity analysis will be undertaken to
check the result variability varying this boundary cond ition.
Selecting randomly logs using the tree height measured on the LiDAR, computing their length randomly
picking a reduction factor (Figure 5A) to assess the log length; computing their diameter with Eq . (1) and
the residual terms of Figure 4B, one can compute the volume of logs assuming a cylinder shape. Supplyin g
1000-3000 m 3 of LW means about 3600-10800 input logs (i.e., 4-13 logs/min) for a flood rising limb of 9h
and 7-20 logs/min for 14h.
2.4 Modelling the Gave- de -Pau at Lourdes
2.4.1 Modelling domain
The nu merical model focused on the city centre of Lourdes. The Gave-de-Pau River chann el was
represented along almost 7 km. The model domain had a surface of 3 km² and about 80 000 mesh elements.
All bridges and weirs were included (Figure 6). The buildings, identified thanks to the IGN BD Topo ® , were
considered to be obstacles to the f low, and were modelled as “ holes ” in the mesh. Topography, vegetation,
land use and data from previous major events, were use d in order to adjust roughness and start fine tuning th e
model.
The study (still in progress) aims at (i) checking that Iber-Wood correctly reproduces t he LW
accumulations and associated flood level observed in Lourdes; and, (ii) studying the best solutions to prevent
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
an increase in flood risk due to LW, notably modelling LW trapping structures as racks upstrea m from
Lourdes.
Figure 6 : Maps with location Lourdes, France (left panel) and of the main structures considered in the model (right
panel)
2.4.2 Modelling of hydraulic structures
The model had 11 bridges and 3 weirs. The bridge piers were taken into ac count and represented by
holes in the mesh. At the present stage of study, bridge decks are not yet included although flood mark s let us
think that four bridges experienced pressure flows (Table 2). Additional orifice and weir l aws will be added
to model the pressure flow at bridge levels.
Bridge # and name
KP
Bridge type
Opening width (m)
Opening height (m)
Freeboard of lower deck
1 : Pont de l’Arrouza
3.16
Central pile
21.6
5.3
-0.41
2 : Pont Pomes
2.69
Central pile
17.5
5.9
-1.79
3 : Pont Vieux
2.28
Two arches
8.5 & 13.0
6.4 & 7.8
-0.1 & 1.3
4 : Pont Saint Michel
1.89
Arch
27.8
7.9
5
1.52
No central pile
35
5.6
6
1.46
No central pile
34.4
4.3
7
1.35
Arch
32.6
3. 8
8
1.14
No central pile
9
1
Arch
31.9
3.8
10 : Route de Batsurguere
0.5
Central pile
23.7
4.8
-0.02
Table 2 : Bridges main features. Freeboard is computed when observed flo od marks are available not too far from the
bridge location. Negative freeboard means that pressure flow occurred. For the Pont Vieux, two values of each
parameter are provided because the two arches are really different .
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
Figure 6 : Map of the study zone with channel, bridges a nd weirs (left panel) , and the mesh (right panel)
2.4.3 Calibration procedure
The floodplain topography was built from LiDAR da ta . Terrestrial topographical data, especially in t he
river channel, w as gathered with the LiDAR data to build a channel bed digital elevation model (DEM).
Manning ’s roughness coefficients were chosen according to topography and land use. They are not provided
here because the calibration phase is still in progress. The model was pre-calibrated and will be fine-tuned by
using past floods’ marks and past events analysis , especially the flood of June 2013. Manning’s c oefficient
will likely be m odified at a la ter stage to reduce friction when the pressure flow at bridges will be added to
the model.
3 PRELIMINARY RESULTS
3.1 Identification of bridges prone to large wood
obstructions
Figure 7 shows the location of the four key
bridges concerned by LW jamming issues (bridges
numbered 1, 2, 3 & 4 in Table 2). The results
presented here are preliminary and a proof of concept.
The fine-tuning of the model is not fully achieved.
Preliminary re sults considering only about 200 logs
showed that around 51 % of the input logs were
transported by the Gave-de-Pau throughout Lourdes
city centre, and 49 % were trapp ed by three bridges
(Figure 7 right panel). These bridges were those with a
central pile, whose presence formed an obstacle
trapping LW . This is cons istent with the fiel d
observation s ince during the June 2013 flood, many
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
logs wer e trapped by these bridges i n the city centre. I n addi tion, trapping probability is higher on the
narrower bridges: 32 % trapping on the 13 m-wide Pont Vieux, 10% trapping on the 17 m-wide Pont Pomes
and 7% trapping on the 21 m-wide Pont de l’Arrouza .
Note that these estimations are temporary and wille be refined. Increase in the trapping probability is
expected when bridge decks will be added to the model, especially at the Pont Pomes and Pont d e l’Arrouza
where the flow level was 1.79 m and 0.41 m, re spectively, above lower deck levels (Table 2).
Figure 7 : Map with percentage of logs trapped by b ridges
Figure 8 : Photo of trapped logs at Pont de l’Arrouza (PLVG ) and in the Iber model at this bridge during the flood of
June 2013 (LW represented by brown lines)
3.2 Large wood-related head losses
Figure 8 displays a longitudinal profile of the channel bed and the free surface maximum level as modelled
by Iber-Wood for the June 2013 flood. Two simulations were m ade so far: with and without LW.
Preliminary results highlighted the increase of the free surface level ( a dozen of centimeters) because of LW
jam at bridges, especially the Pont Vieux, and the Pont Saint-Michel. At a later stage, t hese increases and
their associated effect on increased flood ha zards and risks will be quantified.
Higher head losses are expected to be computed when thousands of logs will be supplied to the model in
the final runs including bridge decks and pressu re flows.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
Figure 9 : Longitudinal profiles of channel b ed and maximum flood level of the June 2013 flood, with and without LW
4 DISCUSSION AND RECOMMENDATIO NS
Many scientific works were recently conducted to assess and predict the suppl y, transport and deposition of
LW in rivers but streamwood transport modelling i s still in its early stages, so many uncertainties remain.
Hence, we will improve our numerical model by studying the LW parameters that fit the hydraulic situation
of Lourdes. Research still has to be made to prop erly consider bridges and LW in the model.
The results presented here are only preliminary results and cannot be used to accurately represent the
situation in Lourdes. Nonetheless, they clearly show some promising fe atures, such as the relevant location
of LW trapping an d increases of the free surface level because o f LW jams at bridges.
Bridge width proved to be a key driver regarding l og trapping probability, which is consistent with
literature data [7 , 6, 19] . It is actually the ratio between log length and bridge width that is criti cal, so
sensitivity analysis will be performed to check the result consistency regarding this uncertain parameter .
Modelling bridge deck will like ly strongly increase the trapping probability of the bridge experiencing
pressure flow as also shown previously in labo ratory works [6, 7].
Once satisfying modelling of the city crossing is achieved, large wood trapping structures will be added
to the model. Several tests will be made to determine the best location for a solution to efficiently trap the
LW upstream from the city. Rack structures are anticipated to be relevant options, but the selection of the
appropriate site is still to be defined. Such rack structures enable to control where log accumulations occur
but trigger high free surface elevation [20]. The best way to include these structures in Iber-Wood is not yet
clear since the associated head losses are both due to friction of the fl ow on t rapped logs and obstruction of
the flow section by l ogs; the f irst effect being explicitly m odelled in Iber-Wood but not the second one.
Another option to trap LW would be to build a side-channel trapping structure as designed by Schmocker
and Weitbrecht [2 2].
The best solution to get rid of LW-related increases in flood hazard would actually be to modify the
geometry of the four bridges having central piles to remove the piles and widen these bottleneck sections, or
to add some structures to the bridges [21]. Th ese options will be discussed but is difficult to implement in the
city of Lourdes, especially on old historical b ridges with high patrimonial value.
5 CONCLUSION
As one of the most serious problems concerning bridges and weirs all around the world is the formation of
large streamwood accumulations, being able to predict the LW transport dur ing a flood would be a
significant step forward in current engineering studies. A study was undertaken to assess the streamwood-
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
related hazards in rivers by applying a 2D numerical model using the software Iber-Wood. This study started
by collecting d ata on the field and talki ng with loca l experts, and then setting model parameters for LW
modelling by estimating the LW supply volume, size, density and discharge time series, to finally modelling
the Gave-de-Pau at Lourdes during the flood event of June 18 th 2013. This study is still in pr ogress, so the
results are only a proof of concept, but they are promising. Using t his numerical model allowed illustrating
the main known effects of a LW accumulation formation, such as the stopping of logs at certain bridges and
the increase of the free surface level becau se of LW jams at bridges.
To conclude, even if LW transport modelling in engineering studies is still i n its early stages, available
models like Iber-Wood seem to be able to accurately represent the LW transport during major flood events,
and cro ss con trol with the empirical and scientific knowledge, predicting large wood behavior in rivers
became easier and very useful for future studies.
The authors would like to thank the PLVG , Rabab YASSINE (Univ. Cote d’Azur) and Nicolas STEE B
(WSL) for sharing the data. The work of ISL was funded by t he PLVG, the Agence de l’Eau Adour -Garonne
and ISL’s internal f unds for R esearch and Development. INRAE was funded by the French Ministry o f
Environment under the Accord Cadre SNRH-IN RAE (Action TorRex).
REFERENCES AND CITATIONS
[1] Bladé, E., Cea, L., Corestein, G., Escolano, E., Puertas, J., Vázquez -Cendón, E., Dolz, J. and Coll, A .
2014. Iber: her ramienta de simulación num érica del flujo en ríos. Revista Internacional de Métodos
Numéricos para Cálculo y Diseño en Ingeniería . 30, 1 (Jan. 2014), 1 – 10.
DOI :https://doi.org/10.1016/j.rimni.2012.07.004.
[2] Comiti, F., Lucía, A. and Rick enmann, D. 2016. Large w ood recruitment and transport during large
floods: A review. Geomorphology . 269, (Sep. 2016), 23 – 39.
DOI:https://doi.org/10.1016/j.geomorph.2016. 06.016.
[3] Deleuze, C., Morneau, F., Renaud, J.P., Vivien, Y., Rivoire, M., Santenoise, F., Longuetaud, F., Hervé,
J.C. and Vallet, P. 2014. Estimer le volume tota l d’unarbre, qu elles que soient l’essence, la ta ille, la
sylviculture, la station. Rendez-vous Techniques ONF . (2014), 22 – 32.
[4] Diehl, T.H. 1997. Potential drift accumulation at bridges . Technical Report #FHWA- RD -97-028. U.S.
Dept. of Transportation, Federal Highway Ad ministration.
[5] Ghaffarian, H., Piégay, H., Lopez, D., Rivière, N., MacVicar, B., Antonio, A. and Mignot, E. 2020.
Video‐monitoring of wood di scharge: first inter ‐basin comparison and recommendations to install video
cameras. Earth Surface Processes and Landforms . 45, 10 (Aug. 2020), 2219 – 2234.
DOI:https://doi.org/10.1002/esp.4875.
[6] Gschnitzer, T., Gems, B., Mazzorana, B. and Aufleger, M. 2017. Towards a robust assessment of bridge
clogging processes in flood risk management. Geomorphology . 279, (Feb. 2017), 128 – 140.
DOI:https://doi.org/10.1016/j.geomorph.2016. 11.002.
[7] Lange, D. and Bezzola, G. 2006. Schwemmholz - Probleme und Lösungsansätze [Driftwood - Problems
and solutions] . Technical Report #188. Versuchsanstalt für Wasserbau Hydrologie und Glaziologie der
Eidgenössischen Technischen Hochschule (VAW ) Zürich.
[8] MacVicar, B.J., Piégay, H., Henderson, A., Comiti, F., Oberlin, C . and Pecorari, E. 2009. Quantifying
the temporal dynamics of wood in large rivers: field trials of wood surveying, dating, t racking, and
monitoring techniques. Earth Surface Processes and Landforms . 34, 15 (Dec. 2009), 2031 – 2046.
DOI:https://doi.org/10.1002/esp.1888.
[9] Mazzorana, B., Zischg, A., Largiader, A. and Hübl, J. 2009. Hazard index maps for woody materi al
recruitment and transport in alpine catchments. Natural Hazards and Earth System Science . 9, 1 (2009),
197 – 209. DOI:https://doi.org/10.5194/nhess-9-197-2009.
[10] Monnet, J.M. 2020. lidaRtRee: Forest Analysis with Airborne Laser Scanning (Lidar) Data [R package
version 2.0.1] https://gitlab.irstea.fr/jean-matth ieu.monnet/lidaRtRee
[11] OFEV 2019. Bois flottant dans l es cours d’eau . Technical Rep ort #Connaissance de l’environ nement
num 1910. Office fédéral de l’environne ment, Berne.
SimHydro 2021: Models for complex and global water issues - Practices and expectations
16 -18 June 2021, Sophia Antipolis – Quiniou et al. – Large Wood Transport-Related Flood Risks Analysis Of Lourdes
[12] Rickli, C., Badoux, A., Rickenmann, D., Steeb, N. and Waldner, P. 2018. Large wood potential, piece
characteristics, and flood effects in Swiss mountain streams. Physical Geography . (Mar. 2018), 1 – 23.
DOI:https://doi.org/10.1080/02723646.2018.1456 310.
[13] Ruiz-Villanueva, V., Bladé, E., Sánchez-Juny, M., Marti-Cardona, B., Díez-Herrero, A. and Bodoque,
J.M. 2014. T wo -dimensional numerical modeling of wood transport. Journal of Hydroinformatics . 16, 5
(Sep. 2014), 1077 – 1096. DOI:https://doi.org/ 10.2166/hydro.2014.026.
[14] Ruiz-Villanueva, V., Bodoque, J.M., Díez-Herrero, A. and Bladé, E. 2014. L arge wood transport a s
significant influence on flood risk in a mountain village. Natural Hazards . 74, 2 (May 2014), 967 – 987.
DOI:https://doi.org/10.1007/s11069-014-1222-4.
[15] Ruiz-Villanueva, V., Mazzorana, B., Bladé, E., Bürkli, L., Iribarren-Anacona, P., Mao, L., Nakamura ,
F., Ravazzolo, D., Rickenmann, D., Sanz-Ramos, M., Stoffel, M. and Wohl, E. 2019. Characterization of
wood-laden flows in rivers. Earth Surface Processes and Landforms . 44, 9 (Feb. 2019), 1694 – 1709.
DOI:https://doi.org/10.1002/esp.4603.
[16] Ruiz-Villanueva, V., Piégay, H., Gurnell, A.M., Marston, R.A. and Stoffel, M. 2016. Recent advances
quantifying the large wood dynamics in river basins: New methods and rema ining challenges. Reviews
of Geophysics . 54, 3 (Sep. 2016), 611 – 652. DOI :https://doi.org/10.1002/2015rg000514.
[17] Ruiz-Villanueva, V., Wyzga, B., Hajdukiewicz, H. and Stoffel, M. 2016. Exploring large wood retention
and deposition in cont rasting river morphologies linking numerical modelling and field observations.
Earth Surface Processes and Landforms . 41, 4 (Oct. 2016), 446 – 459.
DOI:https://doi.org/10.1002/esp.3832.
[18] Ruiz- Villanueva, V., Wyżga, B., Mikuś, P., Hajdukiewicz, H. and Stoffel, M. 2016. T he role of flood
hydrograph in the remobilization of large wood in a wide mountain river. Journal of Hydrology . (2016).
DOI:https://doi.org/10.1016/j.jhydrol.2016.0 2.060.
[19] Ruiz- Villanueva, V., Wyżga, B., Mikuś, P., Hajdukiewicz, M. and Stoffel, M. 2017 . Large wood
clogging during floods in a gravel-bed river: the Dlugopole bridge in the Czarny Dunajec River, Poland.
Earth Surface Processes and Landforms . 42, 3 (2017), 516 – 530. DOI:https://doi.org/10.1002/esp.4091.
[20] Schalko, I., Lageder, C., Schmocker, L., Weitbrecht, V. and Boes, R.M. 2019. Laboratory flume
experiments on the formation of spanwise large wood accumulations Part I: Effect on backwater rise.
Water Resources Research . 55, 6 (May 2019), 4854 – 4 870. DOI:https://doi.org/10.1029/2018wr024649.
[21] Schalko I, Schmocker L, Weitbrecht V, Boes RM. 2020. Risk reductio n measures of large wood
accumulations at bridges. Environmental Fluid Mechanics . 20 : 485 – 502.
DOI:https://doi.org/10.1007/s10652-019-09719-4
[2 2] Schmocker, L. and Weitbrecht, V. 2013. Driftwood: Risk analysis and engineering measures. Journal of
Hydraulic Engineering . 139, 7 (2013), 683 – 695. DOI:https://doi.org/1 0.1061/(ASCE)HY.1943-
7900.0000728.
[2 3] Wohl, E., Kramer, N., Ruiz-Villanueva, V., Scott, D.N., Comiti, F., Gurnell, A.M., Piegay, H., Lininger,
K.B., Jaeger, K.L., Walters, D.M. and Fausch, K.D. 2019. The Natural Wood Regime in Rivers .
BioScience . 69, 4 (Mar. 2019), 259 – 273. DOI:h ttps://doi.org/10.1093/biosci/biz013.
[2 4] Yassine, R. 2020. Evaluation de l’efficience probable d’un projet de rest auration fon ctionnelle et
durable d’un cours d’eau . Univ. Toulouse. [PhD Th esis] http://www.theses.fr/s170742
[2 5] Zhang, Z., Ghaffarian, H., MacVicar, B., Vaudor, L., Antonio, A., Michel, K. and Piégay, H. 2021.
Video monitoring of in‐channel wood: From f lux characterization and prediction to recommendations to
equip stations. Earth Surface Processes and Landforms . (Feb. 2021), esp.5068.
DOI:https://doi.org/10.1002/esp.5068.
Risk reduction measures of large wood accumulations at bridges
Jun 2020
ENVIRON FLUID MECH
Isabella Schalko
Lukas Schmocker
Volker Weitbrecht
Robert Michael Boes
Bridges with and without piers are prone to large wood (LW) accumulations during floods, possibly resulting in an upstream backwater rise, local scour, or destabilization of the structure. To reduce the flood hazard, measures are required that decrease the accumulation probability p of LW. This paper presents a literature review on existing measures to reduce p at bridges. In addition, a series of flume experiments was conducted to examine structural measures at bridge piers regarding their accumulation risk reduction effect. The objective was to test the efficiency of (1) LW fins and (2) bottom sills including various configurations. The resulting p was then compared to the setup without measures. The tested configurations of a LW fin did not decrease p. Bottom sills, in contrast, are a promising measure to reduce p for a defined range of boundary conditions. The installed sills lead to enhanced turbulence and increased surface waves. The best results to reduce p were obtained with two consecutive sills, leading to an average reduction of p by 30%. In contrast to retaining LW with retention structures, LW can be safely guided downstream, thereby preserving its relevant ecological role in rivers. However, the efficiency of bottom sills strongly depends on the approach flow and the sediment transport conditions.
Laboratory flume experiments on the formation of spanwise large wood accumulations Part I: Effect on backwater rise
Jun 2019
WATER RESOUR RES
Isabella Schalko
C. Lageder
Lukas Schmocker
Robert Michael Boes
Link: https://agupubs.onlinelibrary.wiley.com/doi/10.1029/2018WR024649
Transported large wood (LW) in rivers may lead to accumulations at natural or artificial obstructions. The hydraulic and geomorphic conditions change due to these accumulations. Backwater rise as well as scour can evolve in the vicinity of such an accumulation. In this first companion paper, results of hydraulic model tests are presented on backwater rise due to spanwise LW accumulations in combination with a movable bed. The findings are summarized in design equations and allow the estimation of (1) characteristic LW volume generating the primary backwater rise; (2) effect of LW accumulation shape and bed material on resulting backwater rise; and (3) effect of LW volume on backwater rise. Compared to a fixed bed, movable bed reduces backwater rise as the open cross‐section area and thus discharge capacity increase. This work improves the understanding and predictability of the formation and impact of spanwise LW accumulations at natural or artificial obstructions (e.g. LW retention racks).
The Natural Wood Regime in Rivers
Apr 2019
BIOSCIENCE
Ellen Wohl
Natalie Kramer
Virginia Ruiz-Villanueva
Kurt Fausch
The natural wood regime forms the third leg of a tripod of physical processes that supports river science and management, along with the natural flow and sediment regimes. The wood regime consists of wood recruitment, transport, and storage in river corridors. Each of these components can be characterized in terms of magnitude, frequency, rate, timing, duration, and mode. We distinguish the natural wood regime, which occurs where human activities do not significantly alter the wood regime, and a target wood regime, in which management emphasizes wood recruitment, transport, and storage that balance desired geomorphic and ecological characteristics with mitigation of wood-related hazards. Wood regimes vary across space and through time but can be inferred and quantified via direct measurements, reference sites, historical information, and numerical modeling. Classifying wood regimes with respect to wood process domains and quantifying the wood budget are valuable tools for assessing and managing rivers
Characterization of wood‐laden flows in rivers
Feb 2019
EARTH SURF PROC LAND
Bruno Mazzorana
Inorganic sediment is not the only solid-fraction component of river flows; flows may also carry significant amounts of large organic material (i.e., large wood), but the characteristics of these wood-laden flows (WLF) are not well understood yet. With the aim to shed light on these relatively unexamined phenomena, we collected home videos showing natural flows with wood as the main solid component. Analyses of these videos as well as the watersheds and streams where the videos were recorded allowed us to define for the first time WLF, describe the main characteristics of these flows and broaden the definition of wood transport regimes (adding a new regime called here hypercongested wood transport). According to our results, WLF may occur repeatedly, in a large range of catchment sizes, generally in steep, highly confined single thread channels in mountain areas. WLF are typically highly unsteady and the log motion is non-uniform, as described for other inorganic sediment-laden flows (e.g., debris flows). The conceptual integration of wood into our understanding of flow phenomena is illustrated by a novel classification defining the transition from clear water to hypercongested, wood and sediment-laden flows, according to the composition of the mixture (sediment, wood, and water). We define the relevant metrics for the quantification and modelling of WLF, including an exhaustive discussion of different modelling approaches (i.e., Voellmy, Bingham and Manning) and provide a first attempt to simulate WLF. We draw attention to WLF phenomena to encourage further field, theoretical, and experimental investigations that may contribute to a better understanding of flows river basins, leading to more accurate predictions, and better hazard mitigation and management strategies.
Large wood potential, piece characteristics, and flood effects in Swiss mountain streams
Dieter Rickenmann
We present results of two studies on the (1) potential wood load in steep headwater streams and (2) properties of large wood (LW) transported in mountain rivers during the large August 2005 flood event in Switzerland. Ten headwater reaches of 1000 m length were surveyed in different regions of Switzerland. The potential wood load was estimated for in-channel deadwood, and possible driving factors were explored. Correlations were found with dead wood volume on hillslopes and mean channel width. We established size distributions of LW pieces and identified probable recruitment processes. Four reaches were resurveyed after an exceptionally severe flood in August 2005, showing limited LW transport in channels but considerable wood input by mass wasting processes. In addition, characteristics of deposits of LW along mountain rivers affected by the 2005 flood were investigated. Diameter and length distribution of transported and deposited pieces were comparable to those of LW from steep headwater streams, yet with considerably fewer long pieces in the deposits of mountain rivers. Most LW pieces were fresh wood, indicating that the portion of in-channel deadwood transported during the 2005 flood was limited. Findings of the study contribute to a better understanding of LW dynamics in Alpine mountain streams.
Recent advances quantifying the large wood dynamics in river basins: new methods, remaining challenges
Jul 2016
Angela Gurnell
Large wood is an important physical component of woodland rivers and significantly influences river morphology. It is also a key component of stream ecosystems. However, large wood is also a source of risk for human activities as it may damage infrastructure, block river channels, and induce flooding. Therefore, the analysis and quantification of large wood and its mobility is crucial for understanding and managing wood in rivers. As the amount of large-wood-related studies by researchers, river managers, and stakeholders increases, documentation of commonly used and newly available techniques and their effectiveness has also become increasingly relevant as well. Important data and knowledge has been obtained from the application of very different approaches and has generated a significant body of valuable information representative of different environments. This review brings a comprehensive qualitative and quantitative summary of recent advances regarding the different processes involved in large wood dynamics in fluvial systems including wood budgeting and wood mechanics. First, some key definitions and concepts are introduced. Second, advances in quantifying large wood dynamics are reviewed, in particular how measurements and modeling can be combined to integrate our understanding of how large wood moves through and is retained within river systems. Throughout, we present a quantitative and integrated meta-analysis compiled from different studies and geographical regions. Finally, we conclude by highlighting areas of particular research importance and their likely future trajectories, and we consider a particularly under-researched area so as to stress the future challenges for large wood research.
Video monitoring of in‐channel wood: From flux characterization and prediction to recommendations to equip stations
Wood flux (piece number per time interval) is a key parameter for understanding wood budgeting, determining the controlling factors, and managing flood risk in a river basin. Quantitative wood flux data is critically needed to improve the understanding of wood dynamics and estimate wood discharge in rivers. In this study, the streamside videography technique was applied to detect wood passage and measure instantaneous rates of wood transport. The goal was to better understand how wood flux responds to flood and wind events and then predict wood flux. In total, one exceptional wind and 7 flood events were monitored on the Ain River, France, and around 24000 wood pieces were detected visually. It is confirmed that, in general, there is a threshold of wood motion in the river equal to 60% of bankfull discharge. However, in a flood following a windy day, no obvious threshold for wood motion was observed, which confirms that wind is important for the preparation of wood for transport between floods. In two multi‐peaks floods, around two‐thirds of the total amount of wood was delivered on the first peak, which confirms the importance of the time between floods for predicting wood fluxes. Moreover, we found an empirical relation between wood frequency and wood discharge, which is used to estimate the total wood amount produced by each of the floods. The data set is then used to develop a random forest regression model to predict wood frequency as a function of three input variables that are derived from the flow hydrograph. The model calculates the total wood volume either during day or night based on the video monitoring technique for the first time, which expands its utility for wood budgeting in a watershed. A one‐to‐one link is then established between the fraction of detected pieces of wood and the dimensionless parameter “passing time × framerate”, which provides a general guideline for the design of monitoring stations.
Video‐monitoring of wood discharge: first inter‐basin comparison and recommendations to install video cameras
Hossein Ghaffarian Roohparvar
Hervé Piégay
Diego Lopez
Emmanuel Mignot
Wood in rivers plays a major role both ecologically and morphologically. In recent decades, due to human activities in the river channels and along the riparian zone, wood obstruction and jamming has exacerbated flooding hazards and infrastructure damage. Therefore, it is necessary to quantify the wood flux and discharge in rivers to improve wood hazard management. Among the various methods for monitoring the wood flux in a river, the streamside videography technique is effective given its high temporal and spatial resolution. Previous work monitored the wood discharge (m³/s) using this technique in the Ain River (France) during three floods (MacVicar & Piégay, 2012), and the same method is implemented on the Isère River (France) to obtain the statistics of wood discharge for two floods. Comparison between the two sites supports the generalization of both the monitoring technique and the link between wood discharge and flood characteristics. We first show that the maximum wood discharge is observed at bankfull discharge, and we confirm the three stage model proposed by (MacVicar & Piégay, 2012). Additionally, transverse distributions of the number of wood pieces and corresponding wood length appear to be similar for different flood magnitudes on each site. As a technical contribution, the use of the same technique on two sites allows for recommendations on key decisions related to the location and implementation of the equipment. Both statistical and technical contributions can be used by decision makers to implement this monitoring technique, acquire the wood transport parameters, and evaluate the potential wood hazards at local scale or along a river.
Large wood clogging during floods in a gravel-bed river: The Długopole bridge in the Czarny Dunajec River, Poland
Virginia Ruiz-Villanueva
Bartłomiej Wyżga
During floods, large quantities of wood can be mobilized and transported downstream. At critical sections, such as bridges, the transported wood might be entrapped and a quick succession of backwater effects can occur as a result of the reduction of the cross-sectional area. The aim of this work is to explore large wood-related hazards during floods in the gravel-bed river Czarny Dunajec (Polish Carpathians), where the river flows through the village of Długopole. This work is based on the numerical modelling of large wood transport together with flow dynamics in which inlet and boundary conditions were designed based on field observations. The exploratory approach developed in this study uses multiple scenarios (193) to analyse the factors controlling bridge clogging: wood size, wood supply, flow conditions, morphology and obstacles in the riverbed. Results highlighted the strong control of log length (stronger than that of log diameter) on potential blockage probability; however, according to our results the main factor controlling the bridge clogging was the flood discharge. River morphology and wood supply play an important role as well. Especially the river morphology may reduce bridge blockage, as it influences flow velocity and depth, and creates natural retention zones for wood. In addition, the impacts of the bridge blockage were analysed in terms of afflux depth and length, and flooded area. Results showed that the bridge blockage may result in a significant increase in the water depth (up to 0.7 m) and flooded area (up to 33% more), therefore increasing flood risk in the village.
Towards a robust assessment of bridge clogging processes in flood risk management
Nov 2016
GEOMORPHOLOGY
Thomas Gschnitzer
Bernhard Gems
Bruno Mazzorana
Markus Aufleger
River managers are aware that wood-clogging mechanisms frequently trigger damage-causing processes like structural damages at bridges, sudden channel outbursts, and occasionally, major displacements of the water course. To successfully mitigate flood risks related to the transport of large wood (LW), river managers need a guideline for an accurate and reliable risk assessment procedure and the design of river sections and bridges that are endangered of LW clogging.
| https://www.researchgate.net/publication/352572414_Wood_Debris_Risk_Analysis_and_Protection_Scenarios_of_Lourdes_City_Using_Iberwood_Model |
AHTR Mechanical, Structural, And Neutronic Preconceptual Design (Technical Report) | OSTI.GOV
The U.S. Department of Energy's Office of Scientific and Technical Information
Title: AHTR Mechanical, Structural, And Neutronic Preconceptual Design
This report provides an overview of the mechanical, structural, and neutronic aspects of the Advanced High Temperature Reactor (AHTR) design concept. The AHTR is a design concept for a large output Fluoride salt cooled High-temperature Reactor (FHR) that is being developed to enable evaluation of the technology hurdles remaining to be overcome prior to FHRs becoming a commercial reactor class. This report documents the incremental AHTR design maturation performed over the past year and is focused on advancing the design concept to a level of a functional, self-consistent system. The AHTR employs plate type coated particle fuel assemblies with rapid, off-line refueling. Neutronic analysis of the core has confirmed the viability of a 6-month 2-batch cycle with 9 weight-percent enriched uranium fuel. Refueling is intended to be performed automatically under visual guidance using dedicated robotic manipulators. The present design intent is for used fuel to be stored inside of containment for at least 6 months and then transferred to local dry wells for intermediate term, on-site storage. The mechanical and structural concept development effort has included an emphasis on transportation and constructability to minimize construction costs and schedule. The design intent is that all components be factory fabricated into railmore » transportable modules that are assembled into subsystems at an on-site workshop prior to being lifted into position using a heavy-lift crane in an open-top style construction. While detailed accident identification and response sequence analysis has yet to be performed, the design concept incorporates multiple levels of radioactive material containment including fully passive responses to all identified design basis or non-very-low frequency beyond design basis accidents. Key building design elements include: 1) below grade siting to minimize vulnerability to aircraft impact, 2) multiple natural circulation decay heat rejection chimneys, 3) seismic base isolation, and 4) decay heat powered back-up electricity generation. The report provides a preconceptual design of the manipulators, the fuel transfer system, and the salt transfer loops. The mechanical handling of the fuel and how it is accomplished without instrumentation inside the salt is described within the report. All drives for the manipulators reside outside the reactor top flange. The design has also taken into account the transportability of major components and how they will be assembled on site« less
Authors:
Varma, Venugopal Koikal [1] ;
Holcomb, David Eugene [1] ;
Peretz, Fred J [1] ;
Bradley, Eric Craig [1] ;
Ilas, Dan [1] ;
Qualls, A L [1] ;
Zaharia, Nathaniel M [1]
ORNL
Publication Date:
2012-10-01
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1081980
Report Number(s):
ORNL/TM-2012/320 RC0405000; NERC008
DOE Contract Number:
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
MLA
Varma, Venugopal Koikal, Holcomb, David Eugene, Peretz, Fred J, Bradley, Eric Craig, Ilas, Dan, Qualls, A L, and Zaharia, Nathaniel M. AHTR Mechanical, Structural, And Neutronic Preconceptual Design . United States: N. p., 2012.
Web. doi:10.2172/1081980.
Varma, Venugopal Koikal, Holcomb, David Eugene, Peretz, Fred J, Bradley, Eric Craig, Ilas, Dan, Qualls, A L, & Zaharia, Nathaniel M. AHTR Mechanical, Structural, And Neutronic Preconceptual Design . United States. https://doi.org/10.2172/1081980
Varma, Venugopal Koikal, Holcomb, David Eugene, Peretz, Fred J, Bradley, Eric Craig, Ilas, Dan, Qualls, A L, and Zaharia, Nathaniel M. 2012.
"AHTR Mechanical, Structural, And Neutronic Preconceptual Design". United States. https://doi.org/10.2172/1081980. https://www.osti.gov/servlets/purl/1081980.
@article{osti_1081980, title = {AHTR Mechanical, Structural, And Neutronic Preconceptual Design}, author = {Varma, Venugopal Koikal and Holcomb, David Eugene and Peretz, Fred J and Bradley, Eric Craig and Ilas, Dan and Qualls, A L and Zaharia, Nathaniel M}, abstractNote = {This report provides an overview of the mechanical, structural, and neutronic aspects of the Advanced High Temperature Reactor (AHTR) design concept. The AHTR is a design concept for a large output Fluoride salt cooled High-temperature Reactor (FHR) that is being developed to enable evaluation of the technology hurdles remaining to be overcome prior to FHRs becoming a commercial reactor class. This report documents the incremental AHTR design maturation performed over the past year and is focused on advancing the design concept to a level of a functional, self-consistent system. The AHTR employs plate type coated particle fuel assemblies with rapid, off-line refueling. Neutronic analysis of the core has confirmed the viability of a 6-month 2-batch cycle with 9 weight-percent enriched uranium fuel. Refueling is intended to be performed automatically under visual guidance using dedicated robotic manipulators. The present design intent is for used fuel to be stored inside of containment for at least 6 months and then transferred to local dry wells for intermediate term, on-site storage. The mechanical and structural concept development effort has included an emphasis on transportation and constructability to minimize construction costs and schedule. The design intent is that all components be factory fabricated into rail transportable modules that are assembled into subsystems at an on-site workshop prior to being lifted into position using a heavy-lift crane in an open-top style construction. While detailed accident identification and response sequence analysis has yet to be performed, the design concept incorporates multiple levels of radioactive material containment including fully passive responses to all identified design basis or non-very-low frequency beyond design basis accidents. Key building design elements include: 1) below grade siting to minimize vulnerability to aircraft impact, 2) multiple natural circulation decay heat rejection chimneys, 3) seismic base isolation, and 4) decay heat powered back-up electricity generation. The report provides a preconceptual design of the manipulators, the fuel transfer system, and the salt transfer loops. The mechanical handling of the fuel and how it is accomplished without instrumentation inside the salt is described within the report. All drives for the manipulators reside outside the reactor top flange. The design has also taken into account the transportability of major components and how they will be assembled on site}, doi = {10.2172/1081980}, url = {https://www.osti.gov/biblio/1081980},
journal = {}, number = , volume = , place = {United States}, year = {2012}, month = {10} }
Technical Report:
https://doi.org/10.2172/1081980
This report provides an overview of the mechanical, structural, and neutronic aspects of the Advanced High Temperature Reactor (AHTR) design concept. The AHTR is a design concept for a large output Fluoride salt cooled High-temperature Reactor (FHR) that is being developed to enable evaluation of the technology hurdles remaining to be overcome prior to FHRs becoming an option for commercial reactor deployment. This report documents the incremental AHTR design maturation performed over the past year and is focused on advancing the design concept to a level of a functional, self-consistent system. The reactor concept development remains at a preconceptual level more » of maturity. While the overall appearance of an AHTR design is anticipated to be similar to the current concept, optimized dimensions will differ from those presented here. The AHTR employs plate type coated particle fuel assemblies with rapid, off-line refueling. Neutronic analysis of the core has confirmed the viability of a 6-month two-batch cycle with 9 wt. % enriched uranium fuel. Refueling is intended to be performed automatically under visual guidance using dedicated robotic manipulators. The report includes a preconceptual design of the manipulators, the fuel transfer system, and the used fuel storage system. The present design intent is for used fuel to be stored inside of containment for at least six months and then transferred to local dry wells for intermediate term, on-site storage. The mechanical and structural concept development effort has included an emphasis on transportation and constructability to minimize construction costs and schedule. The design intent is that all components be factory fabricated into rail transportable modules that are assembled into subsystems at an on-site workshop prior to being lifted into position using a heavy-lift crane in an open-top style construction. While detailed accident identification and response sequence analysis has yet to be performed, the design concept incorporates fully passive responses to all identified design basis or non-very-low frequency beyond design basis accidents as well as multiple levels of radioactive material containment. Key building design elements include (1) below grade siting to minimize vulnerability to aircraft impact, (2) multiple natural circulation decay heat rejection chimneys, (3) seismic base isolation, and (4) decay heat powered back-up electricity generation. « less
The Advanced High-Temperature Reactor (AHTR) is a design concept for a central station-type [1500 MW(e)] Fluoride salt-cooled High-temperature Reactor (FHR) that is currently undergoing development by Oak Ridge National Laboratory for the US. Department of Energy, Office of Nuclear Energy's Advanced Reactor Concepts program. FHRs, by definition, feature low-pressure liquid fluoride salt cooling, coated-particle fuel, a high-temperature power cycle, and fully passive decay heat rejection. The overall goal of the AHTR development program is to demonstrate the technical feasibility of FHRs as low-cost, large-size power producers while maintaining full passive safety. The AHTR is approaching a preconceptual level of maturity. more » An initial integrated layout of its major systems, structures, and components (SSCs), and an initial, high-level sequence of operations necessary for constructing and operating the plant is nearing completion. An overview of the current status of the AHTR concept has been recently published and a report providing a more detailed overview of the AHTR structures and mechanical systems is currently in preparation. This report documents the refueling components and processes envisioned at this early development phase. The report is limited to the refueling aspects of the AHTR and does not include overall reactor or power plant design information. The report, however, does include a description of the materials envisioned for the various components and the instrumentation necessary to control the refueling process. The report begins with an overview of the refueling strategy. Next a mechanical description of the AHTR fuel assemblies and core is provided. The reactor vessel upper assemblies are then described. Following this the refueling path structures and the refueling mechanisms and components are described. The sequence of operations necessary to fuel and defuel the reactor is then discussed. The report concludes with a discussion of the levels of maturity of the various SSCs to provide guidance for future technology developments. The conceptual design information presented in this report is very preliminary in nature. Significant uncertainty remains about several aspects of the process and even the radiation and mechanical performance of plate-type coated-particle fuel. « less
The Advanced High-Temperature Reactor (AHTR) is a design concept for a central station-type [1500 MW(e)] Fluoride salt–cooled High-temperature Reactor (FHR) that is currently undergoing development by Oak Ridge National Laboratory for the US. Department of Energy, Office of Nuclear Energy’s Advanced Reactor Concepts program. FHRs, by definition, feature low-pressure liquid fluoride salt cooling, coated-particle fuel, a high-temperature power cycle, and fully passive decay heat rejection. The overall goal of the AHTR development program is to demonstrate the technical feasibility of FHRs as low-cost, large-size power producers while maintaining full passive safety. The AHTR is approaching a preconceptual level of maturity. more » An initial integrated layout of its major systems, structures, and components (SSCs), and an initial, high-level sequence of operations necessary for constructing and operating the plant is nearing completion. An overview of the current status of the AHTR concept has been recently published [1], and a report providing a more detailed overview of the AHTR structures and mechanical systems is currently in preparation. This report documents the refueling components and processes envisioned at this early development phase. The report is limited to the refueling aspects of the AHTR and does not include overall reactor or power plant design information. The report, however, does include a description of the materials envisioned for the various components and the instrumentation necessary to control the refueling process. The report begins with an overview of the refueling strategy. Next a mechanical description of the AHTR fuel assemblies and core is provided. The reactor vessel upper assemblies are then described. Following this the refueling path structures and the refueling mechanisms and components are described. The sequence of operations necessary to fuel and defuel the reactor is then discussed. The report concludes with a discussion of the levels of maturity of the various SSCs to provide guidance for future technology developments. The conceptual design information presented in this report is very preliminary in nature. Significant uncertainty remains about several aspects of the process and even the radiation and mechanical performance of plate-type coated-particle fuel. « less
A new reactor plant concept is presented that combines the benefits of ceramic-coated, high-temperature particle fuel with those of clean, high-temperature, low-pressure molten salt coolant. The Advanced High-Temperature Reactor (AHTR) concept is a collaboration of Oak Ridge National Laboratory, Sandia National Laboratories, and the University of California at Berkeley. The purpose of the concept is to provide an advanced design capable of satisfying the top-level functional requirements of the U.S. Department of Energy Next Generation Nuclear Plant (NGNP), while also providing a technology base that is sufficiently robust to allow future development paths to higher temperatures and larger outputs with more » highly competitive economics. This report summarizes the status of the AHTR preconceptual design. It captures the results from an intense effort over a period of 3 months to (1) screen and examine potential feasibility concerns with the concept; (2) refine the conceptual design of major systems; and (3) identify research, development, and technology requirements to fully mature the AHTR design. Several analyses were performed and are presented to quantify the AHTR performance expectations and to assist in the selection of several design parameters. The AHTR, like other NGNP reactor concepts, uses coated particle fuel in a graphite matrix. But unlike the other NGNP concepts, the AHTR uses molten salt rather than helium as the primary system coolant. The considerable previous experience with molten salts in nuclear environments is discussed, and the status of high-temperature materials is reviewed. The large thermal inertia of the system, the excellent heat transfer and fission product retention characteristics of molten salt, and the low-pressure operation of the primary system provide significant safety attributes for the AHTR. Compared with helium coolant, a molten salt cooled reactor will have significantly lower fuel temperatures (150-200-C lower) for the equivalent temperature of heat delivered to either the power conversion system or a hydrogen production plant. Using a comparative cost analysis, the construction costs per unit output are projected to be 50-55% of the costs for modular gas-cooled or sodium-cooled reactor systems. This is primarily a consequence of substantially larger power output and higher conversion efficiency for the AHTR. The AHTR has a number of unique technical challenges in meeting the NGNP requirements; however, it appears to offer advantages over high-temperature helium-cooled reactors and provides an alternative development path to achieve the NGNP requirements. Primary challenges include optimizing the core design for improved response to transients, designing an internal blanket to thermally protect the reactor vessel, and engineering solutions to high-temperature refueling and maintenance. « less
Effective high-temperature thermal energy exchange and delivery at temperatures over 600°C has the potential of significant impact by reducing both the capital and operating cost of energy conversion and transport systems. It is one of the key technologies necessary for efficient hydrogen production and could potentially enhance efficiencies of high-temperature solar systems. Today, there are no standard commercially available high-performance heat transfer fluids above 600°C. High pressures associated with water and gaseous coolants (such as helium) at elevated temperatures impose limiting design conditions for the materials in most energy systems. Liquid salts offer high-temperature capabilities at low vapor pressures, good more » heat transport properties, and reasonable costs and are therefore leading candidate fluids for next-generation energy production. Liquid-fluoride-salt-cooled, graphite-moderated reactors, referred to as Fluoride Salt Reactors (FHRs), are specifically designed to exploit the excellent heat transfer properties of liquid fluoride salts while maximizing their thermal efficiency and minimizing cost. The FHR s outstanding heat transfer properties, combined with its fully passive safety, make this reactor the most technologically desirable nuclear power reactor class for next-generation energy production. Multiple FHR designs are presently being considered. These range from the Pebble Bed Advanced High Temperature Reactor (PB-AHTR) [1] design originally developed by UC-Berkeley to the Small Advanced High-Temperature Reactor (SmAHTR) and the large scale FHR both being developed at ORNL [2]. The value of high-temperature, molten-salt-cooled reactors is also recognized internationally, and Czechoslovakia, France, India, and China all have salt-cooled reactor development under way. The liquid salt experiment presently being developed uses the PB-AHTR as its focus. One core design of the PB-AHTR features multiple 20 cm diameter, 3.2 m long fuel channels with 3 cm diameter graphite-based fuel pebbles slowly circulating up through the core. Molten salt coolant (FLiBe) at 700°C flows concurrently (at significantly higher velocity) with the pebbles and is used to remove heat generated in the reactor core (approximately 1280 W/pebble), and supply it to a power conversion system. Refueling equipment continuously sorts spent fuel pebbles and replaces spent or damaged pebbles with fresh fuel. By combining greater or fewer numbers of pebble channel assemblies, multiple reactor designs with varying power levels can be offered. The PB-AHTR design is discussed in detail in Reference [1] and is shown schematically in Fig. 1. Fig. 1. PB-AHTR concept (drawing taken from Peterson et al., Design and Development of the Modular PB-AHTR Proceedings of ICApp 08). Pebble behavior within the core is a key issue in proving the viability of this concept. This includes understanding the behavior of the pebbles thermally, hydraulically, and mechanically (quantifying pebble wear characteristics, flow channel wear, etc). The experiment being developed is an initial step in characterizing the pebble behavior under realistic PB-AHTR operating conditions. It focuses on thermal and hydraulic behavior of a static pebble bed using a convective salt loop to provide prototypic fluid conditions to the bed, and a unique inductive heating technique to provide prototypic heating in the pebbles. The facility design is sufficiently versatile to allow a variety of other experimentation to be performed in the future. The facility can accommodate testing of scaled reactor components or sub-components such as flow diodes, salt-to-salt heat exchangers, and improved pump designs as well as testing of refueling equipment, high temperature instrumentation, and other reactor core designs. « less
| https://www.osti.gov/biblio/1081980 |
An Intersectional Examination of the Effects of Race/Ethnicity and Immigrant Status on School Victimization in Predominantly Hispanic/Latinx High Schools: School Psychology Review: Vol 50, No 2-3
Guided by the theory of intersectionality and social identity theory, this study examined the interactive influences of both racial/ethnic majority status and immigrant status on students’ school v...
An Intersectional Examination of the Effects of Race/Ethnicity and Immigrant Status on School Victimization in Predominantly Hispanic/Latinx High Schools
Chunyan Yang a University of California, Berkeley Correspondence [email protected] View further author information, Sarah Manchanda a University of California, Berkeley View further author information, Xueqin Lin a University of California, Berkeley View further author information& Zhaojun Teng a University of California, Berkeley;b Southwest University View further author information
Pages 303-315 | Received 01 Jul 2020, Accepted 16 Nov 2020, Published online: 26 Jan 2021
https://doi.org/10.1080/2372966X.2020.1840262
<here is a image 0bcce86e1c11f89a-7cf3060138915a91 CrossMark>
Special Topic Section on Preventing School Violence and Promoting School Safety
An Intersectional Examination of the Effects of Race/Ethnicity and Immigrant Status on School Victimization in Predominantly Hispanic/Latinx High Schools
Abstract
Abstract
Guided by the theory of intersectionality and social identity theory, this study examined the interactive influences of both racial/ethnic majority status and immigrant status on students’ school victimization experiences in predominantly Hispanic/Latinx high schools. Participants included 3,176 high school students in Grades 9 to 12 from four high schools in central California. Results of chi-square tests and regression analyses suggested that, after controlling for students’ gender, grade, parent educational level, and status for receiving free and reduced price meals, Hispanic/Latinx students (racial/ethnic majority) reported lower levels of school victimization, as measured by both the prevalence rate and frequency level, in comparison to non-Hispanic/Latinx students (racial/ethnic minority). Immigrant status was not significantly associated with their school victimization experiences. Moreover, there was a significant interaction between students’ racial/ethnic majority status and immigrant status on students’ school victimization experiences. More specifically, among U.S.-born students, non-Hispanic/Latinx students reported higher victimization incidence rates than Hispanic/Latinx students, but no significant difference was found between Hispanic/Latinx and non-Hispanic/Latinx immigrant students. The findings highlight the importance of understanding context-specific group dynamics and the intersection of multiple group-level and individual-level identities to inform school violence prevention and intervention in diverse school settings.
Impact Statement
The findings highlight the importance of understanding context-specific group dynamics and how the intersection of multiple individual and group identities can inform school violence prevention and intervention in diverse school settings.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2372966X.2020.1840262.
Keywords:
school violence
immigrant status
race/ethnicity
intersectionality
ASSOCIATE EDITOR:
Matthew Mayer
DISCLOSURE
The authors have no conflicts of interest to report.
Additional information
Notes on contributors
ChunyanYangChunyan Yang, PhD, is an assistant professor of school psychology in the Graduate School of Education at the University of California, Berkeley. Her research interests focus on understanding how school members (e.g., students, teachers, parents) interact with their living contexts (e.g., school, family, community, culture) to find their resilience in face of a variety of risk factors in school settings, such as bullying, teacher-targeted violence, and mental health challenges.
SarahManchandaSarah Manchanda is a doctoral candidate in the Joint Doctoral Program between the University of California, Berkeley, and San Francisco State University. Her current research interests include peer victimization and bullying based on disability and race, promoting the capacity of teachers and peer bystanders through investigating moral reasoning, and critical pedagogy and moral education as interventions to address stigma-based bullying.
XueqinLinXueqin Lin, MEd, is a doctoral student in the school psychology program in the Graduate School of Education at the University of California, Berkeley. Her primary research interests focus on adolescents’ risk and resilience and their impacts on adolescents academic and mental health outcomes. She is also interested in cross-cultural comparisons and ethnic identity development and mental health of immigrant adolescents.
ZhaojunTengZhaojun Teng, PhD, is a postdoctoral researcher at Southwest University in China and a visiting scholar in the Graduate School of Education at the University of California, Berkeley (2019–2020). His general research interests are video game use and adolescents’ behavioral outcomes, and his specific research interests are violent video game effects on adolescents’ aggression, bullying, and cyberbullying.
| https://www.informahealthcare.com/doi/abs/10.1080/2372966X.2020.1840262 |
Amphotericin Tops Itraconazole in HIV-Related Talaromycosis
antiretroviral therapy (art) for hiv,antiretroviral therapy (hiv),atazanavir,darunavir,etravirine,fungemia,hiv art (hiv antiretroviral therapy),hiv opportunistic infection,hiv therapy (antiretroviral),hiv-associated opportunistic infection,immune reconstitution,opportunistic infections in hiv,tipranavir
Amphotericin Tops Itraconazole in HIV-Related Talaromycosis
Amphotericin is better than itraconazole for the initial treatment of talaromycosis in patients with HIV, according to results from the Itraconazole vs Amphotericin B for Penicilliosis trial. The study waspublishedin the June 15 issue of the New England Journal of Medicine.
"In this randomized, controlled trial of treatment for talaromycosis, we found that itraconazole induction therapy was noninferior to amphotericin with respect to the primary outcome of death at week 2; however, this effect was soon lost, and by week 24, the risk of death in the itraconazole group was almost twice that in the amphotericin group," Thuy Le, MD, DPhil, from Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam, and colleagues, write.
The results run counter to a shorter case series, which showed about equivalent efficacy for itraconazole compared with amphotericin, and underscore the importance of longer follow-up in clinical trials about treatments for fungal infections.
Talaromycosis is caused by Talaromyces marneffei, a fungus endemic to South and Southeast Asia. It can cause skin infections and life-threatening blood infections in immunocompromised individuals. With a mortality rate approaching 30% even with antifungal therapy, talaromycosis represents a major cause of death in HIV-infected individuals in these regions.
Guidelines recommend treating talaromycosis initially with amphotericin B. However, the drug is only available in intravenous form and requires in-hospital care for monitoring of infusion reactions, as well as toxic effects on the kidneys and blood system. The drug also carries a high price tag and has limited availability in Asia.
In contrast, itraconazole can be taken orally, has fewer severe adverse effects, and costs one seventh the price of amphotericin. Although itraconazole is often used as a replacement for amphotericin in Asia, few randomized trials have compared the efficacy of the two drugs.
To evaluate the issue, the researchers conducted an open-label, noninferiority trial in Vietnam. The trial included 440 HIV-positive adults with talaromycosis confirmed on microscopy or culture and enrolled between October 2012 and December 2015. The investigators randomly assigned 219 participants to receive amphotericin B, 0.7 to 1.0 mg/kg body weight per day, intravenously, for 14 days, and 221 participants to receive itraconazole capsules 300 mg twice daily for 3 days, then 200 mg twice daily for 11 days. Afterward, all patients received maintenance therapy with 200 mg itraconazole twice daily for 10 weeks. Participants continued receiving itraconazole at a reduced dosage of 100 mg twice daily until their CD4 +cell counts increased to more than 100 cells/mm 3for at least 6 months while receiving antiretroviral therapy.
A lower percentage of participants died at week 2 with amphotericin compared with itraconazole (6.5% vs 7.4%; 95% confidence interval, −3.9 to 5.6; P< .001 for noninferiority).
However, by week 24, this trend had reversed and a lower percentage of participants had died in the amphotericin group compared with itraconazole (11.3% vs 21.0%; 95% confidence interval, 2.8 - 16.6; P= .006).
In addition, amphotericin compared with itraconazole showed a significantly faster time to clinical resolution (8 vs 9 days, respectively; P= .049), lower relapse rates (1.5% vs 7.0%, respectively; P= .005), and lower rates of immune reconstitution inflammatory syndrome (0% vs 6.6%, respectively; P< .001).
In addition, amphotericin showed significantly faster early fungicidal activity compared with itraconazole, which may provide a biological explanation for the mortality benefit of amphotericin over itraconazole, according to the authors. Clearance of fungemia by day 8 was 99.2% with amphotericin vs 67.8% with itraconazole.
Compared with itraconazole, the amphotericin group had significantly higher rates of infusion-related reactions ( P< .001), blood and lymphatic disorders ( P= .002), renal failure ( P= .006), hypokalemia ( P< .001), hypomagnesemia ( P= .02), and anemia ( P= .01).
However, the itraconazole group had more serious adverse events thought to be related to the study drug than the amphotericin group (14.7% vs 6.5%, respectively; P= .007).
The authors noted several limitations, including the trial's open-label design, which could have introduced bias. However, an independent expert committee reviewed adverse events, cause of death, and relapse. The trial also used objective outcomes of death and fungal clearance to minimize bias.
"This trial was pragmatic, in that the formulations of the treatments assessed were affordable and the trial had few exclusion criteria; these factors may help to enhance the potential generalizability of the trial across Asia," the authors write.
The study was supported by the Medical Research Council, the Department for International Development, the Wellcome Trust, the Fogarty International Center, and the National Institutes of Health. The authors have disclosed no relevant financial relationships.
N Engl J Med. 2017;376:2329-2340.Full text
| https://www.medscape.com/viewarticle/881732 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Report
Themes
Assistive & Accessible Technology
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Cite
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor
This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies.
Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021
Abstract
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers.
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Type
Workshop
Themes
Assistive & Accessible Technology
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Tabish Ahmed, Sahan Bulathwela
The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need.
Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022
Abstract
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval.
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
These tools help visually impaired scientists read data and journals
Type
Workshop
Themes
Assistive & Accessible Technology
Culture and Participation
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh,Catherine Holloway,Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design.
CHI EA '21: Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems
Abstract
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. The aim is to better understand how we can re-think the senses in technology design for disability interactions and the dynamic self, constructed through continuously changing sensing capabilities either because of changing ability or because of the empowering technology. This workshop will: (i) bring together HCI researchers from different areas, (ii) discuss tools, frameworks and methods, and (iii) form a multidisciplinary community to build synergies for further collaboration.
Cite
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh, Catherine Holloway, Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme. 2021. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 118, 1–5. DOI:https://doi.org/10.1145/341176...
Share
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Giulia Barbareschi,Dafne Zuleima Morgado-Ramirez,Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell.
Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate.
Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems.
Abstract
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate. We will achieve this through sharing of research experiences, and exploration of challenges encountered when planning HCI4D studies featuring participants with disabilities. Thanks to the contributions of all attendees, we will build a roadmap to support researchers aiming to leverage post-colonial and participatory approaches for the development of accessible and empowering technology with truly global ambitions.
Cite
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Giulia Barbareschi, Dafne Zuleima Morgado-Ramirez, Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell. 2021. Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 124, 1–5. DOI:https://doi.org/10.1145/3411763.3441340
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
| https://www.disabilityinnovation.com/publications?page=5&type=article+report+workshop |
{"markup":"\u003C?xml version=\u00221.0\u0022 encoding=\u0022UTF-8\u0022 ?\u003E\n \u003Chtml version=\u0022HTML+RDFa+MathML 1.1\u0022\n xmlns:content=\u0022http:\/\/purl.org\/rss\/1.0\/modules\/content\/\u0022\n xmlns:dc=\u0022http:\/\/purl.org\/dc\/terms\/\u0022\n xmlns:foaf=\u0022http:\/\/xmlns.com\/foaf\/0.1\/\u0022\n xmlns:og=\u0022http:\/\/ogp.me\/ns#\u0022\n xmlns:rdfs=\u0022http:\/\/www.w3.org\/2000\/01\/rdf-schema#\u0022\n xmlns:sioc=\u0022http:\/\/rdfs.org\/sioc\/ns#\u0022\n xmlns:sioct=\u0022http:\/\/rdfs.org\/sioc\/types#\u0022\n xmlns:skos=\u0022http:\/\/www.w3.org\/2004\/02\/skos\/core#\u0022\n xmlns:xsd=\u0022http:\/\/www.w3.org\/2001\/XMLSchema#\u0022\n xmlns:mml=\u0022http:\/\/www.w3.org\/1998\/Math\/MathML\u0022\u003E\n \u003Chead\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022\/\/cdn.jsdelivr.net\/qtip2\/2.2.1\/jquery.qtip.min.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/js\/js_YjAJQgxDlFX6S-O02jj9jCrVbrwlY3CGgCg1FzPlvBs.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\nif(typeof window.MathJax === \u0022undefined\u0022) window.MathJax = { menuSettings: { zoom: \u0022Click\u0022 } };\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/js\/js_gPqjYq7fqdMzw8-29XWQIVoDSWTmZCGy9OqaHppNxuQ.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\n(function(i,s,o,g,r,a,m){i[\u0022GoogleAnalyticsObject\u0022]=r;i[r]=i[r]||function(){(i[r].q=i[r].q||[]).push(arguments)},i[r].l=1*new Date();a=s.createElement(o),m=s.getElementsByTagName(o)[0];a.async=1;a.src=g;m.parentNode.insertBefore(a,m)})(window,document,\u0022script\u0022,\u0022\/\/www.google-analytics.com\/analytics.js\u0022,\u0022ga\u0022);ga(\u0022create\u0022, \u0022UA-141606356-1\u0022, {\u0022cookieDomain\u0022:\u0022auto\u0022});ga(\u0022set\u0022, \u0022page\u0022, location.pathname + location.search + location.hash);ga(\u0022send\u0022, \u0022pageview\u0022);ga(\u0027create\u0027, \u0027UA-189672-38\u0027, \u0027auto\u0027, {\u0027name\u0027: \u0027hwTracker\u0027});\r\nga(\u0027set\u0027, \u0027anonymizeIp\u0027, true);\r\nga(\u0027hwTracker.send\u0027, \u0027pageview\u0027);\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\njQuery.extend(Drupal.settings, {\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022instances\u0022:\u0022{\\u0022highwire_abstract_tooltip\\u0022:{\\u0022content\\u0022:{\\u0022text\\u0022:\\u0022\\u0022},\\u0022style\\u0022:{\\u0022tip\\u0022:{\\u0022width\\u0022:20,\\u0022height\\u0022:20,\\u0022border\\u0022:1,\\u0022offset\\u0022:0,\\u0022corner\\u0022:true},\\u0022classes\\u0022:\\u0022qtip-custom hw-tooltip hw-abstract-tooltip qtip-shadow qtip-rounded\\u0022,\\u0022classes_custom\\u0022:\\u0022hw-tooltip hw-abstract-tooltip\\u0022},\\u0022position\\u0022:{\\u0022at\\u0022:\\u0022right center\\u0022,\\u0022my\\u0022:\\u0022left center\\u0022,\\u0022viewport\\u0022:true,\\u0022adjust\\u0022:{\\u0022method\\u0022:\\u0022shift\\u0022}},\\u0022show\\u0022:{\\u0022event\\u0022:\\u0022mouseenter click \\u0022,\\u0022solo\\u0022:true},\\u0022hide\\u0022:{\\u0022event\\u0022:\\u0022mouseleave \\u0022,\\u0022fixed\\u0022:1,\\u0022delay\\u0022:\\u0022100\\u0022}},\\u0022highwire_author_tooltip\\u0022:{\\u0022content\\u0022:{\\u0022text\\u0022:\\u0022\\u0022},\\u0022style\\u0022:{\\u0022tip\\u0022:{\\u0022width\\u0022:15,\\u0022height\\u0022:15,\\u0022border\\u0022:1,\\u0022offset\\u0022:0,\\u0022corner\\u0022:true},\\u0022classes\\u0022:\\u0022qtip-custom hw-tooltip hw-author-tooltip qtip-shadow qtip-rounded\\u0022,\\u0022classes_custom\\u0022:\\u0022hw-tooltip hw-author-tooltip\\u0022},\\u0022position\\u0022:{\\u0022at\\u0022:\\u0022top center\\u0022,\\u0022my\\u0022:\\u0022bottom center\\u0022,\\u0022viewport\\u0022:true,\\u0022adjust\\u0022:{\\u0022method\\u0022:\\u0022\\u0022}},\\u0022show\\u0022:{\\u0022event\\u0022:\\u0022mouseenter \\u0022,\\u0022solo\\u0022:true},\\u0022hide\\u0022:{\\u0022event\\u0022:\\u0022mouseleave \\u0022,\\u0022fixed\\u0022:1,\\u0022delay\\u0022:\\u0022100\\u0022}},\\u0022highwire_reflinks_tooltip\\u0022:{\\u0022content\\u0022:{\\u0022text\\u0022:\\u0022\\u0022},\\u0022style\\u0022:{\\u0022tip\\u0022:{\\u0022width\\u0022:15,\\u0022height\\u0022:15,\\u0022border\\u0022:1,\\u0022mimic\\u0022:\\u0022top center\\u0022,\\u0022offset\\u0022:0,\\u0022corner\\u0022:true},\\u0022classes\\u0022:\\u0022qtip-custom hw-tooltip hw-ref-link-tooltip qtip-shadow qtip-rounded\\u0022,\\u0022classes_custom\\u0022:\\u0022hw-tooltip hw-ref-link-tooltip\\u0022},\\u0022position\\u0022:{\\u0022at\\u0022:\\u0022bottom left\\u0022,\\u0022my\\u0022:\\u0022top left\\u0022,\\u0022viewport\\u0022:true,\\u0022adjust\\u0022:{\\u0022method\\u0022:\\u0022flip\\u0022}},\\u0022show\\u0022:{\\u0022event\\u0022:\\u0022mouseenter \\u0022,\\u0022solo\\u0022:true},\\u0022hide\\u0022:{\\u0022event\\u0022:\\u0022mouseleave \\u0022,\\u0022fixed\\u0022:1,\\u0022delay\\u0022:\\u0022100\\u0022}}}\u0022,\u0022qtipDebug\u0022:\u0022{\\u0022leaveElement\\u0022:0}\u0022,\u0022highwire\u0022:{\u0022processed\u0022:[\u0022highwire_math\u0022],\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022medrxiv;2020.06.27.20141739v4\u0022}]},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackColorbox\u0022:1,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022\\\/\\\/cdn.jsdelivr.net\\\/qtip2\\\/2.2.1\\\/jquery.qtip.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u00220\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00221\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/advagg_css\/css__dn-cpI1YtkU_iLHgA5WhlkxgYWyat_IxjF_B-WSYrpE__a9hIbt0eaZ7d5nhwnm2weG8R_2eXK4EvoOx9dOxouHE__-EZZOOp_wCSASDV0-vk6gBB76Nh1CchCZigZSlDhGlE.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/cdn.jsdelivr.net\/qtip2\/2.2.1\/jquery.qtip.min.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/advagg_css\/css__HGACIFBlu2o05y3afvqlt5wrE_5Dn6MXsexfuEpeIwg__t4SOPxucAPoV3Os7g8dXqyMB1HRXQridRJ82X7nE33E__-EZZOOp_wCSASDV0-vk6gBB76Nh1CchCZigZSlDhGlE.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-article-tab-full-text\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 class=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EAbstract\u003C\/h2\u003E\u003Cp id=\u0022p-4\u0022\u003EAscertaining the state of coronavirus outbreaks is crucial for public health decision-making. Absent repeated representative viral test samples in the population, public health officials and researchers alike have relied on lagging indicators of infection to make inferences about the direction of the outbreak and attendant policy decisions. Recently researchers have shown that SARS-CoV-2 RNA can be detected in municipal sewage sludge with measured RNA concentrations rising and falling suggestively in the shape of an epidemic curve while providing an earlier signal of infection than hospital admissions data. The present paper presents a SARS-CoV-2 epidemic model to serve as a basis for estimating the incidence of infection, and shows mathematically how modeled transmission dynamics translate into infection indicators by incorporating probability distributions for indicator-specific time lags from infection. Hospital admissions and SARS-CoV-2 RNA in municipal sewage sludge are simultaneously modeled via maximum likelihood scaling to the underlying transmission model. The results demonstrate that both data series plausibly follow from the transmission model specified and provide a 95% confidence interval estimate of the reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E \u2248 2.4 \u00b10.2. Sensitivity analysis accounting for alternative lag distributions from infection until hospitalization and sludge RNA concentration respectively suggests that the detection of viral RNA in sewage sludge leads hospital admissions by 3 to 5 days on average. The analysis suggests that stay-at-home restrictions plausibly removed 89% of the population from the risk of infection with the remaining 11% exposed to an unmitigated outbreak that infected 9.3% of the total population.\u003C\/p\u003E\u003Cspan class=\u0022list-title\u0022\u003EHighlights\u003C\/span\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\u003Cp id=\u0022p-5\u0022\u003EA maximum likelihood method for aligning observed lagged epidemic indicators via an underlying transmission model is derived and illustrated using observed COVID-19 hospital admissions and SARS-CoV-2 RNA concentrations measured in sewage sludge to model a local SARS-CoV-2 outbreak\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\u003Cp id=\u0022p-6\u0022\u003EThe method enables direct estimation of the reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E from the observed indicators along with the initial prevalence of SARS-CoV-2 infection in the population at risk\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\u003Cp id=\u0022p-7\u0022\u003EThe analysis suggests tracking SARS-CoV-2 RNA concentration in sewage sludge provides a 3 to 5 day lead time over tracking hospital admissions, consistent with purely statistical time series analysis previously reported\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\u003Cp id=\u0022p-8\u0022\u003EThe model enables estimation of the fraction of the population compliant with government-mandated stay-at-home restrictions, the size of the exposed population, and the fraction of the population infected with SARS-CoV-2 over the outbreak\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E1 Introduction\u003C\/h2\u003E\u003Cp id=\u0022p-21\u0022\u003EAscertaining the state of coronavirus outbreaks is crucial for public health decision-making. Absent repeated representative viral test samples in the population (\u003Ca id=\u0022xref-ref-12-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003EKaplan and Forman 2020\u003C\/a\u003E), public health officials and researchers alike have relied on lagging indicators of infection to make inferences about the direction of the outbreak and attendant policy decisions. How useful these indicators are depends upon their typical lags behind the incidence of infection. Some indicator lags, such as time from infection to hospitalization, have been studied empirically (\u003Ca id=\u0022xref-ref-16-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-2-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003ECDC 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-17-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003EMIDAS 2020\u003C\/a\u003E). Other indicators have been proposed with the hope that they would greatly reduce the lag time from infection. One such promising indicator is measured SARS-CoV-2 RNA concentration in municipal wastewater (\u003Ca id=\u0022xref-ref-6-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003EFoladori et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-7-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-7\u0022\u003EHart and Halden 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-20-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al 2020\u003C\/a\u003E). How much earlier might such a signal inform officials of changes in the state of the outbreak?\u003C\/p\u003E\u003Cp id=\u0022p-22\u0022\u003EThis paper tackles this question by using an epidemic transmission model to create model-scale versions of whatever indicator is of interest, and then scales these model quantities to match observed indicator values in the real world. This approach clarifies the time lags that should be expected from SARS-CoV-2 incidence to whichever indicator is of interest, and by doing so makes it possible to compare the relative timing of one indicator to another, providing the model fit to the data is sufficiently close.\u003C\/p\u003E\u003Cp id=\u0022p-23\u0022\u003EOur study takes advantage of recently conducted research tracking the local SARS-CoV-2 outbreak in the New Haven, Connecticut, USA metropolitan area. As reported by \u003Ca id=\u0022xref-ref-20-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E, daily SARS-CoV-2 RNA concentrations were obtained by sampling sewage sludge from the local wastewater treatment plant and conducting PCR tests to determine virus RNA concentration. Daily COVID-19 admissions to the Yale New Haven Hospital restricted to residents of the same four towns served by this wastewater treatment plant were also recorded over the same time period. An epidemic model developed by \u003Ca id=\u0022xref-ref-11-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan (2020b)\u003C\/a\u003E was taken as the basis for calibrating these two lagging indicators while simultaneously estimating the initial condition and reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E of this outbreak. This paper details the methodology employed and results obtained from doing so.\u003C\/p\u003E\u003Cp id=\u0022p-24\u0022\u003EThe next section presents a quick description of the transmission model reported in \u003Ca id=\u0022xref-ref-11-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan (2020b)\u003C\/a\u003E. In \u003Ca id=\u0022xref-sec-3-1\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-3\u0022\u003ESection 3\u003C\/a\u003E, a simple method is described for linking model-scale lagging epidemic indicators to SARS-CoV-2 incidence based on the model and appropriately defined lag probability density functions, which enables a model-scale comparison of different indicators to see how they should appear over the course of an outbreak (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). \u003Ca id=\u0022xref-sec-6-1\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-6\u0022\u003ESection 4\u003C\/a\u003E presents a simple statistical approach to analyzing real-world indicator data by scaling modeled indicators up to observed values based on maximum likelihood estimation while also estimating the initial condition and reproductive number of the epidemic wave from the underlying transmission model. We simultaneously scale hospital admissions and the RNA virus concentration observed in the sewage sludge to the epidemic model (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E, \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E and \u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3\u003C\/a\u003E). The results show that accounting for the inherent noise in the data, both the virus RNA concentration in the sewage sludge and hospital admissions match the model expectations reasonably well, and provides a 95% confidence interval for the reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E \u2248 2.4 \u00b1 0.2. \u003Ca id=\u0022xref-sec-7-1\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-7\u0022\u003ESection 5\u003C\/a\u003E reports a sensitivity analysis to allow for different probability distributions for the lags from infection to hospital admissions and sludge RNA concentration respectively. The analysis verifies that there is a 3 to 5 day separation between the sludge RNA concentration and hospital admissions curve, consistent with earlier analysis based on statistical time-series analysis (\u003Ca id=\u0022xref-ref-20-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al 2020\u003C\/a\u003E). \u003Ca id=\u0022xref-sec-8-1\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-8\u0022\u003ESection 6\u003C\/a\u003E uses the preceding analysis to provide epidemic insights suggesting that stay-at-home restrictions effectively bifurcated the local population by plausibly removing 89% of the population from the risk of infection with the remaining 11% exposed to an unmitigated outbreak that infected 9.3% of the total population. \u003Ca id=\u0022xref-sec-9-1\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-9\u0022\u003ESection 7\u003C\/a\u003E provides a summary of the key points of the paper.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Model-scale infection indicators (all units in infections per person per unit time): SARS-CoV-2 incidence (solid line), sludge viral load (dashed line), hospital admissions (dotted line).\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-855590881\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Model-scale infection indicators (all units in infections per person per unit time): SARS-CoV-2 incidence (solid line), sludge viral load (dashed line), hospital admissions (dotted line).\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 1:\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F1.medium.gif\u0022 width=\u0022440\u0022 height=\u0022267\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 1:\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F1.medium.gif\u0022 width=\u0022440\u0022 height=\u0022267\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1:\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1:\u003C\/span\u003E \u003Cp id=\u0022p-25\u0022 class=\u0022first-child\u0022\u003EModel-scale infection indicators (all units in infections per person per unit time): SARS-CoV-2 incidence (solid line), sludge viral load (dashed line), hospital admissions (dotted line).\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/292544\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/292544\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/292544\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1\u003C\/span\u003E \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Daily COVID-19 hospital admissions: observed data {solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-855590881\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Daily COVID-19 hospital admissions: observed data {solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 2:\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F2.medium.gif\u0022 width=\u0022440\u0022 height=\u0022270\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 2:\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F2.medium.gif\u0022 width=\u0022440\u0022 height=\u0022270\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2:\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2:\u003C\/span\u003E \u003Cp id=\u0022p-26\u0022 class=\u0022first-child\u0022\u003EDaily COVID-19 hospital admissions: observed data {solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022SARS-CoV-2 RNA Copies x 105 \/ ml Sludge: observed data (solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-855590881\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;SARS-CoV-2 RNA Copies x 105 \/ ml Sludge: observed data (solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 3:\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022285\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 3:\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022285\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3:\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3:\u003C\/span\u003E \u003Cp id=\u0022p-27\u0022 class=\u0022first-child\u0022\u003ESARS-CoV-2 RNA Copies x 105 \/ ml Sludge: observed data (solid line), model-based expected value (dashed line), 95% prediction interval limits (dotted line).\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E2 Transmission Model\u003C\/h2\u003E\u003Cp id=\u0022p-28\u0022\u003EData detailing person-to-person SARS-CoV-2 transmission in Wuhan were reported by \u003Ca id=\u0022xref-ref-18-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E. These data enabled an early model-based assessment of prospects for containing coronavirus via isolation and quarantine (\u003Ca id=\u0022xref-ref-10-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003EKaplan 2020a\u003C\/a\u003E), while that analysis was extended to a dynamic transmission model for SARS-CoV-2 transmission in Connecticut (\u003Ca id=\u0022xref-ref-11-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan 2020b\u003C\/a\u003E). This latter model incorporates infection-age-dependent transmission, and thus falls into the class of renewal equation epidemic models (\u003Ca id=\u0022xref-ref-9-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003EHeesterbeek and Dietz 1996\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-4-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003EChampredon and Dushoff 2015\u003C\/a\u003E). The key model element is the age-of-infection dependent transmission rate \u03bb(\u003Cem\u003Ea\u003C\/em\u003E), which can be thought of as the instantaneous transmission intensity of an individual who has been infected for \u003Cem\u003Ea\u003C\/em\u003E time units. At the beginning of an outbreak when an infectious person is embedded in an otherwise susceptible population, the expected number of infections transmitted per infectious person equals the reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E, which is given by\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-1\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-5.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-5.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nas is well known. \u003Ca id=\u0022xref-ref-18-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E reported estimates of both the exponential growth rate \u003Cem\u003Er\u003C\/em\u003E and backwards generation time probability density function \u003Cem\u003Eb\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E), enabling \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) to be written as\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-2\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-6.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-6.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-29\u0022\u003E(\u003Ca id=\u0022xref-ref-10-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003EKaplan 2020a\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-11-4\u0022 class=\u0022
xref-bibr\u0022 href=\u0022#ref-11\u0022\u003E2020b\u003C\/a\u003E; \u003Ca id=\u0022xref-ref-1-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003EBritton and Tomba 2019\u003C\/a\u003E; \u003Ca id=\u0022xref-ref-4-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003EChampredon and Dushoff 2015\u003C\/a\u003E; \u003Ca id=\u0022xref-ref-21-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003EWallinga and Lipsitch 2007\u003C\/a\u003E), which together imply a point estimate of \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E =2.26(\u003Ca id=\u0022xref-ref-10-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003EKaplan 2020a\u003C\/a\u003E), consistent with values widely reported elsewhere (\u003Ca id=\u0022xref-ref-5-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-5\u0022\u003EFerguson et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-13-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-13\u0022\u003EKissler et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-17-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003EMIDAS 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-19-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003EPark et al 2020\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-30\u0022\u003EAn alternative representation of \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) is\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-3\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-7.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-7.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nwhere \u003Cem\u003Ef\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E) is the \u003Cem\u003Eforward\u003C\/em\u003E generation time density that dictates the timing of transmission (\u003Ca id=\u0022xref-ref-1-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003EBritton and Tomba 2019\u003C\/a\u003E; \u003Ca id=\u0022xref-ref-4-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003EChampredon and Dushoff 2015\u003C\/a\u003E; \u003Ca id=\u0022xref-ref-21-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003EWallinga and Lipsitch 2007\u003C\/a\u003E). We adopt this representation in the present analysis, as it enables estimation of the underlying reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E directly from the data at our disposal.\u003C\/p\u003E\u003Cp id=\u0022p-31\u0022\u003EThe transmission model developed in \u003Ca id=\u0022xref-ref-11-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan (2020b)\u003C\/a\u003E that will be used to anchor our infection indicators analysis follows. Let\u003C\/p\u003E\u003Cp id=\u0022p-32\u0022\u003E\u003Cem\u003E\u03c8\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) \u2261 transmission potential (or force of infection) at chronological time \u003Cem\u003Et\u003C\/em\u003E;\u003C\/p\u003E\u003Cp id=\u0022p-33\u0022\u003E\u003Cem\u003Es\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) \u2261 fraction of the population that is susceptible to infection at chronological time \u003Cem\u003Et\u003C\/em\u003E;\u003C\/p\u003E\u003Cp id=\u0022p-34\u0022\u003E\u003Cem\u003E\u03c0\u003C\/em\u003E(\u003Cem\u003Ea,t\u003C\/em\u003E) \u2261 density of the population that has been infected for duration \u003Cem\u003Ea\u003C\/em\u003E at time \u003Cem\u003Et\u003C\/em\u003E;\u003C\/p\u003E\u003Cp id=\u0022p-35\u0022\u003E\u003Cem\u003E\u03c0\u003C\/em\u003E(0,\u003Cem\u003Et\u003C\/em\u003E)= incidence of infection at time \u003Cem\u003Et\u003C\/em\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-36\u0022\u003EGiven the initial condition \u003Cem\u003E\u03c0\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E, 0) which implies \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-1\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-1.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-1.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E, the model equations are:\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-4\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-8.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-8.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-5\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-9.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-9.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-6\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-10.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-10.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-7\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-11.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-11.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-37\u0022\u003E\u003Ca id=\u0022xref-disp-formula-4-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-4\u0022\u003EEquation (4)\u003C\/a\u003E defines the transmission potential at time \u003Cem\u003Et\u003C\/em\u003E, which is infection-age-dependent transmission \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) weighted by the infection-age-dependent prevalence of infection in the population \u003Cem\u003E\u03c0\u003C\/em\u003E(\u003Cem\u003Ea,t\u003C\/em\u003E);\u003Ca id=\u0022xref-disp-formula-5-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-5\u0022\u003Eequation (5)\u003C\/a\u003E equates SARSCoV-2 incidence to the product of the fraction of the population that is susceptible and the transmission potential; \u003Ca id=\u0022xref-disp-formula-6-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-6\u0022\u003Eequation (6)\u003C\/a\u003E depletes susceptibles with the incidence of infection; and \u003Ca id=\u0022xref-disp-formula-7-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-7\u0022\u003Eequation (7)\u003C\/a\u003E aligns the fraction of the population infected for duration \u003Cem\u003Ea\u003C\/em\u003E at time \u003Cem\u003Et\u003C\/em\u003E with the incidence of infection at time \u003Cem\u003Et\u003C\/em\u003E \u2212 \u003Cem\u003Ea\u003C\/em\u003E, adjusting for the initial conditions at time zero. There is no additional accounting for the duration of infectiousness because the time course of infection is already built into \u03bb(\u003Cem\u003Ea\u003C\/em\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-38\u0022\u003EThe \u003Cem\u003Efinal size \u03d5\u003C\/em\u003E, defined as the fraction of the population that is infected over the duration of an outbreak described by this model, follows (\u003Ca id=\u0022xref-ref-11-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan 2020b\u003C\/a\u003E)\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-8\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-12.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-12.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-39\u0022\u003EWe will make use of this relationship below.\u003C\/p\u003E\u003Cp id=\u0022p-40\u0022\u003EThe transmission function employed in our base case analysis is given by \u003Ca id=\u0022xref-disp-formula-3-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-3\u0022\u003Eequation (3)\u003C\/a\u003E using the forward generation time density \u003Cem\u003Ef\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E) implied by \u003Ca id=\u0022xref-ref-18-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E, which is a gamma density with mean (standard deviation) equal to 8.86 (4.02) days (see \u003Ca id=\u0022xref-fig-4-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4b\u003C\/a\u003E). The reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E and initial conditions \u003Cem\u003E\u03c0\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E, 0) and hence \u003Cem\u003Es\u003C\/em\u003E(0) are estimated from the data as described below.\u003C\/p\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022a. Hospitalization lag density functions indicating short (mean 12 days), Lewnard et al (mean 13.5 days), and long (mean 15 days) lags. b. Forward generation time densities indicating early transmission (Park et al) and late transmission (Li et al) of infection.\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-855590881\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;a. Hospitalization lag density functions indicating short (mean 12 days), Lewnard et al (mean 13.5 days), and long (mean 15 days) lags. b. Forward generation time densities indicating early transmission (Park et al) and late transmission (Li et al) of infection.\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 4:\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F4.medium.gif\u0022 width=\u0022440\u0022 height=\u0022133\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 4:\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F4.medium.gif\u0022 width=\u0022440\u0022 height=\u0022133\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 4:\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 4:\u003C\/span\u003E \u003Cp id=\u0022p-41\u0022 class=\u0022first-child\u0022\u003Ea. Hospitalization lag density functions indicating short (mean 12 days), Lewnard et al (mean 13.5 days), and long (mean 15 days) lags. b. Forward generation time densities indicating early transmission (Park et al) and late transmission (Li et al) of infection.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E3 Model-Scale Infection Indicators and Time Lags\u003C\/h2\u003E\u003Cp id=\u0022p-42\u0022\u003EIn the absence of repeated representative viral testing in a population, officials and researchers alike have turned to lagging indicators of infection such as diagnosed COVID-19 cases, hospitalizations, and deaths to monitor the state of the outbreak. How useful such indicators are depends upon their lag time from infection. Let \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) be the value of a model-scale infection indicator that represents a distributionally lagged signal of the incidence of infection. Specifically, denote \u003Cem\u003EL\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E as the time lag from infection, and define \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-2\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-2.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-2.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E as the probability density function governing the lag \u003Cem\u003EL\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E. The model-scale infection indicator \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) is then defined as\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-9\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-14.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-14.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nwhere \u003Cem\u003EE\u003Csub\u003EX\u003C\/sub\u003E\u003C\/em\u003E [\u00b7] denotes mathematical expectation with respect to random variable \u003Cem\u003EX\u003C\/em\u003E. A first-order Taylor approximation yields the approximation\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-10\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-15.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-15.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nwhich suggests that the model-scale indicator value can be approximated by incidence evaluated \u003Cem\u003EE\u003C\/em\u003E(\u003Cem\u003EL\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E) time units earlier. The model-scale indicator at time \u003Cem\u003Et\u003C\/em\u003E is just the expected value of SARS-CoV-2 incidence \u003Cem\u003EL\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E time units into the past. Note from \u003Ca id=\u0022xref-disp-formula-8-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-8\u0022\u003Eequation (8)\u003C\/a\u003E that\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-11\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-16.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-16.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nwhich shows that the model-scale indicator solely reflects the \u003Cem\u003Etiming\u003C\/em\u003E at which SARS-CoV-2 incidence is experienced for whatever indicator is of interest while conserving the total incidence of infection. The units for all modelscale indicators thus equal infections per person per unit time, regardless of which real-world indicator is being considered.\u003C\/p\u003E\u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003E3.1 Example: Hospital Admissions\u003C\/h3\u003E\u003Cp id=\u0022p-43\u0022\u003EHospital admissions have been used as an indicator for the coronavirus outbreak under the presumption that the fraction of new infections that require hospitalization remains constant over time. Define \u003Cem\u003EL\u003Csub\u003EH\u003C\/sub\u003E\u003C\/em\u003E as the time from infection to hospitalization for those infected persons that do require hospital treatment. A review of several published studies by \u003Ca id=\u0022xref-ref-16-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al (2020)\u003C\/a\u003E estimated that the time from infection until hospitalization averages 13.5 days with 95% probability coverage ranging from 4.8 to 27.9 days. We approximate this finding by employing a gamma distribution with \u003Cem\u003E\u03b1\u003C\/em\u003E = 4.954 and \u003Cem\u003E\u03b2\u003C\/em\u003E = 2.725 to represent the probability density of \u003Cem\u003EL\u003Csub\u003EH\u003C\/sub\u003E\u003C\/em\u003E, \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-3\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-3.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-3.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E. This distribution also has a mean of 13.5 days with 95% probability coverage ranging from 4.4 to 27.7 days (see \u003Ca id=\u0022xref-fig-4-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4a\u003C\/a\u003E). Similar times from infection to hospitalization are implied by the Centers for Disease Control COVID-19 pandemic planning scenarios (\u003Ca id=\u0022xref-ref-2-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003ECDC 2020\u003C\/a\u003E) and also \u003Ca id=\u0022xref-ref-17-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003EMIDAS (2020)\u003C\/a\u003E. We employ this density in our base case analysis, but will consider distributions with shorter and longer times from infection to hospital admissions in the sensitivity analyses of \u003Ca id=\u0022xref-sec-7-2\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-7\u0022\u003ESection 5\u003C\/a\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-44\u0022\u003EConditional upon the transmission model described in equations (\u003Ca id=\u0022xref-disp-formula-4-2\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-4\u0022\u003E4\u003C\/a\u003E-\u003Ca id=\u0022xref-disp-formula-7-2\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-7\u0022\u003E7\u003C\/a\u003E), the model-scale hospitalization indicator \u003Cem\u003Eh\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) is, following \u003Ca id=\u0022xref-disp-formula-9-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-9\u0022\u003Eequation (9)\u003C\/a\u003E, given by\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-12\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-17.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-17.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-45\u0022\u003E\u003Ca id=\u0022xref-fig-1-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E plots both the model-scale SARS-CoV-2 incidence \u003Cem\u003E\u03c0\u003C\/em\u003E(0,\u003Cem\u003Et\u003C\/em\u003E) and hospitalization indicator \u003Cem\u003Eh\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) assuming \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) as defined in \u003Ca id=\u0022xref-disp-formula-3-2\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-3\u0022\u003Eequation (3)\u003C\/a\u003E with \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E = 2.38 as will be estimated subsequently; the gamma distribution for \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-4\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-4.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-4.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E described above; \u003Cem\u003Es\u003C\/em\u003E(0) = 1 \u2212 0.0161 reflecting the initial prevalence of infection as estimated below (with time 0 taken as February 19, 2020); and \u003Cem\u003E\u03c0\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E, 0) = 0.0161\/30 for 0 \u0026lt; \u003Cem\u003Ea\u003C\/em\u003E \u2264 30 as explained below. The model-scale hospitalization indicator lags incidence by about two weeks, as one would expect given that \u003Cem\u003EE\u003C\/em\u003E(\u003Cem\u003EL\u003Csub\u003EH\u003C\/sub\u003E\u003C\/em\u003E) = 13.5 days by design.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-5\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003E3.2 Example: SARS-CoV-2 RNA in Municipal Sewage Sludge\u003C\/h3\u003E\u003Cp id=\u0022p-46\u0022\u003E\u003Ca id=\u0022xref-ref-20-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E reported daily SARS-CoV-2 RNA concentrations based on sampling sludge from a municipal wastewater treatment plant serving the combined 200,000 population of the towns of New Haven, East Haven, Hamden, and Woodbridge in the state of Connecticut, USA. Virus RNA concentrations in sludge should reflect the amount of virus shed in feces by infected persons in the population served by the treatment plant, resulting in a fecal estimate of community virus RNA concentration. Though virus RNA concentrations in feces degrade exponentially with the time from excretion to sample collection (\u003Ca id=\u0022xref-ref-6-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003EFoladori et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-7-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-7\u0022\u003EHart and Halden, 2020\u003C\/a\u003E), virus RNA concentrations obtained from sludge sampled daily should be discounted by approximately the same degradation factor, rendering the resulting signal a plausible surrogate tracking community virus RNA concentration over time.\u003C\/p\u003E\u003Cp id=\u0022p-47\u0022\u003EReferring back to the epidemic model, the appropriate measure of virus RNA concentration is the transmission potential \u003Cem\u003E\u03c8\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E), as the amount of virus shed in feces should reflect the average infectiousness of the population. However, to use the indicator framework developed above, the age-of-infection transmission rate \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) must be normalized to the scale of a probability density function. This is easily achieved by defining\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-13\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-18.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-18.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nwhich is immediately recognized as the forward generation time probability density \u003Cem\u003Ef\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E) introduced earlier. This density enables the definition of the model-scale virus RNA indicator \u003Cem\u003E\u03c5\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) as\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-14\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-19.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-19.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-48\u0022\u003EFor \u03bb(\u003Cem\u003Ea\u003C\/em\u003E) as defined in \u003Ca id=\u0022xref-disp-formula-3-3\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-3\u0022\u003Eequation (3)\u003C\/a\u003E using the forward generation time density \u003Cem\u003Ef\u003C\/em\u003E(\u003Cem\u003Ea\u003C\/em\u003E) corresponding to \u003Ca id=\u0022xref-ref-18-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E, the expected lag \u003Cem\u003EE\u003C\/em\u003E(\u003Cem\u003EL\u003Csub\u003EV\u003C\/sub\u003E\u003C\/em\u003E) is given by 8.9 days, or 4.6 days shorter than the lag from infection to hospitalization (we consider an alternative generation time distribution in \u003Ca id=\u0022xref-sec-7-3\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-7\u0022\u003ESection 5\u003C\/a\u003E). \u003Ca id=\u0022xref-fig-1-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E reports the model-scale virus RNA indicator \u003Cem\u003E\u03c5\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) under the same epidemic modeling assumptions described for the hospitalization indicator \u003Cem\u003Eh\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E). Given the transmission model, the timing of both the virus RNA concentration and hospitalization indicators is clear, and provides a clue as to what might be expected when examining the timing of observed hospital admissions and SARS-CoV-2 data in sewage sludge. We turn to such an empirical analysis in the next section.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-6\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E4 Scaling Indicators to Transmission: Hospital Admissions and SARS-CoV-2 RNA in Sewage Sludge\u003C\/h2\u003E\u003Cp id=\u0022p-49\u0022\u003EConsider a model-scale infection indicator \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) as earlier described, and let \u003Cem\u003EY\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) be the random variable denoting the real-world-scale observable value of this indicator at time \u003Cem\u003Et\u003C\/em\u003E. For example, corresponding to the model-scale hospitalization indicator \u003Cem\u003Eh\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E), the real-world number of hospital admissions observed on day \u003Cem\u003Et\u003C\/em\u003E is the random variable \u003Cem\u003EH\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E). Similarly, random variable \u003Cem\u003EV\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) denotes the actual concentration of RNA observed in sewage sludge on day \u003Cem\u003Et\u003C\/em\u003E, corresponding with the model-scale virus RNA concentration indicator \u003Cem\u003E\u03c5\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-50\u0022\u003EThe observable indicator \u003Cem\u003EY\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) is modeled as a random variable with mean proportional to \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E), that is,\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-15\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-20.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-20.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nfor some indicator-specific constant \u003Cem\u003Ek\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E. We thus scale observable indicators to their model-scale values in expectation. Note from \u003Ca id=\u0022xref-disp-formula-11-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-11\u0022\u003Eequation (11)\u003C\/a\u003E that\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-16\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-21.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-21.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\na result we will exploit in \u003Ca id=\u0022xref-sec-8-2\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-8\u0022\u003ESection 6\u003C\/a\u003E below.\u003C\/p\u003E\u003Cp id=\u0022p-51\u0022\u003EWe also allow the indicator variance \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-5\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-5.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-5.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E to depend upon \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E). Given the transmission model, we treat \u003Cem\u003EY\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) as conditionally independent of \u003Cem\u003EY\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E\u2032) for all \u003Cem\u003Et \u2260 t\u2032\u003C\/em\u003E, for correlation in observed values across time would almost entirely be due to the underlying epidemic. The specific probability law presumed for \u003Cem\u003EY\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) given \u003Cem\u003Ey\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) can differ by infection indicator, as will become clear by example. Given observed indicator values at different points in time and an underlying epidemic model, one can estimate the scaling constants \u003Cem\u003Ek\u003Csub\u003EY\u003C\/sub\u003E\u003C\/em\u003E (and variance parameters if needed) via maximum likelihood or other methods.\u003C\/p\u003E\u003Cp id=\u0022p-52\u0022\u003EThe \u003Ca id=\u0022xref-ref-20-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E study of sewage sludge obtained daily COVID-19 admissions data to the Yale New Haven Hospital restricted to residents of the same four Connecticut towns served by the local wastewater treatment plant. The data record the first such admission as occurring on March 14, 2020, 24 days following our February 19 starting date (\u003Cem\u003Et\u003C\/em\u003E = 0). We focus here on daily admissions data recorded thr
ough May 1, 2020 (\u003Cem\u003Et\u003C\/em\u003E = 72).\u003C\/p\u003E\u003Cp id=\u0022p-53\u0022\u003EDaily hospital admissions data \u003Cem\u003Eh\u003Csub\u003Et\u003C\/sub\u003E\u003C\/em\u003E are modeled as realizations of a Poisson random variable \u003Cem\u003EH\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) with mean proportional to the model-scale indicator \u003Cem\u003Eh\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) developed earlier, that is,\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-17\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-22.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-22.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-54\u0022\u003EThe Poisson log likelihood corresponding to the hospital admissions data covering March 14 (\u003Cem\u003Et = 24\u003C\/em\u003E) to May 1 (\u003Cem\u003Et = 72\u003C\/em\u003E), \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-6\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-6.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-6.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E, is thus given by\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-18\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-23.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-23.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-55\u0022\u003EAlso as reported in \u003Ca id=\u0022xref-ref-20-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E, sludge samples from the local wastewater treatment plant were tested for SARS-CoV-2 RNA concentrations with two different primers applied to two sample replications daily. These values were adjusted to control for day to day variations in treatment plant flow, sludge solids content, and RNA extraction efficiency (\u003Ca id=\u0022xref-ref-20-7\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al 2020\u003C\/a\u003E). The data we employ here are \u003Cem\u003E\u03c5\u003Csub\u003Et\u003C\/sub\u003E\u003C\/em\u003E, the day \u003Cem\u003Et\u003C\/em\u003E average of these four adjusted values with measurement units 10\u003Csup\u003E5\u003C\/sup\u003E SARS-CoV-2 RNA copies \/ ml sludge. We again focus on data collected from March 19 through May 1 (\u003Cem\u003Et = 29,\u2026, 72\u003C\/em\u003E) for a total of 44 daily observations. We model \u003Cem\u003E\u03c5\u003Csub\u003Et\u003C\/sub\u003E\u003C\/em\u003E as realizations of a Normal random variable \u003Cem\u003EV\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) with mean \u003Cem\u003EE\u003C\/em\u003E[\u003Cem\u003EV\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E)] = \u003Cem\u003Ek\u003Csub\u003EV\u003C\/sub\u003E\u03c5\u003C\/em\u003E(\u003Cem\u003Et\u003C\/em\u003E) and variance \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-7\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-7.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-7.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E to allow for over- or under-dispersion relative to the mean\u003Ca id=\u0022xref-fn-3-1\u0022 class=\u0022xref-fn\u0022 href=\u0022#fn-3\u0022\u003E\u003Csup\u003E1\u003C\/sup\u003E\u003C\/a\u003E. The Normal log likelihood corresponding to the sludge data, \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-8\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-8.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-8.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E, thus equals\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-19\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-24.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-24.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-56\u0022\u003EWe estimate five parameters from the hospital admissions and sludge data via maximum likelihood, conditional upon the epidemic model (which implies the forward generation lag density \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-9\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-9.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-9.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E based on \u003Ca id=\u0022xref-ref-18-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E, and hospital lag density \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-10\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-10.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-10.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E based on \u003Ca id=\u0022xref-ref-16-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al (2020)\u003C\/a\u003E). Three of the parameters estimated are the hospitalization scaling constant \u003Cem\u003Ek\u003Csub\u003EH\u003C\/sub\u003E\u003C\/em\u003E, the sludge RNA scaling constant \u003Cem\u003Ek\u003Csub\u003EV\u003C\/sub\u003E\u003C\/em\u003E, and the sludge RNA variance scaling constant \u003Cem\u003Ec\u003Csub\u003EV\u003C\/sub\u003E\u003C\/em\u003E. The fourth parameter estimated is \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E which scales the strength of the outbreak and enables direct comparison to SARS-CoV-2 epidemics elsewhere. The final parameter estimated is \u003Cem\u003E\u03c0\u003C\/em\u003E(0), which sets the initial condition of the model via the relation\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-20\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-25.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-25.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-57\u0022\u003EThis modeling choice reflects the random arrival of imported infections to the area of study in the thirty days preceding the onset of community transmission, in effect determining the placement of the main epidemic wave without changing its shape. A larger value of \u003Cem\u003E\u03c0\u003C\/em\u003E(0) would pull the epidemic earlier in time, while a smaller value would push the epidemic later. In this way, the hospital admissions and sludge virus RNA concentration data jointly determine the size and the placement of the epidemic wave while impacting the transmission dynamics via the model described in equations (\u003Ca id=\u0022xref-disp-formula-4-3\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-4\u0022\u003E4\u003C\/a\u003E-\u003Ca id=\u0022xref-disp-formula-7-3\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-7\u0022\u003E7\u003C\/a\u003E). Consequently, population susceptibility at time 0 is given by \u003Cem\u003Es\u003C\/em\u003E(0) = 1 \u2212 \u003Cem\u003E\u03c0\u003C\/em\u003E(0).\u003C\/p\u003E\u003Cp id=\u0022p-58\u0022\u003E\u003Ca id=\u0022xref-table-wrap-1-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E reports the maximum likelihood estimates and standard errors computed by inverting the Hessian matrix of the log likelihood function (\u003Ca id=\u0022xref-ref-3-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003ECox and Hinkley 1974\u003C\/a\u003E) following maximization of \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-11\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-11.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-11.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E, while the fit of the observed data to the scaled model indicators is illustrated in \u003Ca id=\u0022xref-fig-2-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigures 2\u003C\/a\u003E and \u003Ca id=\u0022xref-fig-3-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3\u003C\/a\u003E, which plot 95% prediction intervals about the expected indicator values in addition to the data. The hospital admissions data are plotted in \u003Ca id=\u0022xref-fig-2-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E. Though noisy, the admissions data correspond to the modeled pace of the epidemic, with most values falling within the 95% prediction intervals.\u003C\/p\u003E\u003Cp id=\u0022p-59\u0022\u003E\u003Ca id=\u0022xref-fig-3-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E reports the observed and modeled SARS-CoV-2 RNA concentrations (in 10\u003Csup\u003E5\u003C\/sup\u003E RNA copies \/ ml sludge) from the sewage study along with conservative 95% prediction intervals. While peak RNA virus concentrations are higher than what would be expected based on the model, the data again match the estimated pace of the epidemic, suggesting that community virus RNA concentration in sewage sludge can indeed be represented by the transmission potential in an epidemic model. The data rise and fall as expected, albeit with much random noise to be sure.\u003C\/p\u003E\u003Cp id=\u0022p-60\u0022\u003ENote that the estimated reproductive number is 2.38 with a 95% confidence interval ranging from 2.18 to 2.58. This places the local SARS-CoV-2 outbreak in New Haven squarely in the middle of reproductive numbers estimated elsewhere (for examples see \u003Ca id=\u0022xref-ref-2-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003ECDC (2020)\u003C\/a\u003E and \u003Ca id=\u0022xref-ref-17-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003EMIDAS (2020)\u003C\/a\u003E). What is noteworthy is that this reproductive number was estimated from a model linking transmission to hospital admissions and SARS-CoV-2 RNA concentrations measured in sewage sludge. The data, not the model, determinedthe magnitude of \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E, supporting the plausibility of the hospitalization and generation time lag distributions employed to match the observed data to an underlying transmission model.\u003C\/p\u003E\u003Cp id=\u0022p-61\u0022\u003ETogether with the epidemic model, these data help explain one of the findings in the \u003Ca id=\u0022xref-ref-20-8\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E study, which is that the SARS-CoV-2 RNA signal from the sewage sludge led hospital admissions by only 4 days, when many were expecting a much earlier signal. The model shows that the natural time lag for virus RNA concentration is governed by the mean forward generation time, estimated at 8.9 days in this model. Given an average 13.5 day lag from infection to hospitalization documented elsewhere (\u003Ca id=\u0022xref-ref-16-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al 2020\u003C\/a\u003E), tracking the outbreak by relying on the sewage sludge RNA signal leads similar tracking by hospital admissions by 4.6 days on average, which is very close to the purely statistical time series results reported by \u003Ca id=\u0022xref-ref-20-9\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-7\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E5 Sensitivity Analyses\u003C\/h2\u003E\u003Cp id=\u0022p-62\u0022\u003EThe analysis of \u003Ca id=\u0022xref-sec-6-2\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-6\u0022\u003ESection 4\u003C\/a\u003E relies on two particular lag distributions: the forward generation time based on \u003Ca id=\u0022xref-ref-18-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E and the hospital admissions density based on \u003Ca id=\u0022xref-ref-16-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al (2020)\u003C\/a\u003E. Different lag distributions could generate different results yet also appear reasonably consistent with the data. In this section we will summarize maximum likelihood scalings as in the previous section but using alternative lag density combinations.\u003C\/p\u003E\u003Cp id=\u0022p-63\u0022\u003EStarting with the forward generation time density that is used to both drive the epidemic model and provide a model-scale indicator for SARS-CoV-2 RNA in sewage sludge, we turn to the meta-analysis of several published studies reported by \u003Ca id=\u0022xref-ref-19-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003EPark et al (2020)\u003C\/a\u003E. The consensus distribution from that analysis is also a gamma density but with a mean (standard deviation) of 8.5 (6.1) days. \u003Ca id=\u0022xref-fig-4-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4a\u003C\/a\u003E plots both the \u003Ca id=\u0022xref-ref-18-7\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E and \u003Ca id=\u0022xref-ref-19-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003EPark et al (2020)\u003C\/a\u003E generation time densities, from which one can see that the timing of transmission is relatively early under the \u003Ca id=\u0022xref-ref-19-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003EPark et al (2020)\u003C\/a\u003E model relative to our base case of \u003Ca id=\u0022xref-ref-18-8\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E. Regarding the distribution of the time from infection until hospital admission for those requiring hospitalization, \u003Ca id=\u0022xref-ref-2-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003ECDC (2020)\u003C\/a\u003E recommends a mean of 12 days based upon 6 day mean times from infection until the onset of symptoms, and from the onset of symptoms until hospitalization. We model this \u201cshort\u201d hospitalization lag as a gamma distribution with a mean (standard deviation) of 12 (\u003Ca id=\u0022xref-disp-formula-6-2\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-6\u0022\u003E6\u003C\/a\u003E) days. To explore the possibility that sludge RNA provides a longer lead time over COVID-19 hospitalizations, we also consider a \u201clong\u201d hospitalization gamma-distributed lag with a mean (standard deviation) of 15 (6.7) days. \u003Ca id=\u0022xref-fig-4-4\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4b\u003C\/a\u003E plots the short, base case (following \u003Ca id=\u0022xref-ref-16-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al 2020\u003C\/a\u003E), and long hospitalization lag densities.\u003C\/p\u003E\u003Cp id=\u0022p-64\u0022\u003E\u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E reports the mean lead time (given by the difference between the mean hospitalization and forward generation\/sludge RNA lags), log likelihood function, estimated reproductive number \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E and estimated initial fraction infected \u003Cem\u003E\u03c0\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E for all six combinations of the hospitalization and forward generation lags. While all the maximized log likelihood values are comparable, the late transmission \u003Ca id=\u0022xref-ref-18-9\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003ELi et al (2020)\u003C\/a\u003E generation time density fits slightly better than the early transmission \u003Ca id=\u0022xref-ref-19-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003EPark et al (2020)\u003C\/a\u003E generation time density for all three hospital lags, while the hospitalization lag densities fit best from short to \u003Ca id=\u0022xref-ref-16-7\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003ELewnard et al (2020)\u003C\/a\u003E to long for both generation time densities. The point estimates for \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E range from 2.2 (early transmission and long hospitalization lag) to 2.43 (late transmission and short hospitalization lag), and are all within the 95% confidence interval provided by our earlier base case analysis in \u003Ca id=\u0022xref-sec-6-3\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-6\u0022\u003ESection 4\u003C\/a\u003E. The point estimates for the initial fraction infected \u003Cem\u003E\u03c0\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E range from 0.010 to 0.019, and are also all within the 95% confidence interval estimated in our base case. Examining the log likelihood values, there is slightly more evidence favoring shorter RNA sludge lead times. The best fitting model (late transmission and short hospital lag) estimates that sludge RNA provides an expected lead time of only 3.1 days over hospital admissions data, while the worst fitting model (early transmission and long hospital lag) has an expected lead time of 6.5 days. Together these results suggest that the sludge RNA signal provides a 3 to 5 day lead time over hospital admissions, consistent with what was found based on statistical time series analysis in \u003Ca id=\u0022xref-ref-20-10\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E.\u003C\/p\u003E\u003Cdiv id=\u0022T2\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/292537\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/292537\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/292537\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 2\u003C\/span\u003E \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-8\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E6 Epidemic Insights\u003C\/h2\u003E\u003Cp id=\u0022p-65\u0022\u003EThe epidemic model developed describes an unmitigated outbreak among a population at risk for SARS-CoV-2 infection, but in Connecticut where this study took place, social distancing and lockdown-like stay-at-home orders were imposed on March 22 (\u003Ca id=\u0022xref-ref-14-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003ELamont 2020a\u003C\/a\u003E) and extended past the duration of our study period (\u003Ca id=\u0022xref-ref-15-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003ELamont 2020b\u003C\/a\u003E). An unmitigated outbreak with \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E = 2.38 would leave 87.5% of the population infected, but clearly that did not occur in the greater New Haven urban area.\u003C\/p\u003E\u003Cp id=\u0022p-66\u0022\u003ENonetheless, the timing of the sludge and hospital admissions data are consistent with an unmitigated outbreak. Models reflecting the effect of lockdowns and social distancing applied uniformly to large populations show that transmission is both delayed and slowed, resulting in the oft-cited flattening of the epidemic curve (\u003Ca id=\u0022xref-ref-5-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-5\u0022\u003EFerguson et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-13-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-13\u0022\u003EKissler et al 2020\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-11-7\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003EKaplan 2020b\u003C\/a\u003E). The epidemic models we have shown to be consistent with the observed data do not behave this way, suggesting that the effect of the stay-at-home orders was not experienced uniformly. A different possibility is that stay-at-home restrictions essentially bifurcated the population into two groups: a large group of citizens whose compliance with stay-at-home restrictions removed them from potentially infectious interactions, and a smaller group of essential workers, other vulnerable persons such as nursing home residents, or non-compliant individuals that, due to necessity or choice, continued to experience exposures via interactions with others, enabling continued transmission. Were that the case, then members of the \u201cexposed\u201d population could have experienced an unmitigated outbreak while compliant individuals escaped unscathed. The epidemic model of this paper might only portray transmission among the exposed population, yet all infections and hence hospitalizations and SARS-CoV-2 RNA in the sewage sludge would have emanated from this group.\u003C\/p\u003E\u003Cp id=\u0022p-67\u0022\u003ETo investigate this possibility, we will use our model results to produce a back-of-the-envelope estimate of the fraction of the population that was exposed, and consequentially the fraction of the entire population that complied with the stay-at-home restrictions. We will also estimate the implied number of infections that must have occurred under this bifurcation hypothesis, including the initial number of infected persons circa February 19, 2020 (which recall is clock time 0).\u003C\/p\u003E\u003Cp id=\u0022p-68\u0022\u003EFirst, we apply \u003Ca id=\u0022xref-disp-formula-16-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-16\u0022\u003Eequation (16)\u003C\/a\u003E to the expected total number of hospital admissions over all time from this outbreak which yields\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-21\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-27.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-27.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-69\u0022\u003ENext, define \u003Cstrong\u003EN\u003C\/strong\u003E and \u003Cstrong\u003EC\u003C\/strong\u003E as the number of persons in the exposed population and the total number of diagnosed COVID-19 cases that occurred in that population respectively over all time. A second equation for \u003Cstrong\u003EH\u003C\/strong\u003E is given by\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-22\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-28.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-28.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-70\u0022\u003EEquating equations (\u003Ca id=\u0022xref-disp-formula-21-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-21\u0022\u003E21\u003C\/a\u003E) and (\u003Ca id=\u0022xref-disp-formula-22-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-22\u0022\u003E22\u003C\/a\u003E) yields\n\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-23\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-29.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-29.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\nas our estimate for the size of the exposed population. Focusing on the denominator, the ratio \u003Cstrong\u003EC\u003C\/strong\u003E\/\u003Cstrong\u003EN\u003C\/strong\u003E\u003Cem\u003E\u03d5\u003C\/em\u003E is the ratio of diagnosed COVID-19 cases to infections in the exposed population, also known as the case ascertainment ratio. Under the bifurcation hypothesis, this will be the same as the ratio of diagnosed COVID-19 cases to infections in the overall population, as infections and cases only accrue in the exposed group. A direct estimate of the reciprocal of the case ascertainment ratio (that is, the number of infections per diagnosed COVID-19 case) was reported by \u003Ca id=\u0022xref-ref-8-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003EHavers et al (2020)\u003C\/a\u003E forConnecticut covering March 23-May 12 of 2020 viaapopulation-based seroprevalence survey. \u003Ca id=\u0022xref-ref-8-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003EHavers et al (2020)\u003C\/a\u003E estimated an average of 6.0 infections per case (95% confidence interval 4.3\u20137.8). The ratio \u003Cstrong\u003EH\u003C\/strong\u003E\/\u003Cstrong\u003EC\u003C\/strong\u003E can be estimated directly from \u003Ca id=\u0022xref-ref-20-11\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003EPeccia et al (2020)\u003C\/a\u003E who reported that there were 2,674 diagnosed cases and 734 hospital admissions emanating from the four towns served by the local wastewater treatment plant. The constant \u003Cem\u003Ek\u003Csub\u003EH\u003C\/sub\u003E\u003C\/em\u003E was estimated in our base case analysis of \u003Ca id=\u0022xref-sec-6-4\u0022 class=\u0022xref-sec\u0022 href=\u0022#sec-6\u0022\u003ESection 4\u003C\/a\u003E to equal 1006.6 (see \u003Ca id=\u0022xref-table-wrap-1-3\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-71\u0022\u003ESubstituting the values above into \u003Ca id=\u0022xref-disp-formula-23-1\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-23\u0022\u003Eequation (23)\u003C\/a\u003E we obtain\u003C\/p\u003E\u003Cspan class=\u0022disp-formula\u0022 id=\u0022disp-formula-24\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-30.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/graphic-30.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\n\n\u003C\/span\u003E\u003Cp id=\u0022p-72\u0022\u003ERecalling that 200,000 persons are served by the local wastewater treatment plant, we estimate that 22, 000\/200, 000 = 11% of the population were exposed to infection while the stay-at-home restrictions protected the remaining 89% of the population from infection, indicating a high level of compliance with the public health regulations. Further insight can be gained using \u003Ca id=\u0022xref-disp-formula-8-2\u0022 class=\u0022xref-disp-formula\u0022 href=\u0022#disp-formula-8\u0022\u003Eequation (8)\u003C\/a\u003E and our base case estimate of \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E = 2.38 to estimate that the fraction of the exposed population infected over all time in this outbreak is given by \u003Cem\u003E\u03d5\u003C\/em\u003E = 0.875. However, as of May 1 (day 72) when this study concluded, the epidemic model suggests that only \u003Cspan class=\u0022inline-formula\u0022 id=\u0022inline-formula-12\u0022\u003E\u003Cspan class=\u0022highwire-responsive-lazyload\u0022\u003E\u003Cimg src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 class=\u0022highwire-embed lazyload\u0022 alt=\u0022Embedded Image\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-12.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/highwire\/medrxiv\/early\/2020\/09\/29\/2020.06.27.20141739\/embed\/inline-graphic-12.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/span\u003E of the exposed population had been infected, which means that 22, 000 \u00d7 0.847 \u2248 18, 600 persons were infected by May 1 in the New Haven metropolitan area (or 9.3% of the total population). As an independent check, \u003Ca id=\u0022xref-ref-8-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003EHavers et al\u2019s (2020)\u003C\/a\u003E serological estimate for the ratio of infections to cases suggests that given 2,674 diagnosed cases, a 95% confidence interval estimate for the number infected runs from 11,500 to 20,900 persons, in agreement with our model-based result. Finally, given our estimate that 1.6% of the exposed population was already infected as of February 19, 2020 (\u003Cem\u003E\u03c0\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E; see \u003Ca id=\u0022xref-table-wrap-1-4\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E), we estimate that \u003Cem\u003E22\u003C\/em\u003E,000 \u00d7 0.016 \u2248 350 persons were already infected at that early date.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-9\u0022\u003E\u003Ch2 class=\u0022\u0022\u003E7 Summary\u003C\/h2\u003E\u003Cp id=\u0022p-73\u0022\u003EThis paper has focused on modeling lagging epidemic indicators and how they relate to each other. The approach has been to utilize an epidemic model as a basis for scaling indicators like hospital admissions or SARS-CoV-2 RNA observed in sewage sludge. After characterizing how indicators lag incidence, we showed how one could use an epidemic model to simultaneously estimate the placement of an epidemic wave (via estimating the initial condition), the strength of an outbreak (via estimating \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E), and situate lagging indicators appropriately, allowing one to view the data in a more epidemiologically meaningful way. Using data from a recently published study of SARS-CoV-2 RNA concentrations observed in municipal sewage sludge, we showed why the RNA data were only able to shorten the time from infection to signal by 3 to 5 days relative to hospital admissions. The RNA and hospitalization data jointly implied an epidemic with \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E of approximately 2.38, well within the range implied by numerous studies. To reconcile this finding with the fact that Connecticut was under strict lockdown-like stay-at-home orders throughout most of the study period, we postulated that the stay-at-home restrictions effectively bifurcated the population, resulting in an unmitigated outbreak among an estimated 11% of the population who remained exposed to infections while sparing the remaining 89% who complied with the restrictions. Overall we estimated that about 9.3% of the total population became infected. To our knowledge, ours is the first study to develop such population-level findings based on exploiting the infection signal contained in SARS-CoV-2 RNA in sewage sludge and COVID-19 hospital admissions data.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section data-availability\u0022 id=\u0022sec-10\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EData Availability\u003C\/h2\u003E\u003Cp id=\u0022p-74\u0022\u003EData reported in\nhttps:\/\/www.medrxiv.org\/content\/10.1101\/2020.05.19.20105999v2\n\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ack\u0022 id=\u0022ack-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EAcknowledgements\u003C\/h2\u003E\u003Cp id=\u0022p-75\u0022\u003EThe authors thank Doug Brackney, Arnau Casanovas-Massana, Nate Grubaugh, Albert Ko, Saad Omer and Dan Weinberger for comments on an earlier draft of this manuscript.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section fn-group\u0022 id=\u0022fn-group-1\u0022\u003E\u003Ch2\u003EF
ootnotes\u003C\/h2\u003E\u003Cul\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-3\u0022\u003E\u003Cp id=\u0022p-76\u0022\u003E\u003Ca class=\u0022rev-xref\u0022 href=\u0022#xref-fn-3-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cspan class=\u0022fn-label\u0022\u003E1\u003C\/span\u003E We also considered a model with constant variance but the model did not fit the data as well.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ref-list\u0022 id=\u0022ref-list-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EReferences\u003C\/h2\u003E\u003Col class=\u0022cit-list ref-use-labels\u0022\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[1].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-1-1\u0022 title=\u0022View reference [1] in text\u0022 id=\u0022ref-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.1\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBritton\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ET\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ETomba\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EGS\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2019\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EEstimation in emerging epidemics: Biases and remedies\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EJ R Soc Interface\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E16\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E20180670\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/doi.org\/10.1098\/rsif.2018.0670\u0022\u003Ehttps:\/\/doi.org\/10.1098\/rsif.2018.0670\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJ%2BR%2BSoc%2BInterface%26rft.volume%253D16%26rft.spage%253D20180670%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=http:\/\/www.n\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2020%2F09%2F29%2F2020.06.27.20141739.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[2].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-2-1\u0022 title=\u0022View reference [2] in text\u0022 id=\u0022ref-2\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.2\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth cit-collab\u0022\u003ECDC\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E). \u003Cspan class=\u0022cit-article-title\u0022\u003ECOVID-19 Pandemic Planning Scenarios\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EUnited States Centers for Disease Control and Prevention\u003C\/span\u003E, \u003Ca href=\u0022https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/hcp\/planning-scenarios.html\u0022\u003Ehttps:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/hcp\/planning-scenarios.html\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[3].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-3-1\u0022 title=\u0022View reference [3] in text\u0022 id=\u0022ref-3\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-book\u0022 id=\u0022cit-2020.06.27.20141739v4.3\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECox\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDR\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHinkley\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDV\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E1974\u003C\/span\u003E) \u003Cspan class=\u0022cit-source\u0022\u003ETheoretical Statistics\u003C\/span\u003E. \u003Cspan class=\u0022cit-publ-loc\u0022\u003ELondon\u003C\/span\u003E: \u003Cspan class=\u0022cit-publ-name\u0022\u003EChapman and Hall\u003C\/span\u003E.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[4].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-4-1\u0022 title=\u0022View reference [4] in text\u0022 id=\u0022ref-4\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.4\u0022 data-doi=\u002210.1098\/rspb.2015.2026\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EChampredon\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ED\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EDushoff\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2015\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EIntrinsic and realized generation intervals in infectious-disease transmission\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EProc. R. Soc. B\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E282\u003C\/span\u003E: \u003Cspan class=\u0022cit-fpage\u0022\u003E20152026\u003C\/span\u003E. \u003Ca href=\u0022http:\/\/dx.doi.org\/10.1098\/rspb.2015.2026\u0022\u003Ehttp:\/\/dx.doi.org\/10.1098\/rspb.2015.2026\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DProc.%2BR.%2BSoc.%2BB%26rft_id%253Dinfo%253Adoi%252F10.1098%252Frspb.2015.2026%26rft_id%253Dinfo%253Apmid%252F26674948%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1098\/rspb.2015.2026\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=26674948\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2020%2F09%2F29%2F2020.06.27.20141739.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[5].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-5-1\u0022 title=\u0022View reference [5] in text\u0022 id=\u0022ref-5\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.5\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EFerguson\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELaydon\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ED\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGemma\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN-G\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E). \u003Cspan class=\u0022cit-article-title\u0022\u003EImpact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EImperial College COVID-19 Response Team\u003C\/span\u003E, March 16, 2020, \u003Ca href=\u0022https:\/\/tinyurl.com\/tcdy42y\u0022\u003Ehttps:\/\/tinyurl.com\/tcdy42y\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[6].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-6-1\u0022 title=\u0022View reference [6] in text\u0022 id=\u0022ref-6\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.6\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EFoladori\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EP\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECutrupi\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EF\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESegata\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EManara\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EPinto\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EF\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EMalpei\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EF\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBruni\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EL\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELa Rosa\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EG\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E). \u003Cspan class=\u0022cit-article-title\u0022\u003ESARS-CoV-2 from faeces to wastewater treatment: What do we know? A review\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EScience of the Total Environment\u003C\/abbr\u003E (\u003Cspan class=\u0022cit-vol\u0022\u003E743\u003C\/span\u003E), 15 November 2020, \u003Ca href=\u0022https:\/\/tinyurl.com\/y3flzln3\u0022\u003Ehttps:\/\/tinyurl.com\/y3flzln3\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 26, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[7].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-7-1\u0022 title=\u0022View reference [7] in text\u0022 id=\u0022ref-7\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.7\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHart\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EOE\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHalden\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ERU\u003C\/span\u003E\u003C\/span\u003E. \u003Cspan class=\u0022cit-article-title\u0022\u003EComputational analysis of SARS-CoV-2\/COVID-19 surveillance by wastewater-based epidemiology locally and globally: Feasibility, economy, opportunities and challenges\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EScience of The Total Environment\u003C\/abbr\u003E (\u003Cspan class=\u0022cit-vol\u0022\u003E730\u003C\/span\u003E), 15 August \u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E, \u003Ca href=\u0022https:\/\/tinyurl.com\/yb2dux35\u0022\u003Ehttps:\/\/tinyurl.com\/yb2dux35\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[8].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-8-1\u0022 title=\u0022View reference [8] in text\u0022 id=\u0022ref-8\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.8\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHavers\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EFP\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EReed\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EC\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELim\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ET\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003ESeroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-May 12, 2020\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJAMA Internal Medicine\u003C\/span\u003E \u003Ca href=\u0022http:\/\/dx.doi.org\/10.1001\/jamainternmed.2020.4130\u0022\u003Ehttp:\/\/dx.doi.org\/10.1001\/jamainternmed.2020.4130\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 25, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[9].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-9-1\u0022 title=\u0022View reference [9] in text\u0022 id=\u0022ref-9\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.9\u0022 data-doi=\u002210.1111\/j.1467-9574.1996.tb01482.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHeesterbeek\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJAP\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EDietz\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EK\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E1996\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EThe concept of \u003Cem\u003ER\u003C\/em\u003E\u003Csub\u003E0\u003C\/sub\u003E in epidemic theory\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EStatistica Neerlandica\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E50\u003C\/span\u003E(\u003Cspan class=\u0022cit-issue\u0022\u003E1\u003C\/span\u003E):\u003Cspan class=\u0022cit-fpage\u0022\u003E89\u003C\/span\u003E-\u003Cspan class=\u0022cit-lpage\u0022\u003E110\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/tinyurl.com\/y8m37q9l\u0022\u003Ehttps:\/\/tinyurl.com\/y8m37q9l\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DStatistica%2BNeerlandica%26rft.volume%253D50%26rft.spage%253D89%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1467-9574.1996.tb01482.x%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1111\/j.1467-9574.1996.tb01482.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[10].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-10-1\u0022 title=\u0022View reference [10] in text\u0022 id=\u0022ref-10\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.10\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKaplan\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EEH\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020a\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EContaining 2019-nCoV (Wuhan) coronavirus\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EHealth Care Manag Sci\u003C\/span\u003E \u003Ca href=\u0022https:\/\/doi.org\/10.1007\/s10729-020-09504-6\u0022\u003Ehttps:\/\/doi.org\/10.1007\/s10729-020-09504-6\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[11].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-11-1\u0022 title=\u0022View reference [11] in text\u0022 id=\u0022ref-11\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.11\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKaplan\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EEH\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020b\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003ECOVID-19 Scratch Models to Support Local Decisions\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EManufacturing and Service Operations Management\u003C\/span\u003E, \u003Ca href=\u0022https:\/\/doi.org\/10.1287\/msom.2020.0891\u0022\u003Ehttps:\/\/doi.org\/10.1287\/msom.2020.0891\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[12].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-12-1\u0022 title=\u0022View reference [12] in text\u0022 id=\u0022ref-12\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.12\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKaplan\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EEH\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EForman\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EHP\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003ELogistics of aggressive community screening for coronavirus 2019\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJAMA Health Forum\u003C\/span\u003E (May 4), \u003Ca href=\u0022https:\/\/tinyurl.com\/y7tmr5x6\u0022\u003Ehttps:\/\/tinyurl.com\/y7tmr5x6\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[13].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-13-1\u0022 title=\u0022View reference [13] in text\u0022 id=\u0022ref-13\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.13\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKissler\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ETedijanto\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EC\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELipsitch\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGrad\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EYH\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E). \u003Cspan class=\u0022cit-article-title\u0022\u003ESocial distancing strategies for curbing the COVID-19 epidemic\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EHarvard School of Public Health\u003C\/span\u003E, March 2020 \u003Ca href=\u0022http:\/\/nrs.harvard.edu\/urn-3:HUL.InstRepos:42638988\u0022\u003Ehttp:\/\/nrs.harvard.edu\/urn-3:HUL.InstRepos:42638988\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[14].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-14-1\u0022 title=\u0022View reference [14] in text\u0022 id=\u0022ref-14\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.14\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELamont\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020a\u003C\/span\u003E) \u003Cspan class=\u0022cit-source\u0022\u003EExecutive Order No. 7H\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/tinyurl.com\/uvd4r2j\u0022\u003Ehttps:\/\/tinyurl.com\/uvd4r2j\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 26, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[15].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-15-1\u0022 title=\u0022View reference [15] in text\u0022 id=\u0022ref-15\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.15\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELamont\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020b\u003C\/span\u003E) \u003Cspan class=\u0022cit-source\u0022\u003EExecutive Order No. 7X\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/tinyurl.com\/y2wunjo6\u0022\u003Ehttps:\/\/tinyurl.com\/y2wunjo6\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 26, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[16].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-16-1\u0022 title=\u0022View reference [16] in text\u0022 id=\u0022ref-16\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.16\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELewnard\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELiu\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EVX\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EJackson\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EML\u003C\/span\u003E, , \u003Cspan class=\u0022cit-name-prefix\u0022\u003EPhD5\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESchmidt\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EMA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EJewell\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EBL\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EFlores\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJP\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EJentz\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EC\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ENorthrup\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EGR\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EMahmud\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EReingold\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EAL\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EPetersen\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EJewell\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ENP\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EYoung\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBellows\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EIncidence, clinical outcomes, and transmission dynamics of hospitalized 2019 coronavirus disease among 9,596,321 individuals residing in California and Washington, United States: a prospective cohort study\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/doi.org\/10.1101\/2020.04.12.20062943\u0022\u003Ehttps:\/\/doi.org\/10.1101\/2020.04.12.20062943\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[17].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-17-1\u0022 title=\u0022View reference [17] in text\u0022 id=\u0022ref-17\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.17\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth cit-collab\u0022\u003EMIDAS\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EOnline Portal for COVID-19 Modeling Research: COVID-19 parameter estimates\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EModels of Infectious Disease Agent Study (MIDAS)\u003C\/span\u003E, \u003Ca href=\u0022https:\/\/tinyurl.com\/qqe5you\u0022\u003Ehttps:\/\/tinyurl.com\/qqe5you\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[18].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-18-1\u0022 title=\u0022View reference [18] in text\u0022 id=\u0022ref-18\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.18\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELi\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EQ\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGuan\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EX\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWu\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EP\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EEarly transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EN Engl J Med\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/doi.org\/10.1056\/NEJMoa2001316\u0022\u003Ehttps:\/\/doi.org\/10.1056\/NEJMoa2001316\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[19].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-19-1\u0022 title=\u0022View reference [19] in text\u0022 id=\u0022ref-19\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.19\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EPark\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ESW\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBolker\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EBM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EChampredon\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ED\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EEarn\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDJD\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELi\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWeitz\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJS\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGrenfell\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EBT\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EDushoff\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ\u003C\/span\u003E\u003C\/span\u003E. (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EReconciling early-outbreak estimates of the basic reproductive number and its uncertainty: framework and applications to the novel coronavirus (SARS-CoV-2)outbreak\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJournal of the Royal Society Interface\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E1720200144\u003C\/span\u003E, \u003Ca href=\u0022http:\/\/doi.org\/10.1098\/rsif.2020.0144\u0022\u003Ehttp:\/\/doi.org\/10.1098\/rsif.2020.0144\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[20].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-20-1\u0022 title=\u0022View reference [20] in text\u0022 id=\u0022ref-20\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-2020.06.27.20141739v4.20\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EPeccia\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EZulli\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBrackney\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDE\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGrubaugh\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003END\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKaplan\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EEH\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECasanovas-Massana\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKo\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EAI\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EMalik\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EAA\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWang\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ED\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWang\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWarren\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJL\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWeinberger\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDM\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EArnold\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EW\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EOmer\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ESB\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E). \u003Cspan class=\u0022cit-article-title\u0022\u003EMeasurement of SARS-CoV-2 RNA in wastewater tracks community infection dynamics\u003C\/span\u003E. \u003Cspan class=\u0022cit-source\u0022\u003ENature Biotechnology\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/doi.org\/10.1038\/s41587-020-0684-z\u0022\u003Ehttps:\/\/doi.org\/10.1038\/s41587-020-0684-z\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 26, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E[21].\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-21-1\u0022 title=\u0022View reference [21] in text\u0022 id=\u0022ref-21\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2020.06.27.20141739v4.21\u0022 data-doi=\u002210.1098\/rspb.2006.3754\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EWallinga\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELipsitch\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2007\u003C\/span\u003E) \u003Cspan class=\u0022cit-article-title\u0022\u003EHow generation intervals shape the relationship between growth rates and reproductive numbers\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EProc. R. Soc. B\u003C\/abbr\u003E:\u003Cspan class=\u0022cit-vol\u0022\u003E274\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E599\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E604\u003C\/span\u003E. \u003Ca href=\u0022https:\/\/doi.org\/10.1098\/rspb.2006.3754\u0022\u003Ehttps:\/\/doi.org\/10.1098\/rspb.2006.3754\u003C\/a\u003E (accessed \u003Cspan class=\u0022cit-date-in-citation\u0022\u003ESeptember 27, 2020\u003C\/span\u003E)\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DProceedings%2Bof%2Bthe%2BRoyal%2BSociety%2BB%253A%2BBiological%2BSciences%26rft.stitle%253DProc%2BR%2BSoc%2BB%26rft.aulast%253DWallinga%26rft.auinit1%253DJ%26rft.volume%253D274%26rft.issue%253D1609%26rft.spage%253D599%26rft.epage%253D604%26rft.atitle%253DHow%2Bgeneration%2Bintervals%2Bshape%2Bthe%2Brelationship%2Bbetween%2Bgrowth%2Brates%2Band%2Breproductive%2Bnumbers%26rft_id%253Dinfo%253Adoi%252F10.1098%252Frspb.2006.3754%26rft_id%253Dinfo%253Apmid%252F17476782%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1098\/rspb.2006.3754\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=17476782\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2020%2F09%2F29%2F2020.06.27.20141739.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000243354200019\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003C\/div\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan class=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/js\/js_zP7WWIfzbyzvaM63L39cNV2juU_1XVH7wduFK9gcMNI.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}
| https://www.medrxiv.org/panels_ajax_tab/article_tab_full_text/node:98632/1 |
0, 0, 0, 0, 0, 35208796579497
552, R, 2017-01-11 02:06:08, 2017-01-09 14:22:17.404, 2017-01-09 14:22:23.939, 6.535, 0.000000, 0.000000142024, -0.000000171723, 0.000000307199, 0.0303917098790407, 0.6884164810180664, 0.2095192223787308, -0.6937296390533447, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208796953258
553, R, 2017-01-11 02:06:08, 2017-01-09 14:22:23.404, 2017-01-09 14:22:24.036, 0.633, 0.000000, 0.000000142025, -0.000000171720, 0.000000307200, 0.0303914528340101, 0.6884143352508545, 0.2095143049955368, -0.6937332153320312, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208796959657
554, R, 2017-01-11 02:06:08, 2017-01-09 14:22:23.404, 2017-01-09 14:22:24.138, 0.734, 0.000000, 0.000000142026, -0.000000171718, 0.000000307201, 0.0303889866918325, 0.6884123086929321, 0.2095078676939011, -0.6937373280525208, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208796966314
555, R, 2017-01-11 02:06:08, 2017-01-09 14:22:23.404, 2017-01-09 14:22:24.236, 0.832, 0.000000, 0.000000142027, -0.000000171716, 0.000000307201, 0.0303854122757912, 0.6884109973907471, 0.2095028609037399, -0.6937402486801147, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208796972713
556, R, 2017-01-11 02:06:08, 2017-01-09 14:22:23.404, 2017-01-09 14:22:24.337, 0.934, 0.000000, 0.000000142027, -0.000000171715, 0.000000307202, 0.0303849391639233, 0.6884104609489441, 0.2095004320144653, -0.6937415599822998, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 35, 0, 22, 100, 100, 0, 0, 0, 0, 0, 0, 35208796979369
557, R, 2017-01-11 02:06:08, 2017-01-09 14:22:23.404, 2017-01-09 14:22:24.435, 1.031, 0.000000, 0.000000077752, -0.000000388940, 0.000000207942, 0.0303828883916140, 0.6884086728096008, 0.2095017582178116, -0.6937430500984192, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208796985770
558, R, 2017-01-11 02:06:08, 2017-01-09 14:22:24.404, 2017-01-09 14:22:24.540, 0.137, 0.000000, 0.000000077754, -0.000000388941, 0.000000207939, 0.0303804017603397, 0.6884065866470337, 0.2095056325197220, -0.6937440037727356, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 13, 0, 0, 0, 0, 100, 19, 0, 0, 0, 0, 0, 0, 35208796992682
559, R, 2017-01-11 02:06:08, 2017-01-09 14:22:24.404, 2017-01-09 14:22:24.638, 0.234, 0.000000, -0.000000022265, -0.000000347414, 0.000000130679, 0.0303798634558916, 0.6884065270423889, 0.2095119804143906, -0.6937422156333923, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208796999082
560, R, 2017-01-11 02:06:08, 2017-01-09 14:22:24.404, 2017-01-09 14:22:30.337, 5.934, 0.000000, 0.000000141842, -0.000000171901, 0.000000306394, 0.0303825903683901, 0.6884057521820068, 0.2095017135143280, -0.6937459707260132, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797372585
561, R, 2017-01-11 02:06:08, 2017-01-09 14:22:29.404, 2017-01-09 14:22:30.435, 1.031, 0.000000, 0.000000141843, -0.000000171898, 0.000000306396, 0.0303821526467800, 0.6884039044380188, 0.2094966471195221, -0.6937493085861206, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797378986
562, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:30.540, 0.137, 0.000000, 0.000000141844, -0.000000171896, 0.000000306396, 0.0303795207291842, 0.6884013414382935, 0.2094906568527222, -0.6937537789344788, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797385898
563, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:30.638, 0.234, 0.000000, 0.000000141845, -0.000000171895, 0.000000306396, 0.0303763654083014, 0.6884003281593323, 0.2094861418008804, -0.6937562823295593, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797392298
564, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:30.739, 0.336, 0.000000, 0.000000141846, -0.000000171893, 0.000000306397, 0.0303750317543745, 0.6883988380432129, 0.2094831317663193, -0.6937587857246399, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 35, 0, 22, 100, 100, 0, 0, 0, 0, 0, 0, 35208797398954
565, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:30.837, 0.434, 0.000000, 0.000000077583, -0.000000389121, 0.000000207138, 0.0303737968206406, 0.6883971691131592, 0.2094840258359909, -0.6937601566314697, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208797405353
566, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:30.939, 0.535, 0.000000, 0.000000077585, -0.000000389122, 0.000000207137, 0.0303722620010376, 0.6883953809738159, 0.2094873636960983, -0.6937609910964966, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 12, 0, 0, 0, 0, 100, 18, 0, 0, 0, 0, 0, 0, 35208797412010
567, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:31.036, 0.633, 0.000000, -0.000000022245, -0.000000347415, 0.000000130680, 0.0303692482411861, 0.6883960962295532, 0.2094929367303848, -0.6937587857246399, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208797418409
568, R, 2017-01-11 02:06:08, 2017-01-09 14:22:30.404, 2017-01-09 14:22:36.739, 6.336, 0.000000, 0.000000135395, -0.000000213479, 0.000000194931, 0.0303811263293028, 0.6883945465087891, 0.2094815224409103, -0.6937632560729980, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797792170
569, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:36.837, 0.434, 0.000000, 0.000000135397, -0.000000213476, 0.000000194933, 0.0303809307515621, 0.6883924603462219, 0.2094768136739731, -0.6937667131423950, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797798569
570, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:36.939, 0.535, 0.000000, 0.000000135400, -0.000000213474, 0.000000194933, 0.0303777493536472, 0.6883900761604309, 0.2094711661338806, -0.6937709450721741, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797805226
571, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:37.036, 0.633, 0.000000, 0.000000135401, -0.000000213473, 0.000000194933, 0.0303750671446323, 0.6883893013000488, 0.2094674557447434, -0.6937729716300964, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208797811625
572, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:37.138, 0.734, 0.000000, 0.000000135402, -0.000000213473, 0.000000194933, 0.0303738079965115, 0.6883883476257324, 0.2094667553901672, -0.6937741637229919, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 33, 0, 19, 100, 100, 0, 0, 0, 0, 0, 0, 35208797818282
573, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:37.236, 0.832, 0.000000, 0.000000077410, -0.000000389301, 0.000000206341, 0.0303732585161924, 0.6883863210678101, 0.2094673067331314, -0.6937760114669800, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208797824681
574, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:37.337, 0.934, 0.000000, 0.000000077412, -0.000000389303, 0.000000206337, 0.0303688868880272, 0.6883853077888489, 0.2094707489013672, -0.6937761902809143, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 11, 0, 0, 0, 0, 100, 17, 0, 0, 0, 0, 0, 0, 35208797831337
575, R, 2017-01-11 02:06:08, 2017-01-09 14:22:36.404, 2017-01-09 14:22:37.439, 1.035, 0.000000, -0.000000022229, -0.000000347414, 0.000000130685, 0.0303670596331358, 0.6883853673934937, 0.2094763219356537, -0.6937745213508606, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208797837994
576, R, 2017-01-11 02:06:08, 2017-01-09 14:22:37.404, 2017-01-09 14:22:43.138, 5.734, 0.000000, 0.000000132023, -0.000000238883, 0.000000124781, 0.0303738042712212, 0.6883859038352966, 0.2094742655754089, -0.6937743425369263, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798211498
577, R, 2017-01-11 02:06:08, 2017-01-09 14:22:42.404, 2017-01-09 14:22:43.236, 0.832, 0.000000, 0.000000132026, -0.000000238881, 0.000000124783, 0.0303725134581327, 0.6883838772773743, 0.2094692438840866, -0.6937779188156128, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798217897
578, R, 2017-01-11 02:06:08, 2017-01-09 14:22:42.404, 2017-01-09 14:22:43.337, 0.934, 0.000000, 0.000000132029, -0.000000238879, 0.000000124783, 0.0303704515099525, 0.6883812546730042, 0.2094641923904419, -0.6937820911407471, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798224553
579, R, 2017-01-11 02:06:08, 2017-01-09 14:22:42.404, 2017-01-09 14:22:43.439, 1.035, 0.000000, 0.000000132032, -0.000000238877, 0.000000124784, 0.0303681567311287, 0.6883801221847534, 0.2094596475362778, -0.6937847137451172, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798231210
580, R, 2017-01-11 02:06:08, 2017-01-09 14:22:43.404, 2017-01-09 14:22:43.540, 0.137, 0.000000, 0.000000132033, -0.000000238877, 0.000000124783, 0.0303666852414608, 0.6883791089057922, 0.2094586342573166, -0.6937861442565918, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 34, 0, 20, 100, 100, 0, 0, 0, 0, 0, 0, 35208798237866
581, R, 2017-01-11 02:06:08, 2017-01-09 14:22:43.404, 2017-01-09 14:22:43.638, 0.234, 0.000000, 0.000000073752, -0.000000416233, 0.000000133085, 0.0303642787039280, 0.6883777976036072, 0.2094594985246658, -0.6937872171401978, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208798244266
582, R, 2017-01-11 02:06:08, 2017-01-09 14:22:43.404, 2017-01-09 14:22:43.739, 0.336, 0.000000, 0.000000073753, -0.000000416233, 0.000000133084, 0.0303625278174877, 0.6883764863014221, 0.2094629257917404, -0.6937875747680664, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 12, 0, 0, 0, 0, 100, 19, 0, 0, 0, 0, 0, 0, 35208798250922
583, R, 2017-01-11 02:06:08, 2017-01-09 14:22:43.404, 2017-01-09 14:22:43.837, 0.434, 0.000000, -0.000000022216, -0.000000347414, 0.000000130687, 0.0303606986999512, 0.6883761882781982, 0.2094690650701523, -0.6937860846519470, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208798257321
584, R, 2017-01-11 02:06:08, 2017-01-09 14:22:43.404, 2017-01-09 14:22:49.540, 6.137, 0.000000, 0.000000139907, -0.000000181217, 0.000000286963, 0.0303704049438238, 0.6883791089057922, 0.2094677239656448, -0.6937831640243530, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798631082
585, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:49.638, 0.234, 0.000000, 0.000000139908, -0.000000181213, 0.000000286964, 0.0303702615201473, 0.6883767247200012, 0.2094616740942001, -0.6937873363494873, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798637482
586, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:49.740, 0.336, 0.000000, 0.000000139910, -0.000000181210, 0.000000286965, 0.0303688012063503, 0.6883744001388550, 0.2094565480947495, -0.6937913298606873, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798644138
587, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:49.837, 0.434, 0.000000, 0.000000139911, -0.000000181210, 0.000000286965, 0.0303643438965082, 0.6883735060691833, 0.2094526588916779, -0.6937935948371887, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208798650537
588, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:49.939, 0.535, 0.000000, 0.000000139913, -0.000000181209, 0.000000286965, 0.0303636565804482, 0.6883715391159058, 0.2094514966011047, -0.6937958598136902, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 29, 0, 16, 100, 100, 0, 0, 0, 0, 0, 0, 35208798657194
589, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:50.036, 0.633, 0.000000, 0.000000077436, -0.000000389294, 0.000000206344, 0.0303636286407709, 0.6883700489997864, 0.2094518542289734, -0.6937972903251648, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208798663593
590, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:50.138, 0.734, 0.000000, 0.000000077438, -0.000000389295, 0.000000206340, 0.0303604751825333, 0.6883685588836670, 0.2094568610191345, -0.6937973499298096, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 11, 0, 0, 0, 0, 100, 17, 0, 0, 0, 0, 0, 0, 35208798670250
591, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:50.239, 0.836, 0.000000, -0.000000022206, -0.000000347414, 0.000000130689, 0.0303577408194542, 0.6883682012557983, 0.2094623446464539, -0.6937962174415588, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208798676905
592, R, 2017-01-11 02:06:08, 2017-01-09 14:22:49.404, 2017-01-09 14:22:55.939, 6.535, 0.000000, 0.000000139339, -0.000000181774, 0.000000284546, 0.0303625725209713, 0.6883758306503296, 0.2094529420137405, -0.6937912106513977, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799050410
593, R, 2017-01-11 02:06:08, 2017-01-09 14:22:55.404, 2017-01-09 14:22:56.036, 0.633, 0.000000, 0.000000139340, -0.000000181771, 0.000000284548, 0.0303628649562597, 0.6883741021156311, 0.2094474285840988, -0.6937946081161499, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799056809
594, R, 2017-01-11 02:06:08, 2017-01-09 14:22:55.404, 2017-01-09 14:22:56.138, 0.734, 0.000000, 0.000000139341, -0.000000181768, 0.000000284549, 0.0303605366498232, 0.6883714795112610, 0.2094397097826004, -0.6937996745109558, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799063466
595, R, 2017-01-11 02:06:08, 2017-01-09 14:22:55.404, 2017-01-09 14:22:56.239, 0.836, 0.000000, 0.000000139343, -0.000000181767, 0.000000284549, 0.0303567908704281, 0.6883702874183655, 0.2094352990388870, -0.6938022971153259, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799070121
596, R, 2017-01-11 02:06:08, 2017-01-09 14:22:55.404, 2017-01-09 14:22:56.337, 0.934, 0.000000, 0.000000139344, -0.000000181767, 0.000000284549, 0.0303559415042400, 0.6883690357208252, 0.2094357013702393, -0.6938034892082214, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 29, 0, 16, 100, 100, 0, 0, 0, 0, 0, 0, 35208799076521
597, R, 2017-01-11 02:06:08, 2017-01-09 14:22:55.404, 2017-01-09 14:22:56.439, 1.035, 0.000000, 0.000000076876, -0.000000389854, 0.000000203925, 0.0303547810763121, 0.6883680224418640, 0.2094367444515228, -0.6938042640686035, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208799083178
598, R, 2017-01-11 02:06:08, 2017-01-09 14:22:56.404, 2017-01-09 14:22:56.540, 0.137, 0.000000, 0.000000076877, -0.000000389855, 0.000000203923, 0.0303524248301983, 0.6883667707443237, 0.2094393968582153, -0.6938047409057617, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 8, 0, 0, 0, 0, 100, 14, 0, 0, 0, 0, 0, 0, 35208799089834
599, R, 2017-01-11 02:06:08, 2017-01-09 14:22:56.404, 2017-01-09 14:22:56.638, 0.234, 0.000000, -0.000000022196, -0.000000347415, 0.000000130688, 0.0303503815084696, 0.6883661746978760, 0.2094450742006302, -0.6938037276268005, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208799096234
600, R, 2017-01-11 02:06:08, 2017-01-09 14:22:56.404, 2017-01-09 14:23:02.341, 5.937, 0.000000, 0.000000134220, -0.000000213842, 0.000000199560, 0.0303565524518490, 0.6883698105812073, 0.2094435989856720, -0.6938003301620483, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799469993
601, R, 2017-01-11 02:06:08, 2017-01-09 14:23:01.404, 2017-01-09 14:23:02.439, 1.035, 0.000000, 0.000000134222, -0.000000213840, 0.000000199562, 0.0303570665419102, 0.6883680224418640, 0.2094385027885437, -0.6938036084175110, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799476394
602, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:02.540, 0.137, 0.000000, 0.000000134224, -0.000000213838, 0.000000199563, 0.0303555224090815, 0.6883661746978760, 0.2094327360391617, -0.6938072443008423, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799483050
603, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:02.638, 0.234, 0.000000, 0.000000134226, -0.000000213836, 0.000000199563, 0.0303520243614912, 0.6883648037910461, 0.2094279080629349, -0.6938101649284363, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799489450
604, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:02.740, 0.336, 0.000000, 0.000000134227, -0.000000213836, 0.000000199563, 0.0303495116531849, 0.6883640885353088, 0.2094255089759827, -0.6938117742538452, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 26, 0, 13, 100, 100, 0, 0, 0, 0, 0, 0, 35208799496106
605, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:02.837, 0.434, 0.000000, 0.000000072647, -0.000000417349, 0.000000128254, 0.0303487107157707, 0.6883627772331238, 0.2094269096851349, -0.6938126683235168, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208799502505
606, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:02.939, 0.535, 0.000000, 0.000000072647, -0.000000417350, 0.000000128252, 0.0303470008075237, 0.6883614659309387, 0.2094314247369766, -0.6938126683235168, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 6, 0, 0, 0, 0, 100, 13, 0, 0, 0, 0, 0, 0, 35208799509162
607, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:03.036, 0.633, 0.000000, -0.000000022187, -0.000000347416, 0.000000130688, 0.0303445085883141, 0.6883615255355835, 0.2094369977712631, -0.6938110589981079, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208799515561
608, R, 2017-01-11 02:06:08, 2017-01-09 14:23:02.404, 2017-01-09 14:23:08.740, 6.336, 0.000000, 0.000000136630, -0.000000191856, 0.000000261888, 0.0303538721054792, 0.6883680224418640, 0.2094352841377258, -0.6938047409057617, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799889322
609, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:08.837, 0.434, 0.000000, 0.000000136632, -0.000000191853, 0.000000261890, 0.0303535275161266, 0.6883662343025208, 0.2094306498765945, -0.6938078999519348, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799895721
610, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:08.939, 0.535, 0.000000, 0.000000136634, -0.000000191850, 0.000000261891, 0.0303525086492300, 0.6883631348609924, 0.2094253599643707, -0.6938126087188721, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799902378
611, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:09.040, 0.637, 0.000000, 0.000000136635, -0.000000191849, 0.000000261890, 0.0303487740457058, 0.6883623600006104, 0.2094216048717499, -0.6938146352767944, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208799909033
612, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:09.138, 0.734, 0.000000, 0.000000136636, -0.000000191849, 0.000000261890, 0.0303476378321648, 0.6883614063262940, 0.2094205468893051, -0.6938160061836243, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 23, 0, 10, 100, 100, 0, 0, 0, 0, 0, 0, 35208799915434
613, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:09.240, 0.836, 0.000000, 0.000000075941, -0.000000390786, 0.000000199898, 0.0303473845124245, 0.6883595585823059, 0.2094213515520096, -0.6938175559043884, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208799922089
614, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:09.341, 0.937, 0.000000, 0.000000075942, -0.000000390788, 0.000000199895, 0.0303445588797331, 0.6883589029312134, 0.2094244509935379, -0.6938173770904541, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 3, 0, 0, 0, 0, 100, 9, 0, 0, 0, 0, 0, 0, 35208799928745
615, R, 2017-01-11 02:06:08, 2017-01-09 14:23:08.404, 2017-01-09 14:23:09.439, 1.035, 0.000000, -0.000000022181, -0.000000347416, 0.000000130688, 0.0303413271903992, 0.6883590817451477, 0.2094301730394363, -0.6938157081604004, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208799935146
616, R, 2017-01-11 02:06:08, 2017-01-09 14:23:09.404, 2017-01-09 14:23:15.138, 5.734, 0.000000, 0.000000136236, -0.000000194715, 0.000000256486, 0.0303542539477348, 0.6883640289306641, 0.2094307392835617, -0.6938099861145020, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800308650
617, R, 2017-01-11 02:06:08, 2017-01-09 14:23:14.404, 2017-01-09 14:23:15.240, 0.836, 0.000000, 0.000000136237, -0.000000194712, 0.000000256487, 0.0303541626781225, 0.6883622407913208, 0.2094250470399857, -0.6938135623931885, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800315305
618, R, 2017-01-11 02:06:08, 2017-01-09 14:23:14.404, 2017-01-09 14:23:15.341, 0.937, 0.000000, 0.000000136240, -0.000000194710, 0.000000256488, 0.0303515028208494, 0.6883596777915955, 0.2094203084707260, -0.6938176155090332, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800321961
619, R, 2017-01-11 02:06:08, 2017-01-09 14:23:14.404, 2017-01-09 14:23:15.439, 1.035, 0.000000, 0.000000136241, -0.000000194709, 0.000000256488, 0.0303484294563532, 0.6883587241172790, 0.2094162106513977, -0.6938199400901794, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800328362
620, R, 2017-01-11 02:06:08, 2017-01-09 14:23:15.404, 2017-01-09 14:23:15.540, 0.137, 0.000000, 0.000000136242, -0.000000194708, 0.000000256488, 0.0303477663546801, 0.6883574724197388, 0.2094148695468903, -0.6938215494155884, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 21, 0, 8, 100, 100, 0, 0, 0, 0, 0, 0, 35208800335018
621, R, 2017-01-11 02:06:08, 2017-01-09 14:23:15.404, 2017-01-09 14:23:15.638, 0.234, 0.000000, 0.000000076138, -0.000000390597, 0.000000200705, 0.0303443521261215, 0.6883561611175537, 0.2094158530235291, -0.6938227415084839, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208800341418
622, R, 2017-01-11 02:06:08, 2017-01-09 14:23:15.404, 2017-01-09 14:23:15.740, 0.336, 0.000000, 0.000000076138, -0.000000390598, 0.000000200703, 0.0303438566625118, 0.6883545517921448, 0.2094215750694275, -0.6938226819038391, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 4, 0, 0, 0, 0, 100, 10, 0, 0, 0, 0, 0, 0, 35208800348074
623, R, 2017-01-11 02:06:08, 2017-01-09 14:23:15.404, 2017-01-09 14:23:15.837, 0.434, 0.000000, -0.000000022176, -0.000000347415, 0.000000130691, 0.0303417537361383, 0.6883541941642761, 0.2094266861677170, -0.6938215494155884, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208800354473
624, R, 2017-01-11 02:06:08, 2017-01-09 14:23:15.404, 2017-01-09 14:23:21.540, 6.137, 0.000000, 0.000000136825, -0.000000191662, 0.000000262697, 0.0303494054824114, 0.6883627772331238, 0.2094209343194962, -0.6938143968582153, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800728234
625, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:21.638, 0.234, 0.000000, 0.000000136827, -0.000000191660, 0.000000262698, 0.0303479172289372, 0.6883606910705566, 0.2094157040119171, -0.6938181519508362, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800734634
626, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:21.740, 0.336, 0.000000, 0.000000136829, -0.000000191657, 0.000000262698, 0.0303450152277946, 0.6883588433265686, 0.2094097733497620, -0.6938219070434570, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800741290
627, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:21.837, 0.434, 0.000000, 0.000000136830, -0.000000191656, 0.000000262699, 0.0303432904183865, 0.6883577108383179, 0.2094052433967590, -0.6938244700431824, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208800747689
628, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:21.939, 0.535, 0.000000, 0.000000136830, -0.000000191656, 0.000000262698, 0.0303411837667227, 0.6883572340011597, 0.2094038277864456, -0.6938254237174988, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 23, 0, 10, 100, 100, 0, 0, 0, 0, 0, 0, 35208800754346
629, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:22.040, 0.637, 0.000000, 0.000000076144, -0.000000390596, 0.000000200705, 0.0303396992385387, 0.6883560419082642, 0.2094036936759949, -0.6938267946243286, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208800761001
630, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:22.142, 0.738, 0.000000, 0.000000076145, -0.000000390598, 0.000000200702, 0.0303366165608168, 0.6883545517921448, 0.2094085216522217, -0.6938269138336182, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 4, 0, 0, 0, 0, 100, 10, 0, 0, 0, 0, 0, 0, 35208800767657
631, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:22.240, 0.836, 0.000000, -0.000000022169, -0.000000347417, 0.000000130689, 0.0303343068808317, 0.6883539557456970, 0.2094140201807022, -0.6938259601593018, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208800774057
632, R, 2017-01-11 02:06:08, 2017-01-09 14:23:21.404, 2017-01-09 14:23:27.939, 6.535, 0.000000, 0.000000135564, -0.000000196611, 0.000000251771, 0.0303508546203375, 0.6883606910705566, 0.2094201445579529, -0.6938166618347168, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801147562
633, R, 2017-01-11 02:06:08, 2017-01-09 14:23:27.404, 2017-01-09 14:23:28.040, 0.637, 0.000000, 0.000000135566, -0.000000196608, 0.000000251772, 0.0303508769720793, 0.6883585453033447, 0.2094154655933380, -0.6938202381134033, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801154217
634, R, 2017-01-11 02:06:08, 2017-01-09 14:23:27.404, 2017-01-09 14:23:28.142, 0.738, 0.000000, 0.000000135568, -0.000000196606, 0.000000251772, 0.0303486175835133, 0.6883558034896851, 0.2094108760356903, -0.6938244700431824, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801160873
635, R, 2017-01-11 02:06:08, 2017-01-09 14:23:27.404, 2017-01-09 14:23:28.240, 0.836, 0.000000, 0.000000135570, -0.000000196605, 0.000000251772, 0.0303449016064405, 0.6883550286293030, 0.2094059288501740, -0.6938268542289734, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801167273
636, R, 2017-01-11 02:06:08, 2017-01-09 14:23:27.404, 2017-01-09 14:23:28.341, 0.937, 0.000000, 0.000000135571, -0.000000196605, 0.000000251772, 0.0303428731858730, 0.6883538365364075, 0.2094050198793411, -0.6938284039497375, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 20, 0, 7, 100, 100, 0, 0, 0, 0, 0, 0, 35208801173929
637, R, 2017-01-11 02:06:08, 2017-01-09 14:23:27.404, 2017-01-09 14:23:28.439, 1.035, 0.000000, 0.000000075767, -0.000000390969, 0.000000199095, 0.0303414184600115, 0.6883519291877747, 0.2094061672687531, -0.6938300132751465, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208801180330
638, R, 2017-01-11 02:06:08, 2017-01-09 14:23:28.404, 2017-01-09 14:23:28.540, 0.137, 0.000000, 0.000000075767, -0.000000390970, 0.000000199093, 0.0303396917879581, 0.6883506774902344, 0.2094106972217560, -0.6938299536705017, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 2, 0, 0, 0, 0, 100, 8, 0, 0, 0, 0, 0, 0, 35208801186986
639, R, 2017-01-11 02:06:08, 2017-01-09 14:23:28.404, 2017-01-09 14:23:28.638, 0.234, 0.000000, -0.000000022166, -0.000000347416, 0.000000130691, 0.0303366109728813, 0.6883500814437866, 0.2094156146049500, -0.6938291788101196, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208801193386
640, R, 2017-01-11 02:06:08, 2017-01-09 14:23:28.404, 2017-01-09 14:23:34.341, 5.937, 0.000000, 0.000000561105, 0.000002679247, 0.000008138715, 0.0303474906831980, 0.6883596777915955, 0.2094138711690903, -0.6938197016716003, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801567145
641, R, 2017-01-11 02:06:08, 2017-01-09 14:23:33.404, 2017-01-09 14:23:34.439, 1.035, 0.000000, 0.000000561038, 0.000002679279, 0.000008138709, 0.0303464774042368, 0.6883578896522522, 0.2094084024429321, -0.6938232183456421, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801573546
642, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:34.544, 0.141, 0.000000, 0.000000560996, 0.000002679293, 0.000008138707, 0.0303440578281879, 0.6883553266525269, 0.2094042152166367, -0.6938270926475525, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801580458
643, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:34.638, 0.234, 0.000000, 0.000000560942, 0.000002679287, 0.000008138713, 0.0303416140377522, 0.6883546113967896, 0.2094002366065979, -0.6938291192054749, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801586602
644, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:34.740, 0.336, 0.000000, 0.000000560954, 0.000002679286, 0.000008138712, 0.0303401164710522, 0.6883527636528015, 0.2094000279903412, -0.6938310861587524, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 16, 0, 3, 100, 100, 0, 0, 0, 0, 0, 0, 35208801593258
645, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:34.841, 0.438, 0.000000, 0.000000502353, 0.000002491027, 0.000008098452, 0.0303392186760902, 0.6883507966995239, 0.2094007879495621, -0.6938328146934509, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 99, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208801599914
646, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:34.939, 0.535, 0.000000, -0.000002488118, -0.000017686586, -0.000047214057, 0.0303367618471384, 0.6883502602577210, 0.2094049900770187, -0.6938322186470032, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 5, 0, 0, 0, 0, 0, 0, 35208801606314
647, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:35.040, 0.637, 0.000000, -0.000000022163, -0.000000347416, 0.000000130691, 0.0303339436650276, 0.6883495450019836, 0.2094105929136276, -0.6938313841819763, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208801612969
648, R, 2017-01-11 02:06:08, 2017-01-09 14:23:34.404, 2017-01-09 14:23:40.740, 6.336, 0.000000, 0.000000559602, 0.000002671463, 0.000008119222, 0.0303450953215361, 0.6883580088615417, 0.2094095945358276, -0.6938227415084839, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801986474
649, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:40.841, 0.438, 0.000000, 0.000000559536, 0.000002671501, 0.000008119215, 0.0303446725010872, 0.6883563399314880, 0.2094042748212814, -0.6938260793685913, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801993130
650, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:40.943, 0.539, 0.000000, 0.000000559490, 0.000002671509, 0.000008119215, 0.0303422417491674, 0.6883543133735657, 0.2094000726938248, -0.6938294172286987, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208801999785
651, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:41.040, 0.637, 0.000000, 0.000000559430, 0.000002671503, 0.000008119221, 0.0303394328802824, 0.6883533000946045, 0.2093956023454666, -0.6938319206237793, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802006185
652, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:41.142, 0.738, 0.000000, 0.000000559426, 0.000002671494, 0.000008119224, 0.0303376428782940, 0.6883522272109985, 0.2093947380781174, -0.6938332915306091, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 14, 0, 1, 100, 100, 0, 0, 0, 0, 0, 0, 35208802012841
653, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:41.240, 0.836, 0.000000, 0.000000501413, 0.000002486263, 0.000008085181, 0.0303358044475317, 0.6883509755134583, 0.2093958258628845, -0.6938343048095703, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 98, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208802019241
654, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:41.341, 0.937, 0.000000, -0.000002483848, -0.000017659444, -0.000047140028, 0.0303342174738646, 0.6883494257926941, 0.2094000875949860, -0.6938346624374390, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 4, 0, 0, 0, 0, 0, 0, 35208802025897
655, R, 2017-01-11 02:06:08, 2017-01-09 14:23:40.404, 2017-01-09 14:23:41.439, 1.035, 0.000000, -0.000000022161, -0.000000347416, 0.000000130691, 0.0303321890532970, 0.6883492469787598, 0.2094051986932755, -0.6938333511352539, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208802032298
656, R, 2017-01-11 02:06:08, 2017-01-09 14:23:41.404, 2017-01-09 14:23:47.142, 5.738, 0.000000, 0.000001171544, 0.000006816677, 0.000019411270, 0.0303406901657581, 0.6883573532104492, 0.2094064205884934, -0.6938245892524719, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802406057
657, R, 2017-01-11 02:06:08, 2017-01-09 14:23:46.404, 2017-01-09 14:23:47.240, 0.836, 0.000000, 0.000001171428, 0.000006816754, 0.000019411249, 0.0303395427763462, 0.6883547902107239, 0.2094019502401352, -0.6938285231590271, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802412457
658, R, 2017-01-11 02:06:08, 2017-01-09 14:23:46.404, 2017-01-09 14:23:47.341, 0.937, 0.000000, 0.000001171212, 0.000006816786, 0.000019411251, 0.0303371455520391, 0.6883534193038940, 0.2093953639268875, -0.6938319802284241, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802419113
659, R, 2017-01-11 02:06:08, 2017-01-09 14:23:46.404, 2017-01-09 14:23:47.439, 1.035, 0.000000, 0.000001171101, 0.000006816804, 0.000019411251, 0.0303355380892754, 0.6883522272109985, 0.2093917578458786, -0.6938343048095703, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 98, 100, 100, 0, 0, 0, 0, 0, 0, 35208802425514
660, R, 2017-01-11 02:06:08, 2017-01-09 14:23:47.404, 2017-01-09 14:23:47.544, 0.141, 0.000000, -0.000001887501, -0.000013908941, -0.000037029029, 0.0303332637995482, 0.6883511543273926, 0.2093901783227921, -0.6938359141349792, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 11, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208802432426
661, R, 2017-01-11 02:06:08, 2017-01-09 14:23:47.404, 2017-01-09 14:23:47.642, 0.238, 0.000000, 0.000000502218, 0.000002490973, 0.000008098478, 0.0303310845047236, 0.6883497238159180, 0.2093910723924637, -0.6938372254371643, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 99, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208802438826
662, R, 2017-01-11 02:06:08, 2017-01-09 14:23:47.404, 2017-01-09 14:23:47.740, 0.336, 0.000000, -0.000002487345, -0.000017686267, -0.000047214218, 0.0303282123059034, 0.6883482933044434, 0.2093957811594009, -0.6938373446464539, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 5, 0, 0, 0, 0, 0, 0, 35208802445226
663, R, 2017-01-11 02:06:08, 2017-01-09 14:23:47.404, 2017-01-09 14:23:47.841, 0.438, 0.000000, -0.000000022156, -0.000000347418, 0.000000130688, 0.0303260553628206, 0.6883478164672852, 0.2094007283449173, -0.6938364505767822, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208802451882
664, R, 2017-01-11 02:06:08, 2017-01-09 14:23:47.404, 2017-01-09 14:23:53.544, 6.141, 0.000000, 0.000001156156, 0.000006718423, 0.000019150908, 0.0303425677120686, 0.6883546113967896, 0.2094054371118546, -0.6938275098800659, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802825642
665, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:53.642, 0.238, 0.000000, 0.000001155991, 0.000006718545, 0.000019150875, 0.0303430855274200, 0.6883528828620911, 0.2093999385833740, -0.6938308477401733, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802832042
666, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:53.743, 0.340, 0.000000, 0.000001155836, 0.000006718571, 0.000019150876, 0.0303405318409205, 0.6883509159088135, 0.2093946486711502, -0.6938345432281494, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208802838697
667, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:53.841, 0.438, 0.000000, 0.000001155702, 0.000006718542, 0.000019150894, 0.0303375236690044, 0.6883500218391418, 0.2093905657529831, -0.6938367486000061, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 90, 100, 100, 0, 0, 0, 0, 0, 0, 35208802845098
668, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:53.943, 0.539, 0.000000, -0.000001846371, -0.000013624073, -0.000036244706, 0.0303361471742392, 0.6883486509323120, 0.2093899101018906, -0.6938383579254150, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 3, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208802851753
669, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:54.040, 0.637, 0.000000, 0.000000500509, 0.000002481581, 0.000008071883, 0.0303349681198597, 0.6883468031883240, 0.2093906849622726, -0.6938400864601135, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 97, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208802858153
670, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:54.142, 0.738, 0.000000, -0.000002479735, -0.000017632640, -0.000047065863, 0.0303332768380642, 0.6883450746536255, 0.2093951404094696, -0.6938405036926270, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 3, 0, 0, 0, 0, 0, 0, 35208802864809
671, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:54.240, 0.836, 0.000000, -0.000000022155, -0.000000347416, 0.000000130693, 0.0303315203636885, 0.6883447170257568, 0.2094007432460785, -0.6938392519950867, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208802871209
672, R, 2017-01-11 02:06:08, 2017-01-09 14:23:53.404, 2017-01-09 14:23:59.943, 6.539, 0.000000, 0.000000158611, -0.000000186702, 0.000000218893, 0.0303429588675499, 0.6883577704429626, 0.2093957215547562, -0.6938273310661316, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803244969
673, R, 2017-01-11 02:06:08, 2017-01-09 14:23:59.404, 2017-01-09 14:24:00.040, 0.637, 0.000000, 0.000000158612, -0.000000186699, 0.000000218895, 0.0303425118327141, 0.6883562803268433, 0.2093904763460159, -0.6938303709030151, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803251369
674, R, 2017-01-11 02:06:08, 2017-01-09 14:23:59.404, 2017-01-09 14:24:00.142, 0.738, 0.000000, 0.000000158615, -0.000000186697, 0.000000218895, 0.0303400140255690, 0.6883533000946045, 0.2093859314918518, -0.6938348412513733, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803258025
675, R, 2017-01-11 02:06:08, 2017-01-09 14:23:59.404, 2017-01-09 14:24:00.240, 0.836, 0.000000, 0.000000158617, -0.000000186695, 0.000000218895, 0.0303373504430056, 0.6883519291877747, 0.2093823850154877, -0.6938373446464539, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 96, 0, 84, 100, 100, 0, 0, 0, 0, 0, 0, 35208803264425
676, R, 2017-01-11 02:06:08, 2017-01-09 14:23:59.404, 2017-01-09 14:24:00.341, 0.937, 0.000000, 0.000000085606, -0.000000431835, 0.000000115635, 0.0303359273821116, 0.6883515119552612, 0.2093802392482758, -0.6938384771347046, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208803271081
677, R, 2017-01-11 02:06:08, 2017-01-09 14:23:59.404, 2017-01-09 14:24:00.439, 1.035, 0.000000, 0.000000085607, -0.000000431835, 0.000000115634, 0.0303344614803791, 0.6883496642112732, 0.2093820273876190, -0.6938398480415344, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 93, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208803277482
678, R, 2017-01-11 02:06:08, 2017-01-09 14:24:00.404, 2017-01-09 14:24:00.544, 0.141, 0.000000, -0.000000022154, -0.000000347416, 0.000000130693, 0.0303313378244638, 0.6883494853973389, 0.2093850672245026, -0.6938391923904419, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208803284394
679, R, 2017-01-11 02:06:08, 2017-01-09 14:24:00.404, 2017-01-09 14:24:00.642, 0.238, 0.000000, -0.000000022155, -0.000000347417, 0.000000130691, 0.0303287059068680, 0.6883496046066284, 0.2093904167413712, -0.6938376426696777, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208803290794
680, R, 2017-01-11 02:06:08, 2017-01-09 14:24:00.404, 2017-01-09 14:24:06.341, 5.937, 0.000000, 0.000000158765, -0.000000170154, 0.000000270606, 0.0303420145064592, 0.6883574724197388, 0.2093946039676666, -0.6938279867172241, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803664297
681, R, 2017-01-11 02:06:08, 2017-01-09 14:24:05.404, 2017-01-09 14:24:06.443, 1.039, 0.000000, 0.000000158765, -0.000000170151, 0.000000270607, 0.0303425211459398, 0.6883556246757507, 0.2093894630670548, -0.6938313245773315, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803670954
682, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:06.544, 0.141, 0.000000, 0.000000158767, -0.000000170148, 0.000000270608, 0.0303396210074425, 0.6883531808853149, 0.2093841284513474, -0.6938354969024658, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208803677610
683, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:06.642, 0.238, 0.000000, 0.000000158768, -0.000000170147, 0.000000270608, 0.0303368102759123, 0.6883523464202881, 0.2093807011842728, -0.6938374638557434, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 89, 0, 77, 100, 100, 0, 0, 0, 0, 0, 0, 35208803684010
684, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:06.743, 0.340, 0.000000, 0.000000088327, -0.000000401939, 0.000000194516, 0.0303343646228313, 0.6883513331413269, 0.2093795686960220, -0.6938389539718628, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208803690665
685, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:06.841, 0.438, 0.000000, 0.000000088329, -0.000000401939, 0.000000194515, 0.0303328447043896, 0.6883499026298523, 0.2093809545040131, -0.6938399672508240, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 85, 0, 0, 0, 0, 100, 91, 0, 0, 0, 0, 0, 0, 35208803697066
686, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:06.943, 0.539, 0.000000, -0.000000022153, -0.000000347416, 0.000000130692, 0.0303297098726034, 0.6883495450019836, 0.2093834578990936, -0.6938397288322449, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208803703721
687, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:07.040, 0.637, 0.000000, -0.000000022153, -0.000000347417, 0.000000130690, 0.0303270947188139, 0.6883491873741150, 0.2093891203403473, -0.6938385367393494, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208803710121
688, R, 2017-01-11 02:06:08, 2017-01-09 14:24:06.404, 2017-01-09 14:24:12.743, 6.340, 0.000000, 0.000000158841, -0.000000171620, 0.000000268608, 0.0303466655313969, 0.6883566379547119, 0.2093899101018906, -0.6938300132751465, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208804083881
689, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:12.841, 0.438, 0.000000, 0.000000158842, -0.000000171617, 0.000000268608, 0.0303452461957932, 0.6883543729782104, 0.2093859612941742, -0.6938335299491882, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208804090282
690, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:12.943, 0.539, 0.000000, 0.000000158843, -0.000000171615, 0.000000268609, 0.0303425993770361, 0.6883528828620911, 0.2093803733587265, -0.6938368082046509, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35208804096937
691, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:13.040, 0.637, 0.000000, 0.000000158844, -0.000000171614, 0.000000268609, 0.0303401276469231, 0.6883519291877747, 0.2093761563301086, -0.6938391327857971, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 88, 0, 76, 100, 100, 0, 0, 0, 0, 0, 0, 35208804103337
692, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:13.142, 0.738, 0.000000, 0.000000088771, -0.000000401500, 0.000000196400, 0.0303381569683552, 0.6883511543273926, 0.2093752473592758, -0.6938402652740479, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35208804109993
693, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:13.240, 0.836, 0.000000, 0.000000088773, -0.000000401500, 0.000000196399, 0.0303363315761089, 0.6883492469787598, 0.2093770205974579, -0.6938416957855225, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 87, 0, 0, 0, 0, 100, 93, 0, 0, 0, 0, 0, 0, 35208804116393
694, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:13.341, 0.937, 0.000000, -0.000000022151, -0.000000347415, 0.000000130695, 0.0303328149020672, 0.6883472204208374, 0.2093811184167862, -0.6938426494598389, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208804123049
695, R, 2017-01-11 02:06:08, 2017-01-09 14:24:12.404, 2017-01-09 14:24:13.443, 1.039, 0.000000, -0.000000022153, -0.000000347416, 0.000000130693, 0.0303307827562094, 0.6883479356765747, 0.2093872725963593, -0.6938401460647583, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35208804129706
696, R, 2017-01-11 02:06:08, 2017-01-10 04:04:15.437, 2017-01-10 04:08:30.066, 254.629, 0.000000, 0.000000742103, 0.000003900247, 0.000011351454, -0.0338304378092289, -0.6905698180198669, -0.2107661962509155, 0.6910473108291626, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212045316778
697, R, 2017-01-11 02:06:08, 2017-01-10 04:08:29.438, 2017-01-10 04:08:30.164, 0.727, 0.000000, 0.000000742092, 0.000003900267, 0.000011351448, -0.0338309556245804, -0.6905694603919983, -0.2107654660940170, 0.6910479068756104, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212045323177
698, R, 2017-01-11 02:06:08, 2017-01-10 04:08:29.438, 2017-01-10 04:08:30.266, 0.828, 0.000000, 0.000000742067, 0.000003900272, 0.000011351447, -0.0338312461972237, -0.6905699968338013, -0.2107645273208618, 0.6910476684570312, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 352120453298
33
699, R, 2017-01-11 02:06:08, 2017-01-10 04:08:29.438, 2017-01-10 04:08:30.367, 0.930, 0.000000, 0.000000742099, 0.000003900260, 0.000011351449, -0.0338312648236752, -0.6905700564384460, -0.2107660621404648, 0.6910471320152283, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 89, 100, 100, 0, 0, 0, 0, 0, 0, 35212045336489
700, R, 2017-01-11 02:06:08, 2017-01-10 04:08:29.438, 2017-01-10 04:08:30.469, 1.031, 0.000000, -0.000002291292, -0.000016526857, -0.000043862675, -0.0338310115039349, -0.6905703544616699, -0.2107708156108856, 0.6910454034805298, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 1, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212045343146
701, R, 2017-01-11 02:06:08, 2017-01-10 04:08:30.438, 2017-01-10 04:08:30.566, 0.129, 0.000000, 0.000000073949, -0.000000388645, 0.000000210920, -0.0338317193090916, -0.6905708909034729, -0.2107772231101990, 0.6910428404808044, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212045349546
702, R, 2017-01-11 02:06:08, 2017-01-10 04:08:30.438, 2017-01-10 04:08:30.668, 0.230, 0.000000, 0.000000073946, -0.000000388647, 0.000000210917, -0.0338314659893513, -0.6905716657638550, -0.2107862383127213, 0.6910393834114075, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 15, 0, 0, 0, 0, 100, 21, 0, 0, 0, 0, 0, 0, 35212045356202
703, R, 2017-01-11 02:06:08, 2017-01-10 04:08:30.438, 2017-01-10 04:08:30.766, 0.328, 0.000000, -0.000000025848, -0.000000346804, 0.000000131636, -0.0338312983512878, -0.6905732750892639, -0.2107947915792465, 0.6910350918769836, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212045362602
704, R, 2017-01-11 02:06:08, 2017-01-10 04:08:30.438, 2017-01-10 04:08:36.469, 6.031, 0.000000, 0.000000746170, 0.000003911418, 0.000011381378, -0.0339174605906010, -0.6906343698501587, -0.2109002321958542, 0.6909376978874207, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212045736362
705, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:36.566, 0.129, 0.000000, 0.000000746104, 0.000003911439, 0.000011381375, -0.0339159965515137, -0.6906328797340393, -0.2108963280916214, 0.6909404397010803, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212045742762
706, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:36.668, 0.230, 0.000000, 0.000000746030, 0.000003911481, 0.000011381366, -0.0339147634804249, -0.6906306743621826, -0.2108916640281677, 0.6909441351890564, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212045749418
707, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:36.766, 0.328, 0.000000, 0.000000745961, 0.000003911506, 0.000011381361, -0.0339138545095921, -0.6906295418739319, -0.2108878791332245, 0.6909464001655579, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 90, 100, 100, 0, 0, 0, 0, 0, 0, 35212045755818
708, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:36.867, 0.430, 0.000000, -0.000002304135, -0.000016563551, -0.000043962799, -0.0339116565883160, -0.6906285881996155, -0.2108868658542633, 0.6909478306770325, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 2, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212045762474
709, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:36.965, 0.527, 0.000000, 0.000000074011, -0.000000388479, 0.000000211729, -0.0339102372527123, -0.6906275749206543, -0.2108886241912842, 0.6909483671188354, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212045768873
710, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:37.066, 0.629, 0.000000, 0.000000074011, -0.000000388480, 0.000000211728, -0.0339094027876854, -0.6906257867813110, -0.2108939439058304, 0.6909485459327698, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 16, 0, 0, 0, 0, 100, 22, 0, 0, 0, 0, 0, 0, 35212045775530
711, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:37.168, 0.730, 0.000000, -0.000000025957, -0.000000346793, 0.000000131644, -0.0339082069694996, -0.6906257867813110, -0.2108989059925079, 0.6909470558166504, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212045782185
712, R, 2017-01-11 02:06:08, 2017-01-10 04:08:36.438, 2017-01-10 04:08:42.867, 6.430, 0.000000, 0.000000732587, 0.000003824491, 0.000011146983, -0.0339069068431854, -0.6906330585479736, -0.2108737528324127, 0.6909475326538086, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046155690
713, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:42.965, 0.527, 0.000000, 0.000000732514, 0.000003824532, 0.000011146974, -0.0339057892560959, -0.6906309723854065, -0.2108691185712814, 0.6909511089324951, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046162089
714, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:43.066, 0.629, 0.000000, 0.000000732448, 0.000003824544, 0.000011146974, -0.0339028686285019, -0.6906284093856812, -0.2108646184206009, 0.6909552216529846, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046168746
715, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:43.168, 0.730, 0.000000, 0.000000732386, 0.000003824536, 0.000011146981, -0.0339004248380661, -0.6906273961067200, -0.2108611315488815, 0.6909573674201965, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 88, 100, 100, 0, 0, 0, 0, 0, 0, 35212046175401
716, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:43.266, 0.828, 0.000000, -0.000002300648, -0.000016553942, -0.000043936462, -0.0338998250663281, -0.6906256079673767, -0.2108604162931442, 0.6909594535827637, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 1, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212046181801
717, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:43.367, 0.930, 0.000000, 0.000000069922, -0.000000415966, 0.000000136933, -0.0338966585695744, -0.6906245350837708, -0.2108610272407532, 0.6909605264663696, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212046188457
718, R, 2017-01-11 02:06:08, 2017-01-10 04:08:42.438, 2017-01-10 04:08:43.469, 1.031, 0.000000, 0.000000069922, -0.000000415967, 0.000000136930, -0.0338941849768162, -0.6906236410140991, -0.2108653038740158, 0.6909601688385010, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 15, 0, 0, 0, 0, 100, 22, 0, 0, 0, 0, 0, 0, 35212046195114
719, R, 2017-01-11 02:06:08, 2017-01-10 04:08:43.438, 2017-01-10 04:08:43.566, 0.129, 0.000000, -0.000000025940, -0.000000346796, 0.000000131640, -0.0338928103446960, -0.6906229853630066, -0.2108713835477829, 0.6909590959548950, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212046201514
720, R, 2017-01-11 02:06:08, 2017-01-10 04:08:43.438, 2017-01-10 04:08:49.270, 5.832, 0.000000, 0.000000738021, 0.000003862664, 0.000011249403, -0.0338875092566013, -0.6906197667121887, -0.2108654677867889, 0.6909643411636353, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046575273
721, R, 2017-01-11 02:06:08, 2017-01-10 04:08:48.438, 2017-01-10 04:08:49.367, 0.930, 0.000000, 0.000000737958, 0.000003862725, 0.000011249386, -0.0338871404528618, -0.6906172037124634, -0.2108611017465591, 0.6909682750701904, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046581673
722, R, 2017-01-11 02:06:08, 2017-01-10 04:08:48.438, 2017-01-10 04:08:49.469, 1.031, 0.000000, 0.000000737843, 0.000003862743, 0.000011249387, -0.0338843464851379, -0.6906153559684753, -0.2108546495437622, 0.6909722089767456, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046588330
723, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:49.570, 0.133, 0.000000, 0.000000737773, 0.000003862733, 0.000011249395, -0.0338816195726395, -0.6906142830848694, -0.2108507901430130, 0.6909745931625366, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 89, 100, 100, 0, 0, 0, 0, 0, 0, 35212046594986
724, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:49.668, 0.230, 0.000000, -0.000002301841, -0.000016563391, -0.000043964751, -0.0338799469172955, -0.6906132102012634, -0.2108487188816071, 0.6909763813018799, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 2, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212046601386
725, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:49.766, 0.328, 0.000000, 0.000000073674, -0.000000388850, 0.000000210112, -0.0338778235018253, -0.6906116604804993, -0.2108491659164429, 0.6909778714179993, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212046607786
726, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:49.867, 0.430, 0.000000, 0.000000073675, -0.000000388851, 0.000000210110, -0.0338758863508701, -0.6906096935272217, -0.2108541578054428, 0.6909784674644470, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 14, 0, 0, 0, 0, 100, 20, 0, 0, 0, 0, 0, 0, 35212046614442
727, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:49.965, 0.527, 0.000000, -0.000000025917, -0.000000346799, 0.000000131637, -0.0338746458292007, -0.6906093358993530, -0.2108594924211502, 0.6909772157669067, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212046620841
728, R, 2017-01-11 02:06:08, 2017-01-10 04:08:49.438, 2017-01-10 04:08:55.668, 6.230, 0.000000, 0.000000150115, -0.000000138200, 0.000000325301, -0.0338796488940716, -0.6906065344810486, -0.2108504623174667, 0.6909825205802917, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212046994602
729, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:55.766, 0.328, 0.000000, 0.000000150115, -0.000000138197, 0.000000325302, -0.0338791757822037, -0.6906047463417053, -0.2108457088470459, 0.6909857988357544, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047001002
730, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:55.867, 0.430, 0.000000, 0.000000150117, -0.000000138194, 0.000000325302, -0.0338770821690559, -0.6906021833419800, -0.2108398377895355, 0.6909902691841125, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047007658
731, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:55.969, 0.531, 0.000000, 0.000000150117, -0.000000138193, 0.000000325302, -0.0338733457028866, -0.6906012892723083, -0.2108355015516281, 0.6909926533699036, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 99, 0, 87, 100, 100, 0, 0, 0, 0, 0, 0, 35212047014313
732, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:56.066, 0.629, 0.000000, 0.000000073884, -0.000000388656, 0.000000210923, -0.0338732860982418, -0.6905987858772278, -0.2108348757028580, 0.6909953355789185, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047020714
733, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:56.168, 0.730, 0.000000, 0.000000073886, -0.000000388656, 0.000000210922, -0.0338717997074127, -0.6905970573425293, -0.2108365595340729, 0.6909966468811035, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047027369
734, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:56.270, 0.832, 0.000000, 0.000000073887, -0.000000388657, 0.000000210920, -0.0338694937527180, -0.6905953884124756, -0.2108406424522400, 0.6909971833229065, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 15, 0, 0, 0, 0, 100, 21, 0, 0, 0, 0, 0, 0, 35212047034025
735, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:08:56.367, 0.930, 0.000000, -0.000000025897, -0.000000346799, 0.000000131641, -0.0338680371642113, -0.6905952095985413, -0.2108447253704071, 0.6909961700439453, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212047040425
736, R, 2017-01-11 02:06:08, 2017-01-10 04:08:55.438, 2017-01-10 04:09:02.070, 6.633, 0.000000, 0.000000145452, -0.000000167781, 0.000000245824, -0.0338736474514008, -0.6905965805053711, -0.2108309417963028, 0.6909987330436707, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047414185
737, R, 2017-01-11 02:06:08, 2017-01-10 04:09:01.438, 2017-01-10 04:09:02.168, 0.730, 0.000000, 0.000000145454, -0.000000167779, 0.000000245825, -0.0338727682828903, -0.6905942559242249, -0.2108260393142700, 0.6910026073455810, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047420585
738, R, 2017-01-11 02:06:08, 2017-01-10 04:09:01.438, 2017-01-10 04:09:02.270, 0.832, 0.000000, 0.000000145457, -0.000000167776, 0.000000245825, -0.0338707715272903, -0.6905906796455383, -0.2108223140239716, 0.6910073757171631, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047427241
739, R, 2017-01-11 02:06:08, 2017-01-10 04:09:01.438, 2017-01-10 04:09:02.367, 0.930, 0.000000, 0.000000145457, -0.000000167775, 0.000000245826, -0.0338685810565949, -0.6905896663665771, -0.2108185142278671, 0.6910097002983093, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 98, 0, 86, 100, 100, 0, 0, 0, 0, 0, 0, 35212047433641
740, R, 2017-01-11 02:06:08, 2017-01-10 04:09:01.438, 2017-01-10 04:09:02.469, 1.031, 0.000000, 0.000000069612, -0.000000416329, 0.000000135325, -0.0338666737079620, -0.6905885338783264, -0.2108176499605179, 0.6910111904144287, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047440298
741, R, 2017-01-11 02:06:08, 2017-01-10 04:09:02.438, 2017-01-10 04:09:02.570, 0.133, 0.000000, 0.000000069614, -0.000000416329, 0.000000135324, -0.0338653065264225, -0.6905865073204040, -0.2108182609081268, 0.6910130381584167, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047446954
742, R, 2017-01-11 02:06:08, 2017-01-10 04:09:02.438, 2017-01-10 04:09:02.668, 0.230, 0.000000, 0.000000069615, -0.000000416329, 0.000000135322, -0.0338630266487598, -0.6905850172042847, -0.2108220607042313, 0.6910135746002197, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 13, 0, 0, 0, 0, 100, 20, 0, 0, 0, 0, 0, 0, 35212047453354
743, R, 2017-01-11 02:06:08, 2017-01-10 04:09:02.438, 2017-01-10 04:09:02.766, 0.328, 0.000000, -0.000000025880, -0.000000346799, 0.000000131644, -0.0338613055646420, -0.6905851960182190, -0.2108271420001984, 0.6910118460655212, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212047459754
744, R, 2017-01-11 02:06:08, 2017-01-10 04:09:02.438, 2017-01-10 04:09:08.469, 6.031, 0.000000, 0.000000144894, -0.000000169875, 0.000000241144, -0.0338648594915867, -0.6905889511108398, -0.2108112275600433, 0.6910128593444824, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047833514
745, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:08.570, 0.133, 0.000000, 0.000000144895, -0.000000169873, 0.000000241145, -0.0338648557662964, -0.6905868053436279, -0.2108063846826553, 0.6910164356231690, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047840170
746, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:08.668, 0.230, 0.000000, 0.000000144897, -0.000000169870, 0.000000241146, -0.0338621176779270, -0.6905844211578369, -0.2108004093170166, 0.6910207271575928, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212047846570
747, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:08.770, 0.332, 0.000000, 0.000000144898, -0.000000169869, 0.000000241146, -0.0338588096201420, -0.6905834674835205, -0.2107973992824554, 0.6910228133201599, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 97, 0, 85, 100, 100, 0, 0, 0, 0, 0, 0, 35212047853226
748, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:08.867, 0.430, 0.000000, 0.000000069443, -0.000000416512, 0.000000134521, -0.0338572412729263, -0.6905817389488220, -0.2107948362827301, 0.6910253763198853, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047859626
749, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:08.969, 0.531, 0.000000, 0.000000069445, -0.000000416513, 0.000000134520, -0.0338555797934532, -0.6905798912048340, -0.2107967585325241, 0.6910266876220703, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212047866281
750, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:09.070, 0.633, 0.000000, 0.000000069445, -0.000000416513, 0.000000134518, -0.0338531695306301, -0.6905786395072937, -0.2108006030321121, 0.6910269260406494, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 12, 0, 0, 0, 0, 100, 19, 0, 0, 0, 0, 0, 0, 35212047872937
751, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:09.168, 0.730, 0.000000, -0.000000025863, -0.000000346800, 0.000000131644, -0.0338511429727078, -0.6905781626701355, -0.2108061760663986, 0.6910257935523987, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212047879337
752, R, 2017-01-11 02:06:08, 2017-01-10 04:09:08.438, 2017-01-10 04:09:14.867, 6.430, 0.000000, 0.000000144148, -0.000000172160, 0.000000235655, -0.0338550880551338, -0.6905797123908997, -0.2108004838228226, 0.6910257935523987, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048252842
753, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:14.969, 0.531, 0.000000, 0.000000144149, -0.000000172157, 0.000000235656, -0.0338555499911308, -0.6905776858329773, -0.2107957899570465, 0.6910291910171509, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048259497
754, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:15.070, 0.633, 0.000000, 0.000000144151, -0.000000172154, 0.000000235657, -0.0338530577719212, -0.6905745863914490, -0.2107908874750137, 0.6910338997840881, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048266153
755, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:15.168, 0.730, 0.000000, 0.000000144153, -0.000000172153, 0.000000235657, -0.0338498093187809, -0.6905736923217773, -0.2107865959405899, 0.6910363435745239, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 96, 0, 84, 100, 100, 0, 0, 0, 0, 0, 0, 35212048272553
756, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:15.270, 0.832, 0.000000, 0.000000069081, -0.000000416885, 0.000000132909, -0.0338477082550526, -0.6905727386474609, -0.2107848823070526, 0.6910378336906433, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212048279209
757, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:15.367, 0.930, 0.000000, 0.000000069082, -0.000000416885, 0.000000132908, -0.0338468663394451, -0.6905710101127625, -0.2107864320278168, 0.6910392045974731, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212048285609
758, R, 2017-01-11 02:06:08, 2017-01-10 04:09:14.438, 2017-01-10 04:09:15.469, 1.031, 0.000000, 0.000000069083, -0.000000416886, 0.000000132906, -0.0338441990315914, -0.6905696988105774, -0.2107898741960526, 0.6910395622253418, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 10, 0, 0, 0, 0, 100, 17, 0, 0, 0, 0, 0, 0, 35212048292266
759, R, 2017-01-11 02:06:08, 2017-01-10 04:09:15.438, 2017-01-10 04:09:15.570, 0.133, 0.000000, -0.000000025849, -0.000000346801, 0.000000131644, -0.0338420271873474, -0.6905699372291565, -0.2107953429222107, 0.6910377740859985, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212048298922
760, R, 2017-01-11 02:06:08, 2017-01-10 04:09:15.438, 2017-01-10 04:09:21.270, 5.832, 0.000000, 0.000000144159, -0.000000173691, 0.000000233392, -0.0338566303253174, -0.6905708909034729, -0.2107927650213242, 0.6910368800163269, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048672425
761, R, 2017-01-11 02:06:08, 2017-01-10 04:09:20.438, 2017-01-10 04:09:21.367, 0.930, 0.000000, 0.000000144160, -0.000000173688, 0.000000233393, -0.0338566638529301, -0.6905689835548401, -0.2107882797718048, 0.6910401582717896, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048678825
762, R, 2017-01-11 02:06:08, 2017-01-10 04:09:20.438, 2017-01-10 04:09:21.469, 1.031, 0.000000, 0.000000144162, -0.000000173686, 0.000000233394, -0.0338549613952637, -0.6905664205551147, -0.2107829451560974, 0.6910444498062134, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212048685482
763, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:21.570, 0.133, 0.000000, 0.000000144163, -0.000000173685, 0.000000233394, -0.0338507853448391, -0.6905651688575745, -0.2107785791158676, 0.6910471916198730, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 95, 0, 83, 100, 100, 0, 0, 0, 0, 0, 0, 35212048692138
764, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:21.668, 0.230, 0.000000, 0.000000069472, -0.000000416506, 0.000000134527, -0.0338499806821346, -0.6905636191368103, -0.2107785642147064, 0.6910488009452820, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212048698538
765, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:21.770, 0.332, 0.000000, 0.000000069473, -0.000000416506, 0.000000134527, -0.0338487364351749, -0.6905622482299805, -0.2107799351215363, 0.6910498142242432, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212048705194
766, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:21.867, 0.430, 0.000000, 0.000000069475, -0.000000416506, 0.000000134524, -0.0338459722697735, -0.6905604600906372, -0.2107834070920944, 0.6910507082939148, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 12, 0, 0, 0, 0, 100, 19, 0, 0, 0, 0, 0, 0, 35212048711594
767, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:21.969, 0.531, 0.000000, -0.000000025839, -0.000000346799, 0.000000131650, -0.0338444709777832, -0.6905608773231506, -0.2107892632484436, 0.6910485625267029, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212048718249
768, R, 2017-01-11 02:06:08, 2017-01-10 04:09:21.438, 2017-01-10 04:09:27.668, 6.230, 0.000000, 0.000000147503, -0.000000146949, 0.000000304963, -0.0338468104600906, -0.6905670166015625, -0.2107862681150436, 0.6910431981086731, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049091754
769, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:27.770, 0.332, 0.000000, 0.000000147504, -0.000000146946, 0.000000304964, -0.0338466353714466, -0.6905645132064819, -0.2107824534177780, 0.6910468935966492, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049098410
770, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:27.871, 0.434, 0.000000, 0.000000147505, -0.000000146943, 0.000000304965, -0.0338441580533981, -0.6905626058578491, -0.2107764482498169, 0.6910507678985596, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049105065
771, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:27.969, 0.531, 0.000000, 0.000000147506, -0.000000146942, 0.000000304965, -0.0338405556976795, -0.6905615925788879, -0.2107723951339722, 0.6910532116889954, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 95, 0, 83, 100, 100, 0, 0, 0, 0, 0, 0, 35212049111465
772, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:28.070, 0.633, 0.000000, 0.000000072821, -0.000000389764, 0.000000206095, -0.0338385775685310, -0.6905609369277954, -0.2107697427272797, 0.6910547614097595, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049118121
773, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:28.168, 0.730, 0.000000, 0.000000072823, -0.000000389764, 0.000000206095, -0.0338373966515064, -0.6905590295791626, -0.2107718139886856, 0.6910560727119446, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049124521
774, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:28.270, 0.832, 0.000000, 0.000000072824, -0.000000389766, 0.000000206092, -0.0338343121111393, -0.6905589103698730, -0.2107735425233841, 0.6910558342933655, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 9, 0, 0, 0, 0, 100, 15, 0, 0, 0, 0, 0, 0, 35212049131177
775, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:28.367, 0.930, 0.000000, -0.000000025829, -0.000000346802, 0.000000131645, -0.0338322445750237, -0.6905587911605835, -0.2107784003019333, 0.6910545825958252, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212049137577
776, R, 2017-01-11 02:06:08, 2017-01-10 04:09:27.438, 2017-01-10 04:09:34.070, 6.633, 0.000000, 0.000000145818, -0.000000154791, 0.000000288652, -0.0338426120579243, -0.6905621886253357, -0.2107764184474945, 0.6910512447357178, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049511337
777, R, 2017-01-11 02:06:08, 2017-01-10 04:09:33.438, 2017-01-10 04:09:34.168, 0.730, 0.000000, 0.000000145820, -0.000000154788, 0.000000288652, -0.0338421612977982, -0.6905594468116760, -0.2107726186513901, 0.6910551786422730, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049517737
778, R, 2017-01-11 02:06:08, 2017-01-10 04:09:33.438, 2017-01-10 04:09:34.270, 0.832, 0.000000, 0.000000145821, -0.000000154785, 0.000000288653, -0.0338404327630997, -0.6905576586723328, -0.2107676118612289, 0.6910585761070251, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049524393
779, R, 2017-01-11 02:06:08, 2017-01-10 04:09:33.438, 2017-01-10 04:09:34.367, 0.930, 0.000000, 0.000000145821, -0.000000154784, 0.000000288654, -0.0338374637067318, -0.6905570030212402, -0.2107629626989365, 0.6910608410835266, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 91, 0, 79, 100, 100, 0, 0, 0, 0, 0, 0, 35212049530793
780, R, 2017-01-11 02:06:08, 2017-01-10 04:09:33.438, 2017-01-10 04:09:34.469, 1.031, 0.000000, 0.000000072641, -0.000000389950, 0.000000205291, -0.0338350124657154, -0.6905557513237000, -0.2107613682746887, 0.6910626292228699, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049537450
781, R, 2017-01-11 02:06:08, 2017-01-10 04:09:34.438, 2017-01-10 04:09:34.570, 0.133, 0.000000, 0.000000072642, -0.000000389950, 0.000000205290, -0.0338334701955318, -0.6905543804168701, -0.2107630372047424, 0.6910635828971863, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049544106
782, R, 2017-01-11 02:06:08, 2017-01-10 04:09:34.438, 2017-01-10 04:09:34.668, 0.230, 0.000000, 0.000000072643, -0.000000389951, 0.000000205287, -0.0338302068412304, -0.6905542016029358, -0.2107653468847275, 0.6910632252693176, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 8, 0, 0, 0, 0, 100, 14, 0, 0, 0, 0, 0, 0, 35212049550506
783, R, 2017-01-11 02:06:08, 2017-01-10 04:09:34.438, 2017-01-10 04:09:34.770, 0.332, 0.000000, -0.000000025821, -0.000000346802, 0.000000131646, -0.0338282696902752, -0.6905542016029358, -0.2107706069946289, 0.6910616755485535, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212049557162
784, R, 2017-01-11 02:06:08, 2017-01-10 04:09:34.438, 2017-01-10 04:09:40.469, 6.031, 0.000000, 0.000000143752, -0.000000163008, 0.000000270730, -0.0338441953063011, -0.6905587315559387, -0.2107676565647125, 0.6910573244094849, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049930666
785, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:40.570, 0.133, 0.000000, 0.000000143753, -0.000000163005, 0.000000270731, -0.0338442884385586, -0.6905567646026611, -0.2107636332511902, 0.6910605430603027, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049937322
786, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:40.668, 0.230, 0.000000, 0.000000143755, -0.000000163002, 0.000000270732, -0.0338426642119885, -0.6905543804168701, -0.2107584476470947, 0.6910645365715027, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212049943722
787, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:40.770, 0.332, 0.000000, 0.000000143756, -0.000000163001, 0.000000270732, -0.0338393598794937, -0.6905532479286194, -0.2107535451650620, 0.6910673379898071, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 87, 0, 75, 100, 100, 0, 0, 0, 0, 0, 0, 35212049950378
788, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:40.871, 0.434, 0.000000, 0.000000072077, -0.000000390509, 0.000000202879, -0.0338368266820908, -0.6905524134635925, -0.2107516527175903, 0.6910688877105713, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049957033
789, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:40.969, 0.531, 0.000000, 0.000000072079, -0.000000390510, 0.000000202878, -0.0338356532156467, -0.6905507445335388, -0.2107538580894470, 0.6910699009895325, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212049963433
790, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:41.070, 0.633, 0.000000, 0.000000072080, -0.000000390511, 0.000000202875, -0.0338320806622505, -0.6905501484870911, -0.2107573598623276, 0.6910696029663086, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 5, 0, 0, 0, 0, 100, 11, 0, 0, 0, 0, 0, 0, 35212049970089
791, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:41.168, 0.730, 0.000000, -0.000000025815, -0.000000346801, 0.000000131650, -0.0338290520012379, -0.6905500888824463, -0.2107622027397156, 0.6910683512687683, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212049976489
792, R, 2017-01-11 02:06:08, 2017-01-10 04:09:40.438, 2017-01-10 04:09:46.871, 6.434, 0.000000, 0.000000140217, -0.000000186857, 0.000000202882, -0.0338402241468430, -0.6905573606491089, -0.2107603847980499, 0.6910610795021057, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050350249
793, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:46.969, 0.531, 0.000000, 0.000000140218, -0.000000186855, 0.000000202884, -0.0338404476642609, -0.6905550360679626, -0.2107557207345963, 0.6910647749900818, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050356649
794, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:47.070, 0.633, 0.000000, 0.000000140220, -0.000000186852, 0.000000202885, -0.0338380485773087, -0.6905526518821716, -0.2107499539852142, 0.6910690665245056, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050363305
795, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:47.168, 0.730, 0.000000, 0.000000140222, -0.000000186851, 0.000000202885, -0.0338349044322968, -0.6905518770217896, -0.2107455730438232, 0.6910713315010071, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 89, 0, 77, 100, 100, 0, 0, 0, 0, 0, 0, 35212050369705
796, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:47.270, 0.832, 0.000000, 0.000000067800, -0.000000418190, 0.000000127277, -0.0338320657610893, -0.6905509829521179, -0.2107440084218979, 0.6910728812217712, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212050376361
797, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:47.367, 0.930, 0.000000, 0.000000067802, -0.000000418190, 0.000000127276, -0.0338309556245804, -0.6905490756034851, -0.2107451856136322, 0.6910744309425354, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212050382761
798, R, 2017-01-11 02:06:08, 2017-01-10 04:09:46.438, 2017-01-10 04:09:47.469, 1.031, 0.000000, 0.000000067803, -0.000000418191, 0.000000127273, -0.0338277742266655, -0.6905477643013000, -0.2107487916946411, 0.6910747885704040, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 3, 0, 0, 0, 0, 100, 10, 0, 0, 0, 0, 0, 0, 35212050389418
799, R, 2017-01-11 02:06:08, 2017-01-10 04:09:47.438, 2017-01-10 04:09:47.570, 0.133, 0.000000, -0.000000025809, -0.000000346802, 0.000000131649, -0.0338251404464245, -0.6905482411384583, -0.2107541412115097, 0.6910728812217712, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212050396074
800, R, 2017-01-11 02:06:08, 2017-01-10 04:09:47.438, 2017-01-10 04:09:53.270, 5.832, 0.000000, 0.000000142260, -0.000000170664, 0.000000255223, -0.0338327586650848, -0.6905545592308044, -0.2107561528682709, 0.6910655498504639, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050769577
801, R, 2017-01-11 02:06:08, 2017-01-10 04:09:52.438, 2017-01-10 04:09:53.371, 0.934, 0.000000, 0.000000142261, -0.000000170662, 0.000000255223, -0.0338317416608334, -0.6905521750450134, -0.2107524722814560, 0.6910691261291504, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050776233
802, R, 2017-01-11 02:06:08, 2017-01-10 04:09:52.438, 2017-01-10 04:09:53.469, 1.031, 0.000000, 0.000000142263, -0.000000170659, 0.000000255224, -0.0338291749358177, -0.6905499100685120, -0.2107458859682083, 0.6910734772682190, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212050782634
803, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:53.570, 0.133, 0.000000, 0.000000142263, -0.000000170658, 0.000000255225, -0.0338278263807297, -0.6905495524406433, -0.2107419371604919, 0.6910751461982727, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 83, 0, 71, 100, 100, 0, 0, 0, 0, 0, 0, 35212050789290
804, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:53.672, 0.234, 0.000000, 0.000000072090, -0.000000390509, 0.000000202875, -0.0338247120380402, -0.6905485987663269, -0.2107398360967636, 0.6910768747329712, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212050795946
805, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:53.770, 0.332, 0.000000, 0.000000072092, -0.000000390509, 0.000000202874, -0.0338231734931469, -0.6905472278594971, -0.2107414007186890, 0.6910778284072876, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212050802346
806, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:53.871, 0.434, 0.000000, 0.000000072093, -0.000000390510, 0.000000202872, -0.0338206402957439, -0.6905463337898254, -0.2107440382242203, 0.6910780668258667, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 5, 0, 0, 0, 0, 100, 11, 0, 0, 0, 0, 0, 0, 35212050809001
807, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:53.969, 0.531, 0.000000, -0.000000025803, -0.000000346803, 0.000000131647, -0.0338181816041470, -0.6905466318130493, -0.2107487171888351, 0.6910763978958130, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212050815401
808, R, 2017-01-11 02:06:08, 2017-01-10 04:09:53.438, 2017-01-10 04:09:59.672, 6.234, 0.000000, 0.000000571183, 0.000002718582, 0.000008121554, -0.0338358357548714, -0.6905497908592224, -0.2107587307691574, 0.6910693645477295, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051189162
809, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:09:59.770, 0.332, 0.000000, 0.000000571128, 0.000002718611, 0.000008121548, -0.0338348113000393, -0.6905479431152344, -0.2107540667057037, 0.6910727024078369, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051195562
810, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:09:59.871, 0.434, 0.000000, 0.000000571054, 0.000002718644, 0.000008121542, -0.0338334664702416, -0.6905459165573120, -0.2107480615377426, 0.6910765767097473, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051202217
811, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:09:59.969, 0.531, 0.000000, 0.000000571011, 0.000002718644, 0.000008121545, -0.0338308177888393, -0.6905442476272583, -0.2107442617416382, 0.6910795569419861, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 77, 0, 65, 100, 100, 0, 0, 0, 0, 0, 0, 35212051208617
812, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:10:00.070, 0.633, 0.000000, 0.000000503037, 0.000002510256, 0.000008092470, -0.0338274128735065, -0.6905437111854553, -0.2107410877943039, 0.6910812258720398, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212051215273
813, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:10:00.168, 0.730, 0.000000, 0.000000503081, 0.000002510253, 0.000008092469, -0.0338265486061573, -0.6905419230461121, -0.2107429951429367, 0.6910824775695801, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 99, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212051221673
814, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:10:00.270, 0.832, 0.000000, -0.000002522121, -0.000017802595, -0.000047168633, -0.0338226407766342, -0.6905410289764404, -0.2107463777065277, 0.6910825371742249, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 5, 0, 0, 0, 0, 0, 0, 35212051228329
815, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:10:00.371, 0.934, 0.000000, -0.000000025800, -0.000000346802, 0.000000131650, -0.0338212326169014, -0.6905410885810852, -0.2107515037059784, 0.6910809874534607, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212051234985
816, R, 2017-01-11 02:06:08, 2017-01-10 04:09:59.438, 2017-01-10 04:10:06.070, 6.633, 0.000000, 0.000000572601, 0.000002730963, 0.000008164129, -0.0338355377316475, -0.6905477046966553, -0.2107512652873993, 0.6910737752914429, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051608489
817, R, 2017-01-11 02:06:08, 2017-01-10 04:10:05.438, 2017-01-10 04:10:06.168, 0.730, 0.000000, 0.000000572560, 0.000002731006, 0.000008164118, -0.0338353626430035, -0.6905453205108643, -0.2107472717761993, 0.6910774111747742, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051614889
818, R, 2017-01-11 02:06:08, 2017-01-10 04:10:05.438, 2017-01-10 04:10:06.270, 0.832, 0.000000, 0.000000572498, 0.000002731022, 0.000008164117, -0.0338330939412117, -0.6905433535575867, -0.2107421010732651, 0.6910810470581055, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212051621545
819, R, 2017-01-11 02:06:08, 2017-01-10 04:10:05.438, 2017-01-10 04:10:06.371, 0.934, 0.000000, 0.000000572442, 0.000002731004, 0.000008164126, -0.0338300094008446, -0.6905428767204285, -0.2107381969690323, 0.6910828351974487, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 70, 0, 59, 100, 100, 0, 0, 0, 0, 0, 0, 35212051628201
820, R, 2017-01-11 02:06:08, 2017-01-10 04:10:05.438, 2017-01-10 04:10:06.473, 1.035, 0.000000, 0.000000499935, 0.000002487761, 0.000008031744, -0.0338278450071812, -0.6905429363250732, -0.2107357978820801, 0.6910836100578308, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212051634858
821, R, 2017-01-11 02:06:08, 2017-01-10 04:10:06.438, 2017-01-10 04:10:06.570, 0.133, 0.000000, 0.000000499990, 0.000002487765, 0.000008031739, -0.0338271968066692, -0.6905404925346375, -0.2107381373643875, 0.6910853385925293, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212051641258
822, R, 2017-01-11 02:06:08, 2017-01-10 04:10:06.438, 2017-01-10 04:10:06.672, 0.234, 0.000000, -0.000002529486, -0.000017857510, -0.000047316521, -0.0338237732648850, -0.6905400753021240, -0.2107409536838532, 0.6910851001739502, 1, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 7, 0, 0, 0, 0, 0, 0, 35212051647914
823, R, 2017-01-11 02:06:08, 2017-01-10 04:10:06.438, 2017-01-10 04:10:06.770, 0.332, 0.000000, -0.000000025797, -0.000000346802, 0.000000131651, -0.0338201634585857, -0.6905402541160583, -0.2107447087764740, 0.6910839080810547, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212051654314
824, R, 2017-01-11 02:06:08, 2017-01-10 04:10:06.438, 2017-01-10 04:10:12.473, 6.035, 0.000000, 0.000000143430, -0.000000151491, 0.000000325907, -0.0338310711085796, -0.6905519366264343, -0.2107388377189636, 0.6910735368728638, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052028074
825, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:12.570, 0.133, 0.000000, 0.000000143431, -0.000000151489, 0.000000325908, -0.0338301770389080, -0.6905499100685120, -0.2107348293066025, 0.6910768151283264, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052034474
826, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:12.672, 0.234, 0.000000, 0.000000143432, -0.000000151487, 0.000000325909, -0.0338269807398319, -0.6905481815338135, -0.2107286602258682, 0.6910805702209473, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052041130
827, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:12.770, 0.332, 0.000000, 0.000000143433, -0.000000151486, 0.000000325909, -0.0338247977197170, -0.6905470490455627, -0.2107253521680832, 0.6910828351974487, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 68, 0, 57, 100, 100, 0, 0, 0, 0, 0, 0, 35212052047530
828, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:12.871, 0.434, 0.000000, 0.000000071719, -0.000000390881, 0.000000201267, -0.0338219366967678, -0.6905461549758911, -0.2107240706682205, 0.6910842657089233, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212052054185
829, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:12.969, 0.531, 0.000000, 0.000000071722, -0.000000390881, 0.000000201266, -0.0338198691606522, -0.6905437707901001, -0.2107255905866623, 0.6910862326622009, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212052060585
830, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:13.070, 0.633, 0.000000, 0.000000071723, -0.000000390882, 0.000000201264, -0.0338186249136925, -0.6905423998832703, -0.2107296437025070, 0.6910864710807800, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 3, 0, 0, 0, 0, 100, 9, 0, 0, 0, 0, 0, 0, 35212052067241
831, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:13.172, 0.734, 0.000000, -0.000000025795, -0.000000346803, 0.000000131649, -0.0338165611028671, -0.6905427575111389, -0.2107352018356323, 0.6910845041275024, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212052073898
832, R, 2017-01-11 02:06:08, 2017-01-10 04:10:12.438, 2017-01-10 04:10:18.871, 6.434, 0.000000, 0.000000153456, -0.000000174274, 0.000000297325, -0.0338307619094849, -0.6905494928359985, -0.2107443213462830, 0.6910743713378906, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052447401
833, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:18.969, 0.531, 0.000000, 0.000000153458, -0.000000174271, 0.000000297326, -0.0338300988078117, -0.6905469894409180, -0.2107398808002472, 0.6910782456398010, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052453801
834, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:19.070, 0.633, 0.000000, 0.000000153459, -0.000000174269, 0.000000297326, -0.0338284522294998, -0.6905450224876404, -0.2107346653938294, 0.6910818219184875, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 100, 100, 100, 0, 0, 0, 0, 0, 0, 35212052460457
835, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:19.172, 0.734, 0.000000, 0.000000153460, -0.000000174267, 0.000000297327, -0.0338258557021618, -0.6905437707901001, -0.2107307314872742, 0.6910843849182129, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 62, 0, 51, 100, 100, 0, 0, 0, 0, 0, 0, 35212052467114
836, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:19.274, 0.836, 0.000000, 0.000000083988, -0.000000402174, 0.000000195947, -0.0338233821094036, -0.6905436515808105, -0.2107283025979996, 0.6910853981971741, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 35212052473769
837, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:19.371, 0.934, 0.000000, 0.000000083989, -0.000000402174, 0.000000195946, -0.0338225141167641, -0.6905421614646912, -0.2107298821210861, 0.6910864710807800, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 85, 0, 0, 0, 0, 100, 91, 0, 0, 0, 0, 0, 0, 35212052480169
838, R, 2017-01-11 02:06:08, 2017-01-10 04:10:18.438, 2017-01-10 04:10:19.473, 1.035, 0.000000, -0.000000025793, -0.000000346802, 0.000000131653, -0.0338201187551022, -0.6905399560928345, -0.2107345610857010, 0.6910873651504517, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212052486826
839, R, 2017-01-11 02:06:08, 2017-01-10 04:10:19.438, 2017-01-10 04:10:19.570, 0.133, 0.000000, -0.000000025794, -0.000000346803, 0.000000131650, -0.0338174365460873, -0.6905401945114136, -0.2107390761375427, 0.6910858750343323, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 35212052493226
| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20180130T192009/anc/eng/rec/mvn_rec_170107_170111_updated_v03.sff |
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by mal
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by mal
From : Paolo Bonzini Subject : Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() Date : Tue, 5 Dec 2017 15:10:23 +0100 User-agent : Mozilla/5.0 (X11; Linux x86_64; rv:52.0) Gecko/20100101 Thunderbird/52.4.0
On 05/12/2017 07:00, Yang Zhong wrote:
> On Mon, Dec 04, 2017 at 08:26:29PM +0800, Shannon Zhao wrote: > > Hi Yang, > > > > On 2017/12/4 20:03, Yang Zhong wrote: > >> On Fri, Dec 01, 2017 at 01:52:49PM +0100, Paolo Bonzini wrote: > >>>> On 01/12/2017 11:56, Yang Zhong wrote: > >>>>>> This issue should be caused by much times of system call by > >>>>>> malloc_trim(), > >>>>>> Shannon's test script include 60 scsi disks and 31 ioh3420 devices. > >>>>>> We need > >>>>>> trade-off between VM perforamance and memory optimization. Whether > >>>>>> below > >>>>>> method is suitable? > >>>>>> > >>>>>> int num=1; > >>>>>> ...... > >>>>>> > >>>>>> #if defined(CONFIG_MALLOC_TRIM) > >>>>>> if(!(num++%5)) > >>>>>> { > >>>>>> malloc_trim(4 * 1024 * 1024); > >>>>>> } > >>>>>> #endif > >>>>>> > >>>>>> Any comments are welcome! Thanks a lot! > >>>> > >>>> Indeed something like this will do, perhaps only trim once per second? > >>>> > >> Hello Paolo, > >> > >> Thanks for comments! > >> If we do trim once per second, maybe the frequency is a little high, > >> what'e > >> more, we need maintain one timer to call this, this also cost cpu > >> resource. > >> > >> I added the log and did the test here with my test qemu command, when VM > >> bootup, > >> which did more than 600 times free operations and 9 times memory trim in > >> rcu > >> thread. If i use our ClearContainer qemu command, the memory trim will > >> down > >> to 6 times. As for Shannon's test command, the malloc trim number will > >> abosultly > >> increse. > >> > >> In my above method, the trim is only executed in the multiple of 5, which > >> will > >> reduce trim times and do not heavily impact VM bootup performance. > >> > >> I also want to use synchronize_rcu() and free() to replace call_rcu(), > >> but this > >> method serialize to malloc() and free(), which will reduce VM performance. > >> > >> The ultimate aim is to reduce trim system call during the VM bootup and > >> running. > >> It's appreciated that if you have better suggestions. > > > > Maybe we can provide a QMP command or something else for user to trim > > the heap manually like the kernel sysfs interface > > /proc/sys/vm/drop_caches which provides an interface for user to drop > > the caches. > > So let user to decide whether it needs to trim the heap. > > > Hello Shannon, > > Thanks for your comments! > This is also a good solution by QMP interface, but this is only suitable > for few VMs. > If there are millions of VMs in CSP(clouds of provider), it is very hard to > operate. > Thanks! I agree, we only need to tweak the conditions under which malloc_trim is
called.
Thanks,
Paolo
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim()
,
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim()
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/04
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Paolo Bonzini , 2017/12/04
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim()
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim()
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Paolo Bonzini
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/06
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Paolo Bonzini , 2017/12/06
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/07
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Paolo Bonzini , 2017/12/11
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/12
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Shannon Zhao , 2017/12/12
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Shannon Zhao , 2017/12/18
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/18
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Paolo Bonzini , 2017/12/19
Re: [Qemu-devel] [PATCH v3] rcu: reduce more than 7MB heap memory by malloc_trim() , Yang Zhong , 2017/12/08
Index(es):
Date
Thread
| https://lists.gnu.org/archive/html/qemu-devel/2017-12/msg00667.html |
MLB Stats, Scores, History, & Records | Baseball-Reference.com
Complete source for baseball history including complete major league player, team, and league stats, awards, records, leaders, rookies and scores.
Baseball Stats and History The complete source for current and historical baseball players, teams, scores and leaders.
22,906 Major League Players
Then a player Really select a team
Select a Hall of Famer:
,
Dave Frost
,
Don Leppert
,
Mike Baxes
and
Paul Hinrichs
Born On This Day
Jesus Tinoco
,
Walt Walsh
,
Jim Clark
,
Bob Hendley
,
Ryan Hawblitzel
and
Lorenzo Cabrera
Player pages include basic statistics and links to player's gamelogs, splits, and more.
Every Major League Team
2023 MLB Standings
MLB Summary · Scores · Schedule · Leaders · Standings · Transactions AL Summary ·
Leaders: Batting · Pitching · Standings · Attendance NL Summary ·
Leaders: Batting · Pitching · Standings · Attendance
Glossary
Table
AL
W
L
GB
SRS
East
TBR
22
5
--
3.2
BAL
17
8
4.0
0.5
TOR
17
9
4.5
0.6
NYY
15
12
7.0
0.7
BOS
13
14
9.0
0.9
Central
MIN
16
11
--
0.7
CLE
13
13
2.5
-1.4
DET
9
15
5.5
-1.1
CHW
7
20
9.0
-1.1
KCR
6
21
10.0
-1.6
West
TEX
15
11
--
1.9
HOU
14
12
1.0
1.7
LAA
14
13
1.5
-0.3
SEA
11
15
4.0
-0.4
OAK
5
22
10.5
-3.8
Glossary
Table
NL
W
L
GB
SRS
East
ATL
18
9
--
1.2
NYM
15
12
3.0
-0.5
MIA
14
13
4.0
-1.5
PHI
14
13
4.0
-0.5
WSN
9
15
7.5
-0.5
Central
PIT
18
8
--
1.4
MIL
17
9
1.0
1.1
CHC
14
11
3.5
1.8
CIN
11
15
7.0
0.4
STL
10
17
8.5
-0.2
West
ARI
15
12
--
0.0
LAD
14
13
1.0
0.8
SDP
13
14
2.0
-0.5
2023 MLB Rules Changes Effect on Stats and Pace of Play Game time, batting average, stolen bases, clock violations
Most Likely Playoff Scenario NL: Byes: ATL, LAD. Wild Card Series: MIL vs ARI and NYM vs CHC AL: Byes: TBR, HOU. Wild Card Series: CLE vs BAL and TOR vs NYY See Full Playoff Odds
Interleague Play NL leads AL 55-48 (471 runs to 459)
Choose a Team Arizona Diamondbacks Atlanta Braves Baltimore Orioles Boston Red Sox Chicago Cubs Chicago White Sox Cincinnati Reds Cleveland Guardians Colorado Rockies Detroit Tigers Houston Astros Kansas City Royals Los Angeles Angels Los Angeles Dodgers Miami Marlins Milwaukee Brewers Minnesota Twins New York Mets New York Yankees Oakland Athletics Philadelphia Phillies Pittsburgh Pirates San Diego Padres San Francisco Giants Seattle Mariners St. Louis Cardinals Tampa Bay Rays Texas Rangers Toronto Blue Jays Washington Nationals
Choose a page Franchise Index 2023 Stats 2023 Schedule and Results 2023 Roster 2023 Transactions 2023 Uniform Numbers 2022 2021 2020 All-Time Franchise Pages Career Batting Leaders Season Batting Leaders Career Pitching Leaders Season Pitching Leaders Year-By-Year Team Batting Year-By-Year Team Pitching
What's Happening
Follow the impact of the new MLB rule changes
Women's Stats Added to College Basketball Reference!
Congratulations to this year's Hall of Fame inductees:
Fred McGriff,Scott Rolen
2023 Hall of Fame Voting Results
2024 Hall of Fame Projected Ballot
2023 Marcel Projections are Live!
Sign up for the Baseball Reference newsletter!
A daily recap of top performers, scores and statistical highlights, straight to your inbox!
Free FBref World Cup 2023 Newsletter
With the 2023 Women's World Cup around the corner, don't miss any of it by signing up for the FBref World Cup newsletter! Get previews, game recaps, advanced stats, and more delivered to your inbox every morning bysigning up today!
Dive Deeper with Stathead Baseball
Subscribe to Stathead Baseball powered by Baseball Reference. Its your all-access pass to go inside the Baseball Reference database. Get your first month free!
Want to see more? Check out Foolish Baseball’s review of Stathead here.
Team Head to Head Records Tool
The Negro Leagues Are Major Leagues
2023 Negro Leagues Data Update Including Expanded Stats and Bio Info
New book! The Negro Leagues Are Major Leagues: Overdue Recognitionavailable now
The Negro Leagues Are Major Leagues: A Resource for Educators
June 2 : Lou Gehrig Day
June 24-25 : Cubs and Cardinals play in London
July 10 : MLB Home Run Derby
July 11 : MLB All-Star Game at T-Mobile Park in Seattle
Today in Baseball History
Site Last Updated:Saturday, April 29, 3:40AM
MLB Leaders — 2023 & All-Time
Season-by-Season Top 20s
Select a season 2023 Leaders 2022 Leaders 2021 Leaders 2020 Leaders 2019 Leaders 2018 Leaders 2017 Leaders 2016 Leaders 2015 Leaders 2014 Leaders 2013 Leaders 2012 Leaders 2011 Leaders 2010 Leaders 2009 Leaders 2008 Leaders 2007 Leaders 2006 Leaders 2005 Leaders 2004 Leaders 2003 Leaders 2002 Leaders 2001 Leaders 2000 Leaders 1999 Leaders 1998 Leaders 1997 Leaders 1996 Leaders 1995 Leaders 1994 Leaders 1993 Leaders 1992 Leaders 1991 Leaders 1990 Leaders 1989 Leaders 1988 Leaders 1987 Leaders 1986 Leaders 1985 Leaders 1984 Leaders 1983 Leaders 1982 Leaders 1981 Leaders 1980 Leaders 1979 Leaders 1978 Leaders 1977 Leaders 1976 Leaders 1975 Leaders 1974 Leaders 1973 Leaders 1972 Leaders 1971 Leaders 1970 Leaders 1969 Leaders 1968 Leaders 1967 Leaders 1966 Leaders 1965 Leaders 1964 Leaders 1963 Leaders 1962 Leaders 1961 Leaders 1960 Leaders 1959 Leaders 1958 Leaders 1957 Leaders 1956 Leaders 1955 Leaders 1954 Leaders 1953 Leaders 1952 Leaders 1951 Leaders 1950 Leaders 1949 Leaders 1948 Leaders 1947 Leaders 1946 Leaders 1945 Leaders 1944 Leaders 1943 Leaders 1942 Leaders 1941 Leaders 1940 Leaders 1939 Leaders 1938 Leaders 1937 Leaders 1936 Leaders 1935 Leaders 1934 Leaders 1933 Leaders 1932 Leaders 1931 Leaders 1930 Leaders 1929 Leaders 1928 Leaders 1927 Leaders 1926 Leaders 1925 Leaders 1924 Leaders 1923 Leaders 1922 Leaders 1921 Leaders 1920 Leaders 1919 Leaders 1918 Leaders 1917 Leaders 1916 Leaders 1915 Leaders 1914 Leaders 1913 Leaders 1912 Leaders 1911 Leaders 1910 Leaders 1909 Leaders 1908 Leaders 1907 Leaders 1906 Leaders 1905 Leaders 1904 Leaders 1903 Leaders 1902 Leaders 1901 Leaders 1900 Leaders 1899 Leaders 1898 Leaders 1897 Leaders 1896 Leaders 1895 Leaders 1894 Leaders 1893 Leaders 1892 Leaders 1891 Leaders 1890 Leaders 1889 Leaders 1888 Leaders 1887 Leaders 1886 Leaders 1885 Leaders 1884 Leaders 1883 Leaders 1882 Leaders 1881 Leaders 1880 Leaders 1879 Leaders 1878 Leaders 1877 Leaders 1876 Leaders 1875 Leaders 1874 Leaders 1873 Leaders 1872 Leaders 1871 Leaders
All-Time Leaderboards
Go to a leaderboard using the form below. For Example:
Single-Season Career Totals Active Players Record Evolution Year-by-Year Leaders Year-by-Year Top 10
WAR Position Players Offensive WAR Defensive WAR Batting Average On-Base% Slugging % On-Base Plus Slugging Games Played At Bats Plate Appearances Runs Scored Hits Total Bases Doubles Triples Home Runs Runs Batted In Bases on Balls Strikeouts Stolen Bases Singles Adjusted OPS+ Runs Created Adj. Batting Runs Adj. Batting Wins Extra Base Hits Times On Base Offensive Win % Hit By Pitch Sacrifice Hits Sacrifice Flies Intentional Bases on Balls Double Plays Grounded Into Caught Stealing SB % Power-Speed # AB per SO AB per HR Outs Made Base-Out Runs Added (RE24) Win Probability Added (WPA) Situ. Wins Added (WPA/LI) Championship WPA (cWPA) Base-Out Wins Added (REW) WAR for Pitchers Earned Run Average Wins Win-Loss % Walks & Hits per IP Hits per 9 IP Bases On Balls per 9 IP Strikeouts per 9 IP Games Played Saves Innings Pitched Strikeouts Games Started Complete Games Shutouts Home Runs Bases on Balls Hits Strikeouts / Base On Balls Home Runs per 9 IP Losses Earned Runs Wild Pitches Hit By Pitch Batters Faced Games Finished Adjusted ERA+ Fielding Independent Pitching Adj. Pitching Runs Adj. Pitching Wins Base-Out Runs Saved (RE24) Win Probability Added (WPA) Sit. Wins Saved (WPA/LI) Championship WPA (cWPA) Base-Out Wins Saved (REW) Wins Above Replacement Putouts Assists Errors Committed Total Zone Runs Def. Games as C Putouts as C Assists as C Errors Committed as C Double Plays Turned as C Passed Balls Stolen Bases Allowed as C Caught Stealing as C Caught Stealing % Def. Games as 1B Putouts as 1B Assists as 1B Errors Committed as 1B Double Plays Turned as 1B Def. Games as 2B Putouts as 2B Assists as 2B Errors Committed as 2B Double Plays Turned as 2B Def. Games as 3B Putouts as 3B Assists as 3B Errors Committed as 3B Double Plays Turned as 3B Def. Games as SS Putouts as SS Assists as SS Errors Committed as SS Double Plays Turned as SS Def. Games as LF (s.1901) Putouts as LF (s.1901) Assists as LF (s.1901) Errors Committed as LF (s.1901) Double Plays Turned as LF (s.1901) Def. Games as CF (s.1901) Putouts as CF (s.1901) Assists as CF (s.1901) Errors Committed as CF (s.1901) Double Plays Turned as CF (s.1901) Def. Games as RF (s.1901) Putouts as RF (s.1901) Assists as RF (s.1901) Errors Committed as RF (s.1901) Double Plays Turned as RF (s.1901) Def. Games as OF Putouts as OF Assists as OF Errors Committed as OF Double Plays Turned as OF Def. Games as P Putouts as P Assists as P Errors Committed as P Double Plays Turned as P Total Zone Runs as C (s.1953) Range Factor/9Inn as C Range Factor/Game as C Fielding % as C Total Zone Runs as 1B (s.1953) Range Factor/9Inn as 1B Range Factor/Game as 1B Fielding % as 1B Total Zone Runs as 2B (s.1953) Range Factor/9Inn as 2B Range Factor/Game as 2B Fielding % as 2B Total Zone Runs as 3B (s.1953) Range Factor/9Inn as 3B Range Factor/Game as 3B Fielding % as 3B Total Zone Runs as SS (s.1953) Range Factor/9Inn as SS Range Factor/Game as SS Fielding % as SS Total Zone Runs as LF (s.1953) Range Factor/9Inn as LF (s.1948) Range Factor/Game as LF (s.1901) Fielding % as LF (s.1901) Total Zone Runs as CF (s.1953) Range Factor/9Inn as CF (s.1948) Range Factor/Game as CF (s.1901) Fielding % as CF (s.1901) Total Zone Runs as RF (s.1953) Range Factor/9Inn as RF (s.1948) Range Factor/Game as RF (s.1901) Fielding % as RF (s.1901) Total Zone Runs as OF (s.1953) Range Factor/9Inn as OF Range Factor/Game as OF Fielding % as OF Range Factor/9Inn as P Range Factor/Game as P Fielding % as P
2023 MLB Season
| https://www.baseball-reference.com/?__hsfp=3281408855&__hssc=218152582.1.1670464441298&__hstc=218152582.2cfa8bf092fa3a137a3f948b088cbb54.1670464441298.1670464441298.1670464441298.1 |
valid from 30/03 to 29/04 2013 - any spring warmth? united kingdom - month ahead
Will no one rid us of this troublesome high? This is certainly proving to be a major blocking high in the patterns and I'm certain that...
Month ahead - March 30, 2013 Valid from 30/03 to 29/04 2013 Any spring warmth? Issued: Saturday 30th March 2013 Duty forecaster: Simon Keeling & Captain Bob Will no one rid us of this troublesome high?This is certainly proving to be a major blocking high in the patterns and I'm certain that many of us will not recall such a long period were a pattern seems to have been 'locked', however there are many instances where a large and persistent block to the has been observed.For some time now the patterns have been indicating that this current block will follow a certain scenario where it drifts westward and declines away to the south allowing milder Atlantic air flowing around the northern flank to move through the UK, that thinking still holds, however timings at the moment are proving 'troublesome'.The global models have recently been backing up the notion of a westward drift of the block, keeping the flow from a rather chilly 'Arctic' or 'Continentally' sourced ' region, then backing this off to the Atlantic...so hoorah....but when and will the high be as persistent to the west?So in the shorter term it may not be in a hurry to 'warm' with any great enthusiasm but at least the sun should be noticeably stronger, its energy however may be busy for a while longer erasing the accumulated surface cold and remaining snow cover across the UK and near Continent.Any real milder and unsettled conditions seem to be kept to the west of the UK or diving into the central Mediterranean, this will only move through the country when the block and 'locked pattern' is removed. *..............10/04/13*Through this period high pressure remains the dominant factor in the overall 'blocked and locked' pattern, with the emphasis continuing to be tilted in favour a mainly settled, essentially dry and chilly weather.Variable cloud amounts with determine obviously the distribution of both the available sunshine and overnight frost, some wintry showers are still possible, however this is not anticipated to be causing any major headaches.There is likely to be a brisk east to north-easterly flow at times, this accentuating the chilly feeling conditions, mitigated in sheltered spots by increasing sunshine, but not what most of us would call spring. *11/04/13......14/04/12*This period remains the best chance of seeing the signs of a pattern alteration, where 'finally' the block is eroded sufficiently for its dominance in the pattern to be dented, the Atlantic at last 'punching' above its weight, as high pressure remains as a ridge across southern Britain but at least a westerly sets in across the far north, bringing cloud and rain to the north of Britain.Overnight frost and mainly dry conditions remain in force across the bulk of England and Wales. *15/04/13.....21/04/13*High pressure across southern England relinquishes control and low pressure moves into the frame, but gone is the fine settled, dry and sunny weather.All areas will be much more unsettled, strong winds at times with outbreaks of rain for all, these moving through on a brisk west to north-westerly flow, clearing to blustery showers, which will still be wintry with hail and thunder.Milder for the whole of the UK during the period, perhaps chillier later as colder air tucks back in behind low pressure and ahead of building higher pressure to the north and northwest once more. *22/04/13.....26/04/13*High pressure slips into the UK, all areas becoming settled, sunnier and a feeling tad chillier once more, especial overnight with return frosts, daytime temperatures lifting in strong, clear April skies in compensation. *27/04/13......30/04/13*Indications of higher pressure to the north, where it'll be remaining dry, settled, however becoming somewhat more unsettled across southern Britain as low pressure develops and extends northward, so later it'll be more unsettled here and hence be feeling rather cooler as a result. Simon & Capn BobEmail me [email protected]
Scratchbox [April 12, 2013] John [Apr 12 - 06:42] unsettled today with showers across and Wales, these could
be thundery and produce some torrential...
Forecasts [April 12, 2013] Morning Call [Apr 12 - 06:01] Showery-Turning milder ... UK Forecast [Apr 12 - 16:28] Turning warmer-Mainly dry today ... Week ahead [Apr 12 - 06:37] Feeling More like Spring-Much Milder ... Month ahead [Mar 30 - 19:18] Valid from 30/03 to 29/04 2013-Any spring warmth? ... Seasonal outlook [Mar 02 - 20:19] Cool & unsettled April-Better May ... Monthly Lookback [Apr 22 - 20:26] March Lookback-Coldest since 1962 ... Europe Forecast [Apr 12 - 06:00] Warm across Spain-Unsettled across Europe ...
Topics [April 12, 2013] 'Sandy' removed from name list GENEVA, April 12, 2013 (AFP) - The destruction caused by Hurricane Sandy has prompted the World Meteorological ... Northern hemisphere summers warmest in 600 years PARIS, April 10, 2013 (AFP) - Summers in the northern hemisphere are now warmer than at any period ... Which is more important, pandas or pinot? WASHINGTON, April 8, 2013 (AFP) - Which is more important, pandas or pinot? Researchers say that ...
| https://www.weatheronline.co.uk/weather/reports/month-ahead/valid-from-30/03-to-29/04-2013-any-spring-warmth.5.20130412.htm |
Pharmaceutics | Free Full-Text | Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis
To prepare a binary formulation delivering miRNA-146 and evaluate a nucleic acid nasal delivery system by investigating its pharmacodynamic effects in allergic rhinitis. The gel/NPs/miR-146a thermosensitive in situ chitosan hydrogel carrying a nucleic acid was prepared and evaluated for its characteristics, including temperature sensitivity, gel strength, mucosal adhesion and drug release profile. After nasal administration of the formulation to ovalbumin-sensitized rats, the treatment of allergic rhinitis was verified by assessing nasal symptoms, hematology, hematoxylin-eosin (HE) staining and immunohistochemistry. Western Blot(WB) was used to analyze nasal inflammatory factors as well as miRNA-146-related factors, and the miR146 expression level was measured by PCR. Subsequently, the effects of the gel/NPs/miR-146a binary formulation were evaluated for the nasal delivery of nucleic acids in rhinitis therapy. The prepared binary formulation quickly formed a gel in the nasal cavity at a temperature of 34 °C with good mucosal adhesion, which delivered nucleic acids into the nasal mucosa stably and continuously. Gel/NPs/miR-146a was able to sustain the delivery of miRNA into the mucosa after nasal administration. When compared with the monolithic formulations, the gel/NPs/miR-146a binary formulation performed better regarding its nucleic acid delivery ability and pharmacodynamic effects. The gel/NPs/miR-146a binary preparation has a suitable nasal mucosal drug delivery ability and has a positive pharmacodynamic effect for the treatment of ovalbumin-induced rhinitis in rats. It can serve as a potential nucleic acid delivery platform for the treatment of allergic rhinitis.
Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis
by Yu Su , Bixi Sun , Xiaoshu Gao , Shuwen Liu , Rubin Hao and Bing Han *
Received: 31 August 2020 / Revised: 17 September 2020 / Accepted: 21 September 2020 / Published: 23 September 2020
Abstract
:
To prepare a binary formulation delivering miRNA-146 and evaluate a nucleic acid nasal delivery system by investigating its pharmacodynamic effects in allergic rhinitis. The gel/NPs/miR-146a thermosensitive in situ chitosan hydrogel carrying a nucleic acid was prepared and evaluated for its characteristics, including temperature sensitivity, gel strength, mucosal adhesion and drug release profile. After nasal administration of the formulation to ovalbumin-sensitized rats, the treatment of allergic rhinitis was verified by assessing nasal symptoms, hematology, hematoxylin-eosin (HE) staining and immunohistochemistry. Western Blot(WB) was used to analyze nasal inflammatory factors as well as miRNA-146-related factors, and the miR146 expression level was measured by PCR. Subsequently, the effects of the gel/NPs/miR-146a binary formulation were evaluated for the nasal delivery of nucleic acids in rhinitis therapy. The prepared binary formulation quickly formed a gel in the nasal cavity at a temperature of 34 °C with good mucosal adhesion, which delivered nucleic acids into the nasal mucosa stably and continuously. Gel/NPs/miR-146a was able to sustain the delivery of miRNA into the mucosa after nasal administration. When compared with the monolithic formulations, the gel/NPs/miR-146a binary formulation performed better regarding its nucleic acid delivery ability and pharmacodynamic effects. The gel/NPs/miR-146a binary preparation has a suitable nasal mucosal drug delivery ability and has a positive pharmacodynamic effect for the treatment of ovalbumin-induced rhinitis in rats. It can serve as a potential nucleic acid delivery platform for the treatment of allergic rhinitis.
Keywords:
nanoparticles
;
binary formulation
;
allergic rhinitis
;
miR-146a
Graphical Abstract
1. Introduction
Allergic rhinitis (AR) is a type I allergic inflammatory disease that is of the nasal mucosa induced by Immunoglobulin E (IgE) under the chemotaxis of a variety of inflammatory cytokines after a specific individual comes in contact with antigens. Studies have shown that after exposure to allergens, there are changes in the body, such as T cell subpopulation imbalance and abnormal inflammatory cytokine levels, resulting in an imbalance of cell/immune responses between Th1 and Th2. Th2 cytokines stimulate B-lymphocytes to produce IgE [ 1 ]. After IgE binds to the antigen, it activates basophils and mast cells, releases histamine from the cytoplasm, increases vascular permeability, contracts bronchial smooth muscles and activates sensory nerves, resulting in sneezing and nasal itching symptoms [ 2 ]. The prevalence of AR is cited as 10% to 30% in adults and up to 40% in children [ 3 ]. AR undoubtedly brings many inconveniences to the daily lives of patients. Commonly used antiallergic drugs cannot eradicate the disease. Although allergen immunotherapy is effective, it has the disadvantage of a limited number of allergens [ 4 ]. Regulation of AR inflammation and the immune system based on miRNA regulation is a potential intervention method [ 5 ].
MicroRNA (miRNA) is a type of noncoding single-stranded RNA that can target RNA in animals and plants to prevent protein translation or degrade mRNA and participates in posttranscriptional gene expression regulation. miRNAs play a vital role as gene regulators in almost every aspect of controlling cellular functions. Moreover, it has been shown that they actively participate in immune function and allergic inflammation [ 6 , 7 ]. Previous studies have shown that miR-146a is involved in suppressing inflammation, regulating the immune system and suppressing allergic inflammation [ 8 , 9 ]. Existing studies have indicated that miR-146a has an important therapeutic effect on the induction of immune tolerance in AR and is considered a promising biomarker in the pathogenesis and treatment of AR [ 10 , 11 ]. However, naked miRNA has difficulty penetrating the extracellular barrier and is easily degraded in vivo. In addition, it often has a short retention time because of removal by the nasal cilia, reducing the contact time of the drug with nasal epithelial cells [ 12 ]. Therefore, it is necessary to select an appropriate delivery system to promote cellular uptake and protect miRNAs from degradation, thereby improving bioavailability.
Chitosan is biodegradable, safe, nontoxic and mucoadhesive; accordingly, it can be used as a hydrogel matrix for local intranasal administration in order to prolong the retention time of drugs in the nose [ 13 , 14 , 15 ]. Considering the enrichment of multiple enzymes in the nasal cavity, delivery of nucleic acids in the form of a chitosan hydrogel alone may be susceptible to the risk of instability in the nasal cavity [ 16 ]. In addition, the drug carrier for local intranasal treatment should have suitable mucopenetrating ability to achieve sustained and stable drug delivery to the nasal mucosa. polyethylene glycol (PEG)-poly(lactic acid) (PLA) nanoparticles have the proper ability for nucleic acid delivery and maintain nucleic acid stability in vivo as well [ 17 ]. The presence of PEG chains on its surface can enhance the permeability of mucus, allowing the drug to pass through the mucus layer and then transporting the drug to the mucosa [ 18 ]. Various nanotechnology-based systems, such as liposomes, polymeric nanoparticles, dendrimers, cyclodextrin complexes, gold nanoparticles and magnetic nanoparticles, are being explored in the pursuit to improve aqueous solubility and drug delivery to the pathological site [ 19 , 20 ].
21
,
22
,
23
], a thermosensitive in situ hydrogel was designed that is liquid at room temperature for easy preparation and administration with a controllable dosage (
Scheme 1
). After reaching the lesion area, it should be transformed into gel to increase retention time. Our research has proven that the temperature-sensitive PEG-PLA NPs/hydrogel binary formulation has appropriate nasal mucosal adhesion properties. After nasal administration, the miRNA-NPs/CP temperature-sensitive hydrogel steadily delivers miRNA-146 into the nasal mucosa, which significantly inhibits inflammation in the rat allergic rhinitis model, and causes pathological changes to the nasal mucosa, leading to an excellent therapeutic effect. The rationally designed miRNA-NPs/CP thermosensitive hydrogel binary formulation provides the potential for realizing nucleic acid drug therapy for nasal diseases.
2. Materials and Methods
2.1. Materials
Ovalbumin (OVA) was obtained from Sigma-Aldrich (Saint Louis, MO, USA). The antigen adjuvant suspension was composed of 1 mg of ovalbumin and 50 mL of aluminum hydroxide gel. PEG5000-PLA75/25 was purchased from Daigang Biotechnology Co., Ltd. (Shandong, China). Chitosan (viscosity of 100–200 mpa.s and a degree of deacetylation of 95%) and β-GP were purchased from Macklin Biochemical Technology Co., Ltd. (Shanghai, China). Cy3-miRNA-146a was provided by Gene Pharma (Shanghai, China). All reagents, unless otherwise specified, were purchased from Xinjinji Biotechnology Co., Ltd. (Jilin, China). The sources of the instruments used are indicated in the corresponding position.
2.2. Animals
The Sprague Dawley rats used (weight 220–250 g) in this study were purchased from Changsheng Biotechnology Co., Ltd. (Changchun, China). The rats were given free access to OVA-free water and food before the experiment. The experimental procedure was approved by the Ethics Committee of Jilin University. All animal studies were conducted in strict accordance with the approval of the Animal Ethics Committee of the Pharmacy of Jilin University (code: 20180027).
2.3. Preparation and Characterization of miR146a/PEG-PLA NPs
Nanoparticles were prepared by the double emulsion method [
24
,
25
]. The operation process was as follows. First, miR-146a was added into enzyme-free water containing spermidine (N/P ratio 10:1) with stirring to form a spermidine-miR146a complex. PEG-PLA (50 mg) and the spermidine/miR-146a complex were dissolved in dichloromethane (2 mL). The obtained organic solution was poured into 25 mL of PVA aqueous solution (2%,
w
/
v
) and the mixture was sonicated for 60 s in an ice water bath using a probe for emulsification. The nanoparticles were centrifuged at 8000 rpm for 20 min and collected. The particle size and zeta potential of the nanoparticles were measured and analyzed by a dynamic light scattering particle size analyzer (Nano-ZS90, Malvern, UK). The shape and surface morphology of the nanoparticles were observed by transmission electron microscopy (TEM JEM-2200FS, JEOL, Tokyo, Japan).
Using a microplate reader (λex/em = 550/570 nm), (Infinite F200Pro, TECAN, Männedorf, Switzerland), the miRNA in the supernatant was quantified according to the calibration curve of miR-146a, and all experiments were repeated three times. The loading efficiency of miRNA was calculated as follows [
26
]:
(1)
2.4. Preparation of a Thermosensitive In Situ Gel
Sodium glycerophosphate/chitosan was used to prepare composite hydrogels. The preparation method was described in previous reports [ 27 ]. Briefly, deacetylated chitosan was dissolved in 1% acetic acid at various concentrations of 1.5%, 3% and 4.5% ( w / v ). To prepare the hydrogel, 2 mL of chitosan solution was continuously stirred at 4 °C as the prepared nanoparticles (or same equivalent of naked miR-146a 0.07 mg) were slowly added. Then, a β-GP (12% or 16% w / v ) solution was added dropwise. The mixed solution was stirred at room temperature for half an hour.
2.5. Determination of Gelation Time, Gel Strength and Mucosal Adhesion
The gelation time was measured by the rod stop method with some modifications [ 28 ]. A 20 mL beaker was placed on a heated magnetic stirrer (Li chen ke yi, Shanghai, China) and 5 mL of the preparation was added. The liquid was constantly stirred (30 rpm) at 34 °C. When the magnetic rod stopped moving due to gelation, the time was recorded. Three independent experiments were performed in parallel, and the results are the average of the measurements.
Gel strength was determined as the time required for the weight to penetrate 5 cm deep into the gel. Each sample (50 g) was transferred to a 100 mL graduated cylinder and gelled in a constant temperature water bath at 34 °C. Then, a 35 g weight was placed on the gel solution and allowed to penetrate 5 cm in the gel. Time taken by weight to sink 5 cm was measured [ 29 ].
Mucosal adhesion gel strength was based on the two-arm balance method [ 28 ]. At 34 °C, a piece of porcine nose mucosa was stacked on the opening of a glass vial filled with phosphate buffer saline (PBS) (pH 7.4). The glass vial was glued tightly to the center of a beaker containing phosphate buffer (pH 7.4, 34 °C). The fixed-dose preparation was gelled and fixed on the underside of the rubber stopper in advance. The stress required to separate the gel from the mucosal surface per unit area was determined to be the mucosal adhesion strength (g/cm 2 ).
The method for determination of the adhesion time between the gel preparation and mucosa was based on that by Khan et al. [
30
] and slightly modified. At 34 °C, a pregelatinized sample (2 g) with 0.1% methylene blue was added to a sample, and the sample was adhered to porcine nose mucosa. The sample was placed in a constant temperature environment of 34 °C at an angle of 40° and rinsed with the nasal fluid of a simulated patient at pH 7.4 and a rate of 5 mL/min. Based on the color change, the time required to thoroughly wash out the formulation was determined. The results of all the above experiments are shown as the average of 4 independent measurements.
2.6. In Vitro miRNA Release from PEG-PLA Nanoparticles
This test was carried out by the dialysis bag method. PEG-PLA nanoparticles containing Cy3-labeled miRNA were placed in 1 mL of PBS and released into a water bath at 34 °C and 100 rpm. The sample of the supernatant of each formulation was removed at 0 h, 4 h, 8 h, 16 h, 24 h, 32 h, 40 h and 48 h, and replaced with fresh buffer.
The fluorescence intensity of each sample was measured at 550/570 nm with a microplate reader, the amount of miRNA released was determined and PBS solution was used as a blank control.
2.7. Ex Vivo Nasal Mucosal Penetration and Retention of miRNA
The ex vivo nasal mucosal penetration experiment used the Franz vertical diffusion cell method. In short, we first prepared the ex vivo nasal mucosa (code: 20180043). The nasal cavity was removed from the nose of a freshly slaughtered pig, and tweezers were used to carefully peel off the mucosa covering the turbinate bone and nasal septum, followed by rinsing with normal saline. The treated nasal mucosa was fixed on the diffusion cell (the penetration area was 3.14 cm
2
). Five grams of the sample to be tested were paced in the supply tank and evenly covered the surface of the nasal mucosa. Then, the cell was sealed with plastic wrap, fixed with 19 mL of normal saline (34 ± 0.2 °C) in the receiving tank and allowed to come into close contact with the nasal mucosa. The diffusion device was placed in a constant temperature bath at 34 ± 0.2 °C, stirred with a magnetic stirrer (speed of 300 r/min) and a 1 mL sample was removed at 0 h, 4 h, 8 h,16 h, 24 h, 32 h, 40 h and 48 h, and the permeated miR-146a of the different preparations was determined. The permeation of the Cy3-labeled miRNA into the mucosa was plotted with time T as the abscissa and cumulative permeation per unit area Q (μg/cm
2
) as the ordinate. After 48 h, the amount of miRNA retained in the nasal mucosa was determined as follows:
(2)
2.8. Preparation of AR Model Rats and Intranasal miR-146a Administration
Thirty-six rats were randomly divided into 6 groups: the normal group, AR model group, naked miR-146a group, AR + gel/miR-146a group, AR + NPs/miR146a group and AR + gel/NPs/miR-146a group (miR-146a: 1.4 × 10
−3
mg/rat) [
10
]. According to previous reports, the AR model was induced by ovalbumin sensitization. With the prepared allergen suspension containing 0.3 mg OVA + gel 30 mg AL(OH)
3
, 1 mL per mouse was injected intraperitoneally once every other day for a total of 7 administrations as the basic sensitization. From day 15 to day 21, for 7 consecutive days, 50 μL of OVA (25 mg/mL) was applied to each nostril via a micropipette once a day. The rats were administered this treatment for 7 consecutive days after the 22nd day. The rats were fixed during the nasal drip and returned to the cage after 10 min of continuous fixation. The model group was given only sterile saline each time, and approximately 20 μL of miR-146a, NPs/miR-146a, gel/miR-146a and gel/NPs/miR-146a containing 7 × 10
−4
of miR-146a was introduced in one of the nostrils of each rat with a micropipette. Rats in the normal group were injected intraperitoneally with the same amount of normal saline and nasal drops. On the 30th day, the 6 groups of rats were sacrificed by anesthesia, and the mucosal tissues were collected for further examination.
2.9. Evaluation of Rhinitis Symptoms
According to reference [ 31 ], all rats were evaluated for their nasal symptoms as described by Wen et al. On the 30th day, each rat was placed in a separate transparent cage, and after half an hour of adaptation, sneezing, nasal scratching and secretions from the nose were monitored for 10 min. No nose scratching or sneezing received a score of 0, the behaviors 1–3 times/min received a score of 1, the behaviors 4–6 times/min received a score of 2 and the behaviors exceeding 6 times/min received a score of 3. No nasal secretions were scored as 0 points, a single nostril secretion was scored as 1 point, two nostril secretions were scored as 2 points, and an overflow volume was scored as 3 points. From these scores, the total score of nasal symptoms for each rat was calculated and compared.
2.10. Enzyme-Linked Immunosorbent Assay (ELISA)
The levels of the serums IL-4, IL-13, TNF-α, IFN-γ and IgE and histamine were determined by an enzyme-linked immunosorbent assay. Each sample was measured in triplicate, and the average value was recorded. The levels of IL-4, IL-13, TNF-α, IFN-γ, IgE and histamine were determined according to the ELISA kit instructions. The absorbance was measured at 450 nm with a microplate reader (Infinite F200Pro, TECAN, Männedorf, Switzerland). Each measurement was repeated in triplicate, and the average value was recorded. Ig-E, IL-4, TNF-α and INF-γ levels were expressed as pg/mL and IL-13 levels as ng/mL.
2.11. Apoptotic Cell Detection in Nasal Mucosa
The TUNEL method was used to detect cell apoptosis in the nasal mucosa. According to the kit instructions, the rat nasal mucosa was fixed with 10% neutral formaldehyde, embedded in paraffin, dewaxed with conventional xylene and added to a gradient of ethanol in water. Cell apoptosis was observed under a 400× light microscope and 6 different fields of view were randomly selected from each slice to calculate the cell apoptosis rate of each group of nasal mucosa. The nuclei of apoptotic cells were stained brown, normal cells were blue and apoptotic cells were brown.
2.12. qRT-PCR
Total RNA was extracted from the nasal mucosa using TRIzol reagent. cDNA was synthesized using a Prime ScriptTM reverse transcription kit (Invitrogen, NY, USA). The expression of mRNA was quantified by real-time RT-qPCR. The primer sequences used were as follows (5′ to 3′): miR-146a: 5′-CTGCCGCTGAGAACTGAATT-3′ (forward), 5′-CAGAAGCAGGGTCCGAGGTA-3′ (reverse); U6: 5′-CTCGCTTCGGCAGCACA-3′ (forward), 5′-AACGCTTCACGAATTTGCGT-3′ (reverse). The data were analyzed using the 2-ΔΔCT method.
2.13. Western Blot Assay
The classical proteins TLR4 and NF-κB, which are associated with rhinitis, were detected to indirectly investigate the nucleic acid delivery effects of each group of nanoparticles. Specifically, nasal mucosa tissue cells were collected in a RIPA Lysis Buffer (RIPA) buffer containing protease inhibitors and protein samples were collected for SDS-PAGE. After blocking with 5% skim milk for 1 h at room temperature, the primary antibody was added and followed by incubation overnight at 4 °C. After incubating the secondary antibody bound to Horseradish Peroxidase (HRP) for 2 h, the membrane was washed with PBS containing 0.1% Tween-20. ImageJ software (National Institutes of Health, Bethesda, MD, USA) was used to analyze the gray value.
2.14. HE Staining
After the rats were sacrificed, the maxillary skin was stripped, freed from the skull and cut along the midline of the nose to expose the nasal septum and bilateral nasal cavities. After administration for 1 week, the bilateral nasal mucosa tissues were taken immediately and treated with PBS 3 times, fixed with 4% paraformaldehyde, embedded in conventional paraffin and sectioned at a thickness of approximately 5 μm. After dewaxing with xylene and washing with a gradient of ethanol to water, the sections were stained with hematoxylin-eosin (HE). Then, the sections were routinely dehydrated, made transparent and resin-mounted, and the histopathological changes in the nasal mucosa were observed under a microscope (CKX41, Olympus, Tokyo, Japan).
2.15. Immunohistochemistry
The classical protein factors associated with rhinitis, TLR4 and NF-κB, were further studied. Immunohistochemical analysis of the nasal mucosa was performed to assess TLR4 and NF-κB expression in the nasal mucosa after initiation of rhinitis in the normal group, model group and groups with different formulations delivering miR-146a. The miR-146a delivery effects of each formulation were evaluated indirectly.
2.16. Statistical Analysis
Analysis of the data was performed using GraphPad Prism software (GraphPad Software, San Diego, CA, USA). All data are presented as the mean ± standard deviation (SD). One-way ANOVA, followed by Tukey’s test, was used for multiple comparisons. Differences with p -values less than 0.05 were considered to be significant.
3. Results
3.1. Characterization of the PEG-PLA Nanoparticles Carrying miRNA-146a
The average size, zeta potential range and polydispersity index of the nanoparticles were measured by a Malvern particle size analyzer as shown in Figure 1 A and Table 1 .
3.2. The Release Profile of miR-146a In Vitro
Under a simulated nasal environment (34 °C, pH = 7.4), the release profile of miRNA from the nanoparticles was measured. The release curve was constructed by measuring the fluorescence of Cy3-labeled miRNA at different time points. PBS solutions containing only PBS or Cy3-labeled miRNA were used as standard curves. The cumulative release curve of fluorescence intensity was calculated based on the concentration obtained in Figure 1 B.
3.3. Characterization of the Chitosan Thermosensitive In Situ Hydrogel
We optimized a series of formulations ( Table 2 ) to find formula F5. After mixing 1 mL of a chitosan aqueous solution with 16% w / v β-GP, the formulation quickly turned into a gel within 3.8 min at a gelling temperature of 34 °C ( Figure 1 C). Generally, the gel strength of nasal preparations can effectively maintain the integrity of the gel for 20–50 s. The mucosal adhesion strengths of the gel/NPs/miR-146a were 30 ± 1.61 g/cm 2 . It should be noted that there was no significant difference in the mucosal adhesion strength and adhesion duration between the miRNA/chitosan hydrogel and NPs/chitosan hydrogel in the solution and gel state ( Figure 2 ), suggesting that the incorporation of PEG-PLA NPs/miR146a showed little influence on the gel properties ( Table 3 ).
3.4. Ex Vivo Nasal Mucosal Penetration and Retentionabsorption Efficiency of miR146a
The penetration rates of miR-146 from NPs/miR-146a and gel/miR-146a were 61% and 31%, respectively, and the penetration rate of the gel/NPs/miR-146a binary formulation was 40% (
Figure 3
A). The results showed that the use of delivery vehicles significantly hindered the penetration of miRNA from the mucosa, and the hydrogel formulation had a stronger hindering effect. In order to evaluate the effective dose that actually remained in the inflamed mucosa after the topical application of different formulations in the nose, miRNA was recovered from the mucosa 48 h after administration and delivery. The gel/NPs/miR-146a binary formulation showed the highest mucosal retention rate, with 51% of the initial dose remaining in the mucosa. After 48 h, the mucosal retention of NPs/miR-146a was slightly lower at 29%, and that of the gel/miR-146a was 39% (
Figure 3
B).
In general, the formulation with the lowest miRNA penetration and the highest interception is more suitable for local nasal mucosa administration; that is to say, the gel/NPs/miR-146a binary formulation might be the optimal choice.
3.5. The Effects of miR-146a Delivery on the Behavioral Performance of Rats
The AR model rats were prepared successfully. Compared with AR model rats, AR + gel/miR-146a, AR + NPs/miR-146a and AR + gel/NPs/miR-146a treated AR rats had a significant reduction in the number of nasal scratches and sneezing. Among them, the AR + gel-NPs-miR-146a group had the best scores, and the treatment effect was the most obvious. While rats in the naked miR-146a group showed a slight improvement in allergic rhinitis symptoms, the effect was not obvious ( Figure 4 ). This may be because naked miR-146a was easily cleared by nasal cilia or degraded by related enzymes in the nasal cavity.
3.6. miR-146a Delivery Affects Histamine and Inflammatory Cytokine Levels
We measured the expression levels of IL-4, IL-13, TNF-α, IFN-γ, IgE and histamine, measured by ELISA, which play a key role in AR. Figure 5 shows that compared with the AR model group, the groups after miR-146a administration (AR + naked miR-146a, AR + gel-miR-146a, AR + NPs-miR-146a and AR + gel-NPs-miR-146a) had reduced levels of IL-4, IL-13, TNF-α, IFN-γ, IgE and histamine. Overall, the AR + gel/NPs/miR-146a group exhibited the best pharmacodynamic effect. In summary, these results indicate that AR + gel/NPs/miR-146a showed the best regulation of inflammatory cytokines ( Figure 5 ).
3.7. Effect of miR-146a Delivery on Rat Nasal Mucosa Apoptosis
TUNEL staining was used to evaluate the effects of nucleic acid delivery by nasal administration of each preparation on nasal mucosal cells ( Figure 6 ). By observing the conditions of the nasal mucosa in each group, it was found that compared with the normal group, the nasal mucosal synovial cell cytoplasm had a large number of brown particles in the model group, showing more nasal mucosal cell apoptosis. Compared with the model group, the number of apoptotic cells in the nasal mucosa of the nucleic acid delivery group and the naked miR-146a group was significantly reduced, among which the number of apoptotic cells in the gel/NPs/miR146a group was the lowest.
3.8. miR-146a Expression Levels Were Detected by qRT-PCR
Compared with the normal group, the expression of miR-146 in the model group was slightly lower, which was consistent with previous reports ( Figure 7 ). The expression in both the naked miR-146 group and other preparations of miR-146 groups was higher than in the model group, and there was a significant difference between the groups ( p < 0.05). The expression of miR-146 in the gel/NPs/miR146a group increased significantly. This further confirmed the good effect of the binary formulation on the delivery of nucleic acids. The expression of miR-146 in the nanoparticle group was high compared with the two monophyletic formulations gel/miR-146a and PEG-PLA NPs/miR146a. This showed that the protection of nucleic acids during the delivery of nanoparticles and the release of chemical drugs from the monolithic gel group may be better than the release of nucleic acids ( Figure 7 ).
3.9. Western Blot Detection of TLR4 and NF-κB Expression Levels
The experimental results showed that compared with the normal control group, the levels of TLR4 and NF-κB in the nasal mucosa of AR rats increased significantly, while both factors were significantly downregulated in AR rats after the delivery of miR-146a by the gel-NPs-miR-146a binary preparation. As expected, downregulation after administration of the gel-NPs-miR146a binary formulation was significantly stronger than the other monophyletic formulations (NPs-miR146a group and gel-miR146a group). Once again, it was verified that the combined effects of the nanoparticles and hydrogel were stronger than any single nucleic acid delivery effect in vivo ( Figure 8 ).
3.10. HE Staining
The changes in the histopathological tissue of the nasal mucosa also reflect the success of the modeling (
Figure 9
). Observation results with 400× light microscopy showed that the overall structure of the nasal mucosa in the normal group was normal and eosinophil and inflammatory cell infiltration were not observed in the lamina propria; however, there was a large number of inflammatory cells infiltration in the model group. The AR + gel-NPs-miR146a rats’ HE results were consistent with histamine release and were also the best performing group among each of the treatment groups. The overall structure of the nasal mucosa in the AR + gel-miR146a group and AR + NPs-miR146a group did not change significantly, but the individual lamina proprias did. There was rare focal inflammatory cell infiltration. Compared with the nude miR-146a group, the binary preparation and the other two monophyletic formulations showed significantly reduced pathological changes in the nasal mucosa in rhinitis model rats. In summary, the pathological results showed that the AR + gel-NPs-miR146a group could significantly reduce the pathological changes i006E the nasal mucosa. Moreover, the AR + NPs-miR146a and AR + gel-miR146a groups had similar pathological effects and improved the nasal mucosa damage caused by allergic rhinitis. The AR + NPs-miR146a group seemed to cause less inflammation, while the AR + gel-miR146a group had improved nasal mucosal cells.
3.11. Immunohistochemistry
Immunohistochemistry ( Figure 10 ) showed that there was only a small amount of TLR4 and NF-κB expression in the nasal mucosa of the normal group. Compared with the normal group, a large number of brown-yellow particles were observed in the cytoplasm of synovial cells in the nasal mucosa of the model group. Compared with the model group, the expression of TLR4- and NF-κB-positive cells in the nasal mucosa of each dosage from the administration groups decreased, and the decrease in the AR + gel-NPs-miR146a group was the most significant.
4. Discussion
The particularity of the intranasal environment determines that intranasal local administration requires a special delivery system. The clearance rate by nasal cilia shortens the retention time of drugs in the nasal cavity and drug absorption is limited. Moreover, naked nucleic acids are blocked from penetrating through the mucosa due to their large negatively charged structure. Therefore, a delivery vehicle is needed to improve the delivery of nucleic acids to antigen-presenting cells [
32
]. Nanoparticles are currently widely used in drug and gene delivery platforms. Moreover, nanoparticle delivery platforms are increasingly combined with other biological materials to form a hybrid system with novel application prospects [
33
]. Hydrogels can improve the adhesion of preparations of intranasal drug delivery and have attracted much attention. However, when naked RNA is directly physically dispersed into the gel, most naked RNAs have a burst effect and are quickly released into the surroundings [
34
]. The stability of miRNA in medium cannot be guaranteed as it is easily degraded by various enzymes in the body. In order to slow down this rapid release and stabilize RNA, after using nanoparticles to wrap the RNA, the nanoparticles can be physically dispersed into a hydrogel to limit their rapid diffusion, thereby delaying the release rate and further improving the stability and effectiveness of the miRNA during delivery [
35
].
In this study, chitosan was selected as the hydrogel matrix. Chitosan, the product of chitin after removal of the acetyl group, is the main component of the shells, fungi and algae cell membranes of marine arthropods, such as shrimps and crabs, and the shells and bones of mollusks [ 36 ]. Chitosan is well known for its outstanding biodegradability, biocompatibility, nontoxicity and physiological functions, such as immune enhancement. Thermosensitive in situ gels have been used to deliver drugs locally into the nose [ 21 ]. The degree and speed of the phase change of the in situ gel for nasal administration should not be too slow; otherwise, the semisolid state of the preparation will be too long, and the drug or nanoparticles will rapidly diffuse from the gel and cause a sudden release of the drug. In addition, the nasal gel requires the appropriate strength and mucosal adhesion to allow it to continuously deliver the drug at the administration site, improve the efficiency of nasal absorption and prevent irreversible functional damage to the nasal cilia and mucosa [ 37 ]. In order to ensure the adaptability of nasal preparations for nasal administration, the mucosal adhesion degrees of the two prepared gels (chitosan hydrogel and NPs/chitosan hydrogel) were measured, and these preparations were within the desired range. The gel causes little irritation to the nasal cavity and has suitable nasal mucosal adhesion, ensuring that it can deliver nucleic acids stably and continuously. Under physiological conditions, the mucosal adsorption of chitosan polymers has been proven. Because the positively charged amino groups on the chitosan polymer and the anions of the mucus layer (such as sialic acid) produce strong electrostatic interactions, the residence time of the drug in the nasal cavity is prolonged [ 38 ]. The results also showed that, although the release time of miR-146 from the gel was prolonged, the use of pure gel to deliver miR-146a produced a retention efficiency in the nasal mucosa that was not ideal. The gel/NPs/miR146a group was more stable than the gel/miR146a and NPs/miR146a groups in vitro, had a higher retention rate in the nasal mucosa and a reduced amount of permeable miRNA. It may be that the NPs/gel retain the nanoparticles in the three-dimensional polymer matrix so that they can be better delivered to the inflamed area and prolong the contact time with the nasal mucosa, leading to a localized effect on the mucosa. The possibility of nanoparticles carrying miR-146a absorbed by a means other than nasal local absorption should be minimal, while exerting a maximum local therapeutic effect in the nasal mucosa. The in vivo results also showed that the AR + gel/NPs/miR146a group had higher expression levels than the AR + gel/miR146a and AR + NPs/miR146a groups and had better pharmacodynamic effects ( Figure 8 ). The nanoparticles protected the nucleic acids to better treat rhinitis.
For the treatment of nasal diseases, it is more desirable for the drug to be absorbed and act on nasal cells while reducing the absorption of the drug into the brain or the whole body. Reducing drug N2B (nasal-to-brain) behavior can be achieved by inducing or increasing efflux transporters, increasing the size of the nanoparticles, adjusting the site of drug deposition in the nasal cavity and reducing nerve cell endocytosis in nasal epithelial cells [ 39 ]. In order to achieve better intranasal local delivery, it is necessary to design a reasonable delivery method combined with the treatment purpose. Overall, increasing the size of the nanoparticles is a relatively simple and easy method. In most studies that use PEG-PLA or PEG-PLGA nanoparticles to deliver drugs to the brain, the nanoparticles are often modified with lectins or penetrating peptides to promote absorption. In addition, small particle size (<100~200 nm) is a common feature [ 40 , 41 ]. There are also many studies using chitosan nanoparticles to promote delivery from the nose to the brain, which is associated with the properties of chitosan that can temporarily open the tight junctions of the mucosal epithelium, thereby increasing the penetration of extremely polar compounds (such as peptides, proteins or nucleic acids) [ 41 ]. Therefore, we have designed a novel strategy to deliver miRNA by the customized chitosan hydrogel doped with PEG-PLA to better achieve the local treatment and reduce the side effects through other pathways. We chose PEG-PLA nanoparticles with a larger particle size, which can aid in passing through the mucus layer and achieve absorption by the nasal mucosal cells. After administering PEG-modified nanoparticles to deliver nucleic acid for 48 h, both the PEG-PLA NPs and the gel/NPs/miR146a group achieved high Cy3-miRNA-146 retention in the nasal mucosa ( Figure 3 ), but the mucosal permeability of the PEG-PLA NPs group was also high, indicating that there was a risk of transfer to other absorption sites. However, the nanoparticles were uniformly dispersed in the in situ hydrogel to achieve the local, stable and sustained release of miRNA into the nose. The perfect formulation for local administration targeting the nasal mucosa still needs further enhancement. In addition, the reason why miR-146a was selected in this study to be the miRNA that regulates rhinitis symptoms is that miR-146a has no side effects (even in the brain). Unlike miR-155 or miR-466, although miR-146a has the positive effect of interfering with the regulation of rhinitis, it also has an effect on brain nerve cells. Therefore, the treatment of rhinitis requires both binary preparations and selection of appropriate miRNAs.
This study has certain limitations. First, the rat rhinitis model cannot perfectly simulate the symptoms of rhinitis, and the irritation from rhinitis in each rat is not uniform, with individual differences. Additionally, the severity of rhinitis is random. Therefore, the evaluation score and tissue sampling are also random, which interferes with the treatment effects shown in the study. At present, rhinitis is still a niche disease that does not cause substantial harm to the population and has not attracted attention. The application of nanoparticles and water gel in studies of treatments of the disease is low, and although we tried our best, neither good cell simulation nor good simulation of the mucosal system was achieved. It is expected that in future studies, the in vitro cell model and more mature in vitro nasal mucosa model can be used to establish a more perfect in vitro screening method to optimize the preparation parameters.
Author Contributions
Conceptualization, Y.S. and B.H.; methodology, Y.S., S.L. and B.S.; software, R.H.; writing—original draft preparation, Y.S. and B.S.; writing—review and editing, X.G.; funding acquisition, B.H. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the Jilin Province Development and Reform Commission, grant number 2019C050-3.
Conflicts of Interest
The authors declare no conflict of interest.
References
Ren, M.; Tang, Q.; Chen, F.; Xing, X.; Huang, Y.; Tan, X. Mahuang Fuzi Xixin Decoction Attenuates Th1 and Th2 Responses in the Treatment of Ovalbumin-Induced Allergic Inflammation in a Rat Model of Allergic Rhinitis. J. Immunol. Res. 2017 , 2017 , 8254324. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Wheatley, L.M.; Togias, A. Clinical practice. Allergic rhinitis. N. Engl. J. Med. 2015 , 372 , 456–463. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Mims, J.W. Epidemiology of allergic rhinitis. Int. Forum Allergy Rhinol. 2014 , 4 (Suppl. S2), S18–S20. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hoyte, F.C.L.; Nelson, H.S. Recent advances in allergic rhinitis. F1000Research 2018 , 7 . [ Google Scholar ] [ CrossRef ]
Lu, T.X.; Rothenberg, M.E. Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J. Allergy Clin. Immunol. 2013 , 132 , 3–13. [ Google Scholar ] [ CrossRef ][ Green Version ]
Suojalehto, H.; Lindström, I.; Majuri, M.L.; Mitts, C.; Karjalainen, J.; Wolff, H.; Alenius, H. Altered microRNA expression of nasal mucosa in long-term asthma and allergic rhinitis. Int. Arch. Allergy Immunol. 2014 , 163 , 168–178. [ Google Scholar ] [ CrossRef ]
Zhang, X.H.; Zhang, Y.N.; Liu, Z. MicroRNA in chronic rhinosinusitis and allergic rhinitis. Curr. Allergy Asthma Rep. 2014 , 14 , 415. [ Google Scholar ] [ CrossRef ]
Lu, L.F.; Boldin, M.P.; Chaudhry, A.; Lin, L.L.; Taganov, K.D.; Hanada, T.; Yoshimura, A.; Baltimore, D.; Rudensky, A.Y. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 2010 , 142 , 914–929. [ Google Scholar ] [ CrossRef ][ Green Version ]
Rebane, A.; Runnel, T.; Aab, A.; Maslovskaja, J.; Rückert, B.; Zimmermann, M.; Plaas, M.; Kärner, J.; Treis, A.; Pihlap, M.; et al. MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. J. Allergy Clin. Immunol. 2014 , 134 , 836–847.e811. [ Google Scholar ] [ CrossRef ]
Wang, J.; Cui, Z.; Liu, L.; Zhang, S.; Zhang, Y.; Zhang, Y.; Su, H.; Zhao, Y. MiR-146a mimic attenuates murine allergic rhinitis by downregulating TLR4/TRAF6/NF-κB pathway. Immunotherapy 2019 , 11 , 1095–1105. [ Google Scholar ] [ CrossRef ]
Liu, H.J.; Zhang, A.F.; Zhao, N.; Li, X.Z. Role of miR-146a in Enforcing Effect of Specific Immunotherapy on Allergic Rhinitis. Immunol. Investig. 2016 , 45 , 1–10. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Merkus, F.W.; Verhoef, J.C.; Schipper, N.G.; Marttin, E. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv. Drug Deliv. Rev. 1998 , 29 , 13–38. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Varshosaz, J.; Sadrai, H.; Heidari, A. Nasal delivery of insulin using bioadhesive chitosan gels. Drug Deliv. 2006 , 13 , 31–38. [ Google Scholar ] [ CrossRef ]
Gholizadeh, H.; Messerotti, E.; Pozzoli, M.; Cheng, S.; Traini, D.; Young, P.; Kourmatzis, A.; Caramella, C.; Ong, H.X. Application of a Thermosensitive In Situ Gel of Chitosan-Based Nasal Spray Loaded with Tranexamic Acid for Localised Treatment of Nasal Wounds. AAPS PharmSciTech 2019 , 20 , 299. [ Google Scholar ] [ CrossRef ]
Oliveira, P.; Fortuna, A.; Alves, G.; Falcao, A. Drug-metabolizing Enzymes and Efflux Transporters in Nasal Epithelium: Influence on the Bioavailability of Intranasally Administered Drugs. Curr. Drug Metab. 2016 , 17 , 628–647. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Fan, Y.; Chen, M.; Zhang, J.; Maincent, P.; Xia, X.; Wu, W. Updated Progress of Nanocarrier-Based Intranasal Drug Delivery Systems for Treatment of Brain Diseases. Crit. Rev. Ther. Drug Carr. Syst. 2018 , 35 , 433–467. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wang, Y.; Zhang, S.; Benoit, D.S.W. Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery. J. Control. Release 2018 , 287 , 58–66. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Li, B.; Zhang, X.; Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscipl. Rev. Nanomed. Nanobiotechnol. 2019 , 11 , e1530. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wong, K.E.; Ngai, S.C.; Chan, K.G.; Lee, L.H.; Goh, B.H.; Chuah, L.H. Curcumin Nanoformulations for Colorectal Cancer: A Review. Front. Pharmacol. 2019 , 10 , 152. [ Google Scholar ] [ CrossRef ]
Zhao, L.Y.; Zou, Q.L.; Yan, X.H. Self-Assembling Peptide-Based Nanoarchitectonics. Bull. Chem. Soc. Jpn. 2019 , 92 , 70–79. [ Google Scholar ] [ CrossRef ]
Gänger, S.; Schindowski, K. Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa. Pharmaceutics 2018 , 10 , 116. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Nazar, H.; Fatouros, D.G.; van der Merwe, S.M.; Bouropoulos, N.; Avgouropoulos, G.; Tsibouklis, J.; Roldo, M. Thermosensitive hydrogels for nasal drug delivery: The formulation and characterisation of systems based on N-trimethyl chitosan chloride. Eur. J. Pharm. Biopharm. 2011 , 77 , 225–232. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sallam, M.A.; Helal, H.M.; Mortada, S.M. Rationally designed nanocarriers for intranasaltherapy of allergic rhinitis: Influence of carrier type on in vivo nasal deposition. Int. J. Nanomed. 2016 , 11 , 2345–2357. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Sun, B.; Liu, S.; Hao, R.; Dong, X.; Fu, L.; Han, B. RGD-PEG-PLA Delivers MiR-133 to Infarct Lesions of Acute Myocardial Infarction Model Rats for Cardiac Protection. Pharmaceutics 2020 , 12 , 575. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Su, Y.; Sun, B.; Gao, X.; Dong, X.; Fu, L.; Zhang, Y.; Li, Z.; Wang, Y.; Jiang, H.; Han, B. Intranasal Delivery of Targeted Nanoparticles Loaded With miR-132 to Brain for the Treatment of Neurodegenerative Diseases. Front. Pharm. 2020 , 11 , 1165. [ Google Scholar ] [ CrossRef ]
Tabatabaei, S.N.; Derbali, R.M.; Yang, C.; Superstein, R.; Hamel, P.; Chain, J.L.; Hardy, P. Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblastoma. J. Control. Release 2019 , 298 , 177–185. [ Google Scholar ] [ CrossRef ]
Ma, Z.; Yang, C.; Song, W.; Wang, Q.; Kjems, J.; Gao, S. Chitosan hydrogel as siRNA vector for prolonged gene silencing. J. Nanobiotechnol. 2014 , 12 , 23. [ Google Scholar ] [ CrossRef ][ Green Version ]
Yuan, Y.; Cui, Y.; Zhang, L.; Zhu, H.P.; Guo, Y.S.; Zhong, B.; Hu, X.; Zhang, L.; Wang, X.H.; Chen, L. Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide. Int. J. Pharm. 2012 , 430 , 114–119. [ Google Scholar ] [ CrossRef ]
Kumar, M.; Upadhayay, P.; Shankar, R.; Joshi, M.; Bhatt, S.; Malik, A. Chlorpheniramine maleate containing chitosan-based nanoparticle-loaded thermosensitive in situ gel for management in allergic rhinitis. Drug Deliv. Transl. Res. 2019 , 9 , 1017–1026. [ Google Scholar ] [ CrossRef ]
Khan, S.; Patil, K.; Bobade, N.; Yeole, P.; Gaikwad, R. Formulation of intranasal mucoadhesive temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency in rats. J. Drug Targ. 2010 , 18 , 223–234. [ Google Scholar ] [ CrossRef ]
Kilic, K.; Sakat, M.S.; Yildirim, S.; Kandemir, F.M.; Gozeler, M.S.; Dortbudak, M.B.; Kucukler, S. The amendatory effect of hesperidin and thymol in allergic rhinitis: An ovalbumin-induced rat model. Eur. Arch. Oto-Rhino-Laryngol. 2019 , 276 , 407–415. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mao, H.Q.; Roy, K.; Troung-Le, V.L.; Janes, K.A.; Lin, K.Y.; Wang, Y.; August, J.T.; Leong, K.W. Chitosan-DNA nanoparticles as gene carriers: Synthesis, characterization and transfection efficiency. J. Control. Release 2001 , 70 , 399–421. [ Google Scholar ] [ CrossRef ]
Roux, R.; Ladavière, C.; Montembault, A.; Delair, T. Particle assemblies: Toward new tools for regenerative medicine. Mater. Sci. Eng. C 2013 , 33 , 997–1007. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Dang, T.T.; Thai, A.V.; Cohen, J.; Slosberg, J.E.; Siniakowicz, K.; Doloff, J.C.; Ma, M.; Hollister-Lock, J.; Tang, K.M.; Gu, Z.; et al. Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug. Biomaterials 2013 , 34 , 5792–5801. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Gao, W.; Zhang, Y.; Zhang, Q.; Zhang, L. Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery. Ann. Biomed. Eng. 2016 , 44 , 2049–2061. [ Google Scholar ] [ CrossRef ][ Green Version ]
Jabbal-Gill, I.; Watts, P.; Smith, A. Chitosan-based delivery systems for mucosal vaccines. Exp. Opin. Drug Deliv. 2012 , 9 , 1051–1067. [ Google Scholar ] [ CrossRef ]
Wang, X.; Liu, G.; Ma, J.; Guo, S.; Gao, L.; Jia, Y.; Li, X.; Zhang, Q. In situ gel-forming system: An attractive alternative for nasal drug delivery. Crit. Rev. Ther. Drug Carr. Syst. 2013 , 30 , 411–434. [ Google Scholar ] [ CrossRef ]
Abruzzo, A.; Cerchiara, T.; Bigucci, F.; Zuccheri, G.; Cavallari, C.; Saladini, B.; Luppi, B. Cromolyn-crosslinked chitosan nanoparticles for the treatment of allergic rhinitis. Eur. J. Pharm. Sci. 2019 , 131 , 136–145. [ Google Scholar ] [ CrossRef ]
Martins, P.P.; Smyth, H.D.C.; Cui, Z. Strategies to facilitate or block nose-to-brain drug delivery. Int. J. Pharm. 2019 , 570 , 118635. [ Google Scholar ] [ CrossRef ]
Wang, Y.Y.; Lai, S.K.; Suk, J.S.; Pace, A.; Cone, R.; Hanes, J. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew. Chem. 2008 , 47 , 9726–9729. [ Google Scholar ] [ CrossRef ][ Green Version ]
El-Zaafarany, G.M.; Soliman, M.E.; Mansour, S.; Cespi, M.; Palmieri, G.F.; Illum, L.; Casettari, L.; Awad, G.A.S. A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route. Pharmaceutics 2018 , 10 , 3390. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Scheme 1. The miRNA-NPs/CS temperature-sensitive hydrogel steadily delivers miRNA-146 into the nasal mucosa.
Scheme 1. The miRNA-NPs/CS temperature-sensitive hydrogel steadily delivers miRNA-146 into the nasal mucosa.
Figure 1. ( A ) Characterization by transmission electron microscopy. ( B ) miR-146a cumulative release curves from the nanoparticles. The fluorescence intensities of each sample collected at each time point were measured, and the fluorescence from the blank control was subtracted. The cumulative release curve was calculated based on the obtained concentration. ( C ) The formulation at room temperature (a, gel/NPs/miR-146a) and at 34 °C (b, gel/miR-146a; c, gel/NPs/miR-146a). The data are expressed as the mean ± SD, n = 4.
Figure 1. ( A ) Characterization by transmission electron microscopy. ( B ) miR-146a cumulative release curves from the nanoparticles. The fluorescence intensities of each sample collected at each time point were measured, and the fluorescence from the blank control was subtracted. The cumulative release curve was calculated based on the obtained concentration. ( C ) The formulation at room temperature (a, gel/NPs/miR-146a) and at 34 °C (b, gel/miR-146a; c, gel/NPs/miR-146a). The data are expressed as the mean ± SD, n = 4.
Figure 2. Gel properties. ( A ) Gelation gel strength, ( B ) mucosal adhesion strength and ( C ) mucosal adhesion duration of various thermosensitive mucoadhesive gel preparations (for gel composition, please refer to Table 2 ). The data represent the mean ± SD ( n = 4).
Figure 2. Gel properties. ( A ) Gelation gel strength, ( B ) mucosal adhesion strength and ( C ) mucosal adhesion duration of various thermosensitive mucoadhesive gel preparations (for gel composition, please refer to Table 2 ). The data represent the mean ± SD ( n = 4).
Figure 3. ( A ) Cumulative miR-146a curve of permeation in the nasal mucosa from the NPs/miR-146a, gel/miR-146a, and binary gel/NPs/miR-146a formulations. ( B ) Amount of miR-146a retained in the nasal mucosa after 48 h of application of the different formulations.
Figure 3. ( A ) Cumulative miR-146a curve of permeation in the nasal mucosa from the NPs/miR-146a, gel/miR-146a, and binary gel/NPs/miR-146a formulations. ( B ) Amount of miR-146a retained in the nasal mucosa after 48 h of application of the different formulations.
Figure 4. Nasal symptom score results. Each value represents the mean ± SD of the 6 rats in each group. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the allergic rhinitis (AR) group.
Figure 4. Nasal symptom score results. Each value represents the mean ± SD of the 6 rats in each group. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the allergic rhinitis (AR) group.
Figure 5. The effects of miR-146a delivered by binary formulations on cytokines in AR rat serum. The contents of ( A ) IL-4, ( B ) IL-13, ( C ) IFN-γ, ( D ) TNF-α, ( E ) IgE and ( F ) histamine in rat serum were determined by ELISA. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; * p < 0.05, ** p < 0.01 compared with the AR group.
Figure 5. The effects of miR-146a delivered by binary formulations on cytokines in AR rat serum. The contents of ( A ) IL-4, ( B ) IL-13, ( C ) IFN-γ, ( D ) TNF-α, ( E ) IgE and ( F ) histamine in rat serum were determined by ELISA. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; * p < 0.05, ** p < 0.01 compared with the AR group.
Figure 6. ( A ) Apoptosis of nasal epithelial cells determined by TUNEL staining (400×). ( B ) Quantitative analysis of the apoptosis rate of nasal epithelial cells. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 6. ( A ) Apoptosis of nasal epithelial cells determined by TUNEL staining (400×). ( B ) Quantitative analysis of the apoptosis rate of nasal epithelial cells. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 7. Expression of miR-146a determined by RT-qPCR. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 7. Expression of miR-146a determined by RT-qPCR. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 8. The protein bands of TLR4 ( A , B ) and NF-KB ( C , D ) normalized to GAPDH in nasal mucosa determined by Western blot analysis. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 8. The protein bands of TLR4 ( A , B ) and NF-KB ( C , D ) normalized to GAPDH in nasal mucosa determined by Western blot analysis. Data represent the mean ± SD of three independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Figure 9. Histopathological changes in the nasal mucosa of rats were investigated by hematoxylin-eosin (HE) staining (400×).
Figure 9. Histopathological changes in the nasal mucosa of rats were investigated by hematoxylin-eosin (HE) staining (400×).
Figure 10. ( A , B ) Positive expression of the TLR4 protein in nasal mucosa tissues identified by immunohistochemistry (400×). ( C , D ) Positive expression of the NF-κB protein identified by immunohistochemistry in the nasal mucosa (400×). Data represent the mean ± SD of four independent experiments. ## p < 0.01 compared with the control group; ** p < 0.01 compared with the AR group.
Table 1. Physicochemical characteristics of the nanoparticles.
Table 1. Physicochemical characteristics of the nanoparticles.
Formulation Particle Size (nm) Zeta-Potential (mV) PDI Loading Efficiency (%) NPs-miR146a 551.5 ± 53.2 −22.6 ± 1.3 0.217 82.8 ± 9.9
Table 2. Composition and gelation time at 34 °C of formulations based on mixtures of chitosan with β-glycerophosphate (β-GP).
Table 2. Composition and gelation time at 34 °C of formulations based on mixtures of chitosan with β-glycerophosphate (β-GP).
Formulation Code CS ( w / v ) (%) GP ( w / v ) (%) Gelation Time (s) F1 1.5 12 - F2 1.5 16 - F3 3 12 330.8 ± 18.4 F4 3 16 290.7 ± 16.2 F5 4.5 12 228.5 ± 13.4 F6 4.5 16 161.7 ± 11.9
Table 3. Evaluation parameters for miR-146a in chitosan gel.
Table 3. Evaluation parameters for miR-146a in chitosan gel.
Formulation CS ( w / v ) (%) GP ( w / v ) (%) Gelation Time (s) Gelation gel Strength (s) Adhesion Strength (g/cm 2 ) Adhesion Duration (h) gel/miR-146a 4.5 12 198.5 ± 12.4 42.3 ± 3.6 28.6 ± 2.9 4.9 ± 0.7
MDPI and ACS Style
Su, Y.; Sun, B.; Gao, X.; Liu, S.; Hao, R.; Han, B. Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis. Pharmaceutics 2020, 12, 907.
https://doi.org/10.3390/pharmaceutics12100907
AMA Style
Su Y, Sun B, Gao X, Liu S, Hao R, Han B. Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis. Pharmaceutics. 2020; 12(10):907.
https://doi.org/10.3390/pharmaceutics12100907
Chicago/Turabian Style
Su, Yu, Bixi Sun, Xiaoshu Gao, Shuwen Liu, Rubin Hao, and Bing Han. 2020. "Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis" Pharmaceutics12, no. 10: 907.
https://doi.org/10.3390/pharmaceutics12100907
Su Y, Sun B, Gao X, Liu S, Hao R, Han B. Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis. Pharmaceutics. 2020; 12(10):907.
https://doi.org/10.3390/pharmaceutics12100907
Chicago/Turabian Style
Su, Yu, Bixi Sun, Xiaoshu Gao, Shuwen Liu, Rubin Hao, and Bing Han. 2020. "Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis" Pharmaceutics12, no. 10: 907.
https://doi.org/10.3390/pharmaceutics12100907
| https://www.mdpi.com/1999-4923/12/10/907/html |
Biosensors | Free Full-Text | Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives
Minimally invasive continuous glucose monitoring (CGM) sensors are wearable medical devices that provide real-time measurement of subcutaneous glucose concentration. This can be of great help in the daily management of diabetes. Most of the commercially available CGM devices have a wire-based sensor, usually placed in the subcutaneous tissue, which measures a “raw” current signal via a glucose-oxidase electrochemical reaction. This electrical signal needs to be translated in real-time to glucose concentration through a calibration process. For such a scope, the first commercialized CGM sensors implemented simple linear regression techniques to fit reference glucose concentration measurements periodically collected by fingerprick. On the one hand, these simple linear techniques required several calibrations per day, with the consequent patient’s discomfort. On the other, only a limited accuracy was achieved. This stimulated researchers to propose, over the last decade, more sophisticated algorithms to calibrate CGM sensors, resorting to suitable signal processing, modelling, and machine-learning techniques. This review paper will first contextualize and describe the calibration problem and its implementation in the first generation of CGM sensors, and then present the most recently-proposed calibration algorithms, with a perspective on how these new techniques can influence future CGM products in terms of accuracy improvement and calibration reduction.
Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives
by Giada Acciaroli , Martina Vettoretti , Andrea Facchinetti and Giovanni Sparacino *
Department of Information Engineering, University of Padova, 35131 Padova, Italy
Author to whom correspondence should be addressed.
Biosensors 2018 , 8 (1), 24; https://doi.org/10.3390/bios8010024
Received: 20 January 2018 / Revised: 8 March 2018 / Accepted: 9 March 2018 / Published: 13 March 2018
Abstract
:
Minimally invasive continuous glucose monitoring (CGM) sensors are wearable medical devices that provide real-time measurement of subcutaneous glucose concentration. This can be of great help in the daily management of diabetes. Most of the commercially available CGM devices have a wire-based sensor, usually placed in the subcutaneous tissue, which measures a “raw” current signal via a glucose-oxidase electrochemical reaction. This electrical signal needs to be translated in real-time to glucose concentration through a calibration process. For such a scope, the first commercialized CGM sensors implemented simple linear regression techniques to fit reference glucose concentration measurements periodically collected by fingerprick. On the one hand, these simple linear techniques required several calibrations per day, with the consequent patient’s discomfort. On the other, only a limited accuracy was achieved. This stimulated researchers to propose, over the last decade, more sophisticated algorithms to calibrate CGM sensors, resorting to suitable signal processing, modelling, and machine-learning techniques. This review paper will first contextualize and describe the calibration problem and its implementation in the first generation of CGM sensors, and then present the most recently-proposed calibration algorithms, with a perspective on how these new techniques can influence future CGM products in terms of accuracy improvement and calibration reduction.
Keywords:
diabetes
;
glucose sensors
;
continuous glucose monitoring
;
calibration
1. Introduction
Diabetes is a chronic disorder that occurs either when the pancreas is no longer able to produce insulin (type 1 diabetes, T1D), or if body tissues and organs cannot effectively utilize circulating insulin (type 2 diabetes, T2D). In people with diabetes, the deficiencies in glucose control lead to blood glucose (BG) values exceeding the safe range of 70–180 mg/dL. While hyperglycemia (i.e., BG > 180 mg/dL) can result in long-term complications, e.g., retinopathy, nephropathy, cardiovascular disease, hypoglycemia (i.e., BG < 70 mg/dL) can produce short-term adverse conditions that can cause coma, or even death [ 1 , 2 , 3 , 4 ].
Nowadays, diabetes afflicts more than 350 million people worldwide. T2D accounts for about 90% of all cases [ 5 ] and its onset is largely correlated with excessive body weight, physical inactivity, and unhealthy diet. The World Health Organization (WHO) predicts T2D prevalence to significantly grow in the coming years, due to aging populations and sedentary lifestyles [ 6 , 7 ]. Consequently, the total number of cases of diabetes is expected to exceed 500 million by 2030, becoming one of the most challenging socio-health emergencies of the third millennium. Although it is not possible with current knowledge to definitely cure diabetes, a constant and appropriate management of the disease can control and prevent many complications [ 6 , 8 , 9 ]. While T2D management mainly consists of healthy diet, physical exercise, and drug administration, T1D therapy requires daily insulin administration. The most challenging issue is related to insulin administration, being the correct amount of injected insulin determined on the basis of BG concentration levels, which need to be monitored by suitable technologies.
At-home BG monitoring became available only in the 1970s, when the first self-monitoring BG (SMBG) meters were commercialized [ 10 ]. The early SMBG portable devices were based on optical detection of a color change on glucose oxidase-based strips, while the most recent systems rely on electrochemical-based sensing techniques [ 11 ] becoming, by the mid-1980s, the landmark in diabetes management [ 10 ]. Since the advent of SMBG devices for home BG testing, the standard therapy for diabetes management consisted of 3–4 SMBG measurements per day, individually acquired by fingerprick tests [ 6 ]. Although the introduction of self-BG monitoring in everyday life resulted in a general improvement of metabolic control [ 12 , 13 , 14 ], sparse BG measures cannot provide a complete description of glucose dynamics during the day. For instance, hypoglycemic or hyperglycemic events occurring between two BG acquisitions cannot be detected. An example of SMBG time series (data derived from a previously published study [ 15 ]) is depicted in Figure 1 (diamonds), where it is apparent that some critical episodes, e.g., a hypoglycemia event and several hyperglycemic conditions, cannot be revealed due to insufficient sampling frequency. On the one hand, more frequent SMBG measurements would be required to optimize glucose control but, on the other hand, this would increase the patient’s discomfort and increase the number of actions needed daily to manage the disease.
In recent years, technological innovations have been introduced for the treatment of diabetes. In particular, the development of continuous glucose monitoring (CGM) sensors [ 16 , 17 ] have revolutionized diabetes management. CGM systems are wearable devices able to measure subcutaneous glucose concentration almost continuously, e.g., every 1–5 min [ 18 ], for several consecutive days, greatly increasing the information on glucose dynamics compared to standard SMBG-based monitoring, with consequent improvement of glycemic control, quality of life, and reduction of diabetes-related complications [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. See, for instance, in Figure 1 (continuous line) the hypo- and hyperglycemic episodes detected by the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) CGM sensor (data previously published in [ 15 ]).
A variety of sensing techniques (e.g., electrochemical, optical, piezoelectric) have been proposed for CGM [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], but most of the devices currently available on the market exploit the glucose-oxidase electrochemical principle [ 18 , 36 ]. In this family of devices, a minimally-invasive wire-based sensor, placed subcutaneously in the abdomen or in the arm, measures a current signal generated by the glucose-oxidase reaction, transmitting information on glucose concentration in the interstitial fluid. The raw current sensor signal (typically measured in fractions of ampere) is converted to a glucose concentration estimate (expressed in mg/dL) by a calibration process. Usually, the calibration algorithm relies on a calibration function, whose parameters are periodically updated using a few SMBG samples suitably collected by the patient as reference measurements [ 37 , 38 , 39 , 40 , 41 , 42 ].
Most commercialized minimally-invasive CGM systems perform the first calibration a few hours (e.g., one or two) after sensor insertion, when the sensor warm-up period has completed, and the subsequent ones every 12–24 h, usually employing a simple first-order time-independent linear function as the calibration law [ 37 , 38 , 39 , 40 ]. Given the complex nonlinear and time-dependent relationship between measured current and glucose concentration, the use of a simple linear function, as an approximation of the more complex behavior, is acceptable within time-intervals of limited duration. Thus, frequent recalibrations are required to maintain sensor accuracy, as recommended by the manufacturers’ instructions [ 41 , 42 , 43 ]. Patients’ discomfort associated to the frequent calibration of the device on the basis of SMBG fingerprick measurements, and the need to improve CGM sensors’ accuracy and reliability called for the development of more sophisticated calibration techniques. In the last decade, several signal processing, modelling, and machine-learning methods have been proposed by the academic community to address the calibration issue, which led to improvements in CGM sensor accuracy and user acceptability. The aim of the present paper is to review the calibration algorithms proposed for minimally-invasive CGM sensors with a perspective on how these new techniques can influence future CGM products.
2.1. Problem Statement
CGM sensors measure a signal that reflects glucose concentration only indirectly. Indeed, the needle placed in the subcutaneous tissue measures a current signal derived from the glucose-oxidase electrochemical reaction [ 11 , 36 ]. The calibration process consists in the estimation of a mathematical law that converts the current signal (given in fractions of ampere) into meaningful glucose concentration values (in mg/dL).
Letting
x
(
t
)
be the glucose concentration profile,
y
(
t
)
the electrical current profile, and
f
(
·
)
the function of parameters
P
=
[
p
1
,
p
2
,
…
,
p
n
]
that relates
x
(
t
)
and
y
(
t
)
, the calibration process can be schematized in two steps. The first consists in the identification of the calibration parameters. In formal terms, the current signal
y
(
t
)
collected by the sensor and corrupted by measurement error
e
(
t
)
, and the BG measurements (samples of
x
(
t
)
) acquired by the patient at correspondent time instants, are described by the model:
y
(
t
)
=
f
(
P
,
x
(
t
)
)
+
e
(
t
)
(1)
from which a numerical value
P
^
of the calibration parameter vector can be provided using, for instance, parametric estimation techniques. This step can be repeated each time a new BG reference is available, with consequent updates of the calibration parameters
P
^
(e.g., every 12–24 h by acquiring SMBG samples). The second step leads to the estimation of the glucose concentration profile. Formally, from the vector of estimated parameters
P
^
and the measured current profile
y
(
t
)
, the calibrated glycemic profile
x
^
(
t
)
is obtained in real-time by inverting the function
f
(
·
)
:
x
^
(
t
)
=
f
−
1
(
P
^
,
y
(
t
)
)
(2)
The choice of the calibration law
f
(
·
)
is critical. It has to be invertible and it has to precisely describe the relation between the electrical current signal and glucose concentration, which can be, in the most general case, non-linear and time-variant (in this case, time
t
would be, explicitly, an input of
f
(·). Moreover, the choice of using either the electrical current or the BG measurements as independent variables in the calibration law may affect the calibration performance [
44
].
The most common and simplest calibration law adopted by manufacturers of CGM systems is a first-order time-independent linear function [
45
,
46
,
47
,
48
], with parameters
P
=
[
s
,
b
]
, where
s
and
b
are referred to as sensor sensitivity and baseline (or offset), respectively. In this case, the model of the measurements reported in Equation (1) in a general form turns into:
y
(
t
)
=
f
(
P
,
x
(
t
)
)
=
s
·
x
(
t
)
+
b
+
e
(
t
)
(3)
The numerical determination of the estimates
s
^
and
b
^
is, thus, required. For such a scope, if for instance two BG references
x
(
t
1
)
and
x
(
t
2
)
are available at times
t
1
and
t
2
, knowing the electrical current values given by the sensor at the same time instants,
y
(
t
1
)
and
y
(
t
2
)
, the so-called two-point calibration can be performed [
49
], which allows the estimation of sensitivity,
s
^
, and baseline,
b
^
, from the two measured pairs as:
{
s
^
=
y
(
t
2
)
−
y
(
t
1
)
x
(
t
2
)
−
x
(
t
1
)
b
^
=
y
(
t
2
)
−
y
(
t
2
)
−
y
(
t
1
)
x
(
t
2
)
−
x
(
t
1
)
·
x
(
t
2
)
In general, when multiple pairs of electrical current and BG samples are available at times
t
i
(
i
=
1
,
2
…
,
N
)
, a linear regression is used to fit the sensitivity and baseline to the data. In particular, including the measurement noise
e
(
t
i
)
, the model of the measurements becomes:
y
(
t
i
)
=
s
·
x
(
t
i
)
+
b
+
e
(
t
i
)
and the numerical determination of model parameters is done by minimizing the residual sum of squares:
[
s
^
,
b
^
]
=
argmin
s
,
b
∑
i
=
1
N
e
(
t
i
)
2
Finally, the calibrated glucose profile
x
^
(
t
)
is obtained from the measured current signal
y
(
t
)
and the estimated calibration parameters
s
^
and
b
^
by inverting the calibration function:
x
^
(
t
)
=
y
(
t
)
−
b
^
s
^
(7)
The quality of the estimate of the calibration parameters is expected to increase with
N
, i.e., the more electrical current-BG pairs that are available, the more accurately the calibration parameters are estimated. On the other hand, increasing
N
is difficult to satisfy, for practical reasons, e.g., for the discomfort related to the acquisition of SMBG samples, and because CGM manufacturers push to minimize the calibration points to facilitate the ease-of-use of their devices. Moreover, in the presence of measurement uncertainty and/or when only a few data points are available, the standard two-point calibration of Equation (4) could be simplified to a one-point calibration by considering a zero baseline. This simplification may improve the calibration performance by reducing the effect of the noise [
49
,
50
].
Although the use of such linear calibration techniques is appealing for its simplicity and ease of implementation, it introduces several critical aspects that, together with uncertainty on the measured sensor output and BG references, are often a cause of CGM sensor inaccuracy. Two examples of sensor inaccuracy are illustrated in
Figure 2
a,b, where two representative CGM profiles (continuous lines) acquired by the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) CGM sensor (data previously published in [
15
]) are compared with reference BG concentrations measured in parallel by gold-standard laboratory instruments (points). Two major causes of these deviations are discussed in the following section.
2.2. Critical Aspects Affecting Calibration
A first aspect explaining the discrepancies evidenced in
Figure 2
is the distortion introduced by the plasma to interstitium (BG-to-IG) kinetics. Indeed, the needle sensor is inserted in the subcutis and measures a current that is proportional to the interstitial glucose (IG). This is due to the fact that, in order to reduce invasiveness of CGM devices, sensors are placed in the subcutis and measure the glucose-related current signal from the interstitial fluid rather than directly from the blood. Thus, the two measurements available during the calibration process, i.e., the electrical current signal measured by the sensor and the BG references acquired through fingerprick devices, belong to different physiological sites. A widely-established description of the relationship between BG and IG is based on a two-compartment model (
Figure 3
a) [
51
,
52
]. According to this representation, and noting that, in steady-state, BG and IG have equal values, the IG profile can be described by the convolution of the BG profile with a single exponential
1
τ
e
−
t
τ
, a decay function having unitary area under the curve and time constant
τ
The time constant
τ
is related to the parameters of the two-compartment model by the equation
τ
=
1
k
02
+
k
12
[
51
,
52
]. Given the low-pass filtering nature of the system described in
Figure 3
a, the IG signal is a smoothed and delayed version of the BG concentration [
53
]. An example is reported in
Figure 3
b, where the IG profile (obtained by convoluting a given, simulated, BG profile with a single exponential with
τ
= 11 min) clearly shows both amplitude attenuation and phase delay compared to the BG profile. Notably,
τ
shows inter- and intra-subject variability and its numerical identification requires suitable collection of both BG and IG samples. Published values of the time constant
τ
range from 6 to 15 min [
52
]. In practice, the BG-to-IG time constant
τ
is treated as a user parameter, but its role in the calibration process needs to be carefully considered [
54
,
55
].
A second critical aspect behind the differences pointed out in Figure 2 is related to the time variability of sensor sensitivity. The raw electrical current signals acquired by CGM sensors often exhibit a nonphysiological drift, especially in the first day after sensor insertion. An example of nonphysiological drift observed in a raw CGM signal acquired by the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) CGM sensor (data previously published in [ 15 ]) is depicted in Figure 4 , where the continuous line represents the electrical current signal (in units not specified by the manufacturer) and the dashed line shows the drift. This phenomenon is related to a variation of sensor sensitivity after its insertion in the body, when the sensor membrane enters in contact with the biological environment and undergoes the immune system reaction [ 56 , 57 ]. The calibration law has to properly compensate for such time-variability, which is often non-linear.
In the last decade, several techniques have been proposed to deal with these issues affecting CGM sensor calibration. A review and discussion of the most recent algorithms is presented in the following section.
3. State-of-the-Art Calibration Algorithms
One of the major limitations of the calibration linear regression techniques presented in Section 2 is that they all neglect the time lag between the BG and the raw sensor signal, which can lead to a suboptimal estimation of the parameters of the calibration function. Therefore, most of the calibration algorithms developed by the scientific community included more or less sophisticated approaches to overcome this limitation and take BG-to-IG dynamics into account.
The first simple approach is to require calibration of the sensor when glucose is relatively stable. This approach can be applied to any calibration algorithm. The rationale of this heuristic is that, in such a condition, BG and IG concentrations should be at equilibrium and, thus, the estimation of the linear regression parameters should not be influenced by not considering the BG-to-IG dynamics [
58
]. Following this rationale, Aussedat et al. [
59
] developed an automated algorithm that requests sensor calibration only when a window of the stable signal is detected, i.e., when the sensor signal has not changed by more than 1% over a four-minute window, and when the raw current value for the second calibration point differs from the first by ≥2 nA. The study proved that performing calibrations during periods of relative glucose stability minimizes difference between BG references and raw sensor measurements due to the BG-to-IG kinetics.
More sophisticated model-based approaches to account for the BG-to-IG dynamics have been developed relying on Kalman filter theory. In particular, Knobbe et al. [
60
] proposed a five-state extended Kalman filter, which estimates subcutaneous glucose levels, BG levels, time lag between the sensor measured subcutaneous glucose and BG, time-rate-of-change of the BG level, and the subcutaneous glucose sensor scale factor [
61
]. In this study, BG levels are reconstructed in continuous time from CGM measurements, employing a state-space Bayesian framework with a priori knowledge of unknown variables. A direct application of a Kalman filter to improve CGM sensor accuracy was proposed by Kuure-Kinsey and colleagues [
62
], employing a dual-rate Kalman filter and exploiting sparse SMBG measurements to estimate the sensor sensitivity in real-time. Although designed for real-time glucose and its rate of change estimation, the algorithm does not account for BG-to-IG kinetics. A further development, with direct application to the calibration problem and incorporation of the BG-to-IG dynamic model, was given by Facchinetti et al. [
63
]. The authors proposed an extended Kalman filter method that works in cascade to the standard device calibration to enhance sensor accuracy. By taking into account BG-to-IG kinetics, using a model to describe the variability of sensor sensitivity, and exploiting four BG reference samples per day, the method significantly improves CGM accuracy when applied to synthetic data. However, its real-time implementation is not straightforward, requiring the knowledge of the variances of both state and measurement error processes, as well as an initial burn-in interval.
Another approach for real-time glucose estimation based on autoregressive (AR) models was proposed by Leal et al. [
64
]. The study used AR models to estimate BG from raw CGM measurements. Data acquired from 18 T1D patients were used to train a population AR model, which was then incorporated into a calibration algorithm for real-time BG estimation. The raw sensor signal, used as the independent variable, and the BG concentration, considered as a dependent variable, were both normalized based on the maximum range of the available signals. The best overall estimated model, with a third-order Box-Jenkins structure and fixed parameters, enhanced CGM performance, especially in hypoglycemia detection. Significant improvement in hypoglycemia detection was also obtained by the same authors in another study performed on 21 patients with T1D where a new linear regression algorithm with enhanced offset estimation was proposed [
65
].
Barceló-Rico and colleagues proposed an alternative calibration algorithm based on a dynamic global model of the relationship between BG and the interstitial CGM signal [
66
]. The algorithm integrates several local dynamic models, each one representing a different metabolic condition and/or sensor–subject interaction. The local models are then weighted and added to compose the global calibration model. Inputs of the model are the signal measured by the sensor and other signals containing information relevant to glucose dynamics, which are normalized in magnitude using population parameters. The algorithm showed improvements in CGM sensor accuracy, although it was tested on only eight healthy subjects and a more extensive assessment on the diabetic population would be needed to confirm the findings. A further development of the algorithm was proposed in [
67
], where an adaptive scheme is used to estimate patient’s normalization parameters in real-time instead of using simple population parameters. Results on 30 virtual patients showed that the adaptation of normalization parameters further improved the performance of the algorithm, since they were able to compensate for sensor sensitivity variations.
Most of the algorithms proposed for improving CGM performance employ sophisticated models and signal processing features that, although still allowing the implementation on wearable devices/smartphones, increase the computational complexity and processing delay compared to the simple linear regression techniques. With the aim of reducing the delay due to signal processing, Mahmoudi et al. proposed a multistep calibration algorithm based on rate-limiting filtering, selective smoothing, and robust regression [
68
]. The rate-limiting filter limits the rate-of-change if a physiological threshold is exceeded; the selective smoothing is applied if the signal is noisy, i.e., if the number of zero crossings of the signal first-order differences exceeds a predefined threshold; the robust regression then converts the raw measured current to BG levels using reference SMBG measurements (for a maximum of four references per day). The application of the filtering step to only the noisy parts of the signal lowered the delay introduced by the signal processing of the CGM profile.
Another approach that has the low computational complexity as a major strength was proposed by Kirchsteiger and colleagues employing linear matrix inequalities techniques, resulting in convex optimization problems of low complexity [
69
,
70
]. The authors proposed two different parametric descriptions of the relationship between IG and BG and a constructive algorithm to adaptively estimate the unknown parameters. The algorithm explicitly considers the measurement uncertainty of the device used to collect the calibration measurements, which was firstly pointed out by Choleau and colleagues [
71
]. Moreover, the algorithm embeds an automatic feature to detect fingerprick measurements, which are not suitable to be used for calibration.
The uncertainty in the reference SMBG samples used for calibration is a key issue in the development of robust calibration algorithms. The real-time deconvolution-based approach proposed by Guerra et al. [ 72 ] demonstrated its robustness against both temporal misplacement of the SMBG references and uncertainty in the BG-to-IG kinetics model. The authors proposed a real-time signal-enhancement module to be applied to the CGM sensor output to improve the accuracy of the device. The algorithm compensates the distortion due to the BG-to-IG dynamic by means of regularized deconvolution [ 73 ] and relies on a linear regression model that is updated each time a pair of SMBG references is collected. Significant accuracy improvements were observed both on simulated and real datasets. The deconvolution-based approach of [ 72 ] was further developed in [ 74 ], where it was directly applied to the raw measured signal rather than in cascade to the CGM sensor output. The algorithm fits the raw current signal against BG references (collected twice a day) using a time-varying linear calibration function whose parameters are identified in the Bayesian framework using a priori knowledge on their statistical distribution. The BG-to-IG kinetics is compensated, as in [ 72 ], via nonparametric deconvolution. Results showed significant accuracy improvements compared to the manufacturer calibration.
The calibration algorithms discussed so far showed several performance improvements compared to the simple linear regression methods described in
Section 2
. However, none of them explicitly aimed at reducing the frequency of calibrations, i.e., the number of SMBG fingerprick measurements needed as input to the algorithms, which are an obvious reason of discomfort for the patients. At the present time, CGM systems require a calibration about two times per day, as per the manufacturer’s instructions. A first step toward the reduction of calibration frequency was made in [
75
]. The authors applied the same calibration strategy, as in [
74
], but employing day-specific prior calibration parameters that allowed the improvement of sensor performance (mean absolute relative difference, MARD, reduced by 1.2%), especially in the most critical first day of use, while, at the same time, reducing the frequency of calibrations, from twice, to once per day. The study demonstrated that, by formulating the calibration problem in the Bayesian framework, the use of well-tuned priors on calibration parameters can surrogate the information of a second daily SMBG reference while preserving sensor accuracy.
Although showing promising results in terms of accuracy enhancement and calibration frequency reduction, the linear calibration models used in [
74
,
75
] are able to approximate the time-variability of the relationship between the raw current signal and IG only for a time interval of limited duration. Thus, it is not suitable for further reducing the calibrations to less than once per day. To overcome this limitation, Acciaroli et al. [
76
] replaced the time-invariant sensitivity and baseline conventionally used by linear calibration models (see Equation (3)) with more sophisticated time-varying functions, valid for multiple-day periods, with unknown parameters for which an a priori statistical description is available. Calibration parameters are determined online by means of Bayesian estimation and BG-to-IG kinetics are compensated by nonparametric deconvolution. The method showed improved performance compared to manufacturer calibration (MARD reduced by 1.2%) with only two calibrations over the seven days of the sensor’s lifetime instead of twice per day.
Current CGM products are available for continuous use and are replaced after several days. However, none of the methods discussed so far have embedded any features able to capture this essential cyclic nature by exploiting, e.g., the data from prior weeks to better calibrate new CGM data. A first attempt in this direction was made by Lee and colleagues in [
77
], where a run-to-run strategy that personalizes sensor calibration parameters using data from previous weeks’ use was proposed. Before each weekly new sensor insertion, the algorithm minimizes a cost function that penalizes differences between fingerprick reference values and CGM output of previous weeks. Repeated iterations of the run-to-run procedure demonstrated improved performance on synthetic data (summed square error reduced by 20% after two weeks, and up to 50% after six weeks). On the same line, another calibration algorithm, employing a calibration function as in [
74
], was augmented with a weekly updating feature for parameter optimization [
78
]. The algorithm estimates the calibration parameters through the recursive least squares to fit SMBG measurements taken approximately every 12 h. Then, personalized calibration parameters are optimized after the first week of use using past data, employing a forgetting factor to give more weight to the most recent data.
The idea of exploiting past CGM data to optimize calibration has also been exploited for developing offline techniques able to improve the quality of the BG estimations through “retrospective” calibration. For instance, Hovorka et al. [
79
] proposed two algorithms for CGM-based trial assessment. The first is an offline retrospective CGM adjustment, and the second attempts to reduce CGM error by accounting for the possibility that the true BG could be in a different range compared to the CGM output. Del Favero and colleagues [
80
] proposed a “retrofitting” algorithm based on constrained deconvolution to retrospectively increase the accuracy of CGM data acquired on diabetic patients by using some BG reference measurements. The method proved effective when applied to different commercial products [
81
,
82
].
A summary of all revised techniques is reported in
Table 1
, in which, from column one to column seven, we reported the study reference; the calibration technique; whether a model of the BG-IG kinetic is used; whether the algorithm is suitable for real-time use in wearable devices; the number of calibrations required; the data on which the algorithms were validated; and the improvements compared to manufacturer performance (if available). It is worth noting that most of the proposed algorithms, although employing sophisticated signal processing techniques, are suitable for real-time use in the processors of CGM receivers or smartphones, or in dedicated cloud platforms. Moreover, where available, the comparison with the manufacturer calibration algorithm always showed enhanced performance and/or a reduction in the frequency of calibrations, improving sensor ease-of-use and reliability.
4. Current Perspectives
In the past decade, the employment of state-of-the-art signal processing, modelling, and machine learning techniques proved effective in enhancing CGM sensor performance. Moreover, several proposed algorithms gave particular attention to the computational complexity, facilitating their implementation and integration in CGM wearable devices.
The first example of direct implementation of a newly-proposed technique in a commercial CGM product is described in [ 84 ], where Dexcom Inc. (San Diego, CA, USA) and the University of Padova (Padova, Italy) have developed an advanced CGM system, called the G4AP, containing updated denoising and calibration algorithms for improved sensor accuracy and reliability. It is likely that more algorithms will be included in next-generation CGM products, not only to improve the calibration performance, but also to integrate more sophisticated “smart” features, e.g., prediction and alert generation features [ 85 ].
Along with the need to constantly improve sensor performance, the need to reduce the frequency of calibration is among the priorities of CGM sensor manufacturers, as witnessed by the recent commercialization of the FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA), a factory-calibrated flash glucose monitor [
86
]. Next-generation CGM systems are, thus, expected to be less calibration dependent, and the implementation of sophisticated modeling and signal processing techniques would eventually play a role in accomplishing such a requirement. A recent study conducted on a next-generation Dexcom CGM sensor prototype [
83
] showed that the implementation of the Bayesian calibration approach of [
76
] allowed moving toward a calibration-free scenario.
Factory-calibrated sensors appear to be the next future technology for both commercial and practical reasons, i.e., patients are not required to buy and deal with both the CGM and the fingerprick devices. Additionally, CGM technology has been recently approved for nonadjunctive use [
87
], i.e., treatment decisions can be made without fingerpricking. However, SMBG samples are still required by current commercial CGM systems for calibration purposes. Thus, on the one hand, the use of factory-calibrated CGM sensors as nonadjunctive devices would allow to definitively give up fingerpricking. On the other hand, factory-calibrated devices would probably lead to higher sensor bias and this aspect needs to be carefully considered if a factory-calibrated sensor is used as a nonadjunctive device. A possible trade-off between the need to improve the ease-of-use and cost of CGM technology and the need to guarantee safety and reliability would be granted by factory-calibrated systems that could eventually allow the user to perform optional calibrations, from time to time, if necessary for safety reasons.
5. Conclusions
Most of the commercially available CGM sensors need to be calibrated to convert the raw measurements to glucose values. In order to preserve sensor accuracy, manufacturer instructions recommend a calibration at least every 12 h. Simple linear regression techniques have been extensively employed for calibration since the commercialization of the first CGM devices. Although their simplicity and ease-of-implementation in wearable devices represent the fundamental strength of these approaches, sensor inaccuracy problems and the need of frequent recalibrations called for the development of more sophisticated techniques, often coming from the academic community.
In the last decade, several signal processing, modelling, and machine-learning methods have been proposed from the academic community to address the calibration issue, which led to improvements in CGM sensor accuracy and user acceptability. The moderate computational complexity often facilitated the integration of such techniques in the current CGM systems, which are more accurate than the first CGM sensor generation and less calibration-dependent. The proved efficacy of some recently-proposed techniques in improving sensor performance predicts that, in the following years, more sophisticated algorithms will be integrated in next-generation CGM systems.
The increasing availability and lifetime of current- and next-generation CGM products will generate, in the upcoming years, a great amount of data, eventually available for offline processing. It is, thus, easy to expect that some recently-proposed techniques, e.g., for retrospective calibration [ 79 , 80 , 81 , 82 ] and for optimizing calibration parameters based on past data [ 77 , 78 ], would be extremely useful for post-processing CGM outputs in order to facilitate their analysis and improve performance over time by exploiting the cyclic nature of CGM use.
Author Contributions
G.A. wrote the paper. M.V. revised the manuscript. A.F. and G.S. supervised the research activities and revised the manuscript.
Conflicts of Interest
The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
References
World Health Organization (WHO). Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications ; WHO: Geneva, Switzerland, 1999. [ Google Scholar ]
Van Dijk, H.W.; Verbraak, F.D.; Fok, P.H.; Garvin, M.K.; Sonka, M.; Lee, K.; De Vries, J.H.; Michels, R.P.; Van Velthoven, M.E.; Schlingemann, R.O.; et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Investig. Ophthalmol. Vis. Sci. 2010 , 51 , 3660–3665. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Vriesendorp, T.M.; De Vries, J.H.; Van Santen, S.; Moeniralam, H.S.; De Jonge, E.; Roos, Y.B.; Schults, M.J.; Rosendaal, F.R.; Hoekstra, J.B. Evaluation of short-term consequences of hypoglycemia in an intensive care unit. Crit. Care Med. 2006 , 34 , 2714–2718. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lemkes, B.A.; Hermanides, J.; De Vries, J.H.; Holleman, F.; Meijers, J.C.; Hoekstra, J.B. Hyperglycemia: A protrombotic factor? J. Thromb. Haemost. 2010 , 8 , 1663–1669. [ Google Scholar ] [ CrossRef ] [ PubMed ]
You, W.P.; Henneberg, M. Type 1 diabetes prevalence increasing globally and regionally: The role of natural selection and life expectancy at birth. BMJ Open Diabetes Res. Care 2016 , 4 , e000161. [ Google Scholar ] [ CrossRef ] [ PubMed ]
American Diabetes Association. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2018. Diabetes Care 2018 , 41 , S13–S27. [ Google Scholar ]
World Health Organization (WHO). Diabetes Facts Sheet. Available online: http://www.who.int/mediacentre/factsheets/fs312/en/ (accessed on 10 January 2017).
Hayes, C.; Kriska, A. Role of physical activity in diabetes management and prevention. J. Am. Diet. Assoc. 2008 , 108 , S19–S23. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ley, S.H.; Hamdy, O.; Mohan, V.; Hu, F.B. Prevention and management of type 2 diabetes: Dietary components and nutritional strategies. Lancet 2014 , 383 , 1999–2007. [ Google Scholar ] [ CrossRef ]
Clarke, S.F.; Foster, J.R. A history of blood glucose meters and their role in self-monitoring of diabetes mellitus. Br. J. Biomed. Sci. 2012 , 69 , 83–93. [ Google Scholar ] [ PubMed ]
Wang, J. Electrochemical glucose biosensors. Chem. Rev. 2008 , 108 , 814–825. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sonksen, P.H.; Judd, S.L.; Lowy, C. Home monitoring of blood-glucose. Method for improving diabetic control. Lancet 1978 , 1 , 729–732. [ Google Scholar ] [ CrossRef ]
Walford, S.; Gale, E.A.; Allison, S.P.; Tattersall, R.B. Self-monitoring of blood-glucose. Improvement of diabetic control. Lancet 1978 , 1 , 732–735. [ Google Scholar ] [ CrossRef ]
Ikeda, Y.; Tajima, N.; Minami, N.; Ide, Y.; Yokoyama, J.; Abe, M. Pilot study of self-measurement of blood glucose using the Dextrostix-Eyetone system for juvenile-onset diabetes. Diabetologia 1978 , 15 , 91–93. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Christiansen, M.; Bailey, T.; Watkins, E.; Liljenquist, D.; Price, D.; Nakamura, K.; Boock, R.; Peyser, T. A new-generation continuous glucose monitoring system: Improved accuracy and reliability compared with a previous-generation system. Diabetes Technol. Ther. 2013 , 15 , 881–888. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Yoo, E.H.; Lee, S.Y. Glucose biosensors: An overview of use in clinical practice. Sensors 2010 , 10 , 4558–4576. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cappon, G.; Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G. Wearable continuous glucose monitoring sensors: A revolution in diabetes treatment. Electronics 2017 , 6 , 65. [ Google Scholar ] [ CrossRef ]
Lane, J.E.; Shivers, J.P.; Zisser, H. Continuous glucose monitors: Current status and future developments. Curr. Opin. Endocrinol. Diabetes Obes. 2013 , 20 , 106–111. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Pickup, J.C.; Holloway, M.F.; Samsi, K. Real-time continuous glucose monitoring in type 1 diabetes: A qualitative framework analysis of patient narratives. Diabetes Care 2015 , 38 , 544–550. [ Google Scholar ] [ CrossRef ] [ PubMed ]
De Salvo, D.; Buckingham, B. Continuous glucose monitoring: Current use and future directions. Curr. Diabetes Rep. 2013 , 13 , 657–662. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mauras, N.; Fox, L.; Englert, K.; Beck, R.W. Continuous glucose monitoring in type 1 diabetes. Endocrine 2013 , 43 , 41–50. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Haviland, N.; Walsh, J.; Roberts, R.; Bailey, T.S. Update on clinical utility of continuous glucose monitoring in type 1 diabetes. Curr. Diabetes Rep. 2016 , 16 , 115. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Parkin, C.G.; Graham, C.; Smolskis, J. Continuous glucose monitoring use in type 1 diabetes: Longitudinal analysis demonstrates meaningful improvements in HbA1c and reductions in health care utilization. J. Diabetes Sci. Technol. 2017 , 11 , 522–528. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Toschi, E.; Wolpert, H. Utility of continuous glucose monitoring in type 1 and type 2 diabetes. Endocrinol. Metab. Clin. 2016 , 45 , 895–904. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Polonsky, W.H.; Hessler, D.; Ruedy, K.J.; Beck, R.W.; DIAMOND Study Group. The impact of continuous glucose monitoring on markers of quality of life in adults with type 1 diabetes: Further findings from the DIAMOND randomized clinical trial. Diabetes Care 2017 , 40 , 736–741. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Litchman, M.L.; Allen, N.A. Real-time continuous glucose monitoring facilitates feelings of safety in older adults with type 1 diabetes: A qualitative study. J. Diabetes Sci. Technol. 2017 , 11 , 988–995. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Vaddiraju, S.; Burgess, D.J.; Tomazos, I.; Jain, F.C.; Papadimitrakopoulos, F. Technologies for continuous glucose monitoring: Current problems and future promises. J. Diabetes Sci. Technol. 2010 , 4 , 1540–1562. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Srivastava, A.; Chowdhury, M.K.; Sharma, S.; Sharma, N. Blood glucose monitoring using non invasive optical method: Design limitations and challenges. Int. J. Adv. Res. Electr. Electron. Instrum. Eng. 2013 , 2 , 615–620. [ Google Scholar ]
Wang, G.; He, X.; Wang, L.; Gu, A.; Huang, Y.; Fang, B.; Geng, B.; Zhang, X. Non-enzymatic electrochemical sensing of glucose. Microchim. Acta 2013 , 180 , 161–186. [ Google Scholar ] [ CrossRef ]
Mohammadi, L.B.; Klotzbuecher, T.; Sigloch, S.; Welzel, K.; Göddel, M.; Pieber, T.R.; Schaupp, L. In vivo evaluation of a chip based near infrared sensor for continuous glucose monitoring. Biosens. Bioelectron. 2014 , 15 , 99–104. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mortellaro, M.; DeHennis, A. Performance characterization of an abiotic and fluorescent-based continuous glucose monitoring system in patients with type 1 diabetes. Biosens. Bioelectron. 2014 , 61 , 227–231. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhao, H.; Guo, X.; Wang, Y.; Duan, X.; Qu, H.; Zhang, H.; Zhang, D.; Pang, W. Microchip based electrochemical-piezoelectric integrated multi-mode sensing system for continuous glucose monitoring. Sens. Actuators B 2016 , 223 , 83–88. [ Google Scholar ] [ CrossRef ]
Salam, N.A.B.A.; bin Mohd Saad, W.H.; Manap, Z.B.; Salehuddin, F. The evolution of non-invasive blood glucose monitoring system for personal application. J. Telecommun. Electron. Comput. Eng. 2016 , 8 , 59–65. [ Google Scholar ]
Rumpler, M.; Mader, J.K.; Fischer, J.P.; Thar, R.; Granger, J.M.; Deliane, F.; Klimant, I.; Aberer, F.; Sinner, F.; Pieber, T.R. First application of a transcutaneous optical single-port glucose monitoring device in patients with type 1 diabetes mellitus. Biosens. Bioelectron. 2017 , 88 , 240–248. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chen, C.; Zhao, X.L.; Li, Z.H.; Zhu, Z.G.; Qian, S.H.; Flewitt, A.J. Current and emerging technology for continuous glucose monitoring. Sensors 2017 , 17 , 182. [ Google Scholar ] [ CrossRef ] [ PubMed ]
McGarraugh, G. The chemistry of commercial continuous glucose monitors. Diabetes Technol. Ther. 2009 , 11 , S17–S24. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rossetti, P.; Bondia, J.; Vehi, J.; Fanelli, C.G. Estimating plasma glucose from interstitial glucose: The issue of calibration algorithms in commercial continuous glucose monitoring devices. Sensors 2010 , 10 , 10936–10952. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bequette, B.W. Continuous glucose monitoring: Real-time algorithms for calibration, filtering, and alarms. J. Diabetes Sci. Technol. 2010 , 4 , 404–418. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sparacino, G.; Facchinetti, A.; Cobelli, C. “Smart” continuous glucose monitoring sensors: On-line signal processing issues. Sensors 2010 , 10 , 6751–6772. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lodwing, V.; Heinemann, L. Continuous glucose monitoring with glucose sensors: Calibration and assessment criteria. Diabetes Technol. Ther. 2003 , 5 , 572–586. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Dexcom G4 Platinum Continuous Glucose Monitoring System User’s Guide. Available online: https://s3-us-west-2.amazonaws.com/dexcompdf/LBL012528+Rev+004+User’s+Guide%2C+G4+PLATINUM+with+Share+US+Web+with+cover.pdf (accessed on 10 January 2018).
Dexcom G5 Mobile Continuous Glucose Monitoring System User Guide. Available online: https://s3-us-west-2.amazonaws.com/dexcompdf/LBL013990-REV003-G5-Mobile-User-Guide-NA-Android-US.pdf (accessed on 10 January 2018).
Medtronic Diabetes. Sensors & Transmitters. Calibrating Your Sensor. Available online: https://www.medtronicdiabetes.com/customer-support/sensors-and-transmitters-support/calibration-sensor (accessed on 10 January 2018).
Panteleon, A.E.; Rebrin, K.; Steil, G.M. The role of the independent variable to glucose sensor calibration. Diabetes Technol. Ther. 2003 , 5 , 401–410. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mastrototaro, J.J.; Gross, T.M.; Shin, J.J. Glucose Monitor Calibration Methods. U.S. Patent 6,424,847, 23 July 2002. [ Google Scholar ]
Shin, J.J.; Holtzclaw, K.R.; Dangui, N.D.; Kanderian, S., Jr.; Mastrototaro, J.J.; Hong, P.I. Real Time Self-Adjusting Calibration Algorithm. U.S. Patent 6,895,263, 17 May 2005. [ Google Scholar ]
Kamath, A.U.; Simpson, P.C.; Brauker, J.H.; Goode, P.V., Jr. Calibration Techniques for a Continuous Analyte Sensor. U.S. Patent 8,428,678, 23 April 2013. [ Google Scholar ]
Budiman, E.S. Method and Device for Providing Offset Model Based Calibration for Analyte Sensor. U.S. Patent 8,532,935, 10 September 2013. [ Google Scholar ]
Choleau, C.; Klein, J.C.; Reach, G.; Aussedat, B.; Demaria-Pesce, V.; Wilson, G.S.; Gifford, R.; Ward, W.K. Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients: Part 2. Superiority of the one-point calibration method. Biosens. Bioelectron. 2002 , 17 , 647–654. [ Google Scholar ] [ CrossRef ]
Mahmoudi, Z.; Johansen, M.D.; Christiansen, J.S.; Hejlesen, O. Comparison between one-point calibration and two-point calibration approaches in a continuous glucose monitoring algorithm. J. Diabetes Sci. Technol. 2014 , 8 , 709–719. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rebrin, K.; Steil, G.M.; Van Antwerp, W.P.; Mastrototaro, J.J. Subcutaneous glucose predicts plasma glucose independent of insulin: Implications for continuous monitoring. Am. J. Physiol. Endocrinol. Metab. 1999 , 277 , E561–E571. [ Google Scholar ] [ CrossRef ]
Schiavon, M.; Dalla Man, C.; Dube, S.; Slama, M.; Kudva, Y.C.; Peyser, T.; Basu, A.; Basu, R.; Cobelli, C. Modelling plasma-to-interstitium glucose kinetics from multitracer plasma and microdialysis data. Diabetes Technol. Ther. 2015 , 17 , 825–831. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Keenan, D.B.; Mastrototaro, J.J.; Voskanyan, G.; Steil, G.M. Delays in minimally invasive continuous glucose monitoring devices: A review of current technology. J. Diabetes Sci. Technol. 2009 , 3 , 1207–1214. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rebrin, K.; Sheppard, N.F., Jr.; Steil, G.M. Use of subcutaneous interstitial fluid glucose to estimate blood glucose: Revisiting delay and sensor offset. J. Diabetes Sci. Technol. 2010 , 5 , 1087–1098. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Facchinetti, A.; Sparacino, G.; Cobelli, C. Reconstruction of glucose in plasma from interstitial fluid continuous glucose monitoring data: Role of sensor calibration. J. Diabetes Sci. Technol. 2007 , 1 , 617–623. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Helton, K.L.; Ratner, B.D.; Wisniewski, N.A. Biomechanics of the sensor-tissue interface—Effects of motion, pressure, and design on sensor performance and the foreign body response—Part I: Theoretical framework. J. Diabetes Sci. Technol. 2011 , 5 , 632–646. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Klueh, U.; Liu, Z.; Feldman, B.; Henning, T.P.; Cho, B.; Ouyang, T.; Kreutzer, D. Metabolic biofouling of glucose sensors in vivo: Role of tissue microhemorrhages. J. Diabetes Sci. Technol. 2011 , 5 , 583–595. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Diabetes Research in Children Network (Direcnet) Study Group; Buckingham, B.A.; Kollman, C.; Beck, R.; Kalajian, A.; Fiallo-Scharer, R.; Tansey, M.J.; Fox, L.A.; Wilson, D.M.; Weinzimer, S.A.; et al. Evaluation of factors affecting CGMS calibration. Diabetes Technol. Ther. 2006 , 8 , 318–325. [ Google Scholar ]
Aussedat, B.; Thomè-Duret, V.; Reach, G.; Lemmonier, F.; Klein, J.C.; Hu, Y.; Wilson, G.S. A user-friendly method for calibrating a subcutaneous glucose sensor-based hypoglycemic alarm. Biosens. Bioelectron. 1997 , 12 , 1061–1071. [ Google Scholar ] [ CrossRef ]
Knobbe, E.J.; Lim, W.L.; Buckingham, B.A. Method and Apparatus for Real-Time Estimation of Physiological Parameters. U.S. Patent 6,575,905, 10 June 2003. [ Google Scholar ]
Knobbe, E.J.; Buckingham, B. The extended Kalman filter for continuous glucose monitoring. Diabetes Technol. Ther. 2005 , 7 , 15–27. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kuure-Kinsey, M.; Palerm, C.C.; Bequette, B.W. A dual-rate Kalman filter for continuous glucose monitoring. In Proceedings of the 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, New York, NY, USA, 31 August–3 September 2006. [ Google Scholar ]
Facchinetti, A.; Sparacino, G.; Cobelli, C. Enhanced accuracy of continuous glucose monitoring by online extended Kalman filtering. Diabetes Technol. Ther. 2010 , 12 , 353–363. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Leal, Y.; Garcia-Gabin, W.; Bondia, J.; Esteve, E.; Ricart, W.; Fernàndez-Real, J.M.; Vehì, J. Real-time glucose estimation algorithm for continuous glucose monitoring using autoregressive models. J. Diabetes Sci. Technol. 2010 , 4 , 391–403. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Leal, Y.; Garcia-Gabin, W.; Bondia, J.; Esteve, E.; Ricart, W.; Fernàndez-Real, J.M.; Vehì, J. Enhanced algorithm for continuous estimation using the continuous glucose monitoring system. Med. Sci. Monit. 2010 , 16 , MT51–MT58. [ Google Scholar ] [ PubMed ]
Barceló-Rico, F.; Bondia, J.; Díez, J.L.; Rossetti, P. A multiple local models approach to accuracy improvement in continuous glucose monitoring. Diabetes Technol. Ther. 2012 , 14 , 74–82. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Barceló-Rico, F.; Díez, J.L.; Rossetti, P.; Vehi, J.; Bondia, J. Adaptive calibration algorithm for plasma glucose estimation in continuous glucose monitoring. IEEE J. Biomed. Health Inf. 2013 , 17 , 530–538. [ Google Scholar ]
Mahmoudi, Z.; Dencker Johansen, M.; Christiansen, J.S.; Hejlesen, O.K. A multistep algorithm for processing and calibration of microdialysis continuous glucose monitoring data. Diabetes Technol. Ther. 2013 , 15 , 825–835. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kirchsteiger, H.; Zaccarian, L.; Renard, E.; del Re, L. A novel online recalibration strategy for continuous glucose measurement sensors employing LMI techniques. In Proceedings of the 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Osaka, Japan, 3–7 July 2013. [ Google Scholar ]
Kirchsteiger, H.; Zaccarian, L.; Renard, E.; del Re, L. LMI-based approaches for the calibration of continuous glucose measurement sensors. IEEE J. Biomed. Health Inf. 2015 , 19 , 1697–1706. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Choleau, C.; Klein, J.C.; Reach, G.; Aussedat, B.; Demaria-Pesce, V.; Wilson, G.S.; Gifford, R.; Ward, W.K. Calibration of a subcutaneous amperometric glucose sensor: Part 1. Effect of measurement uncertainties on the determination of sensor sensitivity and background current. Biosens. Bioelectron. 2002 , 17 , 641–646. [ Google Scholar ] [ CrossRef ]
Guerra, S.; Facchinetti, A.; Sparacino, G.; De Nicolao, G.; Cobelli, C. Enhancing the accuracy of subcutaneous glucose sensors: A real-time deconvolution-based approach. IEEE Trans. Biomed. Eng. 2012 , 59 , 1658–1669. [ Google Scholar ] [ CrossRef ] [ PubMed ]
De Nicolao, G.; Sparacino, G.; Cobelli, C. Nonparametric input estimation in physiological systems: Problems, methods and case studies. Automatica 1997 , 33 , 851–870. [ Google Scholar ] [ CrossRef ]
Vettoretti, M.; Facchinetti, A.; Del Favero, S.; Sparacino, G.; Cobelli, C. Online calibration of glucose sensor from the measured current by a time-varying calibration function and Bayesian priors. IEEE Trans. Biomed. Eng. 2016 , 63 , 1631–1641. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G.; Cobelli, C. From two to one per day calibration of Dexcom G4 Platinum by a time-varying day-specific Bayesian prior. Diabetes Technol. Ther. 2016 , 18 , 472–479. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G.; Cobelli, C. Reduction of blood glucose measurements to calibrate subcutaneous glucose sensors: A Bayesian multi-day framework. IEEE Trans. Biomed. Eng. 2017 . [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lee, J.B.; Dassau, E.; Doyle, F.J. A run-to-run approach to enhance continuous glucose monitoring accuracy based on continuous wear. IFAC-PapersOnline 2015 , 48 , 237–242. [ Google Scholar ] [ CrossRef ]
Zavitsanou, S.; Lee, J.B.; Pinsker, J.E.; Church, M.M.; Doyle, F.J.; Dassau, E. A personalized week-to-week updating algorithm to improve continuous glucose monitoring performance. J. Diabetes Sci. Technol. 2017 , 11 , 1070–1079. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hovorka, R.; Nodale, M.; Haidar, A.; Wilinska, M. Assessing performance of closed-loop insulin delivery systems by continuous glucose monitoring: Drawbacks and way forward. Diabetes Technol. Ther. 2013 , 15 , 4–12. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Del Favero, S.; Facchinetti, A.; Sparacino, G.; Cobelli, C. Improving accuracy and precision of glucose sensor profiles: Retrospective fitting by constrained deconvolution. IEEE Trans. Biomed. Eng. 2014 , 61 , 1044–1053. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Del Favero, S.; Facchinetti, A.; Sparacino, G.; Cobelli, C.; AP@ home consortium. Retrofitting of continuous glucose monitoring traces allows more accurate assessment of glucose control in outpatient studies. Diabetes Technol. Ther. 2015 , 17 , 355–363. [ Google Scholar ] [ PubMed ]
Del Favero, S.; Facchinetti, A.; Sparacino, G.; Cobelli, C. Retrofitting real-life Dexcom G5 data. Diabetes Technol. Ther. 2017 , 19 , 237–245. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G. Toward calibration-free continuous glucose moitoring sensors: Bayesian calibration approach applied to next-generation technology. Diabetes Technol. Ther. 2018 , 20 , 59–67. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Garcia, A.; Rack-Gomer, A.L.; Bhavaraju, N.C.; Hampapuram, H.; Kamath, A.; Peyser, T.; Facchinetti, A.; Zecchin, C.; Sparacino, G.; Cobelli, C. Dexcom G4AP: An advanced continuous glucose monitor for the artificial pancreas. J. Diabetes Sci. Technol. 2013 , 7 , 1436–1445. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sparacino, G.; Facchinetti, A.; Maran, A.; Cobelli, C. Continuous glucose monitoring time series and hypo/hyperglycemia prevention: Requirements, methods, open problema. Curr. Diabetes Rev. 2008 , 4 , 181–192. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bailey, T.; Bode, B.W.; Christiansen, M.P.; Klaff, L.J.; Alva, S. The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes Technol. Ther. 2015 , 17 , 787–794. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Edelman, S.V. Regulation catches up to reality: Nonadjunctive use of continuous glucose monitoring data. J. Diabetes Sci. Technol. 2017 , 11 , 160–164. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Figure 1. Representative three days of blood glucose (BG) monitoring obtained with self-monitoring BG (SMBG), diamonds, and with continuous glucose monitoring (CGM), continuous line. Horizontal dashed lines indicate the euglycemic range. Data taken from a previously published study [ 15 ].
Figure 1. Representative three days of blood glucose (BG) monitoring obtained with self-monitoring BG (SMBG), diamonds, and with continuous glucose monitoring (CGM), continuous line. Horizontal dashed lines indicate the euglycemic range. Data taken from a previously published study [ 15 ].
Figure 2. Examples in which the continuous glucose monitoring (CGM) sensor output (continuous line) ( a ) overestimates and ( b ) underestimates the reference blood glucose (BG) (points). Data taken from a previously published study [ 15 ].
Figure 2. Examples in which the continuous glucose monitoring (CGM) sensor output (continuous line) ( a ) overestimates and ( b ) underestimates the reference blood glucose (BG) (points). Data taken from a previously published study [ 15 ].
Figure 3.
(
a
) Two-compartment model describing the blood glucose to interstitial glucose (BG-to-IG) kinetics.
R
a
is the rate of appearance;
k
01
,
k
02
,
k
12
,
k
21
are rate constants. The time constant of the BG-to-IG system is
τ
=
1
k
02
+
k
12
. (
b
) Representative blood glucose (BG) (dashed line) and interstitial glucose (IG) (continuous line) concentration profiles simulated as described in the text assuming τ = 11 min.
Figure 3.
(
a
) Two-compartment model describing the blood glucose to interstitial glucose (BG-to-IG) kinetics.
R
a
is the rate of appearance;
k
01
,
k
02
,
k
12
,
k
21
are rate constants. The time constant of the BG-to-IG system is
τ
=
1
k
02
+
k
12
. (
b
) Representative blood glucose (BG) (dashed line) and interstitial glucose (IG) (continuous line) concentration profiles simulated as described in the text assuming τ = 11 min.
Figure 4. Representative raw CGM sensor signal (continuous line, units not specified by the manufacturer) that exhibits a nonphysiological drift (dashed line) due to the time-variability of sensor sensitivity. Data were previously published in [ 15 ].
Figure 4. Representative raw CGM sensor signal (continuous line, units not specified by the manufacturer) that exhibits a nonphysiological drift (dashed line) due to the time-variability of sensor sensitivity. Data were previously published in [ 15 ].
Table 1. Summary of the reviewed calibration techniques.
Table 1. Summary of the reviewed calibration techniques.
Study Calibration Technique Model of BG-IG Dynamic Real-Time Use in Wearable Devices Calibrations per Day Validation Data Improvements Compared to Manufacturer (if Applicable) Aussedat et al. [ 59 ] Linear regression with feature to detect phases of steady state signal No, but use of heuristic technique Yes Not specified Real data from a miniaturized glucose sensor used in rats / Knobbe et al. [ 60 , 61 ] Extended Kalman filter Yes Yes Not specified Real data from the Medronic (Northridge, CA, USA) MiniMed CGM system / Kuure-Kinsey et al. [ 62 ] Dual rate Kalman filter No Yes 3 Synthetic data; data from an experimental glucose sensor used in rats / Facchinetti et al. [ 63 ] Extended Kalman filter Yes Yes 4 Synthetic data / Leal et al. [ 64 ] Auto-regressive models No Yes At least 3 Real data from the Medtronic (Northridge, CA, USA) MiniMed CGMS system gold Median RAD 1 decreased of 4.6% Leal et al. [ 65 ] Linear regression No No At least 3 Real data from the Medtronic (Northridge, CA, USA) MiniMed CGMS system gold Median RAD 1 decreased of 2% Barceló-Rico [ 66 , 67 ] Multiple local dynamic models [ 66 ] with adaptive parameters normalization [ 67 ] Yes Yes 3–4 Real data from the GlucoDay (Menarini, Florence, Italy) sensor [ 66 ]; synthetic data; real data from the Medtronic (Northridge, CA, USA) MiniMed CGMS system gold [ 67 ] MARD 2 decreased of 3.9% in [ 66 ] and of 2.4% in [ 67 ] Mahmoudi et al. [ 68 ] Rate-limiting filtering, selective smoothing, and robust regression No, but use of heuristic technique Yes Maximum 4 Real data from SCGM 1 (Roche Diagnostic, Mannheim, Germany) system / Kirchsteiger et al. [ 69 , 70 ] Linear matrix inequalities Yes Yes Roughly 6 (more in day 1) Real data from the FreeStyle Navigator (Abbott Diabetes Care, Alameda, CA, USA) system MARD 2 decreased of about 4.7% [ 70 ] Guerra et al. [ 72 ] Linear regression and regularized deconvolution Yes Yes 2 Synthetic data; real data from the FreeStyle Navigator (Abbott Diabetes Care, Alameda, CA, USA) and DexCom Seven Plus (Dexcom Inc., San Diego, CA, USA) systems RMSE 3 decreased of 7.2 mg/dL Vettoretti et al. [ 74 ] Linear regression and regularized deconvolution Yes Yes 2 Real data from the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) system MARD 2 decreased of 1.2% Acciaroli et al. [ 75 ] Linear regression and regularized deconvolution Yes Yes 1 Real data from the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) system MARD 2 decreased of 1.2%, calibrations reduced from 2 to 1 per day Acciaroli et al. [ 76 , 83 ] Multiple-day model and regularized deconvolution Yes Yes 0.25 in [ 76 ]; zero in [ 83 ] Real data from the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) system [ 76 ] and a next-generation Dexcom prototype [ 83 ] MARD 2 decreased of 1.2%, calibrations reduced from 2 to 0.25 per day [ 76 ] Lee et al. [ 77 ] Linear regression with run-to-run No Yes, after a few weeks of CGM use 2 Synthetic data / Zavitsanou et al. [ 78 ] Linear regression with weakly updating feature No Yes, after a few weeks of CGM use 2 Real data from the Dexcom G4 Platinum (Dexcom Inc., San Diego, CA, USA) system / Del Favero et al. [ 80 , 81 , 82 ] Linear regression and regularized constrained deconvolution Yes No 13 in [ 80 ]; 10 in [ 82 ] Real data from the DexCom Seven Plus [ 80 , 81 ] and Dexcom G5 Mobile [ 82 ] (Dexcom Inc., San Diego, CA, USA) systems MARD 2 decreased of 6.9% in [ 80 ], of 2.6% and 4.1% in adults and pediatrics in [ 82 ]
1 RAD, relative absolute difference; 2 MARD, mean absolute relative difference; 3 RMSE, root mean square error.
Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G. Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives. Biosensors 2018, 8, 24.
https://doi.org/10.3390/bios8010024
AMA Style
Acciaroli G, Vettoretti M, Facchinetti A, Sparacino G. Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives. Biosensors. 2018; 8(1):24.
https://doi.org/10.3390/bios8010024
Chicago/Turabian Style
Acciaroli, Giada, Martina Vettoretti, Andrea Facchinetti, and Giovanni Sparacino. 2018. "Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives" Biosensors8, no. 1: 24.
https://doi.org/10.3390/bios8010024
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here .
Article Metrics
Acciaroli, G.; Vettoretti, M.; Facchinetti, A.; Sparacino, G. Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives. Biosensors 2018, 8, 24.
https://doi.org/10.3390/bios8010024
Acciaroli G, Vettoretti M, Facchinetti A, Sparacino G. Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives. Biosensors. 2018; 8(1):24.
https://doi.org/10.3390/bios8010024
Chicago/Turabian Style
| https://www.mdpi.com/2079-6374/8/1/24/xml |
Rollston Epigraphy - Ancient Inscriptions from the Levantine World
Rollston Epigraphy. Ancient Inscriptions from the Levantine World
Ancient Inscriptions from the Levantine World
Home Contact Curriculum Vitae
The Problem with Reading the Word ‘Hebrew’ in Sinai 115: An Egyptologist’s Response
23 November 2016 Comments (11)
Reading the Word ‘Hebrew’ in Sinai 115: An Egyptologist’s Response
_____
A Guest Post by Prof. Dr. Thomas Schneider
University of British Columbia
_____
As part of Douglas Petrovich’s proposal that the Early Alphabetic Inscriptions (e.g., Serabit el-Khadem, Wadi el-Hol) are Hebrew, he has proposed (as putatively supporting evidence) to read a word in one of the Egyptian inscriptions (namely: Sinai 115) from Serabit el-Khadem as the word for “Hebrew.” This, however, is just not correct. Here are some of the reasons:
(1) the correct reading is in two lines: Jpn, son of Jrw. Petrovich combines J and p from line one with r from line 2.
(2) Egyptian /j/ is used to render Semitic aleph, never an ayin (and one would need an ayin here to have the word “Hebrew”).
(3) Similarly, in the 12th dynasty, Egyptian /r/ is never a transcription of Semitic /r/, but of /l/ and /d/.
(4) Also, /p/ is a regular rendering of Semitic /p/ and not /b/, although this is less objectionable.
(5) Ultimately, therefore, Petrovich’s proposed reading of this word as “Hebrew” is not possible.
Respectfully,
Dr. Thomas Schneider
The Early History of the Alphabet and the Recent Claim that the Northwest Semitic Inscriptions from Serabit el-Khadem and Wadi el-Hol are Hebrew: Spoiler Alert, They’re Not.
23 November 2016 Comments (7)
The Early History of the Alphabet and the Recent Claim that the Northwest Semitic Inscriptions from Serabit el-Khadm and Wadi el-Hol are Hebrew: Spoiler Alert, They’re Not.
By Christopher Rollston
___
Recently, it has been claimed by Douglas Petrovich that the Early Alphabetic Inscriptions (some of which date to as early as the 18th century BCE) from Serabit el-Khadem and Wadi el-Hol are Hebrew. His volume on these inscriptions will be published by Carta (Jerusalem) in the coming months. Petrovich also presented a paper on this subject at the annual meeting of the American Schools of Oriental Research on Thursday, November 17th, 2016. I was present for his presentation. Alas, I am confident that his proposal for these inscriptions will not get traction with scholars who work in the field, that is, scholars who work in the fields known as Palaeography and Comparative Semitics. I will write a much longer discussion of his proposal fairly soon (around the time the book comes out). But I wish to put pen to paper at this moment as well, so as to help bring some important empirical evidence to the fore.
But before discussing some of the serious problems with the Petrovich proposal, I should like to emphasize first that the core inscriptions that form the basis of Petrovich’s claim are not recent discoveries. (1) In fact, in the case of the Early Alphabetic inscriptions from Serabit el-Khadem (in the Sinai), these have been known for more than a century (with publications on them going back, for example, to 1906 and 1916 by Gardiner). (2) And as for the Early Alphabetic Inscriptions from Wadi el-Hol (also in Egypt), these were published more than a decade ago (Darnell, Dobbs-Allsopp, Lundberg, McCarter, Zuckerman, 2005) in a volume published by the American Schools of Oriental Research for which I served as an external reviewer. Now to some of the salient details about Petrovich’s proposal and some of the empirical problems with it (there are a rather large number of problems, but I’ll focus on some of the most salient ones).
I. Douglas Petrovich argued (in his presentation at ASOR) that root-words such as rb (“great,” “big”), ‘l (“God”), yyn (“wine”) are present in the Early Alphabetic inscriptions and that these are Hebrew words. These words are attested in Hebrew, but that is only part of the story.
Namely, these words are actually not just Hebrew but rather they appear in many Semitic languages.
For example, this root for “big,” “great,” occurs not just in Hebrew, but also in Phoenician, Ugaritic, Aramaic, Akkadian, Old South Arabic (among others). Similarly, the word ‘El for God is also Common Semitic and it occurs in Ugaritic, Phoenician, Akkadian, Aramaic, Old South Arabic (along with some others). Or again, the word for “wine” (sometimes spelled with two yods and sometimes with one) occurs not just in the Semitic languages (such as Ugaritic, Phoenician, Arabic), but even in Indo-European languages such as Hittite! (and it comes into Greek and Latin, and ultimately even into the Romance Languages and even English). In short,
there is no word that can be considered distinctively Hebrew in the Early Alphabetic Inscriptions from Serabit el-Khadem, Wadi el-Hol, or any other Early Alphabetic Inscription
. Rather, for more than a century,
the best that we can say is that these Early Alphabetic inscriptions are written in Canaanite, that is, the language of the Ancient Canaanites (who lived in ancient Canaan and often traveled down into Egypt, a tradition also reflected in Genesis
). Thus, to say that these inscriptions from Serabit el-Khadem and Wadi el-Hol are somehow distinctively Hebrew is just not going to work. After all, if a word occurs in lots of different languages, that word cannot be considered diagnostic for one language. For that to be the case, that word would have to be present ONLY in one language. And that’s just not what we have with these inscriptions.
II. We have hundreds of Hebrew inscriptions and the earliest of these dates to ca. 900 BCE (see my article in Biblical Archaeology Review on “The Oldest Hebrew Inscription” for some of the most relevant inscriptions) and the alphabet of these Hebrew inscriptions has twenty-two consonantal letters. The Early Alphabetic Inscriptions (e.g., from Serabit el-Khadem and Wadi el-Hol), however, have twenty-seven consonantal letters.
Thus, to claim that these inscriptions from Serabit el-Khadem and Wadi el-Hol are Hebrew is an argument that is strained well beyond the breaking point.
III. The Early Alphabetic Inscriptions are written from left-to-right (dextrograde), right-to-left (sinistrograde), and columnar. The Old Hebrew inscriptions are uniformly written from right-to-left (that is, sinistrograde). Thus, even with regard to the direction of writing, the attested inscriptions that are definitively Old Hebrew do not correspond with the diversity of directions that is present in the Early Alphabetic inscriptions. Again, the problem with the claim that these from Serabit and el-Hol are Hebrew is that the evidence doesn’t line up very well. And only the most strained of arguments can make it “line up.”
IV. In one of the Egyptian inscriptions from Serabit el-Khadem (i.e., many inscriptions are present at this site, most of them are written in Egyptian, not Northwest Semitic…and as for one of them written in Egyptian…), Petrovich attempts to read the word ‘br, a word that is the root for the word “to cross over,” and when used as an ethnicon is the basis for the word “Hebrew.” The first thing that I would say is that this is a very, very strained reading of the Egyptian inscription. I am confident that few trained Egyptologists will embrace Petrovich’s reading of this text as having the root ‘br.
Furthermore, even if this root were to be present, the fact of the matter is that even that root word (ayin, bet, resh) is attested in lots of different Semitic languages, including Phoenician, Aramaic, Arabic, Old South Arabic, Akkadian, and Ugaritic.
And in these cases, the word can and normally does mean “to cross over,” “to overstep.” In short,
one must be careful to understand and remember that if a word occurs in multiple Semitic languages, it cannot be considered diagnostic or reflective of just one of those languages…and that holds true for all words, including the root ‘br .
V. In short, the things that Douglas Petrovich considers to be markers of Hebrew are, in fact, just markers of the Semitic languages in general.
We even have a term of these sorts of words that occur in multiple Semitic languages. We call them “Common Semitic,” because they are attested in so many languages.
In short, the only thing that can reasonably be said about the Early Alphabetic inscriptions from Serabit el-Khadem and Wadi el-Hol (etc.) is that they are written in a Northwest Semitic language and script. There is nothing in these inscriptions that is diagnostic for Hebrew. It would be interesting if there were features that could be considered distinctively Hebrew, but there are not.
So, as has been the case for a very long time, we refer to these inscriptions as Canaanite or Early Alphabetic
. And from this script called Canaanite or Early Alphabetic, the Phoenician script will later develop during the final decades of the 2nd millennium (and that’s an interesting story in and of itself). And from the Phoenician script, the Hebrew and Aramaic scripts will come in the early First Millennium (and that’s another interesting story). But that’s a long ways down the line in terms of time…long after the scribes of Serabit el-Khadem and Wadi el-Hol penned their inscriptions. Thus, the Early Alphabetic inscriptions from Serabit el-Khadem and Wadi el-Hol are definitely not Hebrew.
Respectfully submitted,
Dr. Christopher Rollston (Ph.D. Johns Hopkins University)
George Washington University
Department of Classical and Near Eastern Languages and Civilizations
Washington, DC | http://www.rollstonepigraphy.com/miscountacaa/befdaf7349648.shtml/?paged=2 |
What exactly was the grace of God that Barnabas saw at Antoich? | The Puritan Board
Acts 11:23 When he [Barnabas] came and saw the grace of God, he was glad, and he exhorted them all to remain faithful to the Lord with steadfast purpose...
What exactly was the grace of God that Barnabas saw at Antoich?
Acts 11:23 When he [Barnabas] came and saw the grace of God, he was glad, and he exhorted them all to remain faithful to the Lord with steadfast purpose. The NIV 1978 uses the phrase "evidence of the grace of God" although later editions and other translations don't use the word evidence . But still I wonder, just what was it that he witnessed? Raw numbers of believers increasing? Acts of mercy to the poor? Christians speaking in tongues like they did at Cornelius's house? Can we in fact know? Matthew Henry writes: When he came, and had seen the grace of God, the tokens of God's good-will to the people of Antioch and the evidences of his good work among them, he was glad. He took time to make his observations, and not only in their public worship, but in their common conversations and in their families, he saw the grace of God among them. This was a new church so Barnabas wasn't comparing their growth from his visit the previous year. But there must have been something visible, something tangible, something quantifiable that he saw in the church at Antioch. Or am I reading too much into the passage? There was obviously room for further growth because Barnabas finds Paul and takes him to Antioch where they spend a whole year teaching. (What I would give to have been in that Sunday School class!) Of course the application that I am making is this: If an outsider comes to my church, does he see a similar grace of God at work? Or does he leave thinking, what a nice group of people. Pretty much the same reaction he will have at a Rotary Club meeting.
Act.4:36
Act.8:14-15
Act.8:14
The middle of the passage focuses 1) on Barnabas’ work of evaluation and comfort for the believers in Antioch; and 2) his engagement of Saul for the work of establishing the church, organizing and regularizing it. Barnabas was well regarded (we know) for his encouragement. He would find the good in any situation, and build that part up. In Antioch, he found good report running over. “When he had seen the grace of God he was glad.” He didn’t have to hunt for it, turn over a few rocks looking for a hint.
We must read “them all,” whom he encouraged or comforted, as firstly those witnessing, gospelling men. When they set out, they probably had more zeal than experience. Since their success (the success of the hand of the Lord and the grace of God) they were experiencing the ups and downs of being the de facto leaders of a real, but barely organized church. This large body was no more spiritual or sanctified—no more holy—than is a true church today. Plus, it had about sprung up overnight. Antioch Church must have been a challenge.
But also, the rest of these Grecians now professing faith in Christ, Barnabas exhorted them to purpose in their heart, “I will continue with the Lord,” meaning: I will continue with him and his people. This is my people; this is my church.” Barnabas here asks them: “You all in?” Luke then describes pastor Barnabas as: 1) a good man, broad minded in the best sense, fully aboard the Gentile-inclusion mission, a generous spirit (the sense in this context is not his moral virtues). 2) He is described as full of the Holy Spirit and faith, fundamental qualities we’ve already seen mark those called to serve in Christ’s ministry.
It isn’t as if this new church had failed to see such character in those who witnessed to them. Doubtless they had. But in Barnabas, they observed it present, mature, balanced in one who was called to pastor. They heard it in his preaching, acknowledged the Holy Spirit’s work through it, and grew in the grace and knowledge of Jesus Christ. Christians—the real deal—recognize this gift when it is present, and develop a zest for it. Won’t be happy if they lose it.
Then, once he arrived, the division of their labor served the best interest of the church. For a solid year Paul’s powers together with Barnabas’ bathed the congregation of Antioch in the powerful teaching that we have exhibits and excerpts of in Paul’s letters. A “great many people” were taught. They were taught the Lord Jesus Christ, as promised in the Scriptures, now come in the flesh. They were taught to follow Christ. So far did they absorb this doctrine, that outsiders began to call them “Christians,” the party of Christ, followers of Christ, “belongs to” Christ.
1Cor.14:25
I suspect that the "grace of God" mentioned in v. 23 is a shortened way of referring to the same phenomenon explained in more detail earlier in v. 18: "To the Gentiles also God has granted repentance that leads to life." So Barnabas sees repentance and faith, evidence that God is saving people among the largely Gentile population in Antioch. What wondrous grace! This fits the main thrust of God's grace throughout the book of Acts: the expansion of the gospel to the nations.
Thank you for your lucid, helpful replies. I guess I worded my post incorrectly. I was saying that Barnabas wasn't comparing the condition of the church to what he would have seen had he been there the previous year. I agree that this was his first visit to Antoich. Your replies shed light on this passage and I appreciate your insights.
| https://www.puritanboard.com/threads/what-exactly-was-the-grace-of-god-that-barnabas-saw-at-antoich.104377/#post-1262717 |
Latest content added for The Portal to Texas History Title: Perspectives
<feed xmlns =" http://www.w3.org/2005/Atom " xmlns:georss =" http://www.georss.org/georss " xmlns:media =" http://search.yahoo.com/mrss/ " xml:lang =" en-us " >
Latest content added for The Portal to Texas History Title: Perspectives
<link href =" https://texashistory.unt.edu/explore/titles/t03033/browse/?sort=added_d&start=0&t=fulltext " rel =" alternate " />
<link href =" https://texashistory.unt.edu/explore/titles/t03033/feed/?sort=added_d&start=0&t=fulltext " rel =" self " />
<link href =" https://texashistory.unt.edu/explore/titles/t03033/feed/?sort=added_d&start=50&t=fulltext " rel =" next " />
<link href =" https://texashistory.unt.edu/explore/titles/t03033/feed/?sort=added_d&start=0&t=fulltext " rel =" first " />
<link href =" https://texashistory.unt.edu/explore/titles/t03033/feed/?sort=added_d&start=50&t=fulltext " rel =" last " />
<id >
https://texashistory.unt.edu/explore/titles/t03033/browse/?sort=added_d&start=0&t=fulltext
</id >
<updated > 2018-10-16T07:46:55-05:00 </updated >
<author >
<name > UNT Libraries </name >
</author >
<subtitle >
This is a custom feed for browsing The Portal to Texas History Title: Perspectives
</subtitle >
<entry >
<title > Perspectives, Volume 7, Number 2, December 1984 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1065567/ " rel =" alternate " />
<published > 2018-10-16T07:46:55-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1065567/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1065567/"><img alt="Perspectives, Volume 7, Number 2, December 1984" title="Perspectives, Volume 7, Number 2, December 1984" src="https://texashistory.unt.edu/ark:/67531/metapth1065567/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1065567/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 8, Number 3, March 1986 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1065574/ " rel =" alternate " />
<published > 2018-10-16T07:46:55-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1065574/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1065574/"><img alt="Perspectives, Volume 8, Number 3, March 1986" title="Perspectives, Volume 8, Number 3, March 1986" src="https://texashistory.unt.edu/ark:/67531/metapth1065574/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1065574/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 7, Number 3, March,1985 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1065583/ " rel =" alternate " />
<published > 2018-10-16T07:46:55-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1065583/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1065583/"><img alt="Perspectives, Volume 7, Number 3, March,1985" title="Perspectives, Volume 7, Number 3, March,1985" src="https://texashistory.unt.edu/ark:/67531/metapth1065583/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1065583/small/ " />
</entry >
<entry >
<title > Perspectives, December 1985 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1065581/ " rel =" alternate " />
<published > 2018-10-16T07:46:55-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1065581/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1065581/"><img alt="Perspectives, December 1985" title="Perspectives, December 1985" src="https://texashistory.unt.edu/ark:/67531/metapth1065581/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1065581/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 7, Number 1, October 1984 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1065596/ " rel =" alternate " />
<published > 2018-10-16T07:46:55-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1065596/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1065596/"><img alt="Perspectives, Volume 7, Number 1, October 1984" title="Perspectives, Volume 7, Number 1, October 1984" src="https://texashistory.unt.edu/ark:/67531/metapth1065596/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1065596/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 4, Number 4, December 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033055/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033055/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033055/"><img alt="Perspectives, Volume 4, Number 4, December 1981" title="Perspectives, Volume 4, Number 4, December 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033055/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033055/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 6, Number 8, April 1984 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032651/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032651/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032651/"><img alt="Perspectives, Volume 6, Number 8, April 1984" title="Perspectives, Volume 6, Number 8, April 1984" src="https://texashistory.unt.edu/ark:/67531/metapth1032651/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032651/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 5, Number 6, March 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032654/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032654/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032654/"><img alt="Perspectives, Volume 5, Number 6, March 1983" title="Perspectives, Volume 5, Number 6, March 1983" src="https://texashistory.unt.edu/ark:/67531/metapth1032654/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032654/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 5, Number 2, October 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033846/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033846/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033846/"><img alt="Perspectives, Volume 5, Number 2, October 1982" title="Perspectives, Volume 5, Number 2, October 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033846/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033846/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 5, Number 1, September 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033900/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033900/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033900/"><img alt="Perspectives, Volume 5, Number 1, September 1982" title="Perspectives, Volume 5, Number 1, September 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033900/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033900/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 6, Number 6, February 1984 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033857/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033857/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033857/"><img alt="Perspectives, Volume 6, Number 6, February 1984" title="Perspectives, Volume 6, Number 6, February 1984" src="https://texashistory.unt.edu/ark:/67531/metapth1033857/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033857/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 3, Number 8, May 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033801/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033801/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033801/"><img alt="Perspectives, Volume 3, Number 8, May 1981" title="Perspectives, Volume 3, Number 8, May 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033801/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033801/small/ " />
</entry >
<entry >
<title > Perspectives, Volume 2, Number 6, July 1980 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1034145/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1034145/
</id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1034145/"><img alt="Perspectives, Volume 2, Number 6, July 1980" title="Perspectives, Volume 2, Number 6, July 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1034145/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1034145/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 3, Number 7, April 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033718/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033718/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033718/"><img alt="Perspectives, Volume 3, Number 7, April 1981" title="Perspectives, Volume 3, Number 7, April 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033718/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033718/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 3, Number 1, September 1980 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033680/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033680/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033680/"><img alt="Perspectives, Volume 3, Number 1, September 1980" title="Perspectives, Volume 3, Number 1, September 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1033680/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033680/small/ " />
</entry >
<entry >
<title > Perspectives, Special Edition 1, January 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032954/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032954/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032954/"><img alt="Perspectives, Special Edition 1, January 1981" title="Perspectives, Special Edition 1, January 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1032954/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032954/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition, October 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032825/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032825/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032825/"><img alt="Perspectives, Special Edition, October 1981" title="Perspectives, Special Edition, October 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1032825/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032825/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition, February 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033861/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033861/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033861/"><img alt="Perspectives, Special Edition, February 1982" title="Perspectives, Special Edition, February 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033861/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033861/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition, July 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033317/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033317/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033317/"><img alt="Perspectives, Special Edition, July 1981" title="Perspectives, Special Edition, July 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033317/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033317/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition, August 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1031859/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1031859/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1031859/"><img alt="Perspectives, Special Edition, August 1983" title="Perspectives, Special Edition, August 1983" src="https://texashistory.unt.edu/ark:/67531/metapth1031859/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1031859/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition, December 1980 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1031944/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1031944/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1031944/"><img alt="Perspectives, Special Edition, December 1980" title="Perspectives, Special Edition, December 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1031944/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1031944/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Special Edition 2, February 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032111/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032111/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032111/"><img alt="Perspectives, Special Edition 2, February 1981" title="Perspectives, Special Edition 2, February 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1032111/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032111/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 6, Number 5, January 1985 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1031819/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1031819/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1031819/"><img alt="Perspectives, Volume 6, Number 5, January 1985" title="Perspectives, Volume 6, Number 5, January 1985" src="https://texashistory.unt.edu/ark:/67531/metapth1031819/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1031819/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 3, Number 2, October 1980 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1031841/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1031841/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1031841/"><img alt="Perspectives, Volume 3, Number 2, October 1980" title="Perspectives, Volume 3, Number 2, October 1980" src="https://texashistory.unt.edu/ark:/67531/metapth1031841/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1031841/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 2, October 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1031916/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1031916/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1031916/"><img alt="Perspectives, Volume 4, Number 2, October 1981" title="Perspectives, Volume 4, Number 2, October 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1031916/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1031916/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 6, Number 3, November 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032469/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032469/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032469/"><img alt="Perspectives, Volume 6, Number 3, November 1983" title="Perspectives, Volume 6, Number 3, November 1983" src="https://texashistory.unt.edu/ark:/67531/metapth1032469/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032469/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 10, July 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032078/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032078/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032078/"><img alt="Perspectives, Volume 4, Number 10, July 1982" title="Perspectives, Volume 4, Number 10, July 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1032078/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032078/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 8, April 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033542/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033542/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033542/"><img alt="Perspectives, Volume 4, Number 8, April 1982" title="Perspectives, Volume 4, Number 8, April 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033542/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033542/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 6, Number 9, May 1994 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033210/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033210/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033210/"><img alt="Perspectives, Volume 6, Number 9, May 1994" title="Perspectives, Volume 6, Number 9, May 1994" src="https://texashistory.unt.edu/ark:/67531/metapth1033210/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033210/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 6, February 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033219/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033219/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033219/"><img alt="Perspectives, Volume 4, Number 6, February 1982" title="Perspectives, Volume 4, Number 6, February 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033219/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033219/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 3, Number 9, July 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033296/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033296/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033296/"><img alt="Perspectives, Volume 3, Number 9, July 1981" title="Perspectives, Volume 3, Number 9, July 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033296/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033296/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 6, Number 2, October 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033187/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033187/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033187/"><img alt="Perspectives, Volume 6, Number 2, October 1983" title="Perspectives, Volume 6, Number 2, October 1983" src="https://texashistory.unt.edu/ark:/67531/metapth1033187/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033187/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 3, Number 6, March 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033197/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033197/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033197/"><img alt="Perspectives, Volume 3, Number 6, March 1981" title="Perspectives, Volume 3, Number 6, March 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033197/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033197/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 6, Number 4, December 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1032824/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1032824/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1032824/"><img alt="Perspectives, Volume 6, Number 4, December 1983" title="Perspectives, Volume 6, Number 4, December 1983" src="https://texashistory.unt.edu/ark:/67531/metapth1032824/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1032824/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 1, September 1981 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033979/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033979/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033979/"><img alt="Perspectives, Volume 4, Number 1, September 1981" title="Perspectives, Volume 4, Number 1, September 1981" src="https://texashistory.unt.edu/ark:/67531/metapth1033979/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033979/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 4, Number 9, May 1982 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033966/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1033966/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1033966/"><img alt="Perspectives, Volume 4, Number 9, May 1982" title="Perspectives, Volume 4, Number 9, May 1982" src="https://texashistory.unt.edu/ark:/67531/metapth1033966/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1033966/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 2, Number 5, May 1990 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1034109/ " rel =" alternate " />
<published > 2018-07-31T23:58:47-05:00 </published >
<id >
https://texashistory.unt.edu/ark:/67531/metapth1034109/
</id >
<id > ... </id >
<summary type =" html " >
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1034109/"><img alt="Perspectives, Volume 2, Number 5, May 1990" title="Perspectives, Volume 2, Number 5, May 1990" src="https://texashistory.unt.edu/ark:/67531/metapth1034109/small/"/></a></p><p>Publication of the University of Houston System describing campus events, academic programs and research, student and alumni activities, and other informatin of interest to the community.</p>
</summary >
<summary type =" html " > ... </summary >
<media:thumbnail url =" https://texashistory.unt.edu/ark:/67531/metapth1034109/small/ " />
</entry >
<entry > ... </entry >
<entry >
<title > Perspectives, Volume 5, Number 10, July 1983 </title >
<link href =" https://texashistory.unt.edu/ark:/67531/metapth1033522/ " rel =" alternate " />
| https://texashistory.unt.edu/explore/titles/t03033/feed/?sort=added_d&start=0&t=fulltext |
Eight Windows 11 features currently in development
Microsoft is constantly looking to improve Windows 11 with new and better features. Preview these new elements here.
Eight Windows 11 features currently in development
Eight Windows 11 features currently in development
Microsoft is constantly looking to improve Windows 11 with new and better features. Getting a preview of these new elements will give you a head start on future releases.
Image: Mark W. Kaelin/TechRepublic
To keep an edge on any competition, now and in the future, Microsoft is constantly looking to improve and enhance theWindows 11 operating system. Generally, improvements include new features, better features or simply more features. These new and improved elements are in development now and can be previewed before they are released to the public if you are a member of the Windows Insights program.
While few of the new features in development are groundbreaking or paradigm shifting, they will enhance or improve the overall Windows 11 user experience for just about everyone. With this in mind, we look at some of the operating system elements currently in development by Microsoft.
Windows 11 features currently in development
1. Improving the taskbar for tablets
Microsoft has been testing a version of the taskbar that will shrink when a touchscreen device is active without a mouse or keyboard. Essential information like the remaining battery power, time, and the status of the internet connection will be displayed continuously, but users will have to swipe up to access apps, files and other normal taskbar actions.
The feature is currently available for preview for Windows Insiders members in the Dev channel but was almost released with the recentWindows 11 22H2major update. Accordingly, the improved tablet-ready version of the taskbar feature should be released relatively soon.
2. Adding seconds to the taskbar clock
For reasons never explained, Microsoft does not currently allow the display of seconds in the taskbar system clock. Toadd seconds to the taskbar clock in Windows 10, we had to make an edit to the Windows Registry file. In Windows 11, that path was blocked, and we had to resort to athird-party app to add a separate time display to the taskbar.
3. Creating better widgets
The implementation ofwidgets in Windows 11is, charitably speaking, hit and miss. Much more needs to be done to streamline and personalize the content displayed by the widget app. Fortunately, Microsoft agrees with this assessment and is working on improvements and enhancements.
A preview of the improved widgets feature is available in the Dev channel and includes a simple toggle button to expand and contract the widgets screen from its normal half screen view to a full screen view. Microsoft has also turned to third-party partners like Spotify and Meta to develop integrated widgets for their services.
4. Adding Windows Studio effects to Quick Settings
An enhanced version ofWindows Studio Effectsis currently available for preview for Windows Insiders in the Beta channel. This version still allows users to add audio and video effects to their webcams and microphones, including portrait blur, eye contact and background noise removal.
However, Microsoft is also adding access to Windows Studio Effects to the Quick Settings panel in Windows 11. When this feature is widely available, users will be able to turn on an effect quickly without a deep dive into Settings.
5. Improving Microsoft Account management
Windows Insiders participating in the Dev channel can now preview a new and improved version of the Windows 11 Account Manager. The new Account Manager now reveals more detailed information about the cloud storage available in your Microsoft account. This change is necessary because Microsoft has changed how cloud storage usage is measured. For example, Outlook attachments now count towards your total, and users will see that reflected in the Settings app.
For gamers, the new Windows 11 Account Manager in development will now also display detailed information about Xbox-related subscriptions, including Xbox Game Pass for Console, PC Game Pass, Xbox Game Pass Ultimate and Xbox Live Gold.
6. Improving voice access with new commands
Improved accessibility for impaired and special needs users continues to be a priority for Microsoft developers. WhileVoice Activationreceived many improvements in Windows 11 22H2, there are still more improvements in development. New voice commands and accommodations specifically related to Microsoft apps are available for preview in the Dev channel.
7. Adding a tabs feature to Notepad
Consistent with recent updates to other built-in Windows 11 apps, Microsoft is currently testing a new version of Notepad that will support tabs for separate files. This new feature will allow users to manage different documents using a single window. It also includes a redesigned indicator for unsaved changes in a document. This update is currently available for preview in both the Dev and Beta channels.
8. Adding a screen recorder to Snipping Tool
Available for preview to users participating in the Dev and Beta channels is an updated version of theWindows 11 Snipping Tool. This new version will add screen recording the apps capabilities.
When users activate this new record mode, they will then be asked to specify which area of the screen to record. Currently, the version under development only works with a single screen, but multiple screen capability may be in the works.
Participating in Dev and Beta channels
To get preview access to Windows 11 features and applications in development, all you have to do is join theWindows Insider program. The program is free and available to anyone.
Microsoft’sWindows Insider programis designed for developers, systems administrators, journalists and anyone else who wants to get a look at new features before major updates. It’s pretty much a Windows beta program that’s always open to the public.
Microsoft
Software
| https://www.techrepublic.com/article/windows-11-features-development/amp/ |
Households with a householder who is American Indian and Alaska Native alone - RC2000SF3_012_P146C001 - Households by Age of Hhldr by Household Type by Presence of Own Children < 18 Years (AIAN Alone Hhldr) - Census 2000 on 2010 Geographies Summary File 3 (Sample Data) (RC2000SF3) - Survey Census 2000 on 2010 Geographies - Social Explorer
Data Dictionary - Survey Census 2000 on 2010 Geographies; Census 2000 on 2010 Geographies Summary File 3 (Sample Data) (RC2000SF3); Households by Age of Hhldr by Household Type by Presence of Own Children <18 Years (AIAN Alone Hhldr); RC2000SF3_012_P146C001; Households with a householder who is American Indian and Alaska Native alone
Survey: Census 2000 on 2010 Geographies
Data Source:
U.S. Census Bureau & Social Explorer
Data set: Census 2000 on 2010 Geographies Summary File 3 (Sample Data) (RC2000SF3)
Table:
P146C. Households by Age of Hhldr by Household Type by Presence of Own Children <18 Years (AIAN Alone Hhldr) [31]
Universe: Households with a householder who is American Indian and Alaska Native alone
Variable Details
P146C.
Universe: Households with a householder who is American Indian and Alaska Native alone
RC2000SF3_012_P146C001 Households with a householder who is American Indian and Alaska Native alone
Percent base:
None - percentages not computed (variable is table universe)
Aggregation method:
Addition
Relevant Documentation:
Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Household Type and Relationship -> Household Household A household includes all of the people who occupy a housing unit. (People not living in households are classified as living in group quarters.) A housing unit is a house, an apartment, a mobile home, a group of rooms, or a single room occupied (or if vacant, intended for occupancy) as separate living quarters. Separate living quarters are those in which the occupants live separately from any other people in the building and that have direct access from the outside of the building or through a common hall. The occupants may be a single family, one person living alone, two or more families living together, or any other group of related or unrelated people who share living quarters. In 100-percent tabulations, the count of households or householders always equals the count of occupied housing units. In sample tabulations, the numbers may differ as a result of the weighting process. Average household size back to top A measure obtained by dividing the number of people in households by the total number of households (or householders). In cases where household members are tabulated by race or Hispanic origin, household members are classified by the race or Hispanic origin of the householder rather than the race or Hispanic origin of each individual. Average household size is rounded to the nearest hundredth. Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Age Age The data on age, which was asked of all people, were derived from answers to the long-form questionnaire Item 4 and short-form questionnaire Item 6. The age classification is based on the age of the person in complete years as of April 1, 2000. The age of the person usually was derived from their date of birth information. Their reported age was used only when date of birth information was unavailable. Data on age are used to determine the applicability of some of the sample questions for a person and to classify other characteristics in census tabulations. Age data are needed to interpret most social and economic characteristics used to plan and examine many programs and policies. Therefore, age is tabulated by single years of age and by many different groupings, such as 5-year age groups. Median age back to top Median age divides the age distribution into two equal parts: one-half of the cases falling below the median age and one-half above the median. Median age is computed on the basis of a single year of age standard distribution (see the "Standard Distributions" section under "Derived Measures"). Median age is rounded to the nearest tenth. (For more information on medians, see "Derived Measures".) Limitation of the data back to top The most general limitation for many decades has been the tendency of people to overreport ages or years of birth that end in zero or 5. This phenomenon is called "age heaping." In addition, the counts in the 1970 and 1980 censuses for people 100 years old and over were substantially overstated. So also were the counts of people 69 years old in 1970 and 79 years old in 1980. Improvements have been made since then in the questionnaire design and in the imputation procedures that have minimized these problems. Review of detailed 1990 census information indicated that respondents tended to provide their age as of the date of completion of the questionnaire, not their age as of April 1, 1990. One reason this happened was that respondents were not specifically instructed to provide their age as of April 1, 1990. Another reason was that data collection efforts continued well past the census date. In addition, there may have been a tendency for respondents to round their age up if they were close to having a birthday. It is likely that approximately 10 percent of people in most age groups were actually 1 year younger. For most single years of age, the misstatements were largely offsetting. The problem is most pronounced at age zero because people lost to age 1 probably were not fully offset by the inclusion of babies born after April 1, 1990. Also, there may have been more rounding up to age 1 to avoid reporting age as zero years. (Age in complete months was not collected for infants under age 1.) The reporting of age 1 year older than true age on April 1, 1990, is likely to have been greater in areas where the census data were collected later in calendar year 1990. The magnitude of this problem was much less in the 1960, 1970, and 1980 censuses where age was typically derived from respondent data on year of birth and quarter of birth. These shortcomings were minimized in Census 2000 because age was usually calculated from exact date of birth and because respondents were specifically asked to provide their age as of April 1, 2000. (For more information on the design of the age question, see the section below that discusses "Comparability.") Comparability back to top Age data have been collected in every census. For the first time since 1950, the 1990 data were not available by quarter year of age. This change was made so that coded information could be obtained for both age and year of birth. In 2000, each individual has both an age and an exact date of birth. In each census since 1940, the age of a person was assigned when it was not reported. In censuses before 1940, with the exception of 1880, people of unknown age were shown as a separate category. Since 1960, assignment of unknown age has been performed by a general procedure described as "imputation." The specific procedures for imputing age have been different in each census. (For more information on imputation, see "Accuracy of the Data.") Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Household Type and Relationship -> Relationship to Householder -> Householder Householder The data on relationship to householder were derived from the question, "How is this person related to Person 1," which was asked of Persons 2 and higher in housing units. One person in each household is designated as the householder (Person 1). In most cases, the householder is the person, or one of the people, in whose name the home is owned, being bought, or rented. If there is no such person in the household, any adult household member 15 years old and over could be designated as the householder (i.e., Person 1). Households are classified by type according to the sex of the householder and the presence of relatives. Two types of householders are distinguished: family householders and nonfamily householders. A family householder is a householder living with one or more individuals related to him or her by birth, marriage, or adoption. The householder and all of the people in the household related to him or her are family members. A nonfamily householder is a householder living alone or with nonrelatives only. Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Household Type and Relationship Household Type and Relationship Household back to top A household includes all of the people who occupy a housing unit. (People not living in households are classified as living in group quarters.) A housing unit is a house, an apartment, a mobile home, a group of rooms, or a single room occupied (or if vacant, intended for occupancy) as separate living quarters. Separate living quarters are those in which the occupants live separately from any other people in the building and that have direct access from the outside of the building or through a common hall. The occupants may be a single family, one person living alone, two or more families living together, or any other group of related or unrelated people who share living quarters. In 100-percent tabulations, the count of households or householders always equals the count of occupied housing units. In sample tabulations, the numbers may differ as a result of the weighting process. Average household size back to top A measure obtained by dividing the number of people in households by the total number of households (or householders). In cases where household members are tabulated by race or Hispanic origin, household members are classified by the race or Hispanic origin of the householder rather than the race or Hispanic origin of each individual. Average household size is rounded to the nearest hundredth. Relationship to Householder Householder back to top The data on relationship to householder were derived from the question, "How is this person related to Person 1," which was asked of Persons 2 and higher in housing units. One person in each household is designated as the householder (Person 1). In most cases, the householder is the person, or one of the people, in whose name the home is owned, being bought, or rented. If there is no such person in the household, any adult household member 15 years old and over could be designated as the householder (i.e., Person 1). Households are classified by type according to the sex of the householder and the presence of relatives. Two types of householders are distinguished: family householders and nonfamily householders. A family householder is a householder living with one or more individuals related to him or her by birth, marriage, or adoption. The householder and all of the people in the household related to him or her are family members. A nonfamily householder is a householder living alone or with nonrelatives only. Spouse (husband/wife) back to top A spouse (husband/wife) is a person married to and living with a householder. People in formal marriages, as well as people in common-law marriages, are included. The number of spouses is equal to the number of "married-couple families" or "married-couple households" in 100-percent tabulations. Marital status categories cannot be inferred from the 100-percent tabulations since the marital status question was not included on the 100-percent form. In sample tabulations, the number of spouses may not be equal to the number of married-couple households due to the differences in the weighting procedures for sample data. Child back to top A child is a son or daughter by birth, a stepchild, or an adopted child of the householder, regardless of the childs age or marital status. The category excludes sons-in-law, daughters-inlaw, and foster children. Natural-born son/daughter back to top Natural-born son/daughter includes a son or daughter of the householder by birth, regardless of the age of the child. Adopted son/daughter. back to top Adopted son/daughter includes a son or daughter of the householder by legal adoption, regardless of the age of the child. If a stepson/stepdaughter of the householder has been legally adopted by the householder, the child is then classified as an adopted child. Stepson/stepdaughter back to top Stepson/stepdaughter includes a son or daughter of the householder through marriage but not by birth, regardless of the age of the child. If a stepson/stepdaughter of the householder has been legally adopted by the householder, the child is then classified as an adopted child. Own child back to top Own child is a never-married child under 18 years who is a son or daughter of the householder by birth, marriage (a stepchild), or adoption. For 100-percent tabulations, 'own children' consist of all sons/daughters of householders who are under 18 years old. For sample data, 'own children' consist of sons/daughters of householders who are under 18 years old and who have never been married. Therefore, numbers of own children of householders may be different in these two tabulations since marital status was not collected as a 100-percent item in Census 2000. In certain tabulations, own children are further classified as living with two parents or with one parent only. Own children living with two parents are by definition found only in married-couple families. In a subfamily, an "own child" is a child under 18 years old who is a natural-born child, stepchild, or an adopted child of a mother in a mother-child subfamily, a father in father-child subfamily, or either spouse in a married-couple subfamily. (Note: In the tabulation under "EMPLOYMENT STATUS" of own children under 6 years by employment status of parents, the number of "own children" includes any child under 6 years old in a family or a subfamily who is a son or daughter, by birth, marriage, or adoption, of a member of the householder's family, but not necessarily of the householder.) Related children back to top Related children include the sons and daughters of the householder (including natural-born, adopted, or stepchildren) and all other people under 18 years old, regardless of marital status, in the household, who are related to the householder, except the spouse of the householder. Foster children are not included since they are not related to the householder. Other relatives back to top Other relatives include any household member related to the householder by birth, marriage, or adoption, but not included specifically in another relationship category. In certain detailed tabulations, the following categories may be shown: Grandchild back to top A grandchild is a grandson or granddaughter of the householder. Brother/sister back to top Brother/sister refers to the brother or sister of the householder, including stepbrothers, stepsisters, and brothers and sisters by adoption. Brothers-in-law and sisters-in-law are included in the "Other relative" category on the questionnaire. Parent back to top Parent refers to the father or mother of the householder, including a stepparent or adoptive parent. Fathers-in-law and mothers-in-law are included in the "Parent-in-law" category on the questionnaire. Parent-in-law back to top A parent-in-law is the mother-in-law or father-in-law of the householder. Son-in-law/daughter-in-law back to top A son-in-law/daughter-in-law, by definition, is a spouse of the child of the householder. Other relatives back to top Other relatives include anyone not listed in a reported category above who is related to the householder by birth, marriage, or adoption (brother-in-law, grandparent, nephew, aunt, cousin, and so forth). Nonrelatives back to top Nonrelatives include any household member not related to the householder by birth, marriage, or adoption, including foster children. The following categories may be presented in more detailed tabulations: Roomer, boarder back to top A roomer or boarder is a person who lives in a room in the household of Person 1 (householder). Some sort of cash or noncash payment (e.g., chores) is usually made for their living accommodations. Housemate or roommate back to top A housemate or roommate is a person who is not related to the householder and who shares living quarters primarily to share expenses. Unmarried partner back to top An unmarried partner is a person who is not related to the householder, who shares living quarters, and who has a close personal relationship with the householder. Foster child back to top A foster child is a person who is under 18 years old placed by the local government in a household to receive parental care. They may be living in the household for just a brief period or for several years. Foster children are nonrelatives of the householder. If the foster child is also related to the householder, the child should be classified as that specific relative. Other nonrelatives back to top 'Other nonrelatives' includes individuals who are not related by birth, marriage, or adoption to the householder and who are not described by the categories given above. Unrelated Individual back to top An unrelated individual is: (1) a householder living alone or with nonrelatives only, (2) a household member who is not related to the householder, or (3) a person living in group quarters who is not an inmate of an institution. Family Type back to top A family includes a householder and one or more other people living in the same household who are related to the householder by birth, marriage, or adoption. All people in a household who are related to the householder are regarded as members of his or her family. A family household may contain people not related to the householder, but those people are not included as part of the householder's family in census tabulations. Thus, the number of family households is equal to the number of families, but family households may include more members than do families. A household can contain only one family for purposes of census tabulations. Not all households contain families since a household may be comprised of a group of unrelated people or of one person living alone. Families are classified by type as either a "married-couple family" or "other family" according to the presence of a spouse. "Other family" is further broken out according to the sex of the householder. The data on family type are based on answers to questions on sex and relationship that were asked on a 100-percent basis. Married-couple family back to top This category includes a family in which the householder and his or her spouse are enumerated as members of the same household. Other family Male householder, no wife present back to top This category includes a family with a male maintaining a household with no wife of the householder present. Female householder, no husband present back to top This category includes a family with a female maintaining a household with no husband of the householder present. Nonfamily household back to top This category includes a householder living alone or with nonrelatives only. Average family size back to top A measure obtained by dividing the number of people in families by the total number of families (or family householders). In cases where this measure is tabulated by race or Hispanic origin, the race or Hispanic origin refers to that of the householder rather than to the race or Hispanic origin of each individual. Average family size is rounded to the nearest hundredth. Subfamily back to top A subfamily is a married couple with or without own children under 18 years old who are never-married, or a single parent with one or more own never-married children under 18 years old. A subfamily does not maintain their own household, but lives in a household where the householder or householders spouse is a relative. Subfamilies are defined during processing of sample data. In some labor force tabulations, both one-parent families and one-parent subfamilies are included in the total number of children living with one parent, while both married-couple families and married-couple subfamilies are included in the total number of children living with two parents. Unmarried-Partner Household back to top An unmarried-partner household is a household that includes a householder and an "unmarried partner." An "unmarried partner" can be of the same or of the opposite sex of the householder. An "unmarried partner" in an "unmarried-partner household" is an adult who is unrelated to the householder, but shares living quarters and has a close personal relationship with the householder. An unmarried-partner household may also be a family household or a nonfamily household, depending on the presence or absence of another person in the household who is related to the householder. There may be only one unmarried-partner per household, and an unmarried partner may not be included in a married-couple household as the householder cannot have both a spouse and an unmarried partner. Comparability back to top The 1990 relationship category, "Natural-born or adopted son/daughter" has been replaced by "Natural-born son/daughter" and "Adopted son/daughter." The following categories were added in Census 2000: "Parent-in-law" and "Son-in-law/daughter-in-law." The 1990 nonrelative category, "Roomer, boarder, or foster child" was replaced by two categories: "Roomer, boarder" and "Foster child." In 2000, foster children had to be in the local governments foster care system to be so classified. In 1990, foster children were estimated to be those children in households who were not related to the householder and for whom there were no people 18 years old and over who may have been their parents. In 1990, stepchildren who were adopted by the householder were still classified as stepchildren. In 2000, stepchildren who were legally adopted by the householder were classified as adopted children. Own children shown in 100-percent tabulations may be of any marital status. For comparability with previous censuses, own children shown for sample data are still restricted to never-married children. Some tables may show relationship to householder and be labeled "child." These tabulations include all marital status categories of natural-born, adopted, or stepchildren. Because of changes in editing procedures, same sex unmarried-partner households in 1990 should not be compared with same sex unmarried-partner households in Census 2000. Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Household Type and Relationship -> Relationship to Householder -> Child -> Own child Own child Own child is a never-married child under 18 years who is a son or daughter of the householder by birth, marriage (a stepchild), or adoption. For 100-percent tabulations, 'own children' consist of all sons/daughters of householders who are under 18 years old. For sample data, 'own children' consist of sons/daughters of householders who are under 18 years old and who have never been married. Therefore, numbers of own children of householders may be different in these two tabulations since marital status was not collected as a 100-percent item in Census 2000. In certain tabulations, own children are further classified as living with two parents or with one parent only. Own children living with two parents are by definition found only in married-couple families. In a subfamily, an "own child" is a child under 18 years old who is a natural-born child, stepchild, or an adopted child of a mother in a mother-child subfamily, a father in father-child subfamily, or either spouse in a married-couple subfamily. (Note: In the tabulation under "EMPLOYMENT STATUS" of own children under 6 years by employment status of parents, the number of "own children" includes any child under 6 years old in a family or a subfamily who is a son or daughter, by birth, marriage, or adoption, of a member of the householder's family, but not necessarily of the householder.) Excerpt from: Social Explorer, U.S. Census Bureau; 2000 Census of Population and Housing, Summary File 3: Technical Documentation, 2002. Summary File 3 Technical Documentation -> Appendix B. Definitons of Subject Characteristics -> Population Characteristics -> Race -> American Indian or Alaska Native American Indian or Alaska Native A person having origins in any of the original peoples of North and South America (including Central America) and who maintain tribal affiliation or community attachment. It includes people who classified themselves as described below. American Indian back to top This category includes people who indicated their race as "American Indian," entered the name of an Indian tribe, or reported such entries as Canadian Indian, French American Indian, or Spanish American Indian. American Indian tribe back to top Respondents who identified themselves as American Indian were asked to report their enrolled or principal tribe. Therefore, tribal data in tabulations reflect the written entries reported on the questionnaires. Some of the entries (for example, Iroquois, Sioux, Colorado River, and Flathead) represent nations or reservations. The information on tribe is based on self-identification and therefore does not reflect any designation of federally or state-recognized tribe. Information on American Indian tribes is presented in summary files. The information for Census 2000 is derived from the American Indian Tribal Classification List for the 1990 census that was updated based on a December 1997, Federal Register Notice, entitled " Indian Entities Recognized and Eligible to Receive Service From the United States Bureau of Indian Affairs," Department of the Interior, Bureau of Indian Affairs, issued by the Office of Management and Budget. Alaska Native back to top This category includes written responses of Eskimos, Aleuts, and Alaska Indians as well as entries such as Arctic Slope, Inupiat, Yupik, Alutiiq, Egegik, and Pribilovian. The Alaska tribes are the Alaskan Athabascan, Tlingit, and Haida. The information for Census 2000 is based on the American Indian Tribal Classification List for the 1990 census, which was expanded to list the individual Alaska Native Villages when provided as a written response for race.
| https://www.socialexplorer.com/data/RC2000/metadata/?ds=RC2000SF3&var=RC2000SF3_012_P146C001 |
SC0003 90th General Assembly
State of Illinois90 thGeneral AssemblyLegislation
90_SC0003
ILCON Art. IV, Sec. 8
Proposes to amend the Legislature Article of the Illinois
Constitution concerning the passage of bills. Provides that
after November 5, 1998, no portion of a bill may require a
unit of local government or school district to expend
additional public revenue unless the State appropriates the
required additional funds, the bill passes by at least a
three-fifths vote, the bill imposes a federal law that the
unit of local government or school district would otherwise
be required to meet by federal law or imposes a State or
federal court order with no additional requirements imposed
by the State, or the bill creates a criminal law or expands
or modifies the application or enforcement of criminal law.
Also applies to administrative rules, regulations, and
actions absent express and specific authority by law. Does
not apply to limits on the ability to raise revenue.
Effective upon approval by the electors.
LRB9000663KRks
LRB9000663KRks
1 SENATE JOINT RESOLUTION
2 CONSTITUTIONAL AMENDMENT
3 RESOLVED, BY THE SENATE OF THE NINETIETH GENERAL ASSEMBLY
4 OF THE STATE OF ILLINOIS, THE HOUSE OF REPRESENTATIVES
5 CONCURRING HEREIN, that there shall be submitted to the
6 electors of the State for adoption or rejection at the
7 general election next occurring at least 6 months after the
8 adoption of this resolution a proposition to amend Section 8
9 of Article IV of the Illinois Constitution as follows:
10 ARTICLE IV
11 THE LEGISLATURE
12 (ILCON Art. IV, Sec. 8)
13 SECTION 8. PASSAGE OF BILLS
14 (a) The enacting clause of the laws of this State shall
15 be: "Be it enacted by the People of the State of Illinois,
16 represented in the General Assembly."
17 (b) The General Assembly shall enact laws only by bill.
18 Bills may originate in either house, but may be amended or
19 rejected by the other.
20 (c) No bill shall become a law without the concurrence
21 of a majority of the members elected to each house. Final
22 passage of a bill shall be by record vote. In the Senate at
23 the request of two members, and in the House at the request
24 of five members, a record vote may be taken on any other
25 occasion. A record vote is a vote by yeas and nays entered on
26 the journal.
27 (d) A bill shall be read by title on three different
28 days in each house. A bill and each amendment thereto shall
29 be reproduced and placed on the desk of each member before
30 final passage.
31 Bills, except bills for appropriations and for the
32 codification, revision or rearrangement of laws, shall be
-2- LRB9000663KRks
1 confined to one subject. Appropriation bills shall be limited
2 to the subject of appropriations.
3 A bill expressly amending a law shall set forth
4 completely the sections amended.
5 The Speaker of the House of Representatives and the
6 President of the Senate shall sign each bill that passes both
7 houses to certify that the procedural requirements for
8 passage have been met.
9
(e) After November 5, 1998, no portion of any bill shall
10
require a unit of local government or school district to
11
establish, expand, modify, or increase its programs,
12
activities, or services in such a way as to necessitate the
13
expenditure of additional public revenue by a unit of local
14
government or school district, unless at least one of the
15
following applies:
16
(1) the State appropriates additional funds to the
17
unit of local government or school district that fully
18
fund the additional expenditures necessary to carry out
19
the requirement for each year the requirement is in
20
effect;
21
(2) the bill passes with the concurrence of at
22
least three-fifths of the members elected to each house;
23
(3) that portion of the bill imposes a federal law
24
that the unit of local government or school district
25
would otherwise be required to meet by federal law or
26
imposes a State or federal court order, with no
27
additional requirements imposed by the State; or
28
(4) that portion of the bill creates, expands, or
29
modifies a specifically defined crime.
30
A law enacted after November 5, 1998 may not be the basis
31
for administrative rules, restrictions, or actions that
32
require a unit of local government or school district to
33
establish, expand, modify, or increase its programs,
34
activities, or services in such a way as to necessitate the
-3- LRB9000663KRks
1
expenditure of additional public revenue by a unit of local
2
government or school district, unless the law authorizes the
3
rules, regulations, or actions. This subsection (e) does not
4
apply to any portion of a bill that limits or regulates the
5
ability of a unit of local government or school district to
6
raise revenue.
7 (Source: Illinois Constitution.)
8 SCHEDULE
9 This Constitutional Amendment takes effect upon approval
10 by the electors of this State.
| https://www.ilga.gov/legislation/legisnet90/srgroups/sr/900SC0003LV.html |
Starting Strength Forums
200/300/400/500
Thread: 200/300/400/500
Strength Squat: 330 x 3s x 5r Bench: 230 x 5s x 3r Bench: 215 x 2s x 5r Volume Squat: 4,950 Bench: (3,450 + 2,150 = 5,600) ------------------------ Total: 10,550 ***************** Would have liked to have lifted more. Had a lot of energy. But HW was due at midnight so I had to hustle home. At least I broke 10k in volume. The triples on bench got easier and easier as I went on. I wanted to hit 5's on the last two sets.
Squat: 385 x 1 x 1 Press: 185 x 1 x 1 *************** I will press 200lbs in 2017.
I'll be surprised if you don't get 200 this year, hector! Good things come to those who work hard!
Originally Posted by Oldster
I'll be surprised if you don't get 200 this year, hector! Good things come to those who work hard!
Thanks, Oldster! That's my plan!
Strength Deads: 425 x 1s x 5r Deads: 405 x 2s x 5r Press: 170 x 3s x 5r Press: 150 x 4s x 5r Bonus Work Leg Press: 450 x 1s x 5r Leg Press: 540 x 2s x 5r T-Bar: 180 x 4s x 5r Grip CoC #1: 3s x 10r (quality of reps dropped off severely in third set.) Volume Deads: (2,125 + 4,050) = 6,175 Press: (1,530 + 3,000) = 4,530 ---------------------------- Total: 10,705 *************************** Initially I planned on doing only one set of deads because my lower back was sore and tight. After the first set I felt awesome so did two more. Would have done more still, but time was limited and my goals right now are both presses, so I need to prioritize pressing. When I got to the gym all the racks were taken except one. So I thought there was a place for me to train. The f'er next to me had taken the barbell from the rack I planned on using and was using two barbells so he could so some kind of crossfit workout very slowly with lots of breaks. He had the same weight on both bars, 135 lbs. He was alternating deads with squats. I asked him if he really needed both barbells. He said yes. I asked if he knew how to power clean. He said yes. I asked why he couldn't just power clean the barbell after deads and then rack the barbell for squats. He mumbled a response I didn't understand and put his headphones back on. The conversation was, I guess, over. My guess is that he either couldn't power clean the 135, or else was embarrassed because he hadn't thought of such an obvious solution. Earlier today I was so sore that I wondered if I had it in me to do a real workout tonight. Thought maybe I should take it easy instead, just go for a few 1RM's and call it a day. Then I went to a monster Japanese buffet for lunch and had lots of sushi. Which put me into a mild coma when I went back to work and threatened to impact my productivity. But then my energy levels came soaring back when I left work. Could this be an unhealthy diet practice leading to pre-diabetes? Maybe. Did it help me hit my weights? Definitely.
Strength Squat: 335 x 3s x 5r Bench: 235 x 3s x 3r Bench: 215 x 4s x 5r Other Ab Wheel: 1s x 5r Grip CoC(1): 5s x 5r CoC(S): 50R, upside down Volume Squat: 5,025 Bench: (2,115 + 4,300) = 6,415 ------------------------ Total: 11,440 ************************** Benching was good. Thoughts for now are that I'll run some heavier sets of 3's, then follow up with some backup sets of 5's. Just like the other day I felt great and would have liked to have done some more, but time was short.
Bench: 260 x 1 x 1 Squat: 365 x 2s x 1r ***************** Good times. Bench isn't an all time PR, but it's more than 90% of one, and it's a PR for 2017 so far.
Good times and good work, hector. Your bench is doing well!
Your press had really jumped up there.
Originally Posted by vanslix
Your press had really jumped up there.
Thanks!
I just realized my workout above had a typo. I didn't press 170 x 3s x 5r, I pressed 170 x 3s x 3r.
Still working and advancing bit by bit though!
| https://startingstrength.com/resources/forum/general-training-logs/57930-200-300-400-500-a-119.html |
Brain Sciences | Free Full-Text | Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile
Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.
Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile
Yen-Kuang Lin 3 ,
Jing-Huei Lai 4,5 ,
Yu-Chun Lo 6 ,
Yu-Chen S. H. Yang 7 ,
Syuan-You Ye 1 ,
Chia-Jung Lee 8,9 ,
Ching-Chiung Wang 10 ,
Yung-Hsiao Chiang 4,5,11,12 and
Sung-Hui Tseng 13,14,*
1
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
Graduate Institute of Athletics and Coaching Science, National Taiwan Sport University, Taoyuan 333, Taiwan
4
Core Laboratory of Neuroscience, Office of R&D, Taipei Medical University, Taipei 110, Taiwan
5
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 110, Taiwan
6
PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
7
Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 110, Taiwan
8
PhD Program for Clinical Drug Discovery of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
9
Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
10
Department of Pharmaceutical Sciences, Taipei Medical University, Taipei 110, Taiwan
11
Department of Surgery, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
12
Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
13
14
Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei 110, Taiwan
Author to whom correspondence should be addressed.
Brain Sci. 2021 , 11 (8), 1085; https://doi.org/10.3390/brainsci11081085
Received: 16 July 2021 / Revised: 16 August 2021 / Accepted: 16 August 2021 / Published: 18 August 2021
(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: from In Vitro to In Vivo Models )
Abstract
:
Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of
Alistipes
,
Fusobacterium
, and
Ruminococcus
and a lower abundance of
Coprococcus
,
Erysipelotrichaies
, and
Actinobacteria
than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of
Alistipes
and
Actinobacteria
was the most relevant for the profile of defective social behavior, whereas
Fusobacterium
and
Coprococcus
was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.
Keywords:
autism spectrum disorder
;
lipopolysaccharide
;
maternal immune activation
;
microbiota
;
three-chamber test
;
myelination
;
brain–gut–microbiota axis
;
social behavior deficits
Graphical Abstract
1. Introduction
Maternal immune activation (MIA) has been linked to an increased risk of neurodevelopmental psychiatric disorders in offspring [ 1 , 2 ]. Animal models of MIA have been developed by activating the immune system with immunogens during pregnancy and then observing the development of defective behaviors in offspring with autism-like behavior [ 3 ]. MIA generates inflammatory cytokines to which the fetus is exposed during mid-gestation, possibly affecting fetal brain development [ 4 ]. Furthermore, the presence of inflammatory molecules and cytokines can affect central nervous system development [ 5 ] and adversely affect neuron survival [ 6 ].
Gut microbiota plays a critical role in regulating host physiology, metabolism, nutrition, and brain function [
7
]. Microbial dysbiosis is correlated with various adverse consequences, including behavioral abnormalities, neuropathology, immune dysfunction, and deficient gastrointestinal integrity [
7
]. The prenatal environment affects the microbiome of offspring [
8
]. Microbial dysbiosis is associated with the symptoms of autism spectrum disorder (ASD), including impaired social communication and repetitive behaviors [
9
]. However, how prenatal infection affects the brain–gut–microbiota axis, which regulates behavioral phenotypes, remains unclear.
Maternal lipopolysaccharide (LPS) exposure causes reproductive, behavioral, and neurochemical abnormalities in offspring [ 10 ]. LPS, an endotoxin, activates immune cells to release proinflammatory cytokines, which induce maternal cytokine responses and may increase the risk of atypical brain development [ 11 ]. Prenatal LPS treatment causes social behavior deficits in male offspring [ 9 , 12 ]. Pregnant rats injected with intraperitoneal LPS on gestation day (GD) 9.5 were demonstrated to induce the most relevant long-term neuropathological consequences in offspring [ 13 , 14 ]. However, the microbiota changes have not been quantified in these MIA offspring.
In this study, we investigated the relationship between microbiota and ASD-related behavior and demonstrated brain myelination changes in MIA offspring. Furthermore, we used the least absolute shrinkage and selection operator (LASSO) method to determine the most relevant microbiota genera associated with ASD-related behaviors. Taken together, we demonstrated that an abnormal brain–gut–microbiota axis with phenotypes includes a social behavior deficit, anxiety-like and repetitive behavior, hypomyelination, and dysbiosis microbiota in MIA offspring; thus, providing a link between maternal infection and the etiopathogenesis of ASD.
2. Materials and Methods
2.1. LPS-Induced MIA Rat Model
All animal procedures were approved by the Animal Care and Use Committees of Taipei Medical University. Eight-week-old Wistar female rats (BioLASCO, Taipei, Taiwan) in their first pregnancy were used in this study. Female rats were mated overnight with male rats with mating experience and were checked for the presence of a vaginal plug the subsequent morning to confirm mating. Pregnant rats were housed individually and allowed to raise their own litters until weaning. On GD 9.5, 500 μg/kg LPS (
Escherichia coli
O127:B8) or phosphate-buffered saline (PBS) was injected intraperitoneally into pregnant rats. Litters were left undisturbed until weaning at postnatal day 21. Offspring were housed in same-sex cages containing three rats until the end of the experiments. All animals were housed in temperature-controlled rooms under a 12 h light/dark cycle with ad libitum access to water and same food. All behavioral testing was performed during rats’ light cycle between 9 a.m. and 5 p.m. The experiments were performed in accordance with guidelines by the International Council for Laboratory Animal Science (ICLAS) for the care and use of laboratory animals for experiments.
2.2. Three-Chamber Test
The three-chamber social interaction test was adapted from a previous study [ 15 ]. Stranger rats were age- and sex-matched with the testing rats. The body weights of stranger rats at 5 and 7 weeks were 130 and 195 g, respectively. Stranger rat was placed in the right-side chamber of three-chambered apparatus (Deep Brain Tech, Taiwan) to test the social interaction between stranger and the test rat during a 10 min test session ( Figure 1 B). The left chamber remained empty. The sociability score, used to measure the social preference of test rat was defined as the time spent in the social region of the central space near stranger rat during test session ( Figure 1 B). Test rat’s behavior was recorded using a camera (The Imaging Source, DFK 33UP1300, Bremen, Germany). OptiMouse software was used to calculate the total time spent by rats in three zones of the central space (nonsocial, center, and social regions) in a three-chambered apparatus ( Figure 1 B).
2.3. Marble-Burying Test
The marble-burying test was used to examine the test rat’s anxiety-like and repetitive behavior. A clean cage (22 × 45 × 20 cm 3 ) was prepared with a 4 cm corncob bedding material containing 20 embedded marbles. After 30 min, the number of marbles that remained buried in the corncob bedding was recorded.
2.4. Novel Object Recognition Test
Recognition memory was evaluated using the novel object recognition (NOR) test, which was used to compare the amount of time a rat spent investigating a novel object versus a familiar object. The familiar object was a plastic square block, and the novel object was a plastic V-shaped block. First, rats were habituated to an open-field Plexiglas arena (60 × 60 × 100 cm
3
) for 10 min. After habituation, the rats were allowed to explore two identical familiar objects for 10 min during the familiarization phase. After a 24 h intertrial interval, one familiar object was replaced with a novel object, and the rats were returned to the arena and allowed to explore the two objects. A preference index, which measured the time spent by the test rat exploring the novel object over the familiar one, was calculated as a percentage using the following equation: ((Time N − Time F)/(Time N + Time F)) × 100, where F and N represent the time spent near the familiar and novel objects, respectively.
2.5. Open-Field Test
Using an open-field test, we evaluated the general motor activity and anxiety-related exploratory activity in the MIA and control rats. Rats were first habituated to an open-field Plexiglas arena (60 × 60 × 100 cm 3 ) for 10 min. Their locomotor activity and anxiety-like behavior were monitored for 10 min using open-field tests and recorded using an EthoVision system. General locomotor activity was defined as the total distance traveled in the open field. Anxiety-like behavior was measured based on the number of entries and retention times in the wall zone of the open field. The center of the open field was defined as a 30 × 30-cm 2 area in the geometric center of the arena. The wall zone was defined as a peripheral zone 5 cm from all four sides.
2.6. 16S rRNA Gene Sequencing and Next-Generation Sequencing
The stool samples of the rats were purified using the QIAamp Fast DNA Stool Mini Kit (QIAGEN, Germany). Library preparation was conducted following the protocol of 16S ribosomal RNA gene amplicons for the Illumina MiSeq system. Sequence reads were deposited in the European Nucleotide Archive (accession number: PRJEB28574). Universal primers (341F and 805R) were used to amplify the V3–V4 region of bacterial 16S rRNA genes; they were first removed from demultiplexed, paired reads using Cutadapt (v1.12; DOI:10.14806/ej.17.1.200). The filtered reads were then processed using the DADA2 package (v1.3.5) in R (v3.3.3) [ 16 ], following the workflow described by Callahan et al. [ 17 ], but without the rarefying procedure. Briefly, the forward and reverse reads were filtered and trimmed based on the read quality score and read length. Dereplication was then performed to merge identical reads, and the reads were then subjected to the denoising algorithm DADA2; the reads alternated between error rate estimation and sample composition inference until they converge into a consistent solution. Finally, paired reads with ≥20-bp overlap were merged, and chimeras were removed. A list of V3–V4 sequence variants found in the samples, which were inferred with DADA2, and the frequency of each sequence variant in each sample were obtained. Taxonomy assignment was performed using the SILVA database (v128) [ 18 ] for reference with a minimum bootstrap confidence of 80. Multiple sequence alignment of variants was performed using DECIPHER (v2.2.0) and the phylogenetic tree was constructed from the alignment using phangorn (v2.2.0) [ 19 ]. The count table, taxonomy assignment results, and phylogenetic tree were consolidated into a phyloseq object, and community analyses were performed using phyloseq (v1.19.1) [ 20 ]. The alpha-diversity indices were calculated using the estimated richness function of the phyloseq package. Data from the treatment and control groups were compared using the Wilcoxon–Mann–Whitney test (at α = 0.05). UniFrac distances were calculated using the GUniFrac package (v1.1) to assess community dissimilarity between the groups [ 21 ]. Principal coordinate analysis ordination on UniFrac distances was performed, and the adonis and betadisper functions from the vegan package (v2.4; https://CRAN.R-project.org/package=vegan , accessed on 24 August 2017) were used to analyze the dissimilarity of composition among the groups and the homogeneity of dispersion, respectively. Vegan is R package which provides tools for descriptive community ecology. It includes functions of diversity analysis, community ordination, and dissimilarity analysis. Adonis and Betadisper are the sister functions of Vegan package. Adonis analyzes and partitions the sum of squares using distance matrices. It can be seen as an ANOVA using distance matrices (analogous to MANOVA—multivariate analysis of variance). Therefore, it could test if two or more groups have similar compositions. Betadisper first calculates the average distance of group members to the group centroid in multivariate space (generated by a distance matrix). Then, an ANOVA is conducted to test if the dispersions (variances) of groups are different.
2.7. LASSO Method
In the LASSO algorithm, the feature importance was ranked in the framework of general linear models. Specifically, Tibshirani’s LASSO method was adopted (Tibshirani, 1996). LASSO arises from a constrained form of ordinary least squares regression, where the sum of the absolute values of the regression coefficients is constrained to be smaller than a specified parameter. The LASSO procedure offers extensive capabilities for customizing the selection with a wide variety of selection and stopping criteria, such as the Akaike information criterion (AIC).
2.8. Immunohistochemistry
The rats were euthanized and transcardially perfused with 25 mL of PBS and 4% paraformaldehyde. Whole brains were fixed with 4% paraformaldehyde for approximately 3 days. Paraformaldehyde-fixed 2 mm coronal slices were embedded in paraffin and cut into 5 µm thick sections, which were deparaffinized and rehydrated using a graded series of ethanol solutions. The sections then underwent an antigen retrieval process and were stained using horseradish peroxidase anti-myelin basic protein (MBP) antibody (BioLegend, catalog number 808405). Next, 3,3′-diaminobenzidine and hematoxylin staining was performed on sections by using the Chemicon IHC Select system (Millipore, catalog number DAB050). The sections were observed through microscopy (Olympus/Bx43). The MBP-positive area was calculated from sections by using HistoQuest tissue analysis software V2.0 (TissueGnostics, Vienna, Austria).
2.9. Statistical Analysis
Unpaired t -test were performed for behavioral data analyses using GraphPad Prism software. Error bars represent the standard error of mean. Microbiota enrichment analysis between the groups was conducted using the linear discriminant analysis (LDA) effect size (LEfSe) method. Data were compared using the Kruskal–Wallis and Wilcoxon tests; differences were considered significant at p ≤ 0.05 and a logarithmic LDA score of ≥ 2 [ 22 ]. Data were visualized as cladograms created using GraPhlAn [ 23 ].
3. Results
3.1. Maternal LPS Stimulation Causes Social Behavior Deficits and Anxiety-Like and Repetitive Behavior in MIA Male Offspring
No significant alterations in reproductive parameters were found in female rats exposed to prenatal LPS treatment (LPS-treated group) or PBS treatment (control group). The number of pups born in each litter, the parturition day, or individual bodyweight of offspring at 5 and 7 weeks showed no significant difference between prenatal LPS and PBS treatments (data not shown). To test whether MIA offspring began displaying social behavior deficits before or after sexual maturity, we examined their social behavior at 5 and 7 weeks. We used OptiMouse software to track the movement of rats in our three-chamber apparatus during the social behavior tests. Male offspring from the prenatal LPS-treated group spent less time in the social region of the central space in the three-chamber apparatus than those from the PBS-treated control group at both 5 and 7 weeks (
Figure 1
B,C), whereas female offspring had a normal social behavior (data not shown). Thus, male MIA offspring displayed social behavior deficits before and after sexual maturity. MIA male offspring also buried more marbles than the control male offspring (
Figure 1
D), which indicates anxiety-like and repetitive behavior. MIA and control male offspring had no differences in the total distance moved, number of entries, or time spent in the wall zone of the open-field assay (
Figure 1
E). Male offspring from the LPS group demonstrated a similar preference for the novel object compared with male offspring from the control group (
Figure 1
F). Taken together, the results revealed that locomotor activity and cognition were similar in LPS and control groups.
3.2. Fecal Microbiome Profile in Male MIA Offspring Is Similar to That of Patients with ASD
The gut microbiota profile in ASD was determined by identifying fecal microbiota through 16S rRNA gene sequencing and next-generation sequencing [ 24 ]. We observed that the fecal microbiota of prenatal LPS-treated male offspring had slightly, but not significantly, higher alpha diversity than that of the control offspring ( Figure 2 A). An unweighted and weighted UniFrac principal coordinate analysis indicated that the fecal microbiota profile of male MIA offspring was significantly different from that of PBS-treated male offspring ( Figure 2 B). A significant increase in Fusobacteria abundance and decrease in Actinobacteria abundance at the phylum level of microbial composition was observed in MIA offspring compared with that in control offspring ( Figure 3 and Table 1 ). Compared with control offspring, MIA male offspring had a significantly increased abundance of Fusobacteriaceae and Rikenellaceae families ( Figure 4 A), and significantly decreased abundance of Micrococcaceae , Staphylococcaceae , Aerococcaceae , Corynebacteriaceae , and Erysipelotrichaceae families ( Figure 4 B). At the genus level, compared with control offspring, MIA male offspring had significantly increased Ruminococcus_1 , Fusobacterium , Acetatifactor , Alistipes , and DNF00809 ( Figure 4 C), and significantly decreased Coprococcus_3 , Rothia , Sellimonas , Staphylococcus , Aerococcus , Corynebacterium_1 , Candidatus_Stoquefichus , and Blautia ( Figure 4 D).
3.3. Association of Fecal Microbiome Profile with Social Behavior and Anxiety-Like and Repetitive Behavior in MIA Male Offspring
The increased abundance of Alistipes , Fusobacterium , and Ruminococcus and decreased abundance of Coprococcus [ 25 , 26 , 27 ], Erysipelotrichaies , and Actinobacteria in LPS-induced MIA offspring were consistent with that of humans with ASD [ 28 , 29 , 30 ]. Next, we determined the association of ASD-related microbiota (increased or decreased amount of microbiota in the LPS group) with the level of the social behavior deficit and with anxiety-like and repetitive behavior by using the LASSO method. The LASSO procedure offers extensive capabilities to build a model that can determine the coefficient progression of selected microbiota with the profile of the indicated phenotypes (social behavior time and the percentage of buried marbles). The AIC method was applied to determine which microbiota profile was the best fit for the model that could reflect the profile of social behavior time and anxiety-like and repetitive behavior. Figure 5 A indicates that the AIC values of Alistipes and phylum Actinobacteria were the smallest in terms of the information loss; thus, the abundance of Alistipes and phylum Actinobacteria had a higher association level with the profile of defective social behavior than the other microbiota, and Fusobacterium and Coprococcus had a higher association level with the profile of buried marble percentage based on AIC ( Figure 5 B).
3.4. Maternal LPS Stimulation Causes Hypomyelination in the Prefrontal Cortex and Thalamus Nucleus in MIA Male Offspring
Prenatal LPS stimulation at gestation days 15 and 16 causes abnormal myelination in the cortical and limbic brain regions in offspring [ 31 ]. In our study, prenatal LPS stimulation at gestation day 9.5 resulted in a significantly decreased MBP + area in the prefrontal cortex ( Figure 6 A) and thalamic nucleus ( Figure 6 B) of the male MIA offspring (LPS group) than in control offspring by immunohistochemistry staining. In other words, maternal LPS stimulation caused hypomyelination in the prefrontal cortex and thalamic nucleus of adult male offspring.
4. Discussion
MIA causes an altered brain–gut–microbiota profile in male offspring, with autism-like phenotypes. In this study, we demonstrated that prenatal LPS stimulation caused altered social behavior and anxiety-like and repetitive behavior in male offspring, as revealed by our three-chamber test and marble-burying test, respectively. The NOR test and open-field assay demonstrated that MIA male offspring had a behavior profile similar to that of control offspring, indicating normal recognition memory and locomotor activity. MIA-induced hypomyelination in the prefrontal cortex and thalamic nucleus and altered microbiota profile provided evidence to show that LPS stimulation in the gestation stage causes altered brain–gut–microbiota axis phenotypes in offspring.
Patients with ASD have alterations in the gut microbiota composition compared with individuals without ASD [ 7 , 9 ]. In the present study, the gut microbiota diversity in male MIA offspring with ASD phenotypes was similar to the fecal microbiota profiles of children with ASD, such as a significant increase in Ruminococcus , Fusobacterium , and Alistipes [ 25 , 26 , 27 ]. We also observed a significant reduction in Coprococcus , Erysipelotrichaies , and Actinobacteria , which is consistent with the results of previous studies [ 28 , 29 , 30 ]. Compared with children without ASD, multiple microbiota species are elevated or reduced in children with ASD who have complex neurodevelopmental disorders involving disruptions in language and social behavior, restricted interests, and repetitive behaviors [ 9 ]. Microbiota transfer therapies have reported an improvement in ASD behavioral symptoms [ 32 , 33 ], suggesting that correcting the altered microbiota profile is a promising treatment strategy for ASD. Among the various changed microbiota species in MIA offspring, we demonstrated that the abundance of Alistipes and Actinobacteria was associated with the profile of social behavior, and Fusobacterium and Coprococcus was associated with the profile of anxiety-like and repetitive behavior; this suggests that Alistipes, Actinobacteria, Fusobacterium, and Coprococcus may be microbiome biomarkers or treatment targets for ASD.
MIA animal models are unique experimental tools for overcoming the limitations of epidemiological studies, such as the longitudinal evaluation of neurobiological processes from gestation to adulthood. Maternal exposure to LPS induces hypomyelination in the internal capsule and in newborn rats [ 34 ]. Maternal valproic acid stimulation causes hypomyelination of the prefrontal cortex and has been associated with social behavior deficit [ 35 ]. Poly I:C-induced MIA stimulation also causes a disruption in the myelin structure and a weakened thalamocortical connection in offspring [ 36 ]. In the present study, prenatal LPS-induced MIA caused the following changes in adult offspring: social behavior deficit, anxiety-like and repetitive behavior, ASD-related microbiota, and hypomyelination in the prefrontal cortex and thalamic nucleus. Prenatal LPS stimulation causes the inflammatory responses in brain of MIA offspring. The elevated levels of inflammatory cytokine (TNF-α and IL-1β) in the gestational stage are associated with behavioral impairment and hypomyelination [ 34 , 37 ]. The activation of an inflammatory reaction, including pro-inflammatory and anti-inflammatory cytokines, is associated with ASD [ 38 , 39 , 40 , 41 ]. In addition, poly I:C-induced MIA increases TNF-α and IL-1β expression in the colon of MIA offspring with an altered microbiota profile [ 42 ]. These results suggest that maternal LPS stimulation might impart an inflammatory reaction that is associated with an altered brain–gut–microbiota axis. Together, these findings suggest that MIA stress alters the brain–gut–microbiota axis leading to an inflammatory reaction, defective myelination and abnormal microbiota in offspring in ASD-related behavior deficits.
The most commonly used MIA animal models are prenatal poly I:C and LPS stimulation in pregnant animals. Poly I:C is a synthetic analogue of the viral double-strand RNA which activates Toll-like receptors (TLR)-3, whereas LPS is an endotoxin from Gram-negative bacteria which activates TLR-4 [ 43 ]. Prenatal poly I:C stimulation can alter the MIA microbiota profile in MIA offspring with a behavior impairment [ 29 , 42 , 44 , 45 ]. However, the link of an altered microbiota and social behavior impairment remains unclear in the LPS-induced MIA animal model. A previous study demonstrated several different effects of poly I:C and LPS prenatal stimulation on the behavior, development, and inflammatory response in pregnant mice and their offspring [ 46 ]. For example, prenatal LPS stimulation caused a decrease in the astrocytic marker (GFAP) and neuronal marker (NeuN) expression level in offspring at GD18, whereas GFAP and NeuN expression levels were not altered in the poly I:C-induced MIA model [ 46 ]. In addition, plasma cytokine IL-2, IL-5, IL-6, and inflammatory marker mGLuR5 were significantly increased in the brain of poly I:C-induced MIA offspring, but not in LPS-induced MIA offspring [ 46 ]. In this study, we found that human ASD-related Ruminococcus are increased in the LPS-induced MIA model, whereas Ruminococcus are decreased in the poly I:C-induced MIA model [ 29 ]. Taken together, different prenatal stimulation sources (virus or bacteria) may induce a differential profile of brain cell markers and microbiota profile in MIA offspring.
The prevalence of ASD is higher in males, with an approximate male-to-female ratio of 3:1 [ 47 ]. In this study, our MIA female offspring had normal social behavior when compared to the control group. In addition, sex may affect the microbiota profile [ 48 ]. For example, Coprococcus was less present in the microbiota profile of male mice compared to female mice [ 49 ]. These data were consistent to our study, revealing a decreased number of Coprococcus in the microbiota profile of male rats compared to female rats (data not shown). A human study showed that healthy males possess higher levels of Fusobacterium than females [ 50 ]. In an ASD predominantly male cohort study (18 males and 2 females), ASD children had decreased Coprococcus than the healthy subjects [ 28 ]. Another study showed that ASD patients with constipation (25 male and 5 female subjects) had increased Fusobacterium compared with healthy subjects [ 26 ]. Taken together, this evidence suggests that the differences in microbiota profiles between male and female subjects may be correlated to the altered microbiota profiles of ASD patients.
5. Conclusions
In the present study, LPS-induced MIA offspring displayed altered brain–gut–microbiota axis phenotypes, including social behavior deficits, anxiety-like and repetitive behavior, a human ASD-like microbiota profile (higher abundance of
Alistipes
,
Fusobacterium
, and
Ruminococcus
and a lower abundance of
Coprococcus
,
Erysipelotrichaies
, and
Actinobacteria
than control offspring), and hypomyelination in the prefrontal cortex and thalamic nucleus. An abundance of
Alistipes
and
Actinobacteria
was the most relevant for the profile of defective social behavior, whereas the abundance of
Fusobacterium
and
Coprococcus
was associated with anxiety-like and repetitive behavior. These potential ASD-related microbiomes require further studies to prove their direct association to ASD-related behavior, such as fecal transplantation or target microbiome transplantation therapy. The relative mechanisms of ASD etiopathogenesis still remain unknown and further studies are needed to prove the cause–effect relations between microbiome dysbiosis and ASD. Our findings provide insights into the relationship between maternal infection and the etiopathogenesis of ASD with an abnormal brain–gut–microbiota axis.
Conceptualization, G.A.L. and S.-H.T.; methodology, G.A.L. and Y.-K.L.; software, G.A.L.; validation, G.A.L.; formal analysis, Y.-K.L. and Y.-C.S.H.Y.; investigation, S.-Y.Y., J.-H.L. and Y.-C.L.; resources, S.-Y.Y., C.-J.L., C.-C.W. and Y.-H.C.; data curation, G.A.L.; writing—original draft preparation, G.A.L.; writing—review and editing, G.A.L.; visualization, G.A.L.; supervision, S.-H.T.; project administration, S.-H.T.; funding acquisition, S.-H.T. All authors have read and agreed to the published version of the manuscript.
Funding
References
Atladottir, H.O.; Thorsen, P.; Ostergaard, L.; Schendel, D.E.; Lemcke, S.; Abdallah, M.; Parner, E.T. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 2010 , 40 , 1423–1430. [ Google Scholar ] [ CrossRef ]
Ciaranello, A.L.; Ciaranello, R.D. The neurobiology of infantile autism. Annu. Rev. Neurosci. 1995 , 18 , 101–128. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Careaga, M.; Murai, T.; Bauman, M.D. Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol. Psychiatry 2017 , 81 , 391–401. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Dahlgren, J.; Samuelsson, A.M.; Jansson, T.; Holmang, A. Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatr. Res. 2006 , 60 , 147–151. [ Google Scholar ] [ CrossRef ][ Green Version ]
Boksa, P. Effects of prenatal infection on brain development and behavior: A review of findings from animal models. Brain Behav. Immun. 2010 , 24 , 881–897. [ Google Scholar ] [ CrossRef ]
Qiu, Z.; Sweeney, D.D.; Netzeband, J.G.; Gruol, D.L. Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J. Neurosci. 1998 , 18 , 10445–10456. [ Google Scholar ] [ CrossRef ]
Vuong, H.E.; Hsiao, E.Y. Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder. Biol. Psychiatry 2017 , 81 , 411–423. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Conway, F.; Brown, A.S. Maternal Immune Activation and Related Factors in the Risk of Offspring Psychiatric Disorders. Front. Psychiatry 2019 , 10 , 430. [ Google Scholar ] [ CrossRef ]
Rosenfeld, C.S. Microbiome Disturbances and Autism Spectrum Disorders. Drug Metab. Dispos. 2015 , 43 , 1557–1571. [ Google Scholar ] [ CrossRef ][ Green Version ]
Golan, H.M.; Lev, V.; Hallak, M.; Sorokin, Y.; Huleihel, M. Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy. Neuropharmacology 2005 , 48 , 903–917. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Jonakait, G.M. The effects of maternal inflammation on neuronal development: Possible mechanisms. Int. J. Dev. Neurosci. 2007 , 25 , 415–425. [ Google Scholar ] [ CrossRef ]
Kirsten, T.B.; Taricano, M.; Maiorka, P.C.; Palermo-Neto, J.; Bernardi, M.M. Prenatal lipopolysaccharide reduces social behavior in male offspring. Neuroimmunomodulation 2010 , 17 , 240–251. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Meyer, U.; Yee, B.K.; Feldon, J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: The earlier the worse? Neuroscientist 2007 , 13 , 241–256. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Meyer, U.; Nyffeler, M.; Engler, A.; Urwyler, A.; Schedlowski, M.; Knuesel, I.; Yee, B.K.; Feldon, J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J. Neurosci. 2006 , 26 , 4752–4762. [ Google Scholar ] [ CrossRef ][ Green Version ]
Wu, H.F.; Chen, P.S.; Hsu, Y.T.; Lee, C.W.; Wang, T.F.; Chen, Y.J.; Lin, H.C. D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model. Mol. Neurobiol. 2018 , 55 , 4811–4824. [ Google Scholar ] [ CrossRef ]
Callahan, B.J.; McMurdie, P.J.; Rosen, M.J.; Han, A.W.; Johnson, A.J.; Holmes, S.P. DADA2: High-resolution sample inference from Illumina amplicon data. Nat. Methods 2016 , 13 , 581–583. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Callahan, B.J.; Sankaran, K.; Fukuyama, J.A.; McMurdie, P.J.; Holmes, S.P. Bioconductor Workflow for Microbiome Data Analysis: From raw reads to community analyses. F1000Research 2016 , 5 , 1492. [ Google Scholar ] [ CrossRef ]
Quast, C.; Pruesse, E.; Yilmaz, P.; Gerken, J.; Schweer, T.; Yarza, P.; Peplies, J.; Glockner, F.O. The SILVA ribosomal RNA gene database project: Improved data processing and web-based tools. Nucleic Acids Res. 2013 , 41 , D590–D596. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Schliep, K.P. phangorn: Phylogenetic analysis in R. Bioinformatics 2011 , 27 , 592–593. [ Google Scholar ] [ CrossRef ][ Green Version ]
McMurdie, P.J.; Holmes, S. phyloseq: An R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE 2013 , 8 , e61217. [ Google Scholar ] [ CrossRef ][ Green Version ]
Chen, J.; Bittinger, K.; Charlson, E.S.; Hoffmann, C.; Lewis, J.; Wu, G.D.; Collman, R.G.; Bushman, F.D.; Li, H.Z. Associating microbiome composition with environmental covariates using generalized UniFrac distances. Bioinformatics 2012 , 28 , 2106–2113. [ Google Scholar ] [ CrossRef ]
Segata, N.; Izard, J.; Waldron, L.; Gevers, D.; Miropolsky, L.; Garrett, W.S.; Huttenhower, C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011 , 12 , R60. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Asnicar, F.; Weingart, G.; Tickle, T.L.; Huttenhower, C.; Segata, N. Compact graphical representation of phylogenetic data and metadata with GraPhlAn. PeerJ 2015 , 3 , e1029. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zierer, J.; Jackson, M.A.; Kastenmuller, G.; Mangino, M.; Long, T.; Telenti, A.; Mohney, R.P.; Small, K.S.; Bell, J.T.; Steves, C.J.; et al. The fecal metabolome as a functional readout of the gut microbiome. Nat. Genet. 2018 , 50 , 790–795. [ Google Scholar ] [ CrossRef ] [ PubMed ]
De Angelis, M.; Piccolo, M.; Vannini, L.; Siragusa, S.; De Giacomo, A.; Serrazzanetti, D.I.; Cristofori, F.; Guerzoni, M.E.; Gobbetti, M.; Francavilla, R. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE 2013 , 8 , e76993. [ Google Scholar ] [ CrossRef ][ Green Version ]
Liu, S.; Li, E.; Sun, Z.; Fu, D.; Duan, G.; Jiang, M.; Yu, Y.; Mei, L.; Yang, P.; Tang, Y.; et al. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci. Rep. 2019 , 9 , 287. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wang, L.; Christophersen, C.T.; Sorich, M.J.; Gerber, J.P.; Angley, M.T.; Conlon, M.A. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol. Autism 2013 , 4 , 42. [ Google Scholar ] [ CrossRef ][ Green Version ]
Krajmalnik-Brown, R.; Lozupone, C.; Kang, D.W.; Adams, J.B. Gut bacteria in children with autism spectrum disorders: Challenges and promise of studying how a complex community influences a complex disease. Microb. Ecol. Health Dis. 2015 , 26 , 26914. [ Google Scholar ] [ CrossRef ]
Hsiao, E.Y.; McBride, S.W.; Hsien, S.; Sharon, G.; Hyde, E.R.; McCue, T.; Codelli, J.A.; Chow, J.; Reisman, S.E.; Petrosino, J.F.; et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013 , 155 , 1451–1463. [ Google Scholar ] [ CrossRef ][ Green Version ]
Finegold, S.M.; Dowd, S.E.; Gontcharova, V.; Liu, C.; Henley, K.E.; Wolcott, R.D.; Youn, E.; Summanen, P.H.; Granpeesheh, D.; Dixon, D.; et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 2010 , 16 , 444–453. [ Google Scholar ] [ CrossRef ]
Wischhof, L.; Irrsack, E.; Osorio, C.; Koch, M. Prenatal LPS-exposure—A neurodevelopmental rat model of schizophrenia--differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 , 57 , 17–30. [ Google Scholar ] [ CrossRef ]
Kang, D.W.; Adams, J.B.; Gregory, A.C.; Borody, T.; Chittick, L.; Fasano, A.; Khoruts, A.; Geis, E.; Maldonado, J.; McDonough-Means, S.; et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: An open-label study. Microbiome 2017 , 5 , 10. [ Google Scholar ] [ CrossRef ]
Abuaish, S.; Al-Otaibi, N.M.; Abujamel, T.S.; Alzahrani, S.A.; Alotaibi, S.M.; AlShawakir, Y.A.; Aabed, K.; El-Ansary, A. Fecal Transplant and Bifidobacterium Treatments Modulate Gut Clostridium Bacteria and Rescue Social Impairment and Hippocampal BDNF Expression in a Rodent Model of Autism. Brain Sci. 2021 , 11 , 1038. [ Google Scholar ] [ CrossRef ]
Rousset, C.I.; Chalon, S.; Cantagrel, S.; Bodard, S.; Andres, C.; Gressens, P.; Saliba, E. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr. Res. 2006 , 59 , 428–433. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Graciarena, M.; Seiffe, A.; Nait-Oumesmar, B.; Depino, A.M. Hypomyelination and Oligodendroglial Alterations in a Mouse Model of Autism Spectrum Disorder. Front. Cell. Neurosci. 2018 , 12 , 517. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Kreitz, S.; Zambon, A.; Ronovsky, M.; Budinsky, L.; Helbich, T.H.; Sideromenos, S.; Ivan, C.; Konerth, L.; Wank, I.; Berger, A.; et al. Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring. Brain Behav. Immun. 2020 , 83 , 56–67. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Simoes, L.R.; Sangiogo, G.; Tashiro, M.H.; Generoso, J.S.; Faller, C.J.; Dominguini, D.; Mastella, G.A.; Scaini, G.; Giridharan, V.V.; Michels, M.; et al. Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats. J. Psychiatr. Res. 2018 , 100 , 71–83. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Tanaka, M.; Toth, F.; Polyak, H.; Szabo, A.; Mandi, Y.; Vecsei, L. Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway. Biomedicines 2021 , 9 , 734. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Masi, A.; Quintana, D.S.; Glozier, N.; Lloyd, A.R.; Hickie, I.B.; Guastella, A.J. Cytokine aberrations in autism spectrum disorder: A systematic review and meta-analysis. Mol. Psychiatry 2015 , 20 , 440–446. [ Google Scholar ] [ CrossRef ]
Saghazadeh, A.; Ataeinia, B.; Keynejad, K.; Abdolalizadeh, A.; Hirbod-Mobarakeh, A.; Rezaei, N. A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude. J. Psychiatr. Res. 2019 , 115 , 90–102. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Molloy, C.A.; Morrow, A.L.; Meinzen-Derr, J.; Schleifer, K.; Dienger, K.; Manning-Courtney, P.; Altaye, M.; Wills-Karp, M. Elevated cytokine levels in children with autism spectrum disorder. J. Neuroimmunol. 2006 , 172 , 198–205. [ Google Scholar ] [ CrossRef ]
Li, W.; Chen, M.; Feng, X.; Song, M.; Shao, M.; Yang, Y.; Zhang, L.; Liu, Q.; Lv, L.; Su, X. Maternal immune activation alters adult behavior, intestinal integrity, gut microbiota and the gut inflammation. Brain Behav. 2021 , 11 , e02133. [ Google Scholar ] [ CrossRef ]
Maelfait, J.; Vercammen, E.; Janssens, S.; Schotte, P.; Haegman, M.; Magez, S.; Beyaert, R. Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J. Exp. Med. 2008 , 205 , 1967–1973. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Li, Y.; Dugyala, S.R.; Ptacek, T.S.; Gilmore, J.H.; Frohlich, F. Maternal Immune Activation Alters Adult Behavior, Gut Microbiome and Juvenile Brain Oscillations in Ferrets. eNeuro 2018 , 5 . [ Google Scholar ] [ CrossRef ]
Roussin, L.; Prince, N.; Perez-Pardo, P.; Kraneveld, A.D.; Rabot, S.; Naudon, L. Role of the Gut Microbiota in the Pathophysiology of Autism Spectrum Disorder: Clinical and Preclinical Evidence. Microorganisms 2020 , 8 , 1369. [ Google Scholar ] [ CrossRef ]
Arsenault, D.; St-Amour, I.; Cisbani, G.; Rousseau, L.S.; Cicchetti, F. The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring. Brain Behav. Immun. 2014 , 38 , 77–90. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Loomes, R.; Hull, L.; Mandy, W.P.L. What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis. J. Am. Acad. Child Adolesc. Psychiatry 2017 , 56 , 466–474. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Kim, Y.S.; Unno, T.; Kim, B.Y.; Park, M.S. Sex Differences in Gut Microbiota. World J. Men’s Health 2020 , 38 , 48–60. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Org, E.; Mehrabian, M.; Parks, B.W.; Shipkova, P.; Liu, X.; Drake, T.A.; Lusis, A.J. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes 2016 , 7 , 313–322. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Takagi, T.; Naito, Y.; Inoue, R.; Kashiwagi, S.; Uchiyama, K.; Mizushima, K.; Tsuchiya, S.; Dohi, O.; Yoshida, N.; Kamada, K.; et al. Differences in gut microbiota associated with age, sex, and stool consistency in healthy Japanese subjects. J. Gastroenterol. 2019 , 54 , 53–63. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Figure 1.
Maternal lipopolysaccharide (LPS) stimulation caused social behavior deficits and anxiety-like and repetitive behavior in male offspring. (
A
) Timeline for behavioral experiments. The age of the rats in weeks is indicated on the timeline. (
B
) Design of the three-chamber test apparatus for rats. The apparatus contained three parts: two side chambers and one central space. The length of the central space was 60 cm. The right-side chamber housed the stranger rat. The test rat was placed in the central space and allowed to freely interact with the stranger rat. The central space was divided into three regions: social, center, and nonsocial. (
C
) Quantification of time spent in the social region. The social behavior of 5- and 7-week-old maternal immune activation (MIA) and control offspring was detected using a three-chamber apparatus. Their tracks in the central space of the three-chamber apparatus are indicated, with the nonsocial region indicated in red, the center region in green, and the social region in blue. *
p
< 0.05 (
n
= 8 per group). (
D
) Percentage of buried marbles in the MIA and control offspring. *
p
< 0.05 (
n
= 8 per group) (
E
) Locomotor activity evaluation was performed in 7-week-old MIA and control male offspring using the open-field test (
n
= 8 per group). (
F
) The NOR test was performed on 7-week-old MIA and control male offspring (
n
= 8 per group). All data are presented as mean ± SEM.
Figure 1. Maternal lipopolysaccharide (LPS) stimulation caused social behavior deficits and anxiety-like and repetitive behavior in male offspring. ( A ) Timeline for behavioral experiments. The age of the rats in weeks is indicated on the timeline. ( B ) Design of the three-chamber test apparatus for rats. The apparatus contained three parts: two side chambers and one central space. The length of the central space was 60 cm. The right-side chamber housed the stranger rat. The test rat was placed in the central space and allowed to freely interact with the stranger rat. The central space was divided into three regions: social, center, and nonsocial. ( C ) Quantification of time spent in the social region. The social behavior of 5- and 7-week-old maternal immune activation (MIA) and control offspring was detected using a three-chamber apparatus. Their tracks in the central space of the three-chamber apparatus are indicated, with the nonsocial region indicated in red, the center region in green, and the social region in blue. * p < 0.05 ( n = 8 per group). ( D ) Percentage of buried marbles in the MIA and control offspring. * p < 0.05 ( n = 8 per group) ( E ) Locomotor activity evaluation was performed in 7-week-old MIA and control male offspring using the open-field test ( n = 8 per group). ( F ) The NOR test was performed on 7-week-old MIA and control male offspring ( n = 8 per group). All data are presented as mean ± SEM.
Figure 2.
Fecal microbiome distribution in male maternal immune activation (MIA) offspring. The feces of prenatal lipopolysaccharide (LPS)-stimulated male offspring (LPS group) and control rats were prepared for fecal microbiome profiling through high-throughput sequencing of the 16s rRNA gene on the Illumina MiSeq system. (
A
) Alpha diversity of MIA offspring (LPS) and controls. (
B
) Principal coordinate analysis plot based on unweighted or weighted UniFrac distance of omeprazole MIA offspring and control samples. A significant difference in beta diversity was evaluated using permutational multivariate analysis of variance (vegan:adonis, 1000 permutations), and beta dispersion was quantified using a betadisper (vegan:betadisper, 1000 permutations). Both indices achieved adonis
p
< 0.05 and betadisper
p
> 0.05.
Figure 2. Fecal microbiome distribution in male maternal immune activation (MIA) offspring. The feces of prenatal lipopolysaccharide (LPS)-stimulated male offspring (LPS group) and control rats were prepared for fecal microbiome profiling through high-throughput sequencing of the 16s rRNA gene on the Illumina MiSeq system. ( A ) Alpha diversity of MIA offspring (LPS) and controls. ( B ) Principal coordinate analysis plot based on unweighted or weighted UniFrac distance of omeprazole MIA offspring and control samples. A significant difference in beta diversity was evaluated using permutational multivariate analysis of variance (vegan:adonis, 1000 permutations), and beta dispersion was quantified using a betadisper (vegan:betadisper, 1000 permutations). Both indices achieved adonis p < 0.05 and betadisper p > 0.05.
Figure 3. Fecal microbiota was changed in male MIA offspring. ( A ) Linear discriminant analysis (LDA) effect size analysis of gut microbiota changed in MIA offspring (lipopolysaccharide (LPS)) and control rats. Significant biomarkers were defined as taxa with an LDA score (log10) of ≥2. ( B ) Significant taxa differences in MIA offspring (LPS) are highlighted on the cladogram.
Figure 3. Fecal microbiota was changed in male MIA offspring. ( A ) Linear discriminant analysis (LDA) effect size analysis of gut microbiota changed in MIA offspring (lipopolysaccharide (LPS)) and control rats. Significant biomarkers were defined as taxa with an LDA score (log10) of ≥2. ( B ) Significant taxa differences in MIA offspring (LPS) are highlighted on the cladogram.
Figure 4. Fecal microbiota at the family and genus levels with significant changes in abundance in maternal immune activation (MIA) offspring. A significant ( A ) increase and ( B ) decrease in bacteria at the family level in MIA offspring (lipopol ysaccharide (LPS)) compared with control rats. Similarly, significant increase ( C ) and decrease ( D ) in bacteria at the genus level were observed in MIA offspring (LPS) compared with control rats. n = 5 per group. All data had LDA scores ≥ 2. Relative abundance indicates number of reads of targeted microbes per sample/total number of reads per sample.
Figure 4. Fecal microbiota at the family and genus levels with significant changes in abundance in maternal immune activation (MIA) offspring. A significant ( A ) increase and ( B ) decrease in bacteria at the family level in MIA offspring (lipopol ysaccharide (LPS)) compared with control rats. Similarly, significant increase ( C ) and decrease ( D ) in bacteria at the genus level were observed in MIA offspring (LPS) compared with control rats. n = 5 per group. All data had LDA scores ≥ 2. Relative abundance indicates number of reads of targeted microbes per sample/total number of reads per sample.
Figure 5.
Feature importance of bacterial species for social behavior deficit and anxiety-like and repetitive behavior. (
A
) Standardized coefficients of the effects selected (the increased or decreased amount of microbiota genera in the lipopolysaccharide (LPS) group) with social time or (
B
) the percentage of buried marble at a given step of the stepwise method are plotted as a function of the step number. The coefficients plot displays the values of the estimates for each model at each iteration step. The effect was added into the model in an order of its relative importance measured with AIC. The plot labels the added effects at each step. The vertical axis of plot shows standardized estimates that can track the change of AIC for each successive model. Each colored line visualizes the evolution of values for a particular effect. The AIC plots show the relative importance of the effects selected (microbiota species) at steps of the selection process when effects entered the model. Actinobactera-P indicates the relative amount of phylum
Actinobacteria
. Actinobacteria-C indicates the relative amount of class
Actinobacteria
.
Figure 5. Feature importance of bacterial species for social behavior deficit and anxiety-like and repetitive behavior. ( A ) Standardized coefficients of the effects selected (the increased or decreased amount of microbiota genera in the lipopolysaccharide (LPS) group) with social time or ( B ) the percentage of buried marble at a given step of the stepwise method are plotted as a function of the step number. The coefficients plot displays the values of the estimates for each model at each iteration step. The effect was added into the model in an order of its relative importance measured with AIC. The plot labels the added effects at each step. The vertical axis of plot shows standardized estimates that can track the change of AIC for each successive model. Each colored line visualizes the evolution of values for a particular effect. The AIC plots show the relative importance of the effects selected (microbiota species) at steps of the selection process when effects entered the model. Actinobactera-P indicates the relative amount of phylum Actinobacteria . Actinobacteria-C indicates the relative amount of class Actinobacteria .
Figure 6. Myelin basic protein (MBP) expression level in the prefrontal cortex and thalamic nucleus in maternal immune activation (MIA) male offspring. ( A ) The MBP expression level in the prefrontal cortex and ( B ) thalamic nucleus of control and MIA offspring (lipopolysaccharide—(LPS) group) was detected with immunohistochemistry staining. The MBP expression level in whole brain slices are shown in the upper pictures. The MBP expression level in prefrontal cortex and thalamic nucleus are shown in the lower pictures. The quantification of the MBP + area in the prefrontal cortex and thalamic nucleus is shown in the bar graph. * p < 0.05 ( n = 4 per group). All data are presented as mean ± SEM. Scale bar, 100 μm.
Figure 6. Myelin basic protein (MBP) expression level in the prefrontal cortex and thalamic nucleus in maternal immune activation (MIA) male offspring. ( A ) The MBP expression level in the prefrontal cortex and ( B ) thalamic nucleus of control and MIA offspring (lipopolysaccharide—(LPS) group) was detected with immunohistochemistry staining. The MBP expression level in whole brain slices are shown in the upper pictures. The MBP expression level in prefrontal cortex and thalamic nucleus are shown in the lower pictures. The quantification of the MBP + area in the prefrontal cortex and thalamic nucleus is shown in the bar graph. * p < 0.05 ( n = 4 per group). All data are presented as mean ± SEM. Scale bar, 100 μm.
Table 1. Phylum-level microbiome composition in the feces of control and maternal immune activation male offspring. The relative abundance of microbiomes in phylum level from the feces of control and LPS MIA offspring were obtained from 16S rRNA gene sequencing data. The significant difference of group was statistically calculated by U-test. SD: standard deviation.
Table 1. Phylum-level microbiome composition in the feces of control and maternal immune activation male offspring. The relative abundance of microbiomes in phylum level from the feces of control and LPS MIA offspring were obtained from 16S rRNA gene sequencing data. The significant difference of group was statistically calculated by U-test. SD: standard deviation.
Phylum Control LPS Mean SD Mean SD U-Test Actinobacteria 1.7 × 10 −3 1.3 × 10 −3 8 × 10 −4 1.0 × 10 −4 0.01 Bacteroidetes 5.8 × 10 −1 4.0 × 10 −2 6 × 10 −1 1.0 × 10 −2 0.2 Deferribacteres 2.0 × 10 −4 2.0 × 10 −4 4 × 10 −4 1.0 × 10 −4 0.2 Firmicutes 3.8 × 10 −1 3.4 × 10 −2 3.6 × 10 −1 1.0 × 10 −2 0.149 Fusobacteria 1.8 × 10 −5 1.3 × 10 −5 5.3 × 10 −5 2.2 × 10 −5 0.03 Patescibacteria 4.4 × 10 −3 4.8 × 10 −3 5.7 × 10 −3 3.7 × 10 −3 0.037 Proteobacteria 1.1 × 10 −2 3.7 × 10 −3 8.2 × 10 −3 4.4 × 10 −3 0.105 Tenericutes 8.0 × 10 −4 1.8 × 10 −3 4.2 × 10 −3 9.5 × 10 −3 0.416 Verrucomicrobia 5.2 × 10 −3 1.1 × 10 −2 6.7 × 10 −6 1.0 × 10 −5 0.086
MDPI and ACS Style
Lee, G.A.; Lin, Y.-K.; Lai, J.-H.; Lo, Y.-C.; Yang, Y.-C.S.H.; Ye, S.-Y.; Lee, C.-J.; Wang, C.-C.; Chiang, Y.-H.; Tseng, S.-H. Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile. Brain Sci. 2021, 11, 1085.
https://doi.org/10.3390/brainsci11081085
AMA Style
Lee GA, Lin Y-K, Lai J-H, Lo Y-C, Yang Y-CSH, Ye S-Y, Lee C-J, Wang C-C, Chiang Y-H, Tseng S-H. Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile. Brain Sciences. 2021; 11(8):1085.
https://doi.org/10.3390/brainsci11081085
Chicago/Turabian Style
Lee, Gilbert Aaron, Yen-Kuang Lin, Jing-Huei Lai, Yu-Chun Lo, Yu-Chen S. H. Yang, Syuan-You Ye, Chia-Jung Lee, Ching-Chiung Wang, Yung-Hsiao Chiang, and Sung-Hui Tseng. 2021. "Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile" Brain Sciences11, no. 8: 1085.
https://doi.org/10.3390/brainsci11081085
| https://www.mdpi.com/2076-3425/11/8/1085/html |
2 Chronicles 32 - ESV
2 Chronicles 32: After these things and these acts of faithfulness, Sennacherib king of Assyria came and invaded Judah and encamped against the fortified cities, thinking to win them for himself.
2 Chronicles 32 ESV
ASV - American Standard Version BBE - Bible in Basic English DRB - Darby’s Translation ESV - English Standard Version KJV - King James Version NAS - New American Standard Bible NIV - New International Version NKJV - New King James Version NLT - New Living Translation NRS - New Revised Standard Version RSV - Revised Standard Version MSG - The Message Bible WEB - World English Bible YLT - Young’s Literal Translation
< 2 Chronicles 31 2 Chronicles 32 2 Chronicles 33 >
The Invasion of Sennacherib
32 1
After these things and these acts of faithfulness, Sennacherib king of Assyria came and invaded Judah and encamped against the fortified cities, thinking to win them for himself.
2
And when Hezekiah saw that Sennacherib had come and intended to fight against Jerusalem, 3
he planned with his officers and his mighty men to stop the water of the springs that were outside the city; and they helped him. 4
A great many people were gathered, and they stopped all the springs and the brook that flowed through the land, saying, "Why should the kings of Assyria come and find much water?" 5
He set to work resolutely and built up all the wall that was broken down and raised towers upon it, [1]
and outside it he built another wall, and he strengthened the Millo in the city of David. He also made weapons and shields in abundance. 6
And he set combat commanders over the people and gathered them together to him in the square at the gate of the city and spoke encouragingly to them, saying,
7
"Be strong and courageous. Do not be afraid or dismayed before the king of Assyria and all the horde that is with him, for there are more with us than with him.
8
With him is an arm of flesh, but with us is the Lord
our God, to help us and to fight our battles." And the people took confidence from the words of Hezekiah king of Judah.
9
After this, Sennacherib king of Assyria, who was besieging Lachish with all his forces, sent his servants to Jerusalem to Hezekiah king of Judah and to all the people of Judah who were in Jerusalem, saying, 10
"Thus says Sennacherib king of Assyria, 'On what are you trusting, that you endure the siege in Jerusalem?
11
Is not Hezekiah misleading you, that he may give you over to die by famine and by thirst, when he tells you, "The Lord
our God will deliver us from the hand of the king of Assyria"? 12
Has not this same Hezekiah taken away his high places and his altars and commanded Judah and Jerusalem, "Before one altar you shall worship, and on it you shall burn your sacrifices"? 13
Do you not know what I and my fathers have done to all the peoples of other lands? Were the gods of the nations of those lands at all able to deliver their lands out of my hand? 14
Who among all the gods of those nations that my fathers devoted to destruction was able to deliver his people from my hand, that your God should be able to deliver you from my hand?
15
Now, therefore, do not let Hezekiah deceive you or mislead you in this fashion, and do not believe him, for no god of any nation or kingdom has been able to deliver his people from my hand or from the hand of my fathers. How much less will your God deliver you out of my hand!'"
16
And his servants said still more against the Lord
God and against his servant Hezekiah. 17
And he wrote letters to cast contempt on the Lord
, the God of Israel, and to speak against him, saying, "Like the gods of the nations of the lands who have not delivered their people from my hands, so the God of Hezekiah will not deliver his people from my hand."
18
And they shouted it with a loud voice in the language of Judah to the people of Jerusalem who were on the wall, to frighten and terrify them, in order that they might take the city. 19
And they spoke of the God of Jerusalem as they spoke of the gods of the peoples of the earth, which are the work of men's hands.
The LORD Delivers Hezekiah
20
Then Hezekiah the king and Isaiah the prophet, the son of Amoz, prayed because of this and cried to heaven. 21
And the Lord
sent an angel, who cut off all the mighty warriors and commanders and officers in the camp of the king of Assyria. So he returned with shame of face to his own land. And when he came into the house of his god, some of his own sons struck him down there with the sword. 22
So the Lord
saved Hezekiah and the inhabitants of Jerusalem from the hand of Sennacherib king of Assyria and from the hand of all his enemies, and he provided for them on every side. 23
And many brought gifts to the Lord
to Jerusalem and precious things to Hezekiah king of Judah, so that he was exalted in the sight of all nations from that time onward.
Hezekiah's Sickness
24
In those days Hezekiah became sick and was at the point of death, and he prayed to the Lord
, and he answered him and gave him a sign. 25
But Hezekiah did not make return according to the benefit done to him, for his heart was proud. Therefore wrath came upon him and Judah and Jerusalem. 26
But Hezekiah humbled himself for the pride of his heart, both he and the inhabitants of Jerusalem, so that the wrath of the Lord
did not come upon them in the days of Hezekiah.
Hezekiah Receives Envoys from Babylon
27
And Hezekiah had very great riches and honor, and he made for himself treasuries for silver, for gold, for precious stones, for spices, for shields, and for all kinds of costly vessels;
28
storehouses also for the yield of grain, wine, and oil; and stalls for all kinds of cattle, and sheepfolds.
29
He likewise provided cities for himself, and flocks and herds in abundance, for God had given him very great possessions.
30
This same Hezekiah closed the upper outlet of the waters of Gihon and directed them down to the west side of the city of David. And Hezekiah prospered in all his works. 31
And so in the matter of the envoys of the princes of Babylon, who had been sent to him to inquire about the sign that had been done in the land, God left him to himself, in order to test him and to know all that was in his heart.
The Death of Hezekiah
32
Now the rest of the acts of Hezekiah and his good deeds, behold, they are written in the vision of Isaiah the prophet the son of Amoz, in the Book of the Kings of Judah and Israel. 33
And Hezekiah slept with his fathers, and they buried him in the upper part of the tombs of the sons of David, and all Judah and the inhabitants of Jerusalem did him honor at his death. And Manasseh his son reigned in his place.
< 2 Chronicles 31 2 Chronicles 32 2 Chronicles 33 > | https://www.christianity.com/bible/esv/2-chronicles/32 |
Difference between revisions of "Hausmann Study" - LearnLab
Difference between revisions of "Hausmann Study"
Revision as of 17:18, 26 December 2006 (view source) Adele (talk|contribs) (→ Glossary) ← Older edit Latest revision as of 20:15, 15 December 2010 (view source) Alida (talk|contribs) (→ Future plans)
(69 intermediate revisions by 4 users not shown)
Line 1: Line 1:
== A comparison of self-explanation to instructional explanation == == A comparison of self-explanation to instructional explanation ==
−''Robert Hausmann andKurt VanLehn'' + === Summary Table ===
+ {| border="1" cellspacing="0" cellpadding="5" style="text-align: left;"
+ |'' 'PIs''' ||Robert G.M.Hausmann &Kurt VanLehn
+ |-
+ | '''Other Contributors'''<br>* '''Faculty: '''<br>* '''Staff: '''
+ | <br>Donald J. Treacy (USNA), Robert N. Shelby (USNA)<br>Brett van de Sande (Pitt), Anders Weinstein (Pitt)
+ |-
+ | '''Study Start Date''' || Sept. 1, 2005
+ |-
+ | '''Study End Date''' || Aug. 31, 2006
+ |-
+ | '''LearnLab Site''' || USNA Physics II
+ |-
+ | '''LearnLab Course''' || Physics
+ |-
+ | '''Number of Students''' || ''N'' = 104
+ |-
+ | '''Total Participant Hours''' || 190 hrs.
+ |-
+ | '''Data available in DataShop''' || [https://pslcdatashop.web.cmu.edu/DatasetInfo?datasetId=104 Dataset: Self Explanation - Electric Fields - USNA - Spring 2006]<br>
+ * '''Pre/Post Test Score Data:''' No
+ * '''Paper or Online Tests:''' Unknown
+ * '''Scanned Paper Tests:''' Unknown
+ * '''Blank Tests:''' No
+ * '''Answer Keys: ''' No
+ |}
=== Abstract === === Abstract ===
−
This in vivo experiment compared the learning that results from either readingan explanation (instructional explanation) or generating it oneself (self explanation). Students studied a physics example lineby line. For half the students, the example lineswere incomplete(the explanations connecting some lines aremissing) whereas for the other half, the example lineswere complete. Crossed with this isan attempted manipulation of the student’s studying strategy. Half the students were instructed and prompted to self-explain the line, while the other half were prompted to paraphrase it , which has been shown in earlier work to suppress self-explanation(click the following [http://andes3.lrdc.pitt.edu/~bob/mat/cond.html link] for screen shots fromeach condition).
+
This [[in vivo experiment ]]compared the learning that results from either hearingan explanation ( [[instructional explanation ]]) or generating it oneself ( [[self -explanation ]]). Students studied a physics [[example ]]s, which were presented stepby step. For half the students, the [[example ]] stepswere incompletely justified( i.e.,the explanations connecting some steps weremissing) whereas for the other half, the [[example ]] stepswere completely justified. Crossed with this variable wasan attempted manipulation of the student’s studying strategy. Half the students were instructed and prompted to self-explain atthe end of each step, while the other half were prompted to paraphrase it (click the following [http://andes3.lrdc.pitt.edu/~bob/mat/cond.html link] for screen shots ofeach experimentalcondition). Paraphrasing was selected as the contrasting study strategy because earlier work has shown that paraphrasing suppresses [[self-explanation]].
− Of the four conditions, one condition was key to testing our hypothesis: the condition where students viewed complete examplesand were asked to paraphrase them.If the learning gains from this condition had been just as high as those from conditions were self-explanation was encouraged, then instructional explanation would have been just as effective as self-explanation.On the other hand, if the learning gains were just as low as those where instructional explanations were absent and self-explanation was suppressed via paraphrasing, then instructional explanation would have been just as ineffective as no explanation at all. + Of the four conditions, one condition was key to testing our hypothesis: the condition where students viewed completely justified [[example]]sand were asked to paraphrase them. If the learning gains from this condition had been just as high as those from conditions were self-explanation was encouraged, then instructional explanation would have been just as effective as self-explanation. On the other hand, if the learning gains were just as low as those where instructional explanations were absent and self-explanation was suppressed via paraphrasing, then instructional explanation would have been just as ineffective as no explanation at all.
− Preliminary results suggest that the latter case occurred, so instructional explanation were not as effective as self-explanations on tests of basic learning. Analyses are in progress on measures of robust learning. + Preliminary results of the normal and robust learning measuressuggest that the latter case occurred, so instructional explanation were not as effective as self-explanations.
=== Background and Significance === === Background and Significance ===
+
+
The first studies of self-explanation, which were based on analysis of verbal protocols, showed that the amount of self-explaining correlated strongly with performance on post-test measures of problem-solving performance (Bielaczyc, Pirolli, & Brown, 1995; Chi, Bassok, Lewis, Reimann, & Glaser, 1989; Renkl, 1997). Because these studies compared self-explanation to the lack of any explanation at all, there is a confound between the generative act or producing the explanations and the additional content of the explanations themselves. Perhaps if students were simply given these explanations, they would learn just as much. Alternatively, learning from self-explaining might arise from the activity of producing the explanations. Thus, if they were given the explanations, they would not learn just as much. In other words, is it merely attending to the explanations that matters, or is robust learning more likely to occur if students generate the explanations themselves? Let us label these hypotheses as follows:
+
+ # '''The Attention Hypothesis''': learning from self-generated explanations should produce comparable learning gains as author-provided explanation, provided the learner pays attention to them. Both self-generated and author-provided explanations should exhibit better learning than no explanation.
+ # '''The Generation Hypothesis''': learning from self-generated explanations should produce greater learning gains than author-provided explanations because they are produced from the students’ own background knowledge; however, author-provided explanations should be comparable to no explanation.
+
+
There have only been a few empirical studies that attempt to separate the Attention hypothesis from the Generation hypothesis (Brown & Kane, 1988; Schworm & Renkl, 2002). An exemplary case can be found in a study by Lovett (1992) in the domain of permutation and combination problems. Lovett crossed the source of the solution (subject vs. experimenter) with the source of the explanation for the solution (subject vs. experimenter). For our purposes, only two of the experimental conditions matter. The experimenter-subject condition was analogous to experimental materials found in a self-explanation experiment wherein the students self-explained an author’s solution, whereas in the experimenter-experimenter condition, the students studied an author-provided explanation. Lovett found that the experimenter-experimenter condition demonstrated better performance, especially on far-transfer items. Lovett’s interpretation was that the experimenter-experimenter condition was effective because it contained higher quality explanations than those generated by students. Consistent with this interpretation, when Lovett analyzed the protocol data, she found that the participants who generated the key inferences had the same learning gains as participants who read the corresponding inferences. Thus, of our two hypotheses, Lovett’s experiment supports the Attention hypothesis: the content of self-explanations matters, while the source of the explanation does not.
+
+
Brown and Kane (1988) found that children’s explanations, generated either spontaneously or in response to prompting, were much more effective at promoting transfer than those provided by the experimenter. In particular, students were first told a story about mimicry. Some students were then told, "Some animals try to look like a scary animal so they won’t get eaten.” Other students were asked first, “Why would a furry caterpillar want to look like a snake?” and if that did not elicit an explanation, they were asked, "What could the furry caterpillar do to stop the big birds from eating him?" Most students got the question right, and if they did, 85% were able to answer a similar question about two new stories. If they were told the rule, then only 45% were able to answer a similar question about the new stories. This result is consistent with the Generation hypothesis, which is that an explanation is effective when the student generates it. However, the students who were told the rule may not have paid much attention to it, according to Brown and Kane.
+
+ In summary, one study’s results are consistent with the Attention hypothesis, and the other study’s results are consistent with the Generation hypothesis, but both studies confounded two variables. In the Lovett study, the student-produced and author-provided explanations were of different qualities. In the Brown and Kane study, the students in the author-provided explanations condition may not have paid much attention to the explanations.
=== Glossary === === Glossary ===
− * ''Physics example line '': lines from an example are organized around sub-goals, and they include a demonstration of an application of a single [[knowledge component]] . + * [[Physics example line]]
− * ''Complete vs. incomplete example '': an incomplete example omits the justification for applying a knowledge component, whereas a complete example includes both the application of the knowledge component as well as its justification. + * [[Complete vs. incomplete example ]]
− * ''Instructional explanation '': an instruction explanation is generated for a student by an authoritative figure (the textbook, teacher, or researcher). In this research context, the instructional explanation was generated by the experimenters and was delivered to the student in a voice-over narration of an expert solving a problem in Andes. + * [[Instructional explanation ]]
+ See [[: Category:Hausmann_Study|Hausmann_Study Glossary]]
=== Research question === === Research question ===
Line 21: Line 58:
=== Independent variables === === Independent variables ===
Two variables were crossed: Two variables were crossed:
− * Did the example present an explanation with each lineor present just the line? + * Did the [[example ]]present an explanation with each stepor present just the step?
− * After each line(and its explanation, if any) was presented, students were prompted to either explain or paraphrase the linein their own words. + * After each step(and its explanation, if any) was presented, students were prompted to either furtherexplain the stepor paraphrase the stepin their own words.
− The condition where explanations were presented in the example and students were asked to paraphrase them is considered the “instructional explanation” condition. The two conditions where students were asked to self-explain the example lines are considered the “self-explanation” conditions. The remaining condition, where students were asked to paraphrase examplesthat did not contain explanations, was considered the “no explanation” condition. Note, however, that nothing prevents a student in the paraphrasing condition to self-explain (and vice-versa). + The condition where explanations were presented in the [[example ]]and students were asked to paraphrase them is considered the “instructional explanation” condition. The two conditions where students were asked to self-explain the [[example ]]lines are considered the “self-explanation” conditions. The remaining condition, where students were asked to paraphrase [[example]]sthat did not contain explanations, was considered the “no explanation” condition. Note, however, that nothing prevents a student in the paraphrasing condition to self-explain (and vice-versa).
+
+ <b>Figure 1</b>. An example from the Complete Self-explanation condition<Br><Br>
+ [[Image:CSE.JPG]]<Br>
+
+ <b>Figure 2</b>. An example from the Incomplete Self-explanation condition<Br><Br>
+ [[Image:ISE.JPG]]<Br>
+
+ <b>Figure 3</b>. An example from the Complete Paraphrase condition<Br><Br>
+ [[Image:CPP.JPG]]<Br>
+
+ <b>Figure 4</b>. An example from the Incomplete Paraphrase condition<Br><Br>
+ [[Image:IPP.JPG]]<Br>
=== Hypothesis === === Hypothesis ===
For these well-prepared students, self-explanation should not be too difficult. That is, the instruction should be below the students’ zone of proximal development. Thus, the learning-by-doing path (self-explanation) should elicit more robust learning than the alternative path (instructional explanation) wherein the student does less work. For these well-prepared students, self-explanation should not be too difficult. That is, the instruction should be below the students’ zone of proximal development. Thus, the learning-by-doing path (self-explanation) should elicit more robust learning than the alternative path (instructional explanation) wherein the student does less work.
− As a manipulation check on the utility of the explanations in the complete examples, we hypothesize that the instructional explanation condition should produce more robust learning than the no-explanation condition. + As a manipulation check on the utility of the explanations in the complete [[example]]s, we hypothesize that the instructional explanation condition should produce more robust learning than the no-explanation condition.
− === Dependent variables & Results=== + === Dependent variables ===
− * ''Near transfer, immediate'': During training, examples alternated with problems, and the problems were solved using Andes.Each problem was similar to the example that preceded it, so performance on it is a measure of normal learning (near transfer, immediate testing).The log data were analyzed and assistance scores (sum of errors and help requests) were calculated . There was a main effect of Study Strategy on assistance score, reflecting higher assistance scores for the paraphrase condition than the self-explanation condition. + * [[Normal post-test]]
+ ** ''Near transfer, immediate'': During training, [[workedexamples ]]alternated with problems, and the problems were solved using [[Andes ]]. Each problem was similar to the [[worked examples|example ]]that preceded it, so performance on it is a measure of normal learning (near transfer, immediate testing). The log data were analyzed and assistance scores (sum of errors and help requests , normalized by the number of transactions) were calculated.
− * '' Near transfer,retention'': On the student’s regular mid-term exam, one problem was similar to the training. Since this exam occurred a week after the training, and the training took place in just under 2 hours, the student’s performance on this problem is considered a test of retention. Resultson the measurewere mixed. While there were no reliable main effects or interactions, the complete self-explanation groupwas marginally higher thanthe complete paraphrase condition (LSD, p =. 064). + * [[Robust learning]]
+ ** '' [[Long-termretention ]]'': On the student’s regular mid-term exam, one problem was similar to the training. Since this exam occurred a week after the training, and the training took place in just under 2 hours, the student’s performance on this problem is considered a test of [[long-termretention ]].
+ ** ''Near and far [[transfer]]'': After training, students did their regular homework problems using [[Andes]]. Students did them whenever they wanted, but most completed them just before the exam. The homework problems were divided basedon similarity tothe training problems, and assistance scoreswere calculated.
+ ** ''[[Accelerated future learning]]'': The training was on electrical fields, and itwas followed inthe course by a unit on magnetic fields. Log data from the magnetic field homework was analyzed as a measure of acceleration of future learning.
− * ''Near and fartransfer'': After training, students did their regular homework problems using Andes. Students did them whenever they wanted, but most completed them just before the exam. The homework problems were divided based on similarity to the training problems, and assistance scores were calculated. On both similar (near transfer) and dissimilar (far transfer) problems, the results are consistent with self-explanation being more effective than instructional explanation. + === Results ===
+ * [[Normal post-test]]
+ ** ''Near [[transfer ]], immediate'': The self-explanation condition demonstrating lower normalized assistance scores than the paraphrase condition, ''F''(1, 73) = 6. 19, ''p'' =. 02, η<sub>p</sub><sup>2</sup> =.08. <center>[[Image:NTI_results. JPG]]</center>
− * '' Acceleration of future learning'': The training wason electrical fields, and itwas followed inthe course by a unit on magnetic fields. Log data fromthe magnetic fieldhomework was analyzed asa measure of acceleration of future learning. Bothassistance scores and learning curves of the key principles supportthe hypothesis thatself-explanation is more effectivethan instructional explanation. + * [[Robust learning]]
+
** '' Near transfer, retention'': Resultson the measure were mixed. While there were no reliable main effects or interactions, the complete self-explanation groupwas marginally higher thanthe complete paraphrase condition (LSD, p = .06). Moreover, we analyzedthe students’ performance on ahomework problem thatwas isomorphic to the chapter exam in that they shared an identical deep structure (i.e., bothanalyzed the motion ofa charged particle moving in two dimensions). The self-explanation had reliably lower normalizedassistance scores than the paraphrase condition, ''F''(1, 27) = 4.07, ''p'' = .05, η<sub>p</sub><sup>2</sup> = .13. <center>[[Image:FTR_results.JPG]]</center>
+ ** ''Nearand far transfer'':
+ ** ''[[Accelerated futurelearning ]]'': There was no effect for [[example]] completeness; however,the self-explanation condition demonstrating lower normalized assistance scoresthan the paraphrase condition, ''F''(1, 46) = 5.22, ''p'' = .03, η<sub>p</sub><sup>2</sup> = .10. <center>[[Image:AFL_results. JPG]]</center>
=== Explanation === === Explanation ===
Line 49: Line 107:
The IC cluster’s hypothesis actually predicts an attribute-treatment interaction (ATI) here. If some students were under-prepared and thus would find the self-explanation path too difficult, then those students would learn more on the instructional-explanation path. ATI analyzes have not yet been completed. The IC cluster’s hypothesis actually predicts an attribute-treatment interaction (ATI) here. If some students were under-prepared and thus would find the self-explanation path too difficult, then those students would learn more on the instructional-explanation path. ATI analyzes have not yet been completed.
− === Annotated bibliography === + === Further Information ===
+ ==== Annotated bibliography === =
+ * Accepted as a poster at CogSci 2008
+ * Presentation to the Higher-order Cognition Group, led by Timothy J. Nokes, on March 3, 2008
* Presentation to the PSLC Advisory Board, December, 2006 [http://www.learnlab.org/uploads/mypslc/talks/hausmannabvisit2006bv2.ppt] * Presentation to the PSLC Advisory Board, December, 2006 [http://www.learnlab.org/uploads/mypslc/talks/hausmannabvisit2006bv2.ppt]
* Presentation to the NSF Follow-up Site Visitors, September, 2006 * Presentation to the NSF Follow-up Site Visitors, September, 2006
* Preliminary results were presented to the Intelligent Tutoring in Serious Games workshop, Aug. 2006 [http://projects.ict.usc.edu/itgs/talks/Hausmann_Generative%20Dialogue%20Patterns.ppt] * Preliminary results were presented to the Intelligent Tutoring in Serious Games workshop, Aug. 2006 [http://projects.ict.usc.edu/itgs/talks/Hausmann_Generative%20Dialogue%20Patterns.ppt]
* Presentation to the NSF Site Visitors, June, 2006 * Presentation to the NSF Site Visitors, June, 2006
+ * Poster presented at the annual meeting of the Science of Learning Centers, Oct. 2006.
+ * Symposium accepted to EARLI 2007
+ * Symposium accepted at AERA 2007
+ * Full-paper accepted at AIED 2007 [http://www.learnlab.org/uploads/mypslc/publications/hausmannvanlehn2007_final.pdf]
+ * Accepted as a poster at CogSci 2007
+ * Presentation to the NSF Site Visitors, May 31, 2007
+
+ ==== References ====
+ # Anzai, Y., & Simon, H. A. (1979). The theory of learning by doing. ''Psychological Review, 86''(2), 124-140.
+ # Chi, M. T. H., Bassok, M., Lewis, M. W., Reimann, P., & Glaser, R. (1989). Self-explanations: How students study and use examples in learning to solve problems. ''Cognitive Science, 13'', 145-182. [http://rt4rf9qn2y.scholar.serialssolutions.com/?sid=google&auinit=MTH&aulast=CHI&atitle=Self-explanations:+how+students+study+and+use+examples+in+learning+to+solve+problems&title=Cognitive+science&volume=13&issue=2&date=1989&spage=145&issn=0364-0213]
+ # Hausmann, R. G. M., & Chi, M. T. H. (2002). Can a computer interface support self-explaining? ''Cognitive Technology, 7''(1), 4-14. [http://www.pitt.edu/~bobhaus/hausmann2002.pdf]
+ # Lovett, M. C. (1992). Learning by problem solving versus by examples: The benefits of generating and receiving information. ''Proceedings of the Fourteenth Annual Conference of the Cognitive Science Society'' (pp. 956-961). Hillsdale, NJ: Erlbaum.
+ # Schworm, S., & Renkl, A. (2002). Learning by solved example problems: Instructional explanations reduce self-explanation activity. In W. D. Gray & C. D. Schunn (Eds.), ''Proceedings of the 24th Annual Conference of the Cognitive Science Society'' (pp. 816-821). Mahwah, NJ: Erlbaum.[http://www.cognitivesciencesociety.org/confproc/gmu02/final_ind_files/schworm_renkl.pdf]
+ # Schworm, S., & Renkl, A. (2006). Computer-supported example-based learning: When instructional explanations reduce self-explanations. ''Computers & Education, 46,'' 426-445.
+
+ ==== Connections ====
+ This project shares features with the following research projects:
− === References === + * [[Booth | Knowledge component construction vs. recall (Booth, Siegler, Koedinger& Rittle-Johnson) ]]
− Anzai, Y., & Simon, H. A. (1979) .The theoryof learning by doing. ''Psychological Review, 86''( 2), 124-140. + * [[Hausmann Study2 |The Effectsof Interaction on Robust Learning( Hausmann & VanLehn) ]]
+ * [[Craig observing | Learning from Problem Solving while Observing Worked Examples (Craig Gadgil, & Chi)]]
− Chi, M. T. H., Bassok, M., Lewis, M. W., Reimann, P., & Glaser, R. (1989). Self-explanations: How students study and use examples in learning to solve problems. ''Cognitive Science, 13'', 145-182. [http://rt4rf9qn2y.scholar.serialssolutions.com/?sid= google&auinit= MTH&aulast= CHI&atitle= Self-explanations :+how+students+study+and +use+examples+in +learning+to +solve+problems&title=Cognitive+science&volume=13&issue=2&date=1989&spage=145&issn=0364-0213] + ==== Future plans ====
+ Our future plans for June 2007- August 2007:
+ * Code transcripts forexplanations and paraphrases.
+ * Link codes from transcript to knowledge components.
+ * Link transcript to stepsin Andes log files.
+ * Submitto the International Journal of Artificial Intelligence in Education
− Hausmann, R. G. M., & Chi, M. T. H. (2002). Can a computer interface support self-explaining? ''Cognitive Technology, 7''(1), 4-14.[ http: //www.pitt.edu/~bobhaus/hausmann2002.pdf] + [ [Category: Data available in DataShop]]
Latest revision as of 20:15, 15 December 2010
1 A comparison of self-explanation to instructional explanation
1.1 Summary Table
1.2 Abstract
1.3 Background and Significance
1.4 Glossary
1.5 Research question
1.6 Independent variables
1.7 Hypothesis
1.8 Dependent variables
1.9 Results
1.10 Explanation
1.11 Further Information
1.11.1 Annotated bibliography
1.11.2 References
1.11.3 Connections
1.11.4 Future plans
A comparison of self-explanation to instructional explanation
Summary Table
<table><tbody><tr><td> PIs</td><td> Robert G.M. Hausmann & Kurt VanLehn</td></tr><tr><td> Other Contributors
* Faculty:
* Staff:</td><td>
Donald J. Treacy (USNA), Robert N. Shelby (USNA)
Brett van de Sande (Pitt), Anders Weinstein (Pitt)</td></tr><tr><td> Study Start Date</td><td> Sept. 1, 2005</td></tr><tr><td> Study End Date</td><td> Aug. 31, 2006</td></tr><tr><td> LearnLab Site</td><td> USNA Physics II</td></tr><tr><td> LearnLab Course</td><td> Physics</td></tr><tr><td> Number of Students</td><td> N= 104</td></tr><tr><td> Total Participant Hours</td><td> 190 hrs.</td></tr><tr><td> Data available in DataShop</td><td> Dataset: Self Explanation - Electric Fields - USNA - Spring 2006
Pre/Post Test Score Data:No Paper or Online Tests:Unknown Scanned Paper Tests:Unknown Blank Tests:No Answer Keys:No</td></tr></tbody></table>
Abstract
This
in vivo experiment
compared the learning that results from either hearing an explanation (
instructional explanation
) or generating it oneself (
self-explanation
). Students studied a physics
examples
, which were presented step by step. For half the students, the
example
steps were incompletely justified (i.e., the explanations connecting some steps were missing) whereas for the other half, the
example
steps were completely justified. Crossed with this variable was an attempted manipulation of the student’s studying strategy. Half the students were instructed and prompted to self-explain at the end of each step, while the other half were prompted to paraphrase it (click the following
link
for screen shots of each experimental condition). Paraphrasing was selected as the contrasting study strategy because earlier work has shown that paraphrasing suppresses
self-explanation
.
Of the four conditions, one condition was key to testing our hypothesis: the condition where students viewed completely justified
examples
and were asked to paraphrase them. If the learning gains from this condition had been just as high as those from conditions were self-explanation was encouraged, then instructional explanation would have been just as effective as self-explanation. On the other hand, if the learning gains were just as low as those where instructional explanations were absent and self-explanation was suppressed via paraphrasing, then instructional explanation would have been just as ineffective as no explanation at all.
Preliminary results of the normal and robust learning measures suggest that the latter case occurred, so instructional explanation were not as effective as self-explanations.
Background and Significance
The first studies of self-explanation, which were based on analysis of verbal protocols, showed that the amount of self-explaining correlated strongly with performance on post-test measures of problem-solving performance (Bielaczyc, Pirolli, & Brown, 1995; Chi, Bassok, Lewis, Reimann, & Glaser, 1989; Renkl, 1997). Because these studies compared self-explanation to the lack of any explanation at all, there is a confound between the generative act or producing the explanations and the additional content of the explanations themselves. Perhaps if students were simply given these explanations, they would learn just as much. Alternatively, learning from self-explaining might arise from the activity of producing the explanations. Thus, if they were given the explanations, they would not learn just as much. In other words, is it merely attending to the explanations that matters, or is robust learning more likely to occur if students generate the explanations themselves? Let us label these hypotheses as follows:
The Attention Hypothesis: learning from self-generated explanations should produce comparable learning gains as author-provided explanation, provided the learner pays attention to them. Both self-generated and author-provided explanations should exhibit better learning than no explanation.
The Generation Hypothesis: learning from self-generated explanations should produce greater learning gains than author-provided explanations because they are produced from the students’ own background knowledge; however, author-provided explanations should be comparable to no explanation.
There have only been a few empirical studies that attempt to separate the Attention hypothesis from the Generation hypothesis (Brown & Kane, 1988; Schworm & Renkl, 2002). An exemplary case can be found in a study by Lovett (1992) in the domain of permutation and combination problems. Lovett crossed the source of the solution (subject vs. experimenter) with the source of the explanation for the solution (subject vs. experimenter). For our purposes, only two of the experimental conditions matter. The experimenter-subject condition was analogous to experimental materials found in a self-explanation experiment wherein the students self-explained an author’s solution, whereas in the experimenter-experimenter condition, the students studied an author-provided explanation. Lovett found that the experimenter-experimenter condition demonstrated better performance, especially on far-transfer items. Lovett’s interpretation was that the experimenter-experimenter condition was effective because it contained higher quality explanations than those generated by students. Consistent with this interpretation, when Lovett analyzed the protocol data, she found that the participants who generated the key inferences had the same learning gains as participants who read the corresponding inferences. Thus, of our two hypotheses, Lovett’s experiment supports the Attention hypothesis: the content of self-explanations matters, while the source of the explanation does not.
Brown and Kane (1988) found that children’s explanations, generated either spontaneously or in response to prompting, were much more effective at promoting transfer than those provided by the experimenter. In particular, students were first told a story about mimicry. Some students were then told, "Some animals try to look like a scary animal so they won’t get eaten.” Other students were asked first, “Why would a furry caterpillar want to look like a snake?” and if that did not elicit an explanation, they were asked, "What could the furry caterpillar do to stop the big birds from eating him?" Most students got the question right, and if they did, 85% were able to answer a similar question about two new stories. If they were told the rule, then only 45% were able to answer a similar question about the new stories. This result is consistent with the Generation hypothesis, which is that an explanation is effective when the student generates it. However, the students who were told the rule may not have paid much attention to it, according to Brown and Kane.
In summary, one study’s results are consistent with the Attention hypothesis, and the other study’s results are consistent with the Generation hypothesis, but both studies confounded two variables. In the Lovett study, the student-produced and author-provided explanations were of different qualities. In the Brown and Kane study, the students in the author-provided explanations condition may not have paid much attention to the explanations.
Glossary
Physics example line
Complete vs. incomplete example
Instructional explanation
SeeHausmann_Study Glossary
Research question
How is robust learning affected by
self-explanation
vs.
instructional explanation
?
Independent variables
Two variables were crossed:
Did theexamplepresent an explanation with each step or present just the step?
After each step (and its explanation, if any) was presented, students were prompted to either further explain the step or paraphrase the step in their own words.
The condition where explanations were presented in the
example
and students were asked to paraphrase them is considered the “instructional explanation” condition. The two conditions where students were asked to self-explain the
example
lines are considered the “self-explanation” conditions. The remaining condition, where students were asked to paraphrase
examples
that did not contain explanations, was considered the “no explanation” condition. Note, however, that nothing prevents a student in the paraphrasing condition to self-explain (and vice-versa).
Figure 1
. An example from the Complete Self-explanation condition
<here is a image 667ff5e9bf67cbe9-aad9212eb58af14a>
Figure 2
. An example from the Incomplete Self-explanation condition
<here is a image d3692e535d877342-fc3ee16a28ce9a55>
Figure 3
. An example from the Complete Paraphrase condition
<here is a image 9bfac6b8b092033f-65e8820fb6b4c757>
Figure 4
. An example from the Incomplete Paraphrase condition
<here is a image ab075239efca05ef-9c9a11c33fa7bf42>
Hypothesis
For these well-prepared students, self-explanation should not be too difficult. That is, the instruction should be below the students’ zone of proximal development. Thus, the learning-by-doing path (self-explanation) should elicit more robust learning than the alternative path (instructional explanation) wherein the student does less work.
As a manipulation check on the utility of the explanations in the complete
examples
, we hypothesize that the instructional explanation condition should produce more robust learning than the no-explanation condition.
Dependent variables
Normal post-test
Near transfer, immediate: During training,worked examplesalternated with problems, and the problems were solved usingAndes. Each problem was similar to theexamplethat preceded it, so performance on it is a measure of normal learning (near transfer, immediate testing). The log data were analyzed and assistance scores (sum of errors and help requests, normalized by the number of transactions) were calculated.
Robust learning
Long-term retention: On the student’s regular mid-term exam, one problem was similar to the training. Since this exam occurred a week after the training, and the training took place in just under 2 hours, the student’s performance on this problem is considered a test oflong-term retention.
Near and far transfer: After training, students did their regular homework problems usingAndes. Students did them whenever they wanted, but most completed them just before the exam. The homework problems were divided based on similarity to the training problems, and assistance scores were calculated.
Accelerated future learning: The training was on electrical fields, and it was followed in the course by a unit on magnetic fields. Log data from the magnetic field homework was analyzed as a measure of acceleration of future learning.
Results
Normal post-test
Neartransfer, immediate
: The self-explanation condition demonstrating lower normalized assistance scores than the paraphrase condition,
F
(1, 73) = 6.19,
p
= .02, η
p
2
=.08.
<here is a image ae996affcf83b4ba-b8ef6a31ca56c27f>
Robust learning
Near transfer, retention
: Results on the measure were mixed. While there were no reliable main effects or interactions, the complete self-explanation group was marginally higher than the complete paraphrase condition (LSD, p = .06). Moreover, we analyzed the students’ performance on a homework problem that was isomorphic to the chapter exam in that they shared an identical deep structure (i.e., both analyzed the motion of a charged particle moving in two dimensions). The self-explanation had reliably lower normalized assistance scores than the paraphrase condition,
F
(1, 27) = 4.07,
p
= .05, η
p
2
= .13.
<here is a image 074584523503a2b1-ea9c9fbaee04e9e3>
Near and far transfer:
Accelerated future learning
: There was no effect for
example
completeness; however, the self-explanation condition demonstrating lower normalized assistance scores than the paraphrase condition,
F
(1, 46) = 5.22,
p
= .03, η
p
2
= .10.
<here is a image 28ca7028b4c89eff-4b07bc5aa13f0c51>
Explanation
This study is part of the
Interactive Communication cluster
, and its hypothesis is a specialization of the IC cluster’s central hypothesis. The IC cluster’s hypothesis is that robust learning occurs when two conditions are met:
The learning event space should have paths that are mostly learning-by-doing along with alternative paths where a second agent does most of the work. In this study, self-explanation comprises the learning-by-doing path and instructional explanations are ones where another agent (the author of the text) has done most of the work.
The student takes the learning-by-doing path unless it becomes too difficult. This study tried (successfully, it appears) to control the student’s path choice. It showed that when students take the learning-by-doing path, they learned more than when they took the alternative path.
The IC cluster’s hypothesis actually predicts an attribute-treatment interaction (ATI) here. If some students were under-prepared and thus would find the self-explanation path too difficult, then those students would learn more on the instructional-explanation path. ATI analyzes have not yet been completed.
Annotated bibliography
Accepted as a poster at CogSci 2008
Presentation to the Higher-order Cognition Group, led by Timothy J. Nokes, on March 3, 2008
Presentation to the PSLC Advisory Board, December, 2006 [1]
Presentation to the NSF Follow-up Site Visitors, September, 2006
Preliminary results were presented to the Intelligent Tutoring in Serious Games workshop, Aug. 2006 [2]
Presentation to the NSF Site Visitors, June, 2006
Poster presented at the annual meeting of the Science of Learning Centers, Oct. 2006.
Symposium accepted to EARLI 2007
Symposium accepted at AERA 2007
Full-paper accepted at AIED 2007 [3]
Accepted as a poster at CogSci 2007
Presentation to the NSF Site Visitors, May 31, 2007
References
Anzai, Y., & Simon, H. A. (1979). The theory of learning by doing. Psychological Review, 86(2), 124-140.
Chi, M. T. H., Bassok, M., Lewis, M. W., Reimann, P., & Glaser, R. (1989). Self-explanations: How students study and use examples in learning to solve problems. Cognitive Science, 13, 145-182. [4]
Hausmann, R. G. M., & Chi, M. T. H. (2002). Can a computer interface support self-explaining? Cognitive Technology, 7(1), 4-14. [5]
Lovett, M. C. (1992). Learning by problem solving versus by examples: The benefits of generating and receiving information. Proceedings of the Fourteenth Annual Conference of the Cognitive Science Society(pp. 956-961). Hillsdale, NJ: Erlbaum.
Schworm, S., & Renkl, A. (2002). Learning by solved example problems: Instructional explanations reduce self-explanation activity. In W. D. Gray & C. D. Schunn (Eds.), Proceedings of the 24th Annual Conference of the Cognitive Science Society(pp. 816-821). Mahwah, NJ: Erlbaum. [6]
Schworm, S., & Renkl, A. (2006). Computer-supported example-based learning: When instructional explanations reduce self-explanations. Computers & Education, 46,426-445.
Connections
This project shares features with the following research projects:
Knowledge component construction vs. recall (Booth, Siegler, Koedinger & Rittle-Johnson)
The Effects of Interaction on Robust Learning (Hausmann & VanLehn)
Learning from Problem Solving while Observing Worked Examples (Craig Gadgil, & Chi)
Future plans
Our future plans for June 2007 - August 2007:
Code transcripts for explanations and paraphrases.
Link codes from transcript to knowledge components.
Link transcript to steps in Andes log files.
Submit to the International Journal of Artificial Intelligence in Education
Category
:
Data available in DataShop
| https://learnlab.org/wiki/index.php?diff=cur&oldid=2335&title=Hausmann_Study |
Early Detection in Minority Groups Could Help With Pediatric CKD
Early detection of chronic kidney disease (CKD) in adolescents in minority groups can be beneficial to future treatment, according to a recent editorial.
Early Detection in Minority Groups Could Help With Pediatric CKD
Early detection of chronic kidney disease (CKD) in adolescents in minority groups can be beneficial to future treatment, according to a recent editorial.
The authors of an editorial published in Journal of the National Medical Associationfound that pediatric chronic kidney disease (CKD) could be best treated if found early and if minority groups were screened due to their increased risk. They also said that a collaboration between health care systems and pediatric nephrologists could go a long way in achieving these goals.
Children can develop CKD in a variety of ways. Congenital anomalies of the kidney and urinary tract, cystic and hereditary disorders, and glomerulonephritis are some causes of CKD. Heart disease, past acute kidney injury, and family history of CKD are also factors in the pediatric development of CKD.
Congenital causes are the mostly commonly reported etiology from developed countries where CKD is diagnosed in the early stages, according to the authors. However, infectious or acquired causes of CKD are predominant in developing countries. CKD is a common complication of pediatric malignancies and stem cell transplantation because of nephrotoxic chemotherapeutic agents, radiation, surgical interventions, and exposure to other nephrotoxic medications.
Children with sickle cell disease (SCD) can have albuminuria due to glomerular hyperfiltration and have been reported to have a more rapid decline in kidney function. Sickle cell nephropathy can often lead to CKD in adults with SCD, with up to 12% of people with CKD and SCD progressing to end-stage renal disease (ESRD).
Estimates of the causes of CKD in children in America are derived from the Chronic Kidney Disease in Children study and the registry of the North American Pediatric Renal Trials and Collaborative Studies organization. Although CKD stages 2 to 5 are poorly characterized, population-based studies suggest that prevalence of pediatric CKD may be as high as 1%.
The prevalence of decreased glomerular filtration rate (GFR) in adolescents in the United States is approximately 0.51%, according to the United States Renal Data System (USRDS). The USRDS estimates that the prevalence of CKD in children is 2.7 per 1000 children with health care coverage. Black/African American, Latino, American Indian or Alaska Native, Asian American, or Native Hawaiian or Pacific Islanders all have an increased risk of developing CKD.
Black/African American individuals are nearly 4 times as likely to have kidney failure vs White people and are more likely to progress to ESRD. There are biological and nonbiological factors involved in this disparity. Premature birth is associated with increased risk of CKD because of low nephron endowment and birth weight. African American women have a higher rate of premature births.
Gestational determinants, low income, and maternal education can have an effect on socioeconomic status, which in turn can have an impact on development and progression of CKD in children. Low-income neighborhoods are disproportionally exposed to environmental risk factors and have predominantly minority residents.
Children with CKD will have more health problems than those without, the authors highlighted. The risk of cardiovascular mortality is increased in children with CKD with abnormal glucose metabolism, obesity, dyslipidemia, and hypertension. Growth failure or impaired growth can also be found in children with CKD due to malnutrition, fluid and electrolyte disturbances, metabolic acidosis, anemia, renal osteodystrophy, and inflammation.
CKD is a disease that can have a big impact on the lives of children who receive the diagnosis. The authors suggest steps to diagnose and manage the care of CKD in children.
Children who are a high risk of CKD should be identified and screened for CKD using serum creatinine and cyastin measurements to determine estimated GFR and urine albumin to creatinine or protein to creatinine ratios should also be recorded.
Lifestyle modifications, like regular exercise and healthy eating, should be included in a CKD treatment plan for children who are found to have CKD. Blood pressure control and proteinuria management will also help the prevention of progression of CKD. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers should also be used as treatment for pediatric CKD. Nephrologist treatment and early detection by primary care providers is vital for stopping the progression of CKD.
“A strong collaboration between the primary health care system and a nephrologist will create early awareness to address the crucial public health issue of CKD and also trigger the opportunity for effective management of the disease,” the researchers concluded.
Reference
Beng-Ongey H, Robinson JS, Moxey-Mims M. Chronic kidney disease emerging trends in children and what to do about it. J Natl Med Assoc. Published online May 31, 2022. doi:10.1016/j.jnma.2022.05.002
Have Racial Disparities in Home Dialysis Utilization Changed Over Time?
By Virginia Wang, PhD Lindsay Zepel, MS Cynthia J. Coffman, PhD Clarissa J. Diamantidis, MD, MHS Sarah Hudson Scholle, DrPH, MPH Matthew L. Maciejewski, PhD View All
Medicare prospective payment for dialysis modestly increased availability and use of home-based dialysis treatment but did not affect historic racial disparities in home dialysis.
ABSTRACT
Objectives:The Medicare end-stage kidney disease (ESKD) prospective payment system (PPS) for maintenance dialysis, implemented in 2011, resulted in modestly increased access to both home-based peritoneal dialysis (PD) and home hemodialysis (HHD) treatment modalities, but it is unclear whether regional disparities in home dialysis (PD and HHD) were affected. We compared regional home dialysis use by White and non-White individuals over time.
Study Design:Retrospective cohort study of dialysis facilities offering home dialysis in 2006-2016 and of 1,098,579 patients with prevalent ESKD in 2006-2016.
Methods:We compared hospital referral region (HRR) utilization rates of home dialysis between White and non-White patients over time using a generalized estimating equation model with a negative binomial distribution adjusting for regional characteristics.
Results:The mean number of facilities offering home dialysis operating in each HRR increased from 15.6 in 2006 to 22.1 in 2016. Observed mean HRR home dialysis rates increased overall, but White patients maintained greater home dialysis use than non-White patients: 19.7% in 2006 and 26.2% in 2016 among White patients vs 13.0% in 2006 and 17.8% in 2016 among non-White patients. In adjusted analysis, there was no evidence of changes in White/non-White disparities in home dialysis use over time ( P= .84) or after the Medicare ESKD PPS in 2011 (incidence rate ratio, 0.97; 95% CI, 0.92-1.02; P= .29).
Conclusions:Even after modest increases in dialysis facility availability and patient utilization after the implementation of the Medicare ESKD PPS in 2011, significant racial disparities in home dialysis remain.
Am J Manag Care. 2023;29(3):152-158. https://doi.org/10.37765/ajmc.2023.89329
Takeaway Points
Despite increased dialysis facility availability and patient utilization of home dialysis after implementation of the Medicare end-stage kidney disease (ESKD) prospective payment system (PPS) in 2011, racial disparities remain.
Although half of all patients with kidney failure are non-White, regional rates of home dialysis were approximately one-third lower for non-White patients than White patients.
After implementation of the Medicare ESKD PPS, home dialysis utilization increased for both White and non-White dialysis patients with ESKD, but there were no significant changes in White/non-White disparities over time.
Assessing region-level racial disparities is particularly important as new policy efforts target ESKD providers to improve disparities in the utilization of home-based treatment modalities.
_____
As Medicare is the largest payer of dialysis services in the United States, its policies can influence access to home dialysis in various ways. Over the years, Congress has enacted a number of changes to Medicare policy in an effort to improve the quality of dialysis services and control program costs. In 2011, Medicare implemented a bundled end-stage kidney disease (ESKD) prospective payment system (PPS) for maintenance dialysis. This PPS partly reflects Medicare’s attempt to better align patient preferences 1-3and clinical appropriateness for home dialysis 4,5with dialysis facilities, by reducing the relative profitability of in-center hemodialysis (ICHD).
Home dialysis modalities (ie, peritoneal dialysis [PD] and home hemodialysis [HHD]) were developed as an alternative form of dialysis in the 1970s and offer a clinically equivalent, convenient, and less expensive alternative to ICHD. Whereas ICHD is typically performed by clinical staff in dialysis facilities 3 times a week, home dialysis patients self-perform dialysis daily and visit dialysis facilities monthly for maintenance. Although home dialysis is not suitable for all patients, it is generally considered similar or complementary to ICHD. PD is the most common home dialysis modality; compared with ICHD, it has been associated with a similar risk of mortality 6,7but greater patient-reported quality of life, 8-11lower rates of complications, 12,13and lower societal costs. 14-17Nephrologists estimate that roughly half of patients with ESKD are good candidates for home dialysis, 2,5and patients strongly prefer home dialysis. 10,11,18,19Despite these advantages, only 9.4% of patients with ESKD were receiving home dialysis in 2010. 17
The 2011 Medicare ESKD PPS altered payment for dialysis treatment by bundling dialysis, medications, and ancillary services into a single payment, adjusted for patient- and facility-level characteristics, and an additional payment for home dialysis training. 20Because home dialysis is associated with lower costs than ICHD, 14-17provider revenues under the PPS and therefore supply and use of home modalities were expected to increase. One study found that the operating margin of PD would increase from –$185 to $201 per patient-month after the implementation of the ESKD PPS, 21which would encourage greater provision and utilization of home dialysis (chiefly, PD). Prior research found that the 2011 ESKD bundled payment implementation resulted in a modest increase in dialysis facility provision of home dialysis services 22but little change in geographic variability in home dialysis 23or incident utilization of home dialysis by patients with incident ESKD. 24Despite these modest changes, it is possible that racial/ethnic disparities changed over time and place. In other words, modest increases in dialysis provision by dialysis facilities and dialysis utilization by patients could mask offsetting changes in different hospital referral regions (HRRs).
Limited prior work has examined disparities in home dialysis utilization. Wallace and colleagues reported state-level variability in disparities of PD and HHD use in a cross-sectional cohort of Medicare fee-for-service patients with ESKD in 2012. 25Turenne and colleagues’ 2008-2013 patient-level analysis found overall increased use of PD in the initial post-PPS years but no change in persistently lower use among Black and Hispanic patients. 26
We conducted analyses to evaluate the extent of racial disparities in home dialysis utilization (PD and HHD) over time and to determine whether regional disparities in home dialysis use changed after the introduction of the Medicare ESKD PPS in 2011. We describe time trends in racial disparities across HRRs and identify market characteristics associated with provision of home dialysis within HRRs. Assessment of racial disparities at the HRR level is particularly important as new policy efforts target ESKD provider organizations to improve disparities in care and utilization of home-based modalities.
METHODS
Study Design, Population, and Data
We conducted a longitudinal retrospective cohort study of US patients and dialysis facilities at the Dartmouth Atlas HRR level 27between 2006 and 2016. HRRs are used because they reflect home dialysis service areas better than municipal designations (eg, zip codes, counties) for patients receiving dialysis, who often travel outside county boundaries for monthly maintenance visits. 28-31
The primary source of data for this study was the US Renal Data System (USRDS). 32Dialysis facility characteristics were drawn from the CMS Annual Facility Survey (CMS-2744, USRDS FACILITY file) and supplemented with the Medicare Provider of Service file to account for facilities that opened or closed during the study period and for changes in facility ownership. 22,33Facility-level characteristics of patients with prevalent ESKD were based on longitudinal records of their treatment history (USRDS-RXHIST file). Region-level characteristics of patients with prevalent ESKD (eg, age, gender, race and ethnicity, employment status) were drawn from the Medical Evidence Report (CMS-2728, USRDS-PATIENTS and USRDS-MEDEVID files). Such data are required to be reported for all patients, regardless of Medicare enrollment status. Patient race and Hispanic ethnicity were ascertained from the medical evidence form (primary) or documented in the overall USRDS-PATIENTS file (secondary). When Hispanic ethnicity information from all USRDS sources was missing, patient ethnicity was set to non-Hispanic. General region-level demographic characteristics (eg, urban population, per capita income) were drawn from the county-level Area Health Resources Files, which we converted to the zip code level using land-area weighting and then aggregated to HRRs.
For the dialysis facility inclusion, we identified a cohort of all nonfederal outpatient ESKD facilities that ever offered home dialysis services during the study period, which accounted for new facilities, closures, and changes in ownership. 22We excluded facilities that provided only transplant services, never reported home dialysis services, had an invalid zip code, or lacked a valid Medicare provider identifier. The patient cohort included all patients receiving dialysis who had prevalent or incident ESKD, had nonmissing demographic and zip code information, survived 90 days from dialysis initiation, did not receive a kidney transplant within 90 days or recover kidney function within 180 days after initiating dialysis, and had documented dialysis modality. 22,24We generated annual records of the dialysis modality and treating dialysis facility for the resulting 1,098,579 patients with prevalent ESKD, which were then merged with longitudinal dialysis facility data sets (eAppendix Figure 1[eAppendix available at ajmc.com]). All data for this study were available at the zip code level and then aggregated to the HRR market level for each year of the study period.
Outcome and Statistical Analysis
The outcome of interest was the proportion of White (or non-White) patients who used home dialysis (PD or HHD) in each HRR in each year between 2006 and 2016. Given the small mean numbers of home dialysis patients per facility (17.3 in 2006 and 22.9 in 2016) and small or zero number of cases when stratified by racial and ethnic subgroups at the facility level, the home dialysis outcome was aggregated to the HRR level. When aggregating Hispanic, non-Hispanic Asian, or Pacific Islander groups to the HRR-level racial groups, the numbers who used home dialysis or received any type of dialysis numbers were still small or zero for some HRRs in each year. Grouping patients of non-Hispanic Black/African American, Hispanic, non-Hispanic Asian or Pacific Islander, or other race/ethnicity into a general category of non-White in this way reduced the number of HRRs that would have missing outcomes and be dropped from models. For each HRR/year combination, the count for the number of White and non-White home dialysis users and the count for the number of White and non-White users of any dialysis modality were generated.
We examined descriptive statistics of the cohorts and unadjusted outcomes for White patients and non-White patients, as well as White patients and Black patients. Choropleth maps illustrated changes in the regional distribution of home dialysis availability at the HRR level between 2006 and 2016. Informed by prior research on home dialysis utilization 24-26and disparities measurement, 25,34utilization rate ratios in each HRR were used to descriptively compare any home dialysis utilization rates between non-White patients and White patients, such that values greater than 1.00 indicate a non-White home dialysis utilization rate greater than the rate among White patients and values less than 1.00 indicate a non-White home dialysis utilization rate less than the rate among White patients.
A generalized estimating equations model 35was used to account for the repeated HRR-level observations across years with a negative binomial distribution, a log link function, and an exchangeable covariance structure that best accounted for HRR-level repeated measures. 36An offset for the number of White or non-White dialysis users in the HRR for the year was used. Explanatory variables of interest were an indicator for White or non-White dialysis users in the HRR, indicator variables for year, and indicator variables for the interactions between White and non-White dialysis users in the HRR and year.
Adjusted analysis controlled for time-varying composition of regions’ market characteristics ( Table) to adjust for factors that may influence provider service strategies and patient utilization of home dialysis at the HRR level. We first determined whether there were differences in racial disparities in HRR home dialysis use over time, and then examined differences between the prepolicy (2006-2010) and postpolicy (2011-2016) periods. For HRR-level market characteristics, HRR-level dialysis facility composition included the proportion of facilities in HRRs that were for-profit owned, freestanding (vs being hospital based), affiliated with a chain organization, or newly opened or closed in the year; had ownership change in the prior year; and had an urban or rural location based on zip code. Dialysis market competition was calculated using the Herfindahl-Hirschman Index, which is equal to the sum of the square of each dialysis facility’s market share, based on the number of patients receiving dialysis unique to each facility. Facilities within a market under the same chain affiliation were treated as a single firm. 37,38Regional composition of patients with ESKD included ESKD incidence and the proportion of patients with ESKD who were White, younger than 65 years, or employed. General population characteristics included per capita income and proportion of urban residents. Time-varying covariates contributed both cross-sectional and longitudinal sources of variation in our HRR-level home use rate outcomes and were decomposed into between-HRR and within-HRR components, respectively, for inclusion in models 39; linear effects were included for all between- and within-HRR components. This study was approved by the institutional review board of Duke University.
RESULTS
Characteristics of Analytic Cohort
The mean number of dialysis facilities operating in each HRR increased from 15.6 in 2006 to 22.1 in 2016, and the proportion with for-profit ownership increased over time (79.8% in 2006 vs 87.1% in 2016). Chain affiliation of dialysis facilities (82.3% in 2006 vs 91.7% in 2016) also increased over time (Table). Mean ESKD incidence in HRRs grew more slowly (3.8 per 10,000 HRR general population in 2006 vs 4.0 per 10,000 HRR general population in 2016) and the mean percentage of White patients with ESKD in an HRR decreased from 53.1 in 2006 to 50.2 in 2016. The prevalence of PD, the most common form of home dialysis, within HRRs increased over time, from a mean of 75.1 patients receiving PD per 1000 in the 2006 ESKD patient population to 91.0 per 1000 ESKD population in 2016. Overall (2006-2016), 51.2% of patients receiving dialysis were White, 31.2% were Black, 12% were Hispanic, 4% were Asian or Pacific Islander, and 1.6% were other/unknown race (results available from authors).
Disparities in White vs Non-White Patient Utilization of Home Dialysis
The unadjusted mean HRR home dialysis (PD or HHD) utilization rates were higher in 2016 (26.2%) than in 2006 (19.7%) for White patients with ESKD ( Figure 1) and for non-White patients with ESKD (17.8% in 2016 and 13.0% in 2006). In every year, the unadjusted mean utilization rate of HRR home dialysis was approximately one-third lower for non-White patients than White patients. Black patients had similar trends to non-White patients (eAppendix Figure 2). In most HRRs, home dialysis utilization rates in 2006 and 2016 were higher for White patients than non-White patients (utilization ratios < 1.0). Exceptions in 2006 where non-White patients had higher home dialysis utilization rates than White patients were in the upper Midwest, upper New England, and selected parts of California, Oregon, and Washington (utilization ratios > 1.0). However, in 2016, non-White patients had lower home dialysis utilization rates than White patients in most of those regions (eAppendix Figures 3 and 4).
In adjusted analysis, there was no evidence of changes in observed disparities between White and non-White patients in HRR home dialysis utilization over time (χ 2 10= 5.71; P= .84) ( Figure 2andeAppendix Table). Similarly, there was no difference in HRR-level disparities in HRR home dialysis use before vs after the implementation of the Medicare ESKD PPS in 2011 (incidence rate ratio, 0.97; 95% CI, 0.92-1.02; P= .29).
Several market characteristics were associated with HRR home dialysis utilization. HRR home dialysis utilization was positively associated with the proportion of new dialysis facilities in HRRs ( P= .02), less competitive markets ( P= .02), percentage of facilities in HRR in an urban location ( P= .04), percentage of the general population in HRR who are urban residents ( P= .02), and percent of patients with ESKD who are employed ( P= .02); it was negatively associated with facility closures in HRRs ( P= .04) (eAppendix Table).
DISCUSSION
This study described regional trends in White vs non-White disparities in home dialysis utilization between 2006 and 2016. Overall, home dialysis utilization increased for White patients and non-White patients but remained roughly one-third lower among non-White patients before and after the implementation of the Medicare ESKD PPS. In other words, the regional disparity in home dialysis utilization for White patients and non-White patients did not change over time. We also found that less competitive markets and markets with more new dialysis facility openings were associated with greater overall home dialysis utilization.
Despite the fact that just under half of all patients with ESKD are non-White, the 2011 Medicare dialysis PPS had little impact on existing disparities in home dialysis use between White and non-White patients. As noted above, home dialysis utilization increased for both White and non-White dialysis patients with ESKD after the implementation of the ESKD PPS in 2011, but the historic disparities remained. On the other hand, disparities in home dialysis utilization did not worsen. This small observed increase in improved non-White home dialysis utilization could be due to an increasing number of HRRs in which non-White patients have greater utilization than White patients over time, or due to HRRs with lower non-White home dialysis utilization getting better over time, or both. Most likely, the increase is due to non-White utilization increasing in most HRRs and regions, with higher rates of non-White patients receiving home dialysis translating into more equitable White and non-White home dialysis use. Findings from our 2006-2016 region-level analysis are consistent with Turenne and colleagues’ patient-level analysis of disparities in PD use from 2008 to 2013; they found growth in PD among racially diverse subgroups of patients after Medicare payment reform but no change in differences in rates of use across race and ethnicity. 26Thus, more than a decade of utilization trends converge on the conclusion that even after modest increases in dialysis facility availability 22and patient utilization 24after the implementation of the Medicare ESKD PPS in 2011, disparities in home dialysis use remain.
Our findings highlight an important and attainable goal in improving US kidney care: increasing uptake of home dialysis for all patients and reducing disparities in home dialysis for non-White patients. Disparate and low utilization of home dialysis modalities belie the promise of home dialysis for patients. Prior research found that nephrologists consider a greater share of their patients clinically appropriate for home dialysis than actual utilization reflects. 5,40The continued racial disparities observed in home dialysis use over time 24-26,41,42suggest the presence of clinical as well as nonclinical factors that may be driving differences in uptake of home dialysis. Access to predialysis services, comprehensive education, and counseling around renal replacement options are important for raising awareness of home dialysis for patient-informed decision-making; these factors may also drive disparities. This suggests that interventions to increase home dialysis should occur prior to ESKD onset, and that nephrologists and dialysis providers should play critical roles in patient selection of home-based treatment modalities. There has been no empirical examination of the source of racial differences in home dialysis. Investigating structural, systemic, or provider bias in home dialysis in future research will be critical for understanding and reducing racial and socioeconomic disparities in dialysis care. Equitable education and geographic access to home dialysis modalities, offered in roughly half of all US dialysis facilities and in regions with higher average income and proportions of White ESKD patient populations, may also significantly influence patient selection and disparities in home dialysis. 23,31
To date, disparities in ESKD care have largely remained unchanged, and as noted earlier, the implementation of the ESKD PPS in 2011 did not specifically target equity. However, implementation of Medicare alternative payment models may be a promising solution. The Kidney Care Choices model, launched on January 1, 2022, includes financial incentives for health care providers to improve clinical management of Medicare beneficiaries with advanced kidney disease and ESKD, to delay their progression to kidney failure, and to promote kidney transplantation. The 2021 ESKD Treatment Choices (ETC) Model is designed to encourage greater use of home dialysis and kidney transplants for Medicare beneficiaries with ESKD, reduce Medicare expenditures, and enhance the quality of ESKD care. In 2022, the ETC Model was revised to also encourage dialysis facilities and health care providers to decrease disparities in rates of home dialysis and kidney transplants among patients with ESKD of lower socioeconomic status. Our regional findings, assessed at the same HRR level as the ETC Model’s geographic unit of provider selection, are a useful foundation for future evaluation of these policies. Continued monitoring of dialysis facility home dialysis utilization across racial and ethnic groups, as well as case studies of dialysis facility strategies for equitable and effective home dialysis patient identification, education, and adoption, will be important future directions for research to inform improvements and disparities in the care of patients with kidney failure.
Limitations
There are several analytic limitations to acknowledge. Sample sizes of patients receiving home dialysis were small in many facilities (mean was 17 in 2006, 22 in 2016), preventing analysis of facility-level attributes of racial disparities in home dialysis utilization. Aggregating the dialysis use data to the regional level may mask important facility-level variability and patterns in disparity of use. To retain as many patients as possible in the sample, those with missing Hispanic ethnicity data were recoded to non-Hispanic, which may skew results. However, only 0.5% of patients during the observation period had missing ethnicity data, so this was unlikely to alter our findings. In addition, there are several factors potentially associated with changes in home dialysis utilization that we could not assess, such as regional supply of providers with home dialysis training and experience. Finally, our region-level analysis did not adjust for patient-level covariates including the suitability of the patient’s residence for home dialysis, patient educational background, family support, and acuity of dialysis initiation (inpatient vs outpatient) that could affect home dialysis use. 43-45
CONCLUSIONS
Significant racial disparities in home dialysis use that existed years before the 2011 dialysis payment reform did not improve in the 5 years that followed this reform. The continued racial disparities observed in home dialysis use over time suggest that the presence of clinical as well as nonclinical factors may be driving differences in uptake of home dialysis.
Author Affiliations:Center of Innovation to Accelerate Discovery and Practice Transformation, Durham Veterans Affairs Health Care System (VW, CJC, MLM), Durham, NC; Department of Population Health Sciences (VW, LZ, CJD, MLM) and Department of Biostatistics and Bioinformatics (CJC), Duke University School of Medicine, Durham, NC; Division of General Internal Medicine (VW, CJD, MLM) and Division of Nephrology (CJD), Department of Medicine, Duke University School of Medicine, Durham, NC; National Committee for Quality Assurance (SHS), Washington, DC.
Source of Funding:The research in this article was supported by CMS under contract No. HHSM-500-2014-00442G with the National Committee for Quality Assurance. This work was also supported by the Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs. Dr Maciejewski was supported by a Research Career Scientist award from the Department of Veterans Affairs (RCS 10-391).
Author Disclosures:Dr Diamantidis reports a consultancy with Optum Labs, unrelated to this manuscript. Dr Maciejewski has received grant funding via a contract with CMS (HHSM-500-2016-00097G) and owns Amgen stock due to his spouse’s employment. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information:Concept and design (VW, LZ, CJC, CJD, SHS, MLM); acquisition of data (VW, SHS, MLM); analysis and interpretation of data (VW, LZ, CJC, CJD, MLM); drafting of the manuscript (VW, LZ, CJD, MLM); critical revision of the manuscript for important intellectual content (VW, LZ, CJC, CJD, SHS, MLM); statistical analysis (LZ, CJC, MLM); provision of patients or study materials (VW); obtaining funding (SHS, MLM); administrative, technical, or logistic support (SHS); and supervision (VW, SHS).
Address Correspondence to:Virginia Wang, PhD, Department of Population Health Sciences, Duke University School of Medicine, 215 Morris St, Campus Box 104427, Durham, NC 27710. Email: [email protected].
REFERENCES
1. Ahlmén J, Carlsson L, Schönborg C. Well-informed patients with end-stage renal disease prefer peritoneal dialysis to hemodialysis. Perit Dial Int. 1993;13(suppl 2):S196-S198.
2. Stack AG. Determinants of modality selection among incident US dialysis patients: results from a national study. J Am Soc Nephrol. 2002;13(5):1279-1287. doi:10.1681/ASN.V1351279
3. Thodis E, Passadakis P, Vargemezis V, Oreopoulos DG. Peritoneal dialysis: better than, equal to, or worse than hemodialysis? data worth knowing before choosing a dialysis modality. Perit Dial Int. 2001;21(1):25-35.
4. Charest AF, Mendelssohn DC. Are North American nephrologists biased against peritoneal dialysis? Perit Dial Int. 2001;21(4):335-337.
5. Mendelssohn DC, Mullaney SR, Jung B, Blake PG, Mehta RL. What do American nephrologists think about dialysis modality selection? Am J Kidney Dis. 2001;37(1):22-29. doi:10.1053/ajkd.2001.20635
6. Wang V, Coffman CJ, Sanders LL, et al. Comparing mortality of peritoneal and hemodialysis patients in an era of Medicare payment reform. Med Care. 2021;59(2):155-162. doi:10.1097/MLR.0000000000001457
7. Wong B, Ravani P, Oliver MJ, et al. Comparison of patient survival between hemodialysis and peritoneal dialysis among patients eligible for both modalities. Am J Kidney Dis. 2018;71(3):344-351. doi:10.1053/j.ajkd.2017.08.028
8. Queeley GL, Campbell ES. Comparing treatment modalities for end-stage renal disease: a meta-analysis. Am Health Drug Benefits. 2018;11(3):118-127.
9. Tong A, Lesmana B, Johnson DW, Wong G, Campbell D, Craig JC. The perspectives of adults living with peritoneal dialysis: thematic synthesis of qualitative studies. Am J Kidney Dis. 2013;61(6):873-888. doi:10.1053/j.ajkd.2012.08.045
10. Walker RC, Hanson CS, Palmer SC, et al. Patient and caregiver perspectives on home hemodialysis: a systematic review. Am J Kidney Dis. 2015;65(3):451-463. doi:10.1053/j.ajkd.2014.10.020
11. Walker RC, Morton RL, Palmer SC, Marshall MR, Tong A, Howard K. A discrete choice study of patient preferences for dialysis modalities. Clin J Am Soc Nephrol. 2018;13(1):100-108. doi:10.2215/CJN.06830617
12. Johansen KL, Zhang R, Huang Y, et al. Survival and hospitalization among patients using nocturnal and short daily compared to conventional hemodialysis: a USRDS study. Kidney Int. 2009;76(9):984-990. doi:10.1038/ki.2009.291
13. Ramar P, Ahmed AT, Wang Z, et al. Effects of different models of dialysis care on patient-important outcomes: a systematic review and meta-analysis. Popul Health Manag. 2017;20(6):495-505. doi:10.1089/pop.2016.0157
14. Liu FX, Walton SM, Leipold R, Isbell D, Golper TA. Financial implications to Medicare from changing the dialysis modality mix under the bundled prospective payment system. Perit Dial Int. 2014;34(7):749-757. doi:10.3747/pdi.2013.00305
15. Sennfält K, Magnusson M, Carlsson P. Comparison of hemodialysis and peritoneal dialysis—a cost-utility analysis. Perit Dial Int. 2002;22(1):39-47.
16. Shih YC, Guo A, Just PM, Mujais S. Impact of initial dialysis modality and modality switches on Medicare expenditures of end-stage renal disease patients. Kidney Int. 2005;68(1):319-329. doi:10.1111/j.1523-1755.2005.00413.x
17. USRDS 2018 Annual Data Report: Atlas of End-stage Renal Disease in the United States. US Renal Data System; 2018. Accessed February 12, 2023. https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/usrds/prior-data-reports/2018
18. Devoe DJ, Wong B, James MT, et al. Patient education and peritoneal dialysis modality selection: a systematic review and meta-analysis. Am J Kidney Dis. 2016;68(3):422-433. doi:10.1053/j.ajkd.2016.02.053
19. Mehrotra R, Marsh D, Vonesh E, Peters V, Nissenson A. Patient education and access of ESRD patients to renal replacement therapies beyond in-center hemodialysis. Kidney Int. 2005;68(1):378-390. doi:10.1111/j.1523-1755.2005.00453.x
20. End stage renal disease (ESRD) prospective payment system (PPS). CMS. Updated October 31, 2022. Accessed February 12, 2023. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ESRDpayment/index.html
21. Hornberger J, Hirth RA. Financial implications of choice of dialysis type of the revised Medicare payment system: an economic analysis. Am J Kidney Dis. 2012;60(2):280-287. doi:10.1053/j.ajkd.2012.03.010
22. Wang V, Coffman CJ, Sanders LL, Lee SYD, Hirth RA, Maciejewski ML. Medicare’s new prospective payment system on facility provision of peritoneal dialysis. Clin J Am Soc Nephrol. 2018;13(12):1833-1841. doi:10.2215/CJN.05680518
23. Sloan CE, Coffman CJ, Sanders LL, et al. Trends in regional supply of peritoneal dialysis in an era of health reform, 2006 to 2013. Med Care Res Rev. 2021;78(3):281-290. doi:10.1177/1077558720910633
24. Sloan CE, Coffman CJ, Sanders LL, et al. Trends in peritoneal dialysis use in the United States after Medicare payment reform. Clin J Am Soc Nephrol. 2019;14(12):1763-1772. doi:10.2215/CJN.05910519
25. Wallace EL, Lea J, Chaudhary NS, et al. Home dialysis utilization among racial and ethnic minorities in the United States at the national, regional, and state level. Perit Dial Int. 2017;37(1):21-29. doi:10.3747/pdi.2016.00025
26. Turenne M, Baker R, Pearson J, Cogan C, Mukhopadhyay P, Cope E. Payment reform and health disparities: changes in dialysis modality under the new Medicare dialysis payment system. Health Serv Res. 2018;53(3):1430-1457. doi:10.1111/1475-6773.12713
27. Wennberg JE, Cooper MM. The Dartmouth Atlas of Health Care in the United States. American Hospital Publishing; 1996.
28. O’Hare AM, Johansen KL, Rodriguez RA. Dialysis and kidney transplantation among patients living in rural areas of the United States. Kidney Int. 2006;69(2):343-349. doi:10.1038/sj.ki.5000044
29. Osterlund K, Mendelssohn D, Clase C, Guyatt G, Nesrallah G. Identification of facilitators and barriers to home dialysis selection by Canadian adults with ESRD. Semin Dial. 2014;27(2):160-172. doi:10.1111/sdi.12183
30. Prakash S, Coffin R, Schold J, et al. Travel distance and home dialysis rates in the United States. Perit Dial Int. 2014;34(1):24-32. doi:10.3747/pdi.2012.00234
31. Wang V, Maciejewski ML, Coffman CJ, et al. Impacts of geographic distance on peritoneal dialysis utilization: refining models of treatment selection. Health Serv Res. 2017;52(1):35-55. doi:10.1111/1475-6773.12489
32. 2017 Researcher’s Guide to the USRDS Database. US Renal Data System; 2017. Accessed February 12, 2023. https://www.niddk.nih.gov/-/media/Files/USRDS/For-Researchers/Researchers-Guide/2017/2017_usrds_researcher_guide.pdf
33. Wang V, Lee SY, Patel UD, Maciejewski ML, Ricketts TC. Longitudinal analysis of market factors associated with provision of peritoneal dialysis services. Med Care Res Rev. 2011;68(5):537-558. doi:10.1177/1077558711399768
34. Beyene J, Moineddin R. Methods for confidence interval estimation of a ratio parameter with application to location quotients. BMC Med Res Methodol. 2005;5:32. doi:10.1186/1471-2288-5-32
35. Diggle PJ, Heagerty P, Liang KY, Zeger SL. Analysis of Longitudinal Data. Oxford University Press; 2002.
36. Cui J. QIC program and model selection in GEE analyses. Stata J. 2007;7(2):209-220. doi:10.1177/1536867X0700700205
37. Hirth RA, Held PJ, Orzol SM, Dor A. Practice patterns, case mix, Medicare payment policy, and dialysis facility costs. Health Serv Res. 1999;33(6):1567-1592.
38. Pozniak AS, Hirth RA, Banaszak-Holl J, Wheeler JR. Predictors of chain acquisition among independent dialysis facilities. Health Serv Res. 2010;45(2):476-496. doi:10.1111/j.1475-6773.2010.01081.x
39. Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. 2nd ed. Wiley; 2011.
40. Mendelssohn DC. PD and the future: the role of PD in the overall management of ESRD. Blood Purif. 2003;21(1):24-28. doi:10.1159/000067853
41. Mehrotra R, Soohoo M, Rivara MB, et al. Racial and ethnic disparities in use of and outcomes with home dialysis in the United States. J Am Soc Nephrol. 2016;27(7):2123-2134. doi:10.1681/ASN.2015050472
42. Shen JI, Erickson KF, Chen L, et al. Expanded prospective payment system and use of and outcomes with home dialysis by race and ethnicity in the United States. Clin J Am Soc Nephrol. 2019;14(8):1200-1212. doi:10.2215/CJN.00290119
43. Furth SL, Hwang W, Yang C, Neu AM, Fivush BA, Powe NR. Relation between pediatric experience and treatment recommendations for children and adolescents with kidney failure. JAMA. 2001;285(8):1027-1033. doi:10.1001/jama.285.8.1027
44. Mehrotra R, Blake P, Berman N, Nolph KD. An analysis of dialysis training in the United States and Canada. Am J Kidney Dis. 2002;40(1):152-160. doi:10.1053/ajkd.2002.33924
45. Thamer M, Hwang W, Fink NE, et al. US nephrologists’ recommendation of dialysis modality: results of a national survey. Am J Kidney Dis. 2000;36(6):1155-1165. doi:10.1053/ajkd.2000.19829
| https://www.ajmc.com/view/early-detection-in-minority-groups-could-help-with-pediatric-ckd |
Complex 3/10,Michelle Trachtenberg,Drake,Alison Brie,Buffy,Mad Men,NEW | #332298087
Magazine Name: Complex, March 2010 Cover Model: Michelle Trachtenberg; Drake Magazine Condition: Brand New, Store Bought, Never Read, MINT Condition Magazine Content Information: 5 pages on actress Mi...from 1005383190
Complex 3/10,Michelle Trachtenberg,Drake,Alison Brie,Buffy,Mad Men,NEW
<here is a image 8d125e8717022321-3809c85c48082a23>
Sold for Start Free Trial orSign Into see what it's worth.
Sold Date
Magazine Name: Complex, March 2010 Cover Model: Michelle Trachtenberg; Drake Magazine Condition: Brand New, Store Bought, Never Read, MINT Condition Magazine Content Information: 5 pages on actress Michelle Trachtenberg (Buffy the Vampire Slayer, Euro Trip, Gossip Girl, Mercy) with 4 photos (2 full page), 6 pages on Aubrey "Drake" Graham with 3 pages (2 full page), 5 full page photos of rap sensation Theophilus London, 3 pages on actress Alison Brie (Mad Men, Community) with 3 photos (2 full page), 2 pages on hip-hop singer Soulja Boy Tell'Em with 2 photos (1 full page), 1 page on actor Craig Robinson (Hot Tub Time Machine, The Office) with full page photo, 1 page on actor Bryan Greenberg (HBO's How To Make It In America) with full page photo, 6 pages on Adult Swim, 1 page on R&B singer Kelis with photo, 1 full page photo of LeBron James, and more! Magazine History: This magazine was purchased and immedately stored for collection purposes. Shipping and Handling: All magazines are sealed in a heavy duty magazine archival storage bag and are cardboard backed to add stiffness for protection during shipment. United States Shipping Information: $4.95 USPS Priority Mail . Included with this is Delivery Tracking and Delivery Confirmation. Also, if you buy multiple magazines I will combine as many regular sized magazines as possible in this package. Email me with any questions before purchasing if you want to know if magazines you're considering can be combined. United States Multiple Magazine Shipping Information: $11.99 USPS Priority Mail Rate BOX purchase as many magazines as you wish and as long as their stacked height is 3 inches or less you can have them all shipped to you for a combined shipping cost of $11.99. In addition to being boxed they also will be bagged in Magazine Protection bags for additional security and preservation. If you want to know if a particular list of magazines can fit into 1 box just email me, no problem. Canada and Mexico Shipping Information: $12.99 USPS Priority Mail International Also, if you buy multiple magazines I will combine as many regular sized magazines as possible in this package. Email me with any questions before purchasing if you want to know if magazines you're considering can be combined. Worldwide Shipping Information: $14.99 USPS Priority Mail International* *As long as the country of destination has the ability to accept Priority Mail International your purchase will be sent this way. It should arrive in 2-7 business days from the time of purchase. Again, if multiple purchases are made I will try to combine as many magazines into this package as possible. Please email if you have any questions or would like to know the shipping charge to your destination country. If emailing for a shipping estimate, please list the exact magazines (issue, month, year) you are considering so I can get their weight and size for the shipping charge! Worldwide (including Canada) Multiple Magazine Shipping Information: $47.99 United States Priority Mail International Rate BOXED purchase as many magazines as you wish and as long as their stacked height is 3 inches or less you can have them all shipped to you for a combined shipping cost of $45.99 In addition to being boxed they also will be bagged in Magazine Protection bags for additional security and preservation. If you want to know if a particular list of magazines can fit into 1 box just email me!. � read more
| https://www.worthpoint.com/worthopedia/complex-10-michelle-trachtenberg-17298087 |
(PDF) A Tale of Three Drums: An Unfinished Archaic Votive Column in the Sanctuary of Poseidon at Kalaureia
PDF | Three unfinished column drums discovered at the Kalaureia Research Program excavations in 2007–2009 can be shown to have been intended for a... | Find, read and cite all the research you need on ResearchGate
Article
PDF Available
A Tale of Three Drums: An Unfinished Archaic Votive Column in the Sanctuary of Poseidon at Kalaureia
November 2009
Opuscula Annual of the Swedish Institutes at Athens and Rome 2:167–179
DOI: 10.30549/opathrom-02-08
Abstract and Figures
Three unfinished column drums discovered at the Kalaureia Research Program excavations in 2007–2009 can be shown to have been intended for a monumental Archaic Ionic votive column. All drums have systematic masons’ marks on the contact surfaces. The latter parts of the inscriptions indicate the position of the drum in the shaft. Two alternative readings for the first part of the inscription are suggested: the first interprets it as a building instruction and the second as a price indication. The start of the building project took place very likely in the second half of the sixth century BC, and the deposit date of the fill surrounding the blocks indicates that the unfinished project was abandoned in the late sixth century BC. Reconstruction of the column shaft from the known drum dimensions demonstrates that the finished shaft would have been constructed with a slight entasis.
DEM of Area H at the end of the 2007 excavation season (D = Drum, SB = Statue Base block, W = Wall). By J. Pakkanen. …
Drums 1, 2 and 3 (from left to right) from south-east in 2008. Photograph by B. Wells. …
Axonometric representation of the unprocessed total station data with fitted semi-transparent truncated cones (based on 2008 survey data). By J. Pakkanen. …
Drum 1. Scale 1:15. By A. Hooton & J. Pakkanen. …
Drum 2. Scale 1:15. By A. Hooton & J. Pakkanen. …
Figures - uploaded by
Jari Pakkanen
Content uploaded by Jari Pakkanen
Author content
167
A T ALE OF THREE DRUMS:
AN UNFINISHED ARCHAIC V OTIV E COLUMN IN THE
SANCTUARY OF POSEIDON AT KALAUREIA
BY
JARI PAKKANEN
Abstract
Three unfinished column drums discovered at the Kalaureia
Research Program excavations in 2007–2009 can be shown to have
been intended for a monumental Archaic Ionic votive column. All
drums have systematic masons’ marks on the contact surfaces. The
latter parts of the inscriptions indicate the position of the drum in the
shaft. Two alternative readings for the first part of the inscription are
suggested: the first interprets it as a building instruction and the
second as a price indication. The start of the building project took
place very likely in the second half of the sixth century BC, and the
deposit date of the fill surrounding the blocks indicates that the
unfinished project was abandoned in the late sixth century BC.
Reconstruction of the column shaft from the known drum dimensions
demonstrates that the finished shaft would have been constructed
with a slight entasis.
Three column drums of soft limestone were exposed in the
eastern part of the Sanctuary of Poseidon during the excava-
tions of the Kalaureia Research Program in 2007–2009. 1 Ex-
cavations east and southeast of the Temple were initiated as
part of the new campaign in a previously unexcavated part of
the archaeological site. The sector is designated Area H, and
the drums lie c. 20 m southeast of the corner of the Archaic
peribolos wall of the Temple of Poseidon. 2
The digital elevation model presents the state of the exca-
vations in Area H from the south at the end of the 2007 cam-
paign ( Fig. 1 ): the drums, deposited in a row, are only par-
tially visible, with parts of Drums 2 and 3 covered by Wall
50. In 2007 it seemed that the Archaic terrace wall (W49) cov-
ered partially Drum 3, but in the 2009 excavations it became
clear that the fill behind the wall has caused it to incline to-
wards the south-east and that D3 is only abutting it. The
drums were so close to the ground surface that all have been
damaged by routine ploughing of the area. The pottery in the
fill around the drums indicates that the blocks were part of an
Archaic building project abandoned in the late sixth or early
fifth century BC. 3 The continuation of the excavations in
2008 soon brought to light a series of masons’ marks on the
intended contact surfaces of the drums ( Fig. 2 ), and with the
blocks more fully uncovered, it was possible to document
them in greater detail. Even though the excavations on the
north side of the drums were continued in 2009, the drums
have never been fully exposed: some of the drum dimensions
have therefore been extrapolated and this is also the reason
why the drum drawings are partially incomplete.
DOCUMENTATION AND DESCRIPTION
OF THE DRUMS
The column drums were measured using a Leica TCR805 to-
tal station: more than 6,000 points were taken on the drums
with reflectorless laser. 4 A truncated cone was then fitted to
the collected data in AutoCAD, and the dimensions presented
below are based on these cones and analyses of the total sta-
tion data: the precision of the principal measurements was
checked manually on the drums where possible. Figure 3
presents the three-dimensional survey lines taken on the
drums with the cones rendered semi-transparent. The total
station measurements were also used as the basis of the pub-
lication drawings carefully executed by Anne Hooton. The
data was manipulated in AutoCAD to produce scaled
1 On the research program in general and for a detailed account of
the conducted excavations, see Penttinen & W ells et al. 2009, this
volume. I owe warm thanks to Alan Johnston, Manolis Korres,
Petra Pakkanen, Arto Penttinen, Manna Satama and Berit Wells for
their comments on the manuscript. I am also very grateful for the
suggestions made by the anonymous referee.
2 For the position of Area H in the north-east of the archaeological
site, see Penttinen & W ells et al. 2009, fig. 1, this volume; for the
detailed location of the drums in relation to the peribolos , see Pent-
tinen & W ells et al. 2009, fig. 12, this volume: the drums are situ-
ated in the eastern part of H001.
3 The latest pottery in Block 36 in area H001 is late sixth century
BC; on the pottery and stratigraphy in detail, see Penttinen & Wells
et al. 2009, this volume.
4 With a reflectorless laser total station it is possible to take co-ordi-
nate points directly on the stone surfaces of the blocks without the
need of a prism target. All measurements ha ve been carried out by
the author of this paper.
2042.Opuscula.book Page 167 Monday, June 21, 2010 5:21 PM
168 Jari Pakkanen
printouts of the block elevations and plans of each block.
These were used as trace patterns for the final drawings. 5
All the drum surfaces are unfinished. Tool marks indicate
that they were worked with a flat chisel. The lack of final fin-
ish is best demonstrated by the fact that the top and bottom
surfaces of Drums 2 and 3 are not parallel. On Drum 2 the
projected variation in the height on different sides of the block
is 34 mm and on Drum 3 the measured difference is 4 mm.
There are no typical smooth contact bands on the bottom and
top surfaces. Following the usual practice in Greek building,
the sides of the drums would have been finished only after
the erection of the column. Also, perhaps the significantly
greater taper on Drum 2 is best explained by the need to leave
a greater working margin towards the bottom of the shaft. 6
Drum 1
Lower diameter: 0.972 m; upper diameter: 0.940 m; height:
0.672 m.
Inscription: TV (or TI/ )
IIIIIIII
Inscription on bottom surface of the block. Letter heights:
0.140–0.152 m (first line), 0.082–0.096 m
(second line).
Drum 2
Lower diameter: 1.117 m; upper diameter: 1.071 m; height:
0.645–0.679 m.
Inscription: TV (or TI/ )
II
Inscription on bottom surface of the block.
Letter heights: 0.142–0.146 m (first line),
0.118–0.145 m (second line).
Drum 3
Lower diameter: 1.001 m; upper diameter: 0.972 m; height:
0.663–0.667 m.
Inscription: TVIIIIIII 7 (or TI /IIIIIII )
Inscription on top surface of the block and
written from left to right. Letter heights:
0.134–0.146 m (the first letters), 0.084–
0.102 m (the seven vertical strokes).
The diameter of the largest drum is significantly too great for
it to have been a surplus building block meant for the Temple,
and any other substantial building known at the site is ruled
5 Fig. 3 gives the documentation situation at the end of the 2008
season: the north sides of the drums were excavated deeper in 2009,
and further survey was carried out. The necessary modifications to
Figs. 4–6 were done by the author of this paper based on the total
station data.
6 Drum 2 tapers 46 mm and Drums 1 and 3 clearly less at 32 and 29
mm; for an exaggerated illustration of the drum profiles, see the left
side of Fig. 8 .
7 The upsilon, if it indeed is one, is very carelessly cut: the separate
right half of the letter is parallel with the following seven vertical
strokes, but the reading of the two strokes following the T as upsi-
lon could be supported by the two other drums.
Fig. 1. DEM of Area H at the end of the 2007 excavation season (D = Drum, SB = Statue Base block, W = Wall). By J. Pakkanen.
2042.Opuscula.book Page 168 Monday, June 21, 2010 5:21 PM
A Tale of Three Drums 169
out by the Late Archaic deposit date of the blocks. 8 Therefore,
the probability that the drums were intended for a monumen-
tal freestanding votive column is very high. The retrograde
writing on Drum 3 also supports a Late Archaic date for the
blocks.
ANALYSIS OF THE INSCRIPTIONS
Perhaps the most likely reading of the inscriptions is that they
consist of the letters TV followed by a varying number of ver-
tical strokes. The T is not diagnostic, but the V can give some
information on the date of the building project and possibly also
the source of the masons who cut the stones. However, based
on Drum 3, it is possible to put forward an alternative reading
for the first part of the inscription: the first letter tau could also
be followed by a iota or a vertical stroke and a slash (/).
The simplified form V of the letter upsilon came to com-
mon use in inscriptions on stone during the second half of the
sixth century BC. It fell out of favour after c. 450 BC when
the more complex form Y again gained wide usage. 9 Around
the principal centres of the Saronic Gulf, V was the most com-
mon form of the letter in Attica c. 550–500 BC and in Corinth
in formal inscriptions from the early fifth century BC on-
wards. On Aigina it was used in Archaic and Early Classical
inscriptions until c. 450 BC and at Megara from c. 550 BC
onwards. 10 In the eastern Argolid the principal form was Y ,
though there are some fifth-century examples of inscriptions
using a V from Epidauros and Troizen. 11 Therefore, if we take
into account that the deposition date of the drums is the late
sixth century BC, it is most likely that the workmen respon-
sible for the masons’ marks were not local, but, more likely,
came from Aigina, Athens or Megara.
An open form of the letter where the slanting sides do not
meet at the bottom ( \ / ) cannot necessarily be classified as be-
longing to a different script. If it is not intentional, it is most
likely a result of careless execution of the letter by the mason.
In two of the Kalaureia drum inscriptions the slanting strokes
are very close to each other and only on Drum 3 are they clear-
ly separate. I have been able to locate the following further
examples of \ / :
1. Early fifth-century stele of Eurybotas from Kolonna at
Aigina ( IG IV 2 2 902; both upsilons).
2. Early fifth-century ( c. 500–475? BC) bronze vessel in the
Asklepieion at Epidauros dedicated by Mikylos ( IG IV 1 2
136; the upsilon in the name). 12
3. Early fifth-century funerary stele of Hypsis from Selinous
(the upsilon in the name). 13
4. Gravestone of Hermaios from Aigina ( IG IV 2 2 857; the
upsilon in Κυδο ι κο ) probably from the second quarter
of the fifth century. 14
The interpretation of the second part of the inscriptions on the
drums is straight-forward. The vertical hatches indicate the
number of the drum in the sequence counting from the bottom
of the column. The preserved drums are the second, seventh
and eighth ( Fig. 7 ). Their physical dimensions correspond to
the numbering, so this reading of the inscriptions can be re-
garded as certain. The system of numbering the order of
8 The width of the foundation trench of the Temple of Poseidon is
15.2 m (this width is based on new fieldwork carried out at the
Temple in 2009; the dimension gi ven in Welter 1941, pl. 31 is sig-
nificantly less at 14.40 m); for comparison, the Late Archaic temple
of Aphaia on Aigina has an overall width of 15.48 m at the euthyn-
teria level and the maximum lower diameter of the facade columns
is 1.01 m (Bankel 1993, 8, 113).
9 Jeffery 1990 (1961), 35.
10 Jeffery 1990 (1961), 67, 109–113, 116, 133; see also Guarducci
1967, 195, 309.
11 IG IV 1 2 136 (on a small bronze phiale of c. 500–475? BC; Jef-
fery 1990 [1961], 179–180, 182, pl. 34.10); IG IV 1 2 142 (on the lip
of a bronze lebes from the Asklepieion at Epidauros of c. 500–475?
BC; Jeffery 1990 [1961] 180, 182); IG IV 1 2 46 (stone stele from
Epidauros of c. 440–425? BC; Jeffery 1990 [1961] 182, pl. 34.17);
and IG IV 1 760 (stele from Troizen of c. 425–400 BC; Jeffery 1990
[1961], 182, pl. 33.6).
12 Jeffery 1990 (1961), 179–180, 182, pl. 34.10.
13 Guarducci 1967, 320.
14 In the illustration of IG IV 1 47c the letter is drawn as V , but the
photograph in Jeffery 1990 (1961), pl. 17.18 shows that the lower
ends do not touch. For the date, see Jeffery 1990 (1961), 113 with
further references.
Fig. 2. Drums 1, 2 and 3 (from left to right) from south-east in 2008.
Photograph by B. Wells.
2042.Opuscula.book Page 169 Monday, June 21, 2010 5:21 PM
170 Jari Pakkanen
building blocks with simple strokes has been attested in
Greece in the early fifth century BC in the Treasury of the
Athenians at Delphi 15 and later in the fifth century in the Pro-
pylaia of the Athenian Acropolis ( c. 437–432 BC). In the case
of the Treasury the numbers on the architrave blocks indicate
that they were the fifth and eighth blocks at the same level on
the south side of the building counting from the south-west
corner. 16 At the Propylaia, a column drum is marked with ver-
tical strokes which indicates that it was the tenth drum from
the bottom. In this case the use of vertical hatches for num-
bering has an exact parallel in the system used for the three
drums at the Sanctuary of Poseidon. 17
Short masons’ marks are often very difficult to interpret:
The first part of the inscription TV could, for example, refer
to the group of masons who cut the block or, especially if the
column was being built at the same time as the Temple, to
the monument for which they were intended. The second part
of each inscription, however, relates to the construction of the
monument. It is very tempting to interpret the first part as in-
structions for the builders as well. The first letter, T, could
stand for
τομη
(or
τομα
in the Doric dialect): the first entry
for the word in LSJ is ‘end left after cutting, stump of a tree’,
but it is used, e.g., by Thucydides, for ‘stones cut square’
(1.93: εν τομη ε γγω νιοι ). The parallel to a column drum
shaped like a section of a tree trunk is too striking to miss.
The second letter could be an abbreviation indicating the ap-
proximate location of the block, so meant perhaps simply
υ περω α
, ‘upper’, or
υ πε ργ εια
, ‘above ground’ ( s.v. LSJ ). 18
If the monument was intended to be Ionic, as I will argue in
the next section, the first reading
υ περω α
is perhaps slightly
more likely: in that case the second letter would indicate that
the blocks were meant for the shaft and not for the base or
the ground level blocks, and in that sense they were ‘upper’.
I know of no parallels for this interpretation in masons’
marks, so it must remain speculative.
Reading the first part as TI / makes it necessary to look
at other possibilities of interpretation. For all these signs
there are parallels where they are used for sums of
15 The traditionally accepted date of the Treasury is c. 500 BC, but
Cooper 1990, 317–318, convincingly argues that the dedication was
made by the Athenians after Marathon 490 BC. Cooper also
attributes the numbering of the blocks to a fourth-century-BC repair
and reassembly of the building after it had been damaged in an
earthquake and not as part of the original construction.
16 Audiat 1933, 34–35.
17 Martin 1965, 225–226; Orlandos 1966, 84–85. Numbering by
simple strokes is well-attested also in other contexts such as indicat-
ing the capacity of vessels: see, e.g ., Lang 1956, 2–4.
18 Both terms are known to have been used in architectural con-
texts; see the references in Orlandos & Travlos 1986, s.v .
‘ υ περω ο ’ and ‘ υ πε ργ ειο ’.
Fig. 3. Axonometric representation of the unprocessed total station
data with fitted semi-transparent truncated cones (based on 2008
survey data). By J. Pakkanen.
A Tale of Three Drums 171
Fig. 4. Drum 1. Scale 1:15. By A. Hooton & J. Pakkanen.
172 Jari Pakkanen
Fig. 5. Drum 2. Scale 1:15. By A. Hooton & J. Pakkanen.
A Tale of Three Drums 173
Fig. 6. Drum 3. Scale 1:15. By A. Hooton & J. Pakkanen.
174 Jari Pakkanen
Fig. 7. Comparison of votive columns on Aigina, at Kalaureia and at Marathon (reconstruction of Aigina based on Gruben 1965, pl. 3, and
Marathon on Petrakos 1996, fig. 8, and physical reconstruction at Marathon). By J. Pakkanen.
A Tale of Three Drums 175
money: 19 T is used for both a talant and a quarter obol, 20
the vertical stroke stands usually for an obol but it can also
denote a drachma before the introduction of a specific sign
for it, 21 and the slash is used for chalkous , one twelfth of an
obol, in Hellenistic inscriptions from Delos. 22 Talant is ob-
viously too large a sum in relation to a single column drum,
and the alternative total sum of an obol and a third 23 is a
rather small figure in an architectural context. 24 Also, the
late date for this parallel from Delos renders this reading
very unlikely.
However, pottery trademarks might offer a more plausible
alternative: TI followed by numerals is well-attested as an ab-
breviation for τι με . 25 The earliest examples are on early fifth-
century, Attic red-figure vases, and none of these early ex-
amples uses the drachma sign. 26 In this reading the most like-
ly interpretation for the slash would be one drachma: the rea-
son for writing it diagonally would be to separate it from the
iota. One drachma is attested as a craftsman’s day wage in
the fifth century BC, 27 but since the inscription is on an un-
finished drum, the sum should relate to quarrying and/or
transport of the block. The price of quarrystone is difficult to
resolve even based on the well-preserved fourth-century
building accounts from Epidauros, but the majority if not all
of the costs were due to labour expenses and transport. 28
Dressing a soft limestone block into a cylindrical drum prob-
ably took less than three working days. 29 Limestone outcrops
are common on the island, so the transport costs were prob-
ably relatively small. 30 Therefore, the price tag of one drach-
ma for quarrying and even transporting a column drum to the
Sanctuary of Poseidon from a local quarry is conceivable.
The parallels in Late Archaic pottery trademarks makes this
reading rather attractive: if the alternative is accepted for
Drum 3, the first parts of the inscriptions on the two other
drums should also be read as a tau and a stroke followed by
a slash for a drachma sign.
RECONSTRUCTION OF THE COLUMN
SHAFT AND DATE
The shaft diameters of the known cases of Archaic, free-
standing, Doric columns in the Saronic are considerably
smaller than the drums from Kalaureia, 31 but for monumen-
tal Ionic votive columns there are parallels. 32 Therefore, it
is very likely that if the column in the Sanctuary of Poseidon
had been finished, it, too, would have been crowned by an
Ionic capital. Figure 7 presents a hypothetical reconstruc-
tion of the Kalaureia column shaft sandwiched between the
early sixth-century sphinx column from the sanctuary of
Aphaia on Aigina 33 and the Late Archaic/Early Classical
tropaion of the Battle of Marathon. 34 The Aigina column
has a reconstructed height range of 10.7–12.6 m and a lower
19 A numeric reading of the first part of the inscription was sug-
gested to me by N. Stampolidis.
20 See, e.g., T od 1911–1912, 101.
21 Tod 1911–1912, 101; Johnston 1979, 233.
22 Tod 1911–1912, 116; Tod 1936–1937, 250.
23 So 1/4 obol + obol + chalkous = 1 obol 4 chalkous. This reading
also requires that a quarter obol would be written before a whole
obol (there is a parallel, though, in an Attic abacus IG II 2 2781
where the order is reversed; see T od 1936–1937, 237).
24 Johnston (2006, 22) lists the known prices for Archaic, lar ge,
closed vases and they vary from 4 to 7 obols.
25 Johnston 1979, 169; Johnston 2006, 165.
26 Troilos painter: TI followed by 12 (Johnston 1979, 226, fig. 9x);
Berlin painter: TI followed by 7 (Johnston 1979, 226–227, fig.
12p); imitation of Berlin painter: TI followed by 7 (Johnston 1979,
226–227, fig. 9w); near Berlin painter: TI followed by 5 (Amyx
1958, 297–298, pl. 54d; Johnston 1979, 226–227); T yszkiewitz
painter: TI followed by 4 (Johnston 1979, 226–227).
27 See, e.g., Burford 1972, 138–140, with references to sources.
28 Burford 1969, 168–175.
29 In the reconstruction of the Stoa of Attalos at the Athenian Agora, it
took 100–120 man-days to dress a single Doric column of Pentelic
marble from quarry-face to tapering cylinder, and soft limestone is
approximately five times faster to work with (Burford 1969, 246–247,
also on the limitations of modern comparisons); the height of the stoa
columns is 5.24 m (Coulton 1976, fig. 28), so c. 7.5 Kalaureia drums
of 0.67 m are needed to match the height of the stoa column shaft:
110 man-days / (7.5 × 5) ≈ 3 man-days. The contact surfaces of the
Kalaureia drums are only preliminarily worked, so the time-consum-
ing matching of the drums together was not done on our blocks.
30 The fourth-century transport of c. 400 tons of limestone from
Corinth to the Temple of Asklepios at Epidauros, a distance of c. 60
km by sea and land, costed 1,700 drachmas: 1,700 dr. / 400 tons /
60 km ≈ 0.42 ob. / ton / km (Burford 1969, 190).
31 The largest example in the Saronic is a funerary column from Troi-
zen: the octagonal shaft has a lower width of 0.715 m and preserved
height of 3.50 m; it was crowned by a now lost capital so it could well
have been unusual or a variation of Doric (550–525 BC; McGow an
1995, 621–622, esp. n. 45), but a close parallel for this type in the
region is provided by the interior octagonal Doric columns from a
fountain house at Megara (Gruben 1996, 75–77). More typical cases
are provided by the two preserved Doric votiv e capitals from the
Athenian Acropolis which both have an abacus width of 0.495 m
(550–525 BC; Kissas 2000, 22–23, 176–179). For further references
to freestanding Doric columns used as grave markers or votiv es, see
McGowan 1995, 615–622, and Kissas 2000, 22–23. Monumental
Doric votive columns are known in the Peloponnese, e.g., from the
Sanctuary of Apollo K orythos at Longa (Luraghi 2009, 119, pl. 5; no
dimensions for the capital given).
32 In addition to the examples discussed below , there is a very large
drum next to the small theatre at Epidauros, so it is quite possible that
there would have been also other monumental votiv e columns in the
region.
33 Gruben 1965, pl. 3, illustrates minimum and maximum height
reconstructions of the shaft.
34 The preserved blocks in Fig. 7 are based on I. Y armenitis’ recon-
struction published in Petrakos 1996, fig. 8, but I have redrawn the
base: it is unlikely that an early fifth-century monument would have
had a Classical Attic base. The drawing in Fi g. 7 is an approxima-
tion of how the base is reconstructed at Marathon (warm thanks are
due to M. Korres for discussing the base of the monument with me).
On the date of the monument as c. 490–470 BC, see Shoe Meritt
1996, 128 (the capital obviously postdates the battle, and since the
capital is quite damaged, I would prefer the wider range to Shoe
Meritt’s rather precise date of 480–470 BC).
2042.Opuscula.book Page 175 Monday, June 21, 2010 5:21 PM
176 Jari Pakkanen
Fig. 8. Hypothetical reconstructions of the profile and column shaft. By J. Pakkanen.
2042.Opuscula.book Page 176 Monday, June 21, 2010 5:21 PM
A Tale of Three Drums 177
column diameter of c. 1.19 m. 35 Both the minimum and
maximum reconstructions are presented on the left of Fig-
ure 7 . The largest Ionic capital on the Greek mainland be-
longs to a votive column on the Athenian Acropolis: the
width of the capital is 2.50 m and the height of the column
can be reconstructed as at least 11 m. Two large fragments
of it have been documented, and it can most probably be
dated towards the end of the sixth century BC. 36
It is possible to estimate the lower diameter of the column
shaft at Kalaureia based on the inscription defining Drum 2
as the second in the sequence of drums in the shaft. The dif-
ference in the lower and upper diameters is 46 mm, much
greater than that of the other two drums where the differ-
ences are 29 and 32 mm, respectively. This is perhaps best
explained by the need to leave extra room at the bottom of
the shaft for the projection of the profile at the lower part
of the column (see the reconstruction on the right of Fig. 8 ).
A bottom drum or a joint block for a combined column base
and lower shaft would have flared even more, so the best
estimate for the lower diameter can be gained by extrapo-
lating between the diameters of the seventh and eighth
drums and the upper diameter of the second drum. The
height of the drums seems standard, though the thickness of
the protective layer of extra stone left on the blocks in the
quarry needs to be subtracted from all the measured dimen-
sions: 37 the soft limestone would possibly have been fluted
and it certainly would have been covered by a layer of plas-
ter when finished. The estimated final drum dimensions
used in the calculations are 20 mm less than the recorded
height and diameter measurements. 38
An elliptical curve is fitted to the estimated diameter points
of the column drums marked. The diameters are marked by
a small circle on the left of Figure 8 . Comparison of the curve
with the line connecting the tops of Drum 1 and 2 shows that
the shaft profile was planned with entasis and did not taper
in a straight line. 39 Due to entasis the shaft profile is nearly
vertical over the first two drums, so the lower diameter above
the apophyge can be estimated as c. 1.05 m. Because the
thickness of the layer of protective stone on Drum 2 is not
known, the lower diameter should be regarded as hypotheti-
cal. Even though the shaft profile of the top part of the column
can be extrapolated as curving, its precise shape can only be
suggested here because the height of the shaft remains un-
known. In Fig. 8 the shaft height of the Kalaureia column is
hypothetically reconstructed as 8.5 times the lower diameter.
These proportions are based on those of the minimum column
height of the Aigina sphinx column, and the base is tentative-
ly reconstructed on the basis of the unusual base of the interior
Ionic columns of Stoa A in the Sanctuary. The stoa at Kalau-
reia has been variously dated between the second and fourth
quarters of the fifth century, but the base type was known al-
ready in the late sixth century. 40
The lower diameter of the Marathon tropaion would have
been smaller than the shaft diameter at Kalaureia. The height
of the Marathon column in Fig. 7 is hypothetical, reconstruct-
ed from Vanderpool’s report that the diameter of the lower
surface of the capital is 0.73 m and that the largest drum dia-
meter he was able to measure is 0.82 m. However, since the
uppermost drum would have most likely been carved at the
top with the usual apophyge and a half round, the under sur-
face of the capital does not directly indicate the upper dia-
meter of the shaft. 41 Taking this and any possible entasis of
35 The total height range includes the round plinth and the capital;
Gruben 1965, 187–190.
36 Wiegand 1904, 173, fig. 172; K orres 1997, 95–107.
37 The depth of the protective surface varies, b ut an overview can
be gained from the plates in Kalpaxis 1986: 14 mm in the Hephaist-
eion at Athens (pl. 16.1); 10, 18 and 22 mm in the Older Parthenon
(pl. 16.3 and 20.5); 45 mm in the Treasury of Kyrene, Delphi; 31
mm in the Hieron at Samothrace (pl. 19.5).
38 Reduction of the principal dimensions by 20 mm is equivalent to a
protective layer thickness of 15 mm and stucco of 5mm for the sides
of the drums (the difference 10 mm is multiplied by 2 since the extra
stone was cut away all around the block, and the same applies to the
extra layer of stucco) and cutting away 10 mm from both the upper
and lower surfaces. Dimensions for the second drum used in calcula-
tions: upper diameter 1.051 m, height 0.625 m (the height of the
drum varies greatly , but the dimension is based on the minimum
height); seventh drum: diameters 0.981 and 0.952 m, height 0.643 m;
eighth drum: same dimensions 0.952 and 0.920 m, 0.654 m.
39 Not all votive columns had entasis, e.g. the column of the Naxi-
ans at Delphi had none (Amandry 1953, 9). On curve fitting and
shaft profiles, see Pakkanen 1997, 336–341; Pakkanen 1998, 62–
72. The porch columns of the T emple of Zeus at Stratos provide a
parallel for unfinished drums with shaft entasis taken into account
(Pakkanen 2004, 108–111).
40 For a comparison of the base profiles of the late sixth-century
Temple of Athena at Paestum and Stoa A at Kalaureia, see Coulton
1977, fig. 40, profiles 12–13. W elter’s date of Stoa A in the last
quarter of the fifth century is supported by Coulton, but Martin
dates the building to the second quarter of the fifth century, proba-
bly following W ide & Kjellberg’s argumentation; Wide & Kjellber g
1895, 274–277; W elter 1941, 45–47; Martin 1951, table 2; Coulton
1976, 100, esp. n. 3. The Ionic base of Stoa A has a close parallel in
Argive architecture of the second quarter of the fifth century: the
interior base of the Hypostyle Hall at Argos has a vertical band and
a single torus with a flaring apophyge in the lower part of the shaft
(Bommelaer & Courtils 1994, 27, 29–30, fig. 15. The base at Ar gos
has also an astragal at the bottom of the vertical band). The base
type is closely linked with the sixth-century bases from Samos con-
sisting of a disk and a single torus, a type also attested in Athenian
Archaic and Early Classical architecture (Shoe Meritt 1969, 186–
188, pl. 49c), so a date for the Kalaureian base in the last quarter of
the fifth century would be quite anomalous. An initial analysis
shows that the Stoa A capital proportions are in line with capitals
from the second half of the fifth century. Excav ations inside Stoa A
at Kalaureia were started in 2009: the packed earth floor is pre-
served, so obtaining a pottery date for the structure is a possibility.
41 Cf., e.g., the column shafts of the Stoa of Athenians in Amandry
1953, pl 27. In the reconstruction drawing by Yarmenitis (Petrakos
1996, fig. 8), it seems that the smaller shaft diameter due to narrow-
ing of the shaft at the top has not been taken into account, so I have
shifted the drums further down in Fig. 7 .
178 Jari Pakkanen
the shaft into account and based on the available evidence, it
is not possible to estimate the lower diameter any more pre-
cisely than as within a range of 0.9–1.0 m. 42
The two comparative columns from Aigina and Marathon
also represent the upper and lower boundaries of the time
frame during which the column drums could have been
carved. The known monumental Ionic votive columns that
support sphinxes cluster in the first half of the sixth century
BC. 43 The late-sixth-century material in the fill where the
three column drums at the Sanctuary of Poseidon at Kalau-
reia were deposited places the building project firmly in the
sixth century. The best parallel for the intended Ionic capital
is probably provided by the very large votive monument
from the Athenian Acropolis. 44 If the two strokes following
the T at the beginning of the masons’ marks are interpreted
as V, the Archaic shape of the upsilon suggests that the vo-
tive column project was begun in the second half of the sixth
century BC. If the first part of the inscription is read as a price
indication for quarrying and/or transport, the earliest paral-
lels in pottery trademarks are Late Archaic, so an even tight-
er sequence between the beginning and abandonment of the
project could be proposed. In conclusion, a date after 550
BC can be suggested for the start of the project and a date
towards the end of the century for the abandonment of the
uncompleted project.
Jari Pakkanen
Department of Classics
Royal Holloway, University of London
Egham, Surrey TW20 0EX, UK
E-mail: [email protected]
BIBLIOGRAPHY
Amandry 1953 P. Amandry, FdD II. La Colonne des Naxiens
et le Portique des Athéniens , Paris 1953.
Amyx 1958 D.A. Amyx, ‘The Attic Stelai: Part III. Vases
and Other Containers’, Hesperia 27, 1958,
255–310.
Audiat 1933 J. Audiat, FdD II. Le trésor des Athéniens , Paris
1933.
Bankel 1993 H. Bankel, Der spätarchaische Tempel der
Aphaia auf Aegina (Denkmäler Antiker Ar-
chitektur, 19), Berlin & New York 1993.
Bommelaer 1991 J.-F. Bommelaer, Guide de Delphes. Le site,
Paris 1991.
Bommelaer & J.-F. Bommelaer & J. des Courtils, La Salle
Courtils 1994 Hypostyle d’Argos (= Études Péloponnési-
ennes 10), Paris 1994.
Bruneau & Ducat P. Bruneau & J. Ducat, Guide de Délos , 4th
2005 edition, Athens 2005.
Burford 1969 A. Burford, The Greek Temple Builders at
Epidauros. A Social and Economic Study of
Building in the Asklepian Sanctuary, during the
Fourth and Early Third Centuries B.C. , Liver-
pool 1969.
Burford 1972 A. Burford, Craftsmen in Greek and Roman
Society , London 1972.
Cooper 1990 F.A. Cooper, ‘Reconstruction of the Athenian
Treasury at Delphi in the fourth century BC’,
AJA 94, 1990, 317–318.
Coulton 1976 J.J. Coulton, The Architectural Development of
the Greek Stoa , Oxford 1976.
Coulton 1977 J.J. Coulton, Greek Architects at Work. Prob-
lems of Structure and Design , London 1977.
Guarducci 1967 M. Guarducci, Epigrafia greca 1. Caratteri e
storia della disciplina. La scrittura greca dale
origini all’età imperiale , Roma 1967.
Gruben 1965 G. Gruben, ‘Die Sphinx-Säule von Aigina’, AM
80, 1965, 170–208.
Gruben 1996 G. Gruben, ‘Griechische Un-Ordnungen’, in
Säule und Gebälk. Zu Struktur und Wandlungs-
prozeß griechisch-römischer Architektur (Dis-
kussionen zur Archäologischen Bauforschung,
6), ed. E.-L. Schwandner, Mainz am Rhein
1996, 61–77.
Jeffery 1990 (1961) L.H. Jeffery, The Local Scripts of Archaic
Greece. A Study of the Origin of the Greek
Alphabet and Its Development from the Eighth
to the Fifth Centuries B.C. , revised edition with
a supplement by A.W. Johnston, Oxford 1990.
Johnston 1979 A.W. Johnston, Trademarks on Greek vases ,
Warminster 1979.
Johnston 2006 A.W. Johnston, Trademarks on Greek vases.
Addenda , Oxford 2006.
Kalpaxis 1986 Th.E. Kalpaxis, Hemiteles. Akzidentelle Unfer-
tigkeit und “Bossen-Stil” in der griechischen
Baukunst , Mainz am Rhein 1986.
Kissas 2000 K. Kissas, Die attischen Statuen- und Stelen-
basen archaischer Zeit , Bonn 2000.
Korres 1997 M. Korres, ‘An early Attic Ionic capital and the
Kekropion on the Athenian Acropolis’, in
Palagia 1997, 95–107.
Lang 1956 M. Lang, ‘Numerical notation on Greek vases’,
Hesperia 25, 1956, 1–24.
Luraghi 2008 N. Luragi, The Ancient Messenians. Construc-
tions of Ethnicity and Memory , Cambridge
2008.
Martin 1951 R. Martin, Recherches sur l’agora grecque ,
Paris 1951.
Martin 1965 R. Martin, Manuel d’architecture grecque 1.
Matériaux et techniques , Paris 1965.
42 A conservative estimate for the upper diameter of the shaft below
the apophyge would be in the range of 0.68 m, so if the known
diameter of 0.82 was in the centre of the shaft and the taper was
constant, the lower diameter could be calculated as 0.82 m + (0.82
m – 0.68 m) = 0.96 m, so a range of 0.9–1.0 m is reasonable taking
into consideration all the unknown factors related to drum dimen-
sions; for the capital and drums, see V anderpool 1966, 96–101.
43 In addition to the Aigina column, relativ ely well preserved exam-
ples include the column of the Naxians at Delphi (second quarter of
the sixth century BC; column height c. 10 m; Amandry 1953, 3–32;
for a suggestion of a date c. 570–560 BC, see Bommelaer 1991,
146), a column at Kyrene ( c. 550 BC; column height c. 6.5–6.9 m;
White 1971, 49–54), and a column on Delos ( c. 550 BC; column
height c. 5 m; Amandry 1953, 19, n. 1; for the date, see Bruneau &
Ducat 2005, 96).
44 Korres 1997, 95–107.
2042.Opuscula.book Page 178 Monday, June 21, 2010 5:21 PM
A Tale of Three Drums 179
McGowan 1995 E.P. McGowan, ‘Tomb marker and turning
post: funerary columns in the Archaic period’,
AJA 99, 1995, 615–632.
Orlandos 1968 A.K. Orlandos, Les matériaux de construction
et la technique architecturale des anciens grecs
2. Paris 1968.
Orlandos & Travlos A.K. Orlandos & I. Travlos,
Λεξικο ν Αρχαιων
1986
Αρχιτεκτονι κω ν Ορων
, Athens 1986.
Pakkanen 1997 J. Pakkanen, ‘Entasis in Fourth-Century BC
Doric Buildings in the Peloponnese and at
Delphi’, BSA 92, 1997, 323–344.
Pakkanen 1998 J. Pakkanen, The Temple of Athena Alea at
Tegea. A Reconstruction of the Peristyle
Column (Publications by the Department of Art
History at the University of Helsinki, 18),
Helsinki 1998.
Pakkanen 2004 J. Pakkanen, ‘The Temple of Zeus at Stratos:
new observations on the building design’,
Arctos 38, 2004, 95–121.
Palagia 1997 Greek Offerings. Essays on Greek Art in
Honour of John Boardman (Oxbow Mono-
graph, 89), ed. O. Palagia, Oxford 1997.
Penttinen & Wells A. Penttinen & B. Wells, with contributions by
et al. 2009 D. Mylona, P. Pakkanen, J. Pakkanen, A.
Karivieri, A. Hooton, E. Savini & T. Theodoro-
poulou, ‘Report on the excavations in the years
2007 and 2008 southeast of the Temple to
Poseidon at Kalaureia’, Opuscula 2, 2009, 89–
134.
Petrakos 1996 B. Petrakos, Marathon (The Archaeological
Society at Athens Library, 155), Athens 1996.
Shoe Meritt 1969 L. Shoe Meritt, ‘The geographical distribution
of Greek and Roman Ionic bases’, Hesperia 38,
1969, 186–204.
Shoe Meritt 1996 L. Shoe Meritt, ‘Athenian Ionic capitals from
the Athenian Agora’, Hesperia 65, 1996, 121–
174.
Tod 1911–1912 M.N. Tod, ‘Greek numeral notation’, BSA 18,
1911–1912, 98–132.
Tod 1936–1937 M.N. Tod, ‘The Greek acrophonic numerals’,
BSA 18, 1936–1937, 236–258.
Vanderpool 1966 E. Vanderpool, ‘A monument to the Battle of
Marathon’, Hesperia 35, 1966, 93–106.
Welter 1941 G. Welter, Troizen und Kalaureia , Berlin 1941.
Wide & Kjellberg S. Wide & L. Kjellberg, ‘Ausgrabungen auf
1895 Kalaureia’, AM 20, 1895, 267–282.
Wiegand 1904 Th. Wiegand, Die archaische Poros-arkitektur
der Akropolis zu Athen , Cassel & Leipzig 1904.
White 1971 D. White, ‘The Cyrene Sphinx, its capital and
its column’, AJA 75, 1971, 46–55.
2042.Opuscula.book Page 179 Monday, June 21, 2010 5:21 PM
... More generally on the institution of asylia (asylum) and the sanctuary of Poseidon at Kalaureia, see Sinn 1993. 4 Strabo 8.6.14. 5 For the function of the sanctuary in the Early Iron Age, see Wells in preparation; for other periods of use, see Wells, Penttinen & Billot 2003;Wells et al. 2005;Wells, Penttinen & Hjohlman 2007;Penttinen & Wells et al. 2009;Wells 2009;
Pakkanen 2009;
Wallensten & Pakkanen 2009. 6 Wide & Kjellberg 1895 ;Welter 1941; for a synopsis of the early research, see Wells, Penttinen & Billot 2003, 33-35. ...
Integrating archaeology and science in a Greek sanctuary: issues of practise and interpretation in the study of the bioarchaeological remains from the sanctuary of Poseidon at Kalaureia
Chapter
Full-text available
Jan 2013
Dimitra Mylona
Maria Ntinou
Petra Pakkanen
Tatiana Theodoropoulou
The archaeological research carried out in the sanctuary of Poseidon at Kalaureia is one of the few cases of a Classical excavation, where a broad and multifaceted program for the retrieval and analysis of bioarchaeological remains has been adopted. The nature and dating of the site presents us with the particular challenge of how to integrate the analysis of the bio- archaeological remains with other aspects of research such as architecture, stratigraphy, pottery, small finds etc. Can the dif- ferent approaches to the material culture which are most often exercised by the practitioners of Classical archaeology and those of ‘science based’ archaeology produce compatible results? This paper describes certain modes of integration as they have been applied in the Kalaureia Research Program. Emphasis on con- textuality, research around certain key themes which are consid- ered relevant to the life in a Greek sanctuary, and the compre- hensive use of the ancient written record are some of these modes
... Poseidon seems generally to have been an important god in the early Lagid Kingdom, not surprisingly against the background of the sea-faring Ptolemies 24 (and he was otherwise perhaps most closely associated with his self-proclaimed descendant Demetrios Poliorketes and his family).
25
The locality surely guided the polis of Arsinoe in its choice of god: the newly discovered dedication was presented to Poseidon of Kalaureia as the owner and main deity of the sanctuary. ...
A New Inscribed Statue Base from the Sanctuary of Poseidon at Kalaureia
Article
Full-text available
Nov 2009
Jenny Wallensten
Jari Pakkanen
In the Kalaureia Research Program excavations of 2007 and 2008, four joining blocks of a statue base were unearthed. The monument is a dedication from the polis of Arsinoe in the Peloponnese: its inhabitants offered two statues, of King Ptolemaios and his sisterwife Arsinoe Philadelphos, to Poseidon. The present article publishes the monument and its inscription, and proceeds to present a reconstruction and an attempt at positioning the monument in its historical context.
Refitting the Local Horizon of Ancient Greek Religion (Including Some Remarks on the Sanctuary of Poseidon on Kalaureia)
Chapter
Apr 2023
Hans Beck
Which dimensions of the religious experience of the ancient Greeks become tangible only if we foreground its local horizons? This book explores the manifold ways in which Greek religious beliefs and practices are encoded in and communicate with various local environments. Its individual chapters explore 'the local' in its different forms and formulations. Besides the polis perspective, they include numerous other places and locations above and below the polis-level as well as those fully or largely independent of the city-state. Overall, the local emerges as a relational concept that changes together with our understanding of the general or universal forces as they shape ancient Greek religion. The unity and diversity of ancient Greek religion becomes tangible in the manifold ways in which localizing and generalizing forces interact with each other at different times and in different places across the ancient Greek world.
Archaic pottery and terracottas from the Sanctuary of Poseidon at Kalaureia
Article
Nov 2013
Alexandra Alexandridou
The excavation season of 2009 in the Sanctuary of Poseidon at Kalaureia brought to light a deposit of Archaic pottery and associated metal and other objects in conjunction with a long terrace wall (Wall 49) southeast of the Temple of Poseidon. The deposit in question is the largest accumulation of Archaic material recovered from the entire sanctuary thus far. The fine-decorated, black-glazed and coarse pottery together with the terracotta figurines are discussed in detail in this article. Furthermore, the results of the quantitative analysis of the pottery are presented. The study of the deposit provides an overview of the ceramic vessels and other terracotta objects originally dedicated to the deity or used in the sanctuary during the Archaic period. Moreover, based on the chronology of its deposition, it seems possible to incorporate it into a narrative of the development of the sanctuary over time. The significance of the deposit as a whole will be more fully discussed in the forthcoming final publication of the Kalaureia Research Program. The context and the condition of the deposited pottery and terracottas allows for associating it with a period of important redefinition of the sanctuary's sacred space, which took place towards the end of the 6th or the early 5th century BC.
The Temple of Athena Alea at Tegea. A Reconstruction of the Peristyle Column
Book
Dec 1998
Jari Pakkanen
The Temple of Zeus at Stratos: New Observations on the Building Design
Article
Full-text available
Jan 2004
Jari Pakkanen
Based on new fieldwork at the sanctuary of Zeus at Stratos, the height of the temple peristyle column can be established as 7.88–7.93 m. The proportional column height of 6.11–6.15 times the lower diameter is very conservative for an Early Hellenistic building; the great diameter difference between the partially carved top drum and the finished capital suggests that the temple was originally designed with one more drum per column. The change in plans can plausibly be connected with the economic strain the large-scale urban development caused to the polis finances at the end of the fourth century BC. The planned height can be estimated as 8.67–8.73 m, which is 6.72–6.77 times the lower diameter. The roughly finished exterior columns do not allow for a reconstruction of the final shaft profile, but the porch columns were worked one step further and demonstrate how the entasis was taken into consideration in the final preliminary phase before cutting the fluting could have begun. The shaft displays a gentle curvature with a maximum projection of 13 mm. Any study which attempts to discover the proportional relationships and metrological units used in Greek architecture must start with a statistical analysis of the building dimensions: this is the only way to assure that all relevant possibilities are taken into account. Cosine quantogram analysis of the Stratos data shows that the length of the unit used in the design of building elements is 0.1053 m. The layout of the temple follows nearly in its entirety a strictly modular pattern; the only exception is the lengthwise placement of the cella according to the sides of the flank columns. The fit of the facade dimensions to the design unit, especially the ones of the superstructure above the krepis, is not as good as the plan data: the use of a successive proportional design system where the upper elements are not directly derived from the module could be a possible explanation for this. The length of the design unit suggests that a foot standard of 0.316 m was employed in the temple construction, but its relationship to the local unit at Stratos remains unresolved.
The Greek Numeral Notation
Article
Dec 2013
Marcus Niebuhr Tod
The object of the following articles is to set forth as briefly as possible the epigraphical evidence at our disposal for determining the numerical systems employed in the various cities of Greece, and to state afresh some of the conclusions which we are entitled to draw from it. I am not sanguine enough to believe that I have overlooked none of the available materials, but I hope that my essay may contribute something towards a fuller understanding, at least in this country, of a department of Greek epigraphy which has, as it seems to me, been unduly neglected by recent scholars.
The Ancient Messenians: Constructions of Ethnicity and Memory
Article
Jan 2008
Nino Luraghi
Early in the archaic period of Greek history, Messenia was annexed and partially settled by its powerful neighbour, Sparta. Achieving independence in the fourth century BC, the inhabitants of Messenia set about trying to forge an identity for themselves separate from their previous identity as Spartan subjects, refunctionalising or simply erasing their Spartan heritage. Professor Luraghi provides a thorough examination of the history of Messenian identity and consequently addresses a range of questions and issues whose interest and importance have only been widely recognised by ancient historians during the last decade. By a detailed scrutiny of the ancient written sources and the archaeological evidence, the book reconstructs how the Messenians perceived and constructed their own ethnicity at different points in time, by applying to Messenian ethnicity insights developed by anthropologists and early medieval historians.
The Greek Temple Builders at Epidauros: A Social and Economic Study of Building in the Asklepian Sanctuary, during the Fourth and Early Third Centuries B.C.
Article
Nov 1971
| https://www.researchgate.net/publication/275730194_A_Tale_of_Three_Drums_An_Unfinished_Archaic_Votive_Column_in_the_Sanctuary_of_Poseidon_at_Kalaureia |
Notice of copyright infringement | Statista
Find statistics, consumer survey results and industry studies from over 22,500 sources on over 60,000 topics on the internet& #39;s leading statistics database
Skip to main content
statista.com
statista.es
statista.de
statista.fr
Prices & Access
Single Accounts
Business Solutions
Academia and Government
Statistics
All Industries
Consumer Goods & FMCG
Internet
Media & Advertising
Retail & Trade
Sports & Recreation
Technology & Telecommunications
Transportation & Logistics
Travel, Tourism & Hospitality
Most-viewed Statistics
Recent StatisticsPopular Statistics
Facebook: quarterly number of MAU (monthly active users) worldwide 2008-2023
Quarterly smartphone market share worldwide by vendor 2009-2023
Number of apps available in leading app stores Q3 2022
OPEC oil price annually 1960-2023
Big Mac index worldwide 2023
Topics
Topic Overview
Smartphones - statistics & facts
Social media - Statistics & Facts
Top Report
View Report
Industry Overview
Reports
Report Shop
Search our report database
Digital & Trend reports
Overview and forecasts on trending topics
Industry & Market reports
Industry and market insights and forecasts
Companies & Products reports
Key figures and rankings about companies and products
Consumer & Brand reports
Consumer and brand insights and preferences in various industries
Politics & Society reports
Detailed information about political and social topics
Country & Region reports
All key figures about countries and regions
Find your information in our database containing over 20,000 reports
New
Market Insights
Market forecast and expert KPIs for 1000+ markets in 190+ countries & territories
Explore Market Insights
Consumer
Digital
Mobility
Consumer Insights
Insights on consumer attitudes and behavior worldwide
2,000,000+ interviews
15,000+ brandsExplore Consumer Insights
Company Insights
Business information on 70m+ public and private companies
100+ industries
200+ countries and territories
Explore Company Insights
eCommerce Insights
Detailed information for 35,000+ online stores and marketplaces
70+ KPIs per store
Revenue analytics and forecastsExplore eCommerce Insights
Daily Data
Services
The Statistics Portal
Directly accessible data for 170 industries from 150+ countries and over 1 Mio. facts.
About Statista
Why trust Statista
First Steps and Help Centre
Live webinars & recordings
Tools
Business Plan Export
Publication Finder
Statista Services
Statista Q
Customized Research & Analysis projects:Statista Q
askStatista
Get quick analyses with our professional research serviceaskStatista
Statista R
The best of the best: the portal for top lists & rankings:Statista R
Statista Content & Design
Transforming Data into Design:
Customized infographic service
Presentation Design
Animated videos
Whitepapers, E-Books, etc.
Statista Content & Design
nxt statista
Strategy and business building for the data-driven economy:nxt statista
Single Accounts
Business Solutions
Academia and Government
Popular Statistics
Topics
Markets
Reports
Market Insights
Consumer Insights
Company Insights
eCommerce Insights
Daily Data
Content & Design
Research projects
Ask Statista
Business Plan Export
Publication Finder
Statista R
DE
ES
FR
Notice of copyright infringement
Information on when we delete personal data, the countries where we save data (e.g., US, EU, Singapore), and the companies we collaborate with can be found in ourprivacy statement.
Home
About Statista
Career
Contact
Help & FAQ
Report Bug
Our Media Partners
Privacy
Imprint
Menu
Prices & Access
Popular Statistics
Industries
Daily Data
Content & Design projects
Research projects
AskStatista
statista.de
statista.es
statista.fr
Cookie Consent Manager
General Information
General Information
When you visit any website, it may store or retrieve information on your browser, mostly in the form of cookies. This information might be about you, your preferences or your device and is mostly used to make the site work as you expect it to. The information does not usually directly identify you, but it can give you a more personalized web experience. Because we respect your right to privacy, you can choose not to allow some types of cookies. Click on the different category headings to find out more and change our default settings. However, blocking some types of cookies may impact your experience of the site and the services we are able to offer.
More information
Necessary Cookies
Necessary Cookies
Always Active
These cookies are necessary for the website to function and cannot be switched off in our systems. They are usually only set in response to actions made by you which amount to a request for services, such as setting your privacy preferences, logging in or filling in forms. You can set your browser to block or alert you about these cookies, but some parts of the site will not then work. These cookies do not store any personally identifiable information.
Functional Cookies
Functional Cookies
Functional CookiesInactive
These cookies enable the website to provide enhanced functionality and personalisation. They may be set by us or by third party providers whose services we have added to our pages. If you do not allow these cookies then some or all of these services may not function properly.
Performance Cookies
Performance Cookies
Performance CookiesInactive
These cookies allow us to count visits and traffic sources so we can measure and improve the performance of our site. They help us to know which pages are the most and least popular and see how visitors move around the site. All information these cookies collect is aggregated and therefore anonymous. If you do not allow these cookies we will not know when you have visited our site, and will not be able to monitor its performance.
Targeting Cookies
Targeting Cookies
Targeting CookiesInactive
These cookies may be set through our site by our advertising partners. They may be used by those companies to build a profile of your interests and show you relevant adverts on other sites. They do not store directly personal information, but are based on uniquely identifying your browser and internet device. If you do not allow these cookies, you will experience less targeted advertising.
Back
Vendor Search
ConsentLeg.Interest
checkbox labellabel
checkbox labellabel
checkbox labellabel
Name
cookie name
checkbox labellabel
By clicking “Accept all,” you agree to the storage of cookies on your device to improve website navigation, analyze website usage, and assist with our marketing efforts. If you click on "Only necessary," only cookies that are required for technical reasons to operate the website will be used.Privacy Statement
| https://www.statista.com/statistics/report-content/statistic/259489 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Journal Paper
Themes
Assistive & Accessible Technology
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Jamie Danemayer,Cathy Holloway,Youngjun Cho, Nadia Berthouze, Aneesha Singh, William Bhot, Ollie Dixon, Marko Grobelnik, John Shawe-Taylor
Paper highlights: Assistive technology (AT) information networks are insular among stakeholder groups, causing unequal access to information. Participants often cited fragmented international marketplaces as a barrier and valued info-sharing across industries. Current searches produce biased results in marketplaces influenced by commercial interests and high-income contexts. Smart features could facilitate searching, update centralised data sources, and disseminate information more inclusively.
International Journal of Human-Computer Studies; 2023
Abstract
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain.
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Type
Journal Paper
Themes
Assistive & Accessible Technology
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Cite
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Type
Journal Paper
Themes
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Cite
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
Cite
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Emma M Smith, Maria Luisa Toro Hernandez, Ikenna D Ebuenyi, Elena V Syurina,Giulia Barbareschi, Krista L Best,Jamie Danemayer,Ben Oldfrey, Nuha Ibrahim,Catherine Holloway, Malcolm MacLachlan
The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
International Journal of Health Policy and Management; 2020
Abstract
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Abstract
Background:The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
Methods:This study was a rapid, international online qualitative survey in the 6 United Nations (UN) languages (English, French, Spanish, Russian, Arabic, Mandarin Chinese) facilitated by extant World Health Organization (WHO) and International Disability Alliance networks. Themes and subthemes of the qualitative responses were identified using Braun and Clarke's 6-phase analysis.
Results:Four primary themes were identified in in the data: Disruption of Services, Insufficient Emergency Preparedness, Limitations in Existing Technology, and Inadequate Policies and Systems. Subthemes were identified within each theme, including subthemes related to developing resilience in AT systems, based on learning from the pandemic.
Conclusion:COVID-19 has disrupted the delivery of AT services, primarily due to infection control measures resulting in lack of provider availability and diminished one-to-one services. This study identified a need for stronger user-centred development of funding policies and infrastructures that are more sustainable and resilient, best practices for remote service delivery, robust and accessible tools and systems, and increased capacity of clients, caregivers, and clinicians to respond to pandemic and other crisis situations.
Cite
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Smith EM, Toro Hernandez ML, Ebuenyi ID, Syurina EV, Barbareschi G, Best KL, Danemayer J, Oldfrey B, Ibrahim N, Holloway C, MacLachlan M. Assistive Technology Use and Provision During COVID-19: Results From a Rapid Global Survey. Int J Health Policy Manag. 2022 Jun 1;11(6):747-756. doi: 10.34172/ijhpm.2020.210. PMID: 33201656;
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
| https://www.disabilityinnovation.com/publications?order=date&type=article+phd+journal-paper+working-paper+editorial |
CME Activity | Dyspnea on Exertion | MDs & PAs
https://www.statpearls.com/physician/cme/activity/80595/?deg=MD& specialty=PA-Cardiovascular%20Thoracic
Dyspnea on Exertion
Overview
4.5 out of 5 (8 Reviews)
Credits
1.50
Post Assessment Questions
10
Expiration Date
28 Feb 2026
Last Reviewed
1 Mar 2023
Estimated Time To Finish
90 Minutes
Activity Description
Dyspnea, also called shortness of breath, is a patient's perceived difficulty to breathe. Sensations and intensity can vary and are subjective. It is a prevalent symptom impacting millions of people. It may be the primary manifestation of respiratory, cardiac, neuromuscular, psychogenic, or systemic illnesses, or a combination of these. Dyspnea on exertion is a similar sensation; however, this shortness of breath is present with exercise and improves with rest. This activity reviews the etiology, evaluation, and management of exertional dyspnea and highlights the role of the interprofessional team in evaluating and improving care for patients with exertional dyspnea.
Target Audience
This activity has been designed to meet the educational needs of physicians.
Learning Objectives
At the conclusion of this activity, the learner will be better able to:
Outline the various potential etiologies of dyspnea on exertion.
Describe the pathophysiology of dyspnea on exertion in cases where it represents a physiological problem.
Summarize the management of patients with dyspnea on exertion based on the etiology.
Explain the importance of interprofessional team strategies for improving care coordination and communication to aid in prompt diagnosis of exertional dyspnea and improving outcomes in patients diagnosed with the condition.
Disclosures
StatPearls requires everyone who influences the content of an educational activity to disclose relevant financial relationships with ineligible companies that have occurred within the past 24 months. All relevant conflict(s) of interest have been mitigated. Hover over contributor names for financial disclosures. None of the planners of this educational activity have any relevant financial relationships to disclose.
COMMERCIAL SUPPORT: This activity has received NO commercial support.
Authors: Sandeep Sharma , Muhammad F. Hashmi
Editors: Madhu Badireddy
Editors-In-Chief: James J. Jones Chief Medical Reviewer: Maria S. Horenstein
Nurse Planner/Reviewer: Sandra Coleman
Pharmacy Planner/Reviewer: Mark V. Pellegrini
Physician Planner/Reviewer: Scott C. Dulebohn
Continuing Education Accreditation Information
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Quillen College of Medicine, East Tennessee State University, and StatPearls, LLC. The Quillen College of Medicine, East Tennessee State University is accredited by the ACCME to provide continuing medical education for physicians.
Quillen College of Medicine, East Tennessee State University designates this activity for a
maximum of
1.50
AMA PRA Category 1 Credits TM
.
Physicians should only claim credit commensurate with the extent of their participation in the activity.
This activity is reported to the following Maintenance of Certification (MOC) boards:
American Board of Internal Medicine
Adolescent Medicine
Advanced Heart Failure and Transplant Cardiology
Cardiovascular Disease
Internal Medicine
Pulmonary Disease
American Board of Pathology
Cardiovascular
Pulmonary, Mediastinum
American Board of Pediatrics
Adolescent Medicine
General Pediatrics
Pediatric Cardiology
Pediatric Pulmonology
Instructions for Credit
Register for the activity and create a StatPearls login.
Review the target audience, learning objectives, and disclosure information.
Study the educational content in the activity.
Choose the best answer to each activity test question. To receive credit, you must pass the test questions with a minimum score of 100%.
Complete the post-activity assessment.
Obtain a certificate.
For information on the applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.
If you have any concerns regarding the CME system, please contact [email protected]
If you have a question about the ETSU CME providership, please contact [email protected] .
Disclaimer
Faculty may discuss investigational products or off-label uses of products regulated by the US Food and Drug Administration. Readers should verify all information before employing any therapies described in this educational activity.
The information provided for this activity is for continuing education purposes only and is not meant to substitute for the independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. The information presented does not necessarily reflect the views of StatPearls or any commercial supporters of educational activities on statpearls.com. StatPearls specifically disclaims responsibility for any adverse consequences resulting directly or indirectly from information in the course, for undetected error, or through a participant's misunderstanding of the content.
Cancellation Policy: Cancellations must be received in writing and a money-back guarantee is provided if not completely satisfied.
StatPearlsand and Quillen College of Medicine, East Tennessee State University reserve the right to cancel any course due to unforeseen circumstances. StatPearls andQuillen College of Medicine, East Tennessee State University will not be responsible for other expenses incurred by the participant in the unlikely event that the program is canceled.
Medium or Media Used:
Computer Requirements: Internet Access
E-mail Address
Equal Opportunity
StatPearls andQuillen College of Medicine, East Tennessee State University are Equal Opportunity/Affirmative Action/Equal Access Institutions.
Media Usage Rights
The contributors and editors of StatPearls have attested that all associated media (images and video) have been legally cleared for use with this activity. All copyrights are reserved.
Unlimited Physician CME
Stay up to date on the latest medical knowledge with 6673 CME activities. In these online self-assessment activities, read our reference articles and test your knowledge with more than 7930 hours of CME.
Learn About Lifetime CME
Single Activity
Take this single activity
$39 1 activity
6 Month Unlimited Physician CME
Access to all the Unlimited Physician CME activities in all specialties.
$289 per half year per user
1 Year Unlimited Physician CME
Access to all the Unlimited Physician CME activities in all specialties.
$399 per 1 year per user
Use the mouse wheel to zoom in and out, click and drag to pan the image
| https://www.statpearls.com/physician/cme/activity/80595/?deg=MD&specialty=PA-Cardiovascular%20Thoracic |
Sensors | Free Full-Text | Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy
Using a biomedical sensor setup RIfS we have investigated the kinetic behavior of human albumin (Alb), human fibrinogen (Fib), and human immunoglobulin G (IgG) adsorbed onto surfaces of chitosan. Polystyrene (PS) was used as the control material in this study. The optical thickness of three kinds of proteins measured by RIfS was related to their molecular dimensions and potential orientations on a film surface. According to the operation principle of RIfS and the molecular dimensions of three kinds of proteins, the adsorbed layers of proteins onto the surface of chitosan and PS was calculated by using a newly introduced equation. The microstructure of the chitosan and polystyrene film and the surfaces with adsorbed proteins were imaged by atomic force microscopy (AFM). With AFM analyses the lateral distribution of the protein molecules on surfaces have been recognized. The results show that the number of adsorbed layers of the three proteins on the surface of chitosan are 0.635 for Alb, 0.158 for Fib and 0.0967 for IgG, and of polystyrene are: 0.577 for IgG, 0.399 for Fib, 0.336 for Alb. This study confirmed that RIfS is a useful tool for the analysis of plasma proteins adsorbed on a surface of biomaterials. Results show that at first on the surface of chitosan film much more Alb than Fib was adsorbed which demonstrated that chitosan has a antithrombus function. Secondly, on the surface of chitosan film more Alb and less Fib were adsorbed than on the surface of PS film, which demonstrated that chitosan has a better blood compatibility than polystyrene. Thirdly, the calculated layer number of the three proteins indicated that on both chitosan and PS substrates monolayer coatings form.
Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy
by Xiao Ying Lü * , Yan Huang and Chao Qun Ma
Key Laboratory of Molecular and Biomolecular Electronics of the Ministry of Education, P. R. China. Southeast University, 210096, Nanjing, China
Author to whom correspondence should be addressed.
Sensors 2001 , 1 (5), 148-160; https://doi.org/10.3390/s10500148
Published: 12 October 2001
Abstract
:
Using a biomedical sensor setup RIfS we have investigated the kinetic behavior of human albumin (Alb), human fibrinogen (Fib), and human immunoglobulin G (IgG) adsorbed onto surfaces of chitosan. Polystyrene (PS) was used as the control material in this study. The optical thickness of three kinds of proteins measured by RIfS was related to their molecular dimensions and potential orientations on a film surface. According to the operation principle of RIfS and the molecular dimensions of three kinds of proteins, the adsorbed layers of proteins onto the surface of chitosan and PS was calculated by using a newly introduced equation. The microstructure of the chitosan and polystyrene film and the surfaces with adsorbed proteins were imaged by atomic force microscopy (AFM). With AFM analyses the lateral distribution of the protein molecules on surfaces have been recognized. The results show that the number of adsorbed layers of the three proteins on the surface of chitosan are 0.635 for Alb, 0.158 for Fib and 0.0967 for IgG, and of polystyrene are: 0.577 for IgG, 0.399 for Fib, 0.336 for Alb. This study confirmed that RIfS is a useful tool for the analysis of plasma proteins adsorbed on a surface of biomaterials. Results show that at first on the surface of chitosan film much more Alb than Fib was adsorbed which demonstrated that chitosan has a antithrombus function. Secondly, on the surface of chitosan film more Alb and less Fib were adsorbed than on the surface of PS film, which demonstrated that chitosan has a better blood compatibility than polystyrene. Thirdly, the calculated layer number of the three proteins indicated that on both chitosan and PS substrates monolayer coatings form.
1. Introduction
Optical interferomertry is well known for the measurement of physical parameters such as speed and distance. Further, light interference was used for visual detection of antigen-antibody reactions [ 1 ]. Spectral interferometry has been considered as an interesting approach to detecting sensitively and rapidly any changes of optical path length in thin polymer films caused by antigen–antibody interaction in immunochemical sensing [ 2 ]. After the development of surface plasmon resonance (SPR) [ 3 , 4 ], another successful optical approach, Reflectometry Interference Spectroscopy (RIfS), was introduced as a highly sensitive and robust technique for direct label-free monitoring of the interaction of biomolecules [ 5 , 6 , 7 ].
RIfS is based on the spectral distribution of white-light reflectance from transparent thin layers. A distinct reflectance pattern with alternating maxima and minima results from the interference of beams partially reflected from each interface of the interference layer. Binding detection with RIfS shows little temperature dependence, allows avoidance of gold layers, and is promising for high throughput screening. The simple test format and high sensitivity makes RIfS attractive for detecting and characterizing the interaction of biomolecules. Biological material deposited at the surface during a binding event increases the optical thickness of the interference layer, leading to a shift in the interference pattern. This approach allows on-line monitoring of binding reactions with high resolution [
8
]. The main advantages of the RIfS transducer are its ruggedness, the small active area, and the simple construction [
9
].
A sensitive dynamic determination made on gaseous or liquid hydrocarbons as well as immunoreactions with RIfS was reported in 1993 [ 6 ]. Then, an investigation of the specific binding of low molecular weight ligands to immobilized receptors was carried out by using RIfS; two model systems were studied in which the binding event was successfully detected [ 10 ]. Next, RIfS was utilized for studying the hybridization of antisense with its complementary target sequences and especially to investigate the interaction of terminal- and backbone-modified antisense ONs targeted to multidrug resistance1b-mRNA [ 8 ]. Other applications with RIfS were in a dyeless optical detection of ammonia in the gas phase, by using pH-responsive polymers. Also, clinical detection of HbsAGb was accomplished [ 11 , 12 ]. Recently, the application of RIfS for the evaluation of the biocompatibility of biomaterials has been described [ 13 ].
Since the protein adsorption on the surface of biomaterials is an important factor for the adhesion of platelet and biocompatibility, the characterization of adsorbed proteins on the surface of various biomaterials, such as biopolymers, alloys, ceramics etc., has been extensively investigated by means of different techniques [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].
Chitosan is a natural source polymer prepared by N-deacetylation of chitin, which is the main structural component of crab and shrimp shells [ 27 ]. Intensive investigations have been carried out for the structure, the chemistry, the biological properties, and the applications of chitosan [ 28 ].
Chitosan has been widely used as a new biomaterial since it is safe and has a good biocompatibility with the human body [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Chitosan also has a haemostatic function [ 36 ] and may have an antithrombogenic function. Some investigators reported the platelet adhesion on the surface of modified chitosan [ 37 , 38 ]. However, the protein adsorption occurrs before the platelet adhesion and is the first step of thrombosis. The aim of this study is to evaluate the protein adsorption behavior of human albumin (Alb), human fibrinogen (FIb), and human IgG on chitosan, by using RIfS. The kinetics of the adsorption process is investigated. Polystyrene is used as the control material, since its surface chemistry is well defined and it is frequently used as a model system in protein adsorption studies [ 39 ].
2. Materials and Methods
2.1 RIfS Apparatus
The RIfS setup used has been developed in our laboratory [ 40 ]. The main elements of the setup were a CCD spectrometer with a bifurcated optical fiber and an adsorption cell with a volume of about 30 μL. The bifurcated optical fiber was used to illuminate the transducer chip and to collect the light reflected from the chip. The chip is a glass substrate on which a 20-nm Ta 2 O 5 film was deposited in order to enhance the interference efficiency. An original software was used to control the collection of full spectra, to analyze the experimental data in real-time, and to draw the experimental curves on-line.
Chitosan with a degree of deacetylation of 93.2% and of an average molecular weight of 750,000 Da was purchased from Ocean Institute of Jiangsu, China. The material is powder form with 80-100nm granularities and has a white color. The thin films of chitosan exposed to proteins were prepared by the spin-coating method. At first, the chitosan was immersed in 0.5% acetic acid (Factory of Chemical Reagents of Nanjing, China) with 10mg/mL. After the chitosan was dissolved completely, the solution was filtered with a middle speed qualitative filter paper (Factory of Fuyang Special Paper of Hangzhou, China). Then, 50-μL chitosan solution was pipetted out and dropped onto the surface of the transducer chip (1.2cm*1.2cm ). A chitosan film was spin-coated on the transducer chip using a spinning-machine at 1700 rpm. Typically, the film thickness was ~650 nm.
Polystyrene (Nunc Inc. Denmark) was dissolved in toluene ( Factory of Chemical Reagents of Nanjing, China) at a concentration of 40mg/mL. The coating process of polystyrene film on the transducer chip is same with the chitosan film. All materials and reagents as well as chemicals were of analytical grade or better.
2.3. Proteins
Three kinds of proteins were used : human albumin (Alb), human fibrinogen (Fib), and human IgG (Sigma, Dorset, UK). For each measurement a protein solution was prepared freshly in 10mM phosphate buffer solution (PBS, pH=7.4) of a concentration of 0.1mg/mL. Deionized water was used to prepare the aqueous solutions.
2.4 Protein Adsorption Measurement
The protein adsorption measurement has been performed as follows: the sensor chip coated with chitosan/PS film was mounted into the adsorption cell carefully and fixed with two clips. Then, the peristaltic pump was started to drive PBS (pH=7.4) flow into the adsorption cell. The PBS cleaned the surface of the chitosan/PS film, drove out air bubbles that may be present in the adsorption cell. Most importantly, it produced a physiological pH-environment for the adsorption of proteins. After this treatment, the protein solution flowed into the adsorption cell at a rate of 200 μL/min and the kinetic adsorption process of proteins on the surface of the chitosan/PS film can be oberseved in situ on the monitor of the computer. Until the kinitic adsorption curve of proteins became stable, PBS was pumped into the adsorption cell again to wash the proteins which did not adsorb tightly onto the material surface. The wash handing would get a response on the adsorption curve. The mark on the Y axis of the
Figure 1
,
Figure 2
,
Figure 3
and
Figure 4
give the thickness of the proteins adsorbted on the chitosan/PS film. For each kind of proteins, at least three tests were performed (n=3).
2.5 Calculation of the Adsorbed Layer of Protein
Since the molecular dimensions of various proteins are different, a normalized treatment of the experimental data was performed using a previously defined equation [
13
] in order to obtain the effective adsorbed layer number
L
p
(Eq.1):
(1)
where
D
p
is the molecular dimension of a single protein and
, the average thickness of each type of proteins on the surface of the material intended to be probed with RIfS.
2.6 AFM Imaging
The microstructure of the chitosan and polystyrene films and the surfaces with adsorbed proteins were imaged with a commercial atomic force microscope (AFM, Nanoscope IIIa, Digital Instrument, Santababara, USA). The instrument was operated in Tapping Mode using silicon cantilevers oscillating with the average amplitude of 100 nm and a resonance frequency between 200 and 450 kHz. The scanning rate selected was 1 Hz. All images presented in this paper were obtained repeatedly and were stable under the experimental conditions.
3. Results and Discussion
3.1 Kinetics of Protein Adsorption onto PS Films
In
Fig.1
the kinetic adsorption curves of human Alb, IgG and Fib onto the surface of a PS film are shown. The curves evidence that the adsorption behavior of the three proteins onto PS film are similar: initially, the processes of all three proteins increase quickly in the initial stage and reach their equilibrium values after about 500 s. Secondly, after washed with PBS the adsorption curves have different tendencies: the curve of IgG falls about 0.2nm, which means some loosely adsorbed molecules were removed from the PS film. Nevertheless, the curves of Alb and Fib show almost no response, which shows the adsorption process of albumin and fibrinogen onto the surface of PS film have not been affected.
Figure 1. Kinetic curves of protein adsorption onto the surfaces of PS film: a) IgG, b) Fib, c) Alb.
Figure 1. Kinetic curves of protein adsorption onto the surfaces of PS film: a) IgG, b) Fib, c) Alb.
This result can be derived from the difference of sizes and structures of three kinds of proteins. The adsorbed process of proteins onto the surface of biomaterials is pictured schematically in
Fig. 2
. According to Green et al. [
39
], albumin is a globular protein and the potential orientation on a surface is ca. 4 nm. Fibrinogen has a rod-like structure with approximately 10-nm width and the molecules may lie planar on the biomaterials interface. IgG has a relatively globular Y shaped structure with a height of ~12 nm. Therefore, the different molecular dimensions of the three proteins are responsible for the difference of the thickness. The smallest height of Alb molecules, for example, yields the thinnest film. The intermediate molecular dimension of Fib results in an intermediate optical thickness between Alb and IgG. The random orientation of IgG molecules adsorbed on a PS film results in a thickest adsorptive layer as measured by RIfS. The curve family is similar to that reported by Green et al. for PS material by an analysis using SPR [
39
] and by us for hydroxyapatite using RIfS.
Figure 2. Sketch map of adsorbed process of proteins onto the surface of biomaterials: (a) before and (b) after adsorption.
Figure 2. Sketch map of adsorbed process of proteins onto the surface of biomaterials: (a) before and (b) after adsorption.
3.2 Kinetics of Protein Adsorption onto Chitosan Films
The kinetic adsorption curves of human Alb, Fib, and IgG on the surface of a chitosan film are shown in
Fig. 3
,
Fig. 4
and
Fig. 5
. According to these curves the adsorption behavior of three kinds of proteins onto chitosan is dissimilar. For Alb, the adsorption processes amplifies slowly in the initial stage and reaches its stable values after about 8000 s. This means that during this period the adsorption of albumin on chitosan continued. Nevertheless, for Fib and IgG the adsorption processes is fast in the initial stage and reaches its stable values after about 1500 s, which means that the adsorption process of Fib and IgG on chitosan films reaches saturation fast. After washed with PBS, the curves of Alb, Fib, and IgG fall apparently, which indicates more loosely adsorbed molecules were removed from the chitosan film.
Figure 3. Kinetic curves of adsorbed Alb on the surface of chitosan film.
Figure 3. Kinetic curves of adsorbed Alb on the surface of chitosan film.
Figure 4. Kinetic curves of adsorbed Fib on the surface of chitosan film.
Figure 4. Kinetic curves of adsorbed Fib on the surface of chitosan film.
Figure 5. Kinetic curves of adsorbed IgG on the surfaces of chitosan film.
Figure 5. Kinetic curves of adsorbed IgG on the surfaces of chitosan film.
3.3 Comparing of the Kinetic Curves on Chitosan and PS
Fig. 6 , Fig. 7 and Fig. 8 compare the adsorption of the three kinds of proteins onto the surface of chitosan and PS films. The curves reveal that on the surface of chitosan film more Alb was adsorbed than on the surface of PS film, and conversely, on the surface of PS film more Fib and IgG were adsorbed than on the surface of chitosan films.
Figure 6. Adsorbed Alb on the surfaces of chitosan and PS: a) chitosan, b) PS.
Figure 6. Adsorbed Alb on the surfaces of chitosan and PS: a) chitosan, b) PS.
Figure 7. Adsorbed Fib on the surfaces of chitosan and PS: a) PS, b) chitosan.
Figure 7. Adsorbed Fib on the surfaces of chitosan and PS: a) PS, b) chitosan.
Figure 8. Adsorbed IgG on the surfaces of chitosan and PS: a) PS, b) chitosan.
Figure 8. Adsorbed IgG on the surfaces of chitosan and PS: a) PS, b) chitosan.
3.4 Adsorbed Layers of Alb, Fib, and IgG on Chitosan and PS Films
As discussed above, each adsorption curve indicates the thickness of one particular protein adsorbed onto the surface of one kind of material. Thus, the adsorptive thickness of one kind of proteins on films of different materials can be compared directly according to the curve family as in
Fig. 6
,
Fig. 7
and
Fig. 8
. But with the RIfS thickness a comparison of the adsorbed amount of different proteins on the same materials cannot be carried out directly. Since the structure and size of three proteins are very different. After a normalized treatment of the experimental data using the equation, the thickness of the adsorbed protein layers was calculated, which indicates the effectively adsorbed amount of different proteins on one particular material.
RIfS thickness of three kinds of proteins on the PS surface decreases in the order ( Tab. 1 ): IgG (6.35nm) > Fib (3.59nm) > Alb (1.34nm). The adsorbed layer number, calculated using the equation, PS has same series: IgG (0.577) > Fib (0.399) > Alb. (0.336).
The thickness determined by RIfS for the three kinds of proteins on the chitosan surface decreases in the order (
Tab. 2
): Alb (2.54nm) > Fib (1.42nm) > IgG (1.06nm). By this order a special phenomena for albumin adsorbed onto chitosan film is recognized. Despite the smallest structure the adsorbed RIfS thickness of Alb is greatest among the three kinds of proteins. This result is very different from the results of PS and of another studies [
13
,
39
]. It indicates that chitosan adsorbed much more Alb than Fib and IgG. In this case the adsorbed layer number of three kinds of proteins on chitosan decreases in the same order: Alb (0.635) > Fib (0.158) > IgG (0.0967).
The calculated layer numbers of three kinds of proteins show that the total amount of each kind of protein adsorbed on chitosan and PS occurs as monolayer adsorption.
According to previous studies, albumin has a thrombus-resistant ability, whereas fibrinogen promotes platelet adhesion on a polymer surface [ 41 ]. The calculated number of adsorbed layers of the three proteins on chitosan and PS evidences that the chitosan material shows a higher affinity to Alb and lower affinity to Fib than PS. This means that chitosan has a better antithrombus function relative to PS films.
Table 1. RIfS thickness and adsorbed layer number of three kinds of proteins on the PS film.
Table 1. RIfS thickness and adsorbed layer number of three kinds of proteins on the PS film. Thickness Proteins x ¯ (n=3) SD Adsorbed Layer Alb 1.34 0.0868 0.336 Fib 3.59 0.0586 0.399 IgG 6.35 0.0430 0.577
Table 2. RIfS thickness and adsorbed layer number of three kinds of proteins on the chitosan film.
Table 2. RIfS thickness and adsorbed layer number of three kinds of proteins on the chitosan film. Thickness Proteins x ¯ (n=3) SD Adsorbed Layer Alb 2.54 0.0193 0.635 Fib 1.42 0.0220 0.158 IgG. 1.06 0.0505 0.0967
3.5 AFM characteristic
AFM analysis is useful for probing the lateral distribution of the protein molecules with the monolayer and confirmed indirectly the presence of the passively adsorbed protein on the surfaces of biomaterials. The AFM image in Figs. 9 (a) and figure 10 (a) are the microstructure of the chitosan and PS surface, while in Fig. 9 (b) and Fig. 10 (b) the same surfaces with adsorbed protein albumin.
From the AFM image in Fig. 9 (a), the pattern in the surface of chitosan material can be revealed. The AFM images of albumin coated chitosan surface in figure9 (b) reveal that the most area of the surface of chitosan film was covered with the proteins.
The AFM image of PS film in Fig. 10 (a) termed as ultra-flat film [ 42 ]. The AFM image in Fig. 10 (b) reveal that there is fewer albumin on PS film than on chitosan film in figure9 (b).
AFM analyses are consistent with the calculated adsorbed layer in Tab. 1 and Tab. 2 .
Figure 9. AFM image of microstructure of a chitosan surface (a) and with adsorbed albumin (b).
Figure 9. AFM image of microstructure of a chitosan surface (a) and with adsorbed albumin (b).
Figure 10. AFM image of microstructure of a PS surface (a) and with adsorbed albumin (b).
Figure 10. AFM image of microstructure of a PS surface (a) and with adsorbed albumin (b).
4. Conclusions
This study confirmed that RIfS is a useful tool for analysis of plasma proteins adsorbed on a surface of biomaterials. The number of adsorbed layers of three kinds of proteins on the surface of chitosan has a series: Alb > Fib > IgG and PS has a series: IgG > Fib > Alb. Results reported in this paper show that at first on the surface of chitosan film more Alb and fewer Fib adsorbs, which demonstrates that chitosan has a antithrombus function and secondly, on the surface of chitosan film more Alb and less Fib than on the surface of PS film, which demonstrated that chitosan has a better blood compatibility than polystyrene. And thirdly, according to the calculated layer number of the three proteins all the proteins on chitosan and on PS materials represents a monolayer adsorption.
Acknowledgements
We are thankful to the Ministry of Education of China for the support by the “Promotion Foundation for Scholars from Abroad” (1998-2000).
References
Kawaguchi, T.; Shiro, T.; Iwata, K. A highly sensitive device for visual detection of antigens and antibodies by means of light interference. Sensors and Actuators B 1991 , 3 , 113–121. [ Google Scholar ] [ CrossRef ]
Brecht, A.; Gauglitz, G.; Nahm, W. Interferometric measurement used in chemical and biochemical sensors. Analysis 1992 , 20 , 135–140. [ Google Scholar ]
Myszka, D.G. Kinetic analysis of macromolecular interactions using surface plasmon resonance biosensors. Current Opinion in Biotechnology 1997 , 8 , 50–57. [ Google Scholar ] [ CrossRef ]
Green, R.J.; Frazier, R.A.; Shakesheff, K.M.; Davies, M.C.; Roberts, C.J.; Tendler, S.J.B. Surface plasmon resonance analysis of dynamic biological interactions with biomaterials. Biomaterials 2000 , 21 , 1823–1835. [ Google Scholar ] [ CrossRef ]
Brecht, A.; Ingenhoff, J.; Gauglitz, G. Direct monitoring of antigen-antibody interactions by spectral interferometry. Sensors and Actuators B 1992 , 6 , 96–100. [ Google Scholar ] [ CrossRef ]
Gauglitz, G.; Brecht, A.; Kraus, G.; Nahm, W. Chemical and biochemical sensors based on interferometry at thin (multi-) layers. Sensors and Actuators B 1993 , 11 , 21–27. [ Google Scholar ] [ CrossRef ]
Schmitt, H.M.; Brecht, A.; Piehler, J.; Gauglitz, G. An integrated system for optical biomolecular interaction analysis. Biosensors & Bioelectronics 1997 , 12 (8), 809–816. [ Google Scholar ]
Sauer, M.; Brecht, A.; Charissé, K.; Maier, M.; Gerster, M.; Stemmler, I.; Gauglitz, G.; Bayer, E. Interaction of Chemically Modified antisense oligonucleotides with sense DNA: a label-free interaction study with reflectometric interference spectroscopy. Analytical Chemistry 1999 , 71 , 2850–2857. [ Google Scholar ] [ CrossRef ]
Brecht, A.; Gauglitz, G. Optimised layer systems for immunosensors used on the RIFS transducer. J Anal Chem. 1994 , 349 , 360–366. [ Google Scholar ] [ CrossRef ]
Piehler, J.; Brecht, A.; Gauglitz, G.; Maul, C.; Grabley, S.; Zerlin, M. Specific binding of lowmolecular weight ligands with direct optical detection. Biosensors & Bioelectronics 1997 , 12 (6), 531–538. [ Google Scholar ] [ CrossRef ]
Rathgeb, F.; Gauglitz, G. Dyeless optical detection of ammonia in the gas phase using pH- responsive polymers with reflectometric interference spectroscopy. Analytica Chimica Acta 1998 , 372 , 333–340. [ Google Scholar ] [ CrossRef ]
Yu, F.; Yao, D.F.; Qian, W.P.; et al. Reflectometry. interference spectroscopy in detection of hepatitis B surface antigen. Clin. Chem. 2000 , 46 (9), 1489–1490. [ Google Scholar ]
Lü, X.Y.; Huang, H.F.; Chen, D.M.; et al. Real time in situ kinetic analysis of proteins adsorbed onto the surface of hydroxyapatite film using RIfS. In Proceedings of the first international conference on biomaterials (China), Beijing, China, July 24–26,2001.
Sharma, C.P.; Sunny, M.C. Albumin adsorption on to aluminum oxide and polyurethane surfaces. Biomaterials 1990 , 11 , 255–257. [ Google Scholar ] [ CrossRef ]
Zhang, S.J.; Li, D.J.; Zhao, J.; Gu, H.Q. A study of blood protein adsorption on diamond-like carbon. In Chinese Conference on Biomaterials, Panyu. China; November 1999; pp. 5–8. [ Google Scholar ]
Babensee, J.E.; Cornelius, R.M.; Brash, J.L.; Sefton, M.V. Immunoblot analysis of proteins associated with HEMA-MMA microcapsules: Human serum proteins in vitro and rat proteins following implantation. Biomaterials 1998 , 19 , 839–849. [ Google Scholar ] [ CrossRef ]
Kandori, K.; Fujiwara, A.; Mukai, M.; Yasukawa, A.; Ishikawa, T. Evaluation of the adsorption affinity of proteins to calcium hydroxyapatites by desorption and pre-adsorption methods. Colloids and Surfaces B: Biointerfaces 1998 , 11 , 313–320. [ Google Scholar ] [ CrossRef ]
Klomp, A.J.A.; Engbers, G.H.M.; Mol, J.; Terlingen, J.G.A.; Feijen, J. Adsorption of proteins from plasma at polyester non-wovens. Biomaterials 1999 , 20 , 1203–1211. [ Google Scholar ] [ CrossRef ]
Chittur, K.K. FTIR/ATR for protein adsorption to biomaterial surfaces. Biomaterials 1998 , 19 , 357–369. [ Google Scholar ]
Zeng, H.; Chittur, K.K.; Lacefield, W.R. Analysis of bovine serum albumin adsorption on calcium phosphate and titanium surfaces. Biomaterials 1999 , 20 , 377–384. [ Google Scholar ] [ CrossRef ]
Kingshott, P.; Heather, A.W.; John, S.T.; Griesser, H.J. Direct detection of proteins adsorbed on synthetic materials by matrix-assisted laser desorption ionization-mass spectrometry. Analytical Biochemistry 1999 , 273 , 156–162. [ Google Scholar ] [ CrossRef ]
Oleschuk, R.D.; McComb, M.E.; Chow, A.; Ens, W.; Standing, K.G.; Perresult, H.; Mariois, Y.; King, M. Characterization of plasma proteins adsorbed onto biomaterials by MALDI-TOFMS. Biomaterials 2000 , 21 , 1701–1710. [ Google Scholar ] [ CrossRef ]
Ortega-Vinuesa, J.L.; Tengvall, P.; Wälivaara, B.; Lundström, I. Stagnant versus dynamic conditions: a comparative adsorption study of blood proteins. Biomaterials 1998 , 19 , 251–262. [ Google Scholar ] [ CrossRef ]
Zhang, M.; Desai, T.; Ferrari, M. Proteins and cells on PEG immobilized silicon surfaces. Biomaterials 1998 , 19 , 953–960. [ Google Scholar ] [ CrossRef ]
Elwing, H. Protein absorption and ellipsometry in biomaterial research. Biomaterials 1998 , 19 , 397–406. [ Google Scholar ] [ CrossRef ]
Tengyall, P.; Lundström, I.; Liedberg, B. Protein adsorption studies on model organic surfaces: an ellipsometric and infrared spectroscopic approach. Biomaterials 1998 , 19 , 407–422. [ Google Scholar ] [ CrossRef ]
Hirano, S.; Zhang, M.; Nakagawa, M.; Miyata, T. Wet spun chitosan-collagen fibers, their chemical N -modifications, and blood compatibility. Biomaterials 2000 , 21 , 997–1003. [ Google Scholar ] [ CrossRef ]
Gu, H.Q.; Xu, G.F. Biomedical Materials. Publishing Company. Of Translate for Sci and Tech.: Tianjing, China, 1993; pp. 316–324. [ Google Scholar ]
Zhang, J.X.; Tang, J.; Xu, B. Biocompatibility and safety evaluation of chitosan rod. J Biomed Eng. (Chinese) 1996 , 13 (4), 293–297. [ Google Scholar ]
Jiang, X.S.; Wang, B.S.; Chen, C.; Li, X.G.; Sun, F.Y. The bioactivity and medical appliance of chitin and its ramification. J Biomed Eng. (Chinese) 1996 , 13 (4), 353–356. [ Google Scholar ]
Andrew, C.A.W.; Khor, E.; Hastings, G.W. The influence of anionic chitin derivatives on calcium phosphate crystallization. Biomaterials 1998 , 19 , 1309–1316. [ Google Scholar ] [ CrossRef ]
Leroux, L.; Freche, Z.; Frèche, M.; Lacout, J.L. Effects of various adjuvants (lactic acid, glycerol, and chitosan) on the injectability of a calcium phosphate cement. Bone 1999 , 25 (2), 318–348. [ Google Scholar ] [ CrossRef ]
Chenite, A.; Chaput, C.; Wang, D.; Combes, C.; Buschmann, M.D.; Hoemann, C.D.; Leroux, J.C.; Atkinson, B.L.; Binette, F.; Selmani, A. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 2000 , 21 , 2155–2161. [ Google Scholar ] [ CrossRef ]
Campos, A.M.D.; Sánchez, A.; Alonso, M.J. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. International Journal of Pharmaceutics 2001 , 224 , 159–168. [ Google Scholar ] [ CrossRef ]
Van der Lubben, I.M.; Verhoef, J.C.; Van Aelst, A.C.; Borchard, G.; Junginger, H.E. Chitosan microparticles for oral vaccination: preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches. Biomaterials 2001 , 22 (7), 687–694. [ Google Scholar ] [ CrossRef ]
Yang, J.; Tian, F.; Chen, S.Q. The mechanism of chitosan hemostasis and its application. Alien Medical: Biomedical and engineering 2001 , 24 (2), 77–80. [ Google Scholar ]
Amiji, M.M. Platelet adhension and activation on an amphoteric chitosan derivative bearing sulfonate groups. Colloids and Surfaces B:Biointerfaces 1998 , 10 , 263–271. [ Google Scholar ] [ CrossRef ]
Lin, C.W.; Lin, J.C. Surface characterization and platelet compatibility evalution of surface- sulfonated chitosan membrane. J Biomater Sci Polym Ed. 2001 , 12 (5), 543–557. [ Google Scholar ] [ CrossRef ]
Green, R.J.; Davies, J.; Davies, M.C.; Robert, C.J.; Tendler, S.J.B. Surface plasmon resonance for real time in situ analysis of protein adsorption to polymer surfaces. Biomaterials 1997 , 18 , 405–413. [ Google Scholar ] [ CrossRef ]
Yu, F. The establishment of reflectometry interference spectroscopy and its use in the token of interface biomolecule. M.S.Thesis, Biomedical and Engineering Department of Southeast University, Nanjing, China, July 2000. [ Google Scholar ]
Huang, S.L.; Chao, M.S.; Ruan, R.C.; Lai, J.Y. Microphase separated structure and protein adsorption of polyurethanes with butadiene soft segment. European Polymer Journal 2000 , 36 , 285–294. [ Google Scholar ] [ CrossRef ]
Qian, W.P.; Yao, D.F.; Yu, F.; Xu, B.; Zhou, R.; Bao, X.; Lu, Z.H. Immobilization of antibodies on ultraflat polystyrene surfaces. In AACC’s Oak Ridge Conference, Bosten, USA, 2000 May; pp. 5–6.
Sample Availability: Available from the author.
© 2001 by MDPI (http://www.mdpi.net) Reproduction is permitted for noncommercial purposes.
Lü, X.Y.; Huang, Y.; Ma, C.Q. Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy. Sensors 2001, 1, 148-160.
https://doi.org/10.3390/s10500148
AMA Style
Lü XY, Huang Y, Ma CQ. Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy. Sensors. 2001; 1(5):148-160.
https://doi.org/10.3390/s10500148
Chicago/Turabian Style
Lü, Xiao Ying, Yan Huang, and Chao Qun Ma. 2001. "Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy" Sensors1, no. 5: 148-160.
https://doi.org/10.3390/s10500148
Article Metrics
MDPI and ACS Style
Lü, X.Y.; Huang, Y.; Ma, C.Q. Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy. Sensors 2001, 1, 148-160.
https://doi.org/10.3390/s10500148
AMA Style
Lü XY, Huang Y, Ma CQ. Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy. Sensors. 2001; 1(5):148-160.
https://doi.org/10.3390/s10500148
Chicago/Turabian Style
Lü, Xiao Ying, Yan Huang, and Chao Qun Ma. 2001. "Evaluation of Protein Adsorption on Chitosan Surfaces with Reflectometry Interference Spectroscopy" Sensors1, no. 5: 148-160.
https://doi.org/10.3390/s10500148
| https://www.mdpi.com/1424-8220/1/5/148/xml |
Zip code 33040 Florida Education data and school information 33042 and 33043
Zip code 33040 Florida Education data with local analysis and research 33042 and 33043
ZIP code 33040 Education Attainment Charts
This section of charts contains education data for ZIP code 33040 Florida based mainly on the latest year 2022 Census data using the American Community Survey but also the survey from Common Core Data available for Public Elementary through Secondary Schools. In
Figure 1
, the percent of all people aged 25 years or older, who have either graduated from high school or completed the Graduate Equivalency Degree (GED) or some equivalent certification/credential.
33040
shows it has a High School Grad or higher of 91% which is the second smallest when ranked by percent high school graduates or better of all the other zip codes in the metro area. The zip code with the highest percent high school graduates or better in the area is
33042
which depicts a high school graduates of 97% (6.2% larger).
In
Figure 2
, the percentage of people aged 25 years or older who have graduated from college/university with at least a bachelor's degree is provided. Note that the bachelor's degree is also called a four-year degree because it normally takes four years of full-time study to finish the course curriculum required to obtain the degree. This chart portrays the proportion of the population in this region who are college graduates with at least a bachelor degree or higher. In many ways, this analysis alongside the prior chart are very quick measures of the level of education in any particular area. ZIP code 33040 depicts it has a Bachelors Degree or higher of 35% which is in the mid point range of other zip codes in the area. The zip code with the highest percent with a bachelors degree or higher in the area is
33051
which shows a percent with a bachelors degree of 44% (23.9% larger).
Figure 4
shows the percentage of people 25 years of age or older who either have no schooling at all or dropped out of school before being able to complete high school. Additionally, these are people who also do not have a Graduate Equivalency Degree (GED) or some other high school level type credential/student achievement. This analysis, along with the last two charts, provides another high level review and comparative data on the ZIP code 33040 Florida educational level.
33040
depicts it has a School Dropout Rate of 9% which is the second most percent who dropped out of school of all the zip codes in the greater ZIP code 33040 region. The zip code with the highest percent who dropped out of school in the area is
33050
which indicates a percent who dropped out of school of 11% (24.5% larger).
Figure 5
provides a more detailed look at the educational attainment for ZIP code 33040 Florida. This chart provides the proportion of people aged 25 years of age or older and what was their level of educational attainment. The chart provides 5 broad categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. ZIP code 33040 has one of the largest proportions of percent of people with no schooling at 8% of the total and is ranked #2. The only larger zip code being
33050
with 10%. Second, it has one of the largest proportions of percent of people with less than a high school education at 29% of the total and is ranked #3. Only #2
33050
(29%), and #1
33001
(60%) are larger.
The next chart shows a break down of people who have received a bachelor's degree or higher advanced degree generally in a campus learning environment. In particular,
Figure 6
, provides the proportional breakdown of all the people who have received a postsecondary education along with what the level of advanced degree that was obtained. Note that these categories do not include any type professional development type activities such as those related to maintaining professional credentials in workshop lessons. Note Professional Degree includes medical, dental, lawyers, etc. ZIP code 33040 has the largest proportion of percent of people with a bachelors degree at 24% of the total and is ranked #1. Second, it has one of the largest proportions of percent of people with a professional school degree at 4% of the total and is ranked #2. The only larger zip code being
33042
with 6%.
The chart in
Figure 7
shows the broad area of academic concentration or the discipline for people who have received a bachelors degree. This high level classification is essentially the field of study for which a degree was obtained. ZIP code 33040 has the largest proportion of percent of people with a degree in a science or engineering related at 28.9% of the total and is ranked #1.
The next chart (
Figure 8
) provides a more detailed deep dive on the category of major degree obtained for people aged 25 years or older who earned a bachelor's degree or higher. Specifically, this frequency distribution details out what the major field of study was the degree obtained. ZIP code 33040 has the smallest proportion of percent of people with a degree in computers, mathematics and statistics at 5.1% of the total. Second, it has the largest proportion of percent of people with a degree in physical and related sciences at 5.4% of the total and is ranked #1. Third, it has the largest proportion of percent of people with a degree in visual and performing arts at 5.1% of the total and is ranked #1.
Figure 9
provides comparative data between the places in the greater ZIP code 33040 Florida region for broad educational attainment. This analysis uses provides five broad education attainment categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. ZIP code 33040 has the percentage of percent of people with high school (or ged) the second smallest as measured by percent of people with no schooling of all the other zip codes in the area at 27.2% of the total.
A more detailed frequency distribution of educational attainment is provided in
Figure 10
. In particular this illustration breaks out the highest levels of university educational opportunities beyond the four year college degree. Included in the breakout are the relative proportion of masters degrees, PhD/Doctorate/Doctorial holders, and professional degrees such as medicine, dentistry, lawyers, etc. ZIP code 33040 has one of the largest proportions of percent of people with no schooling at 7.8% of the total and is ranked #2. The only larger zip code being
33050
with 10.1%. Second, it has one of the largest proportions of percent of people with less than high school at 28.6% of the total and is ranked #3. Only #2
33050
(29.1%), and #1
33001
(60.4%) are larger. Third, it has the smallest proportion of percent of people with some college but not a graduate at 7.1% of the total. The next exhibit (
Figure 11
) provides detailed cross tabulation analysis that provides education success data broken out or cross tabulated by age group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
Figure 12
is a cross tabulation analysis that shows large educational success categories and is broken out or cross tabulated by racial group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.The final cross tabulation analysis is provided in
Figure 13
and shows education success broken out by gender. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
ZIP code 33040 School Enrollment Charts
The next section of chart resources look at school enrollment by a variety of educational institutions and are categorized into a number of other groupings.
Figure 14
provides the overall school enrollment by broad range of school age/level groupings. ZIP code 33040 has one of the largest proportions of percent of children in grades 5 to 8 at 23.4% of the total and is ranked #3. Only #2
33050
(26.4%), and #1
33051
(50.0%) are larger. Second, it has one of the largest proportions of percent of children in grades 9 to 12 at 21.0% of the total and is ranked #2. The only larger zip code being
33042
with 26.9%. Third, it has one of the largest proportions of percent of people in undergraduate colleges at 6.3% of the total and is ranked #3. Only #2
33043
(10.8%), and #1
33001
(100.0%) are larger.
Figure 15
provides a simple high level comparison of the proportion of students that are enrolled in public schools versus students enrolled in private schools in the ZIP code 33040 Florida region. ZIP code 33040 depicts percent enrolled in public schools substantially bigger as the percent enrolled in private schools.
The next comparison provided in
Figure 16
shows the proportion of students enrolled in private schools versus students enrolled public schools for students enrolled in Kindergarten through 8th grade (grade 8) or (K through 8). ZIP code 33040 shows percent of children enrolled in public k-8 grades considerably bigger as the percent of children enrolled in private k-8 grades.
Figure 17
provides a comparative analysis all students enrolled in a public high school versus those students who are enrolled in private high school schools. ZIP code 33040 depicts percent enrolled in a public high school markedly bigger as the percent enrolled in a private high school.
The next chart (
Figure 18
) provides a similar analysis to the last chart but provides the data for public post secondary education versus private higher education colleges. ZIP code 33040 shows percent enrolled in a public college approximately 3.2 times bigger as the percent enrolled in a private college.
Figure 19
shows another view of students enrolled in public or private schools-postsecondary schools or colleges/universities. This analysis shows the proportion for all graduate and professional schools (such as law or medical school) and whether those students are enrolled in private or public institutions. ZIP code 33040 depicts percent enrolled in a public gradudate or professional school about twice as large as the percent enrolled in a private gradudate or professional school.
The next chart in this series of resources shown in
Figure 20
looks at the total number of students enrolled in any educational institution for each place in the greater ZIP code 33040 region. (Total enrollment in this case includes all students from preschool all the way through students enrolled in graduate school.) ZIP code 33040 depicts it has a Total Enrolled of 6,181 which is the most of all zip codes in the greater ZIP code 33040 region. Comparing total population enrolled in school to the
United States
average of 81,076,829, ZIP code 33040 is only about 0.0% the size. Also, measured against the state of
Florida
, total population enrolled in school of 4,786,330, ZIP code 33040 is only about 0.1% the size.
The final chart in this series is
Figure 22
and provides analysis data for the school year shown. The chart shows the proportion of kids/children that are enrolled in a pre-school public district versus those kids/children who are enrolled in a private pre-school oriented tuition institution (private salary/superintendent/etc.) ZIP code 33040 Florida has one of the largest proportions of public preschool enrollment at 13% of the total and is ranked #3. Only #2
33043
(28%), and #1
33050
(90%) are larger.
ZIP code 33040 Area Schools Charts
Figure 23
lists all the schools in the area along with the school district, county location and other program information/credential such as if they are a public charter school or private charter school or magnet school. Some of the Area Schools are: Keys Center, Glynn Archer Elementary School, Key West Montessori Charter School, Inc, Horace Obryant Middle School, and Key West High School. The next illustration in
Figure 24
shows the total child school enrollment for all grades (through 12th grade) at the school shown using NCES data (Common Core of Data, Public Elementary-Secondary School Universe Survey.) Looking at Enrollment for Area Schools we find that Key West High School ranks the largest with a value of 1,218 enrolled students. The next largest values are for: Horace Obryant Middle School (638), Marathon High School (636), Poinciana Elementary School (612), and Sugarloaf School (574). The difference between the highest value (Key West High School) and the next highest (Horace Obryant Middle School) is that the enrolled students is about about twice as large.
Figure 25
show the ratio of the number of students to the number of teachers in the classroom. A good student to teacher ratio should be low because it indicates that there are less students for any one teacher to educate in a class and generally a better learning environment, better success and optimal teaching excellence. Teachers includes all educational staff such as special education teachers and any other educator. Note that distance learning (online learning/remote learning) is not included in these values. Looking at Student to Teacher Ratio for Area Schools we find that Keys Center ranks the largest with a value of 7.5 student to teacher ratio. The next largest values are for: Big Pine Academy (12.5), Sigsbee Charter School (13.3), Key West Montessori Charter School, Inc (14.4), and Stanley Switlik Elementary School (14.5). The difference between the lowest value (Keys Center) and the next lowest (Big Pine Academy) is that the student to teacher ratio is 67.1% larger.
The next chart,
Figure 26
, shows the racial mix of students at each location in this district of the state of Florida department of education.
Zip code 33040, FloridaEducation Data
<table><tr><th> Figure 1: 33040, FL At least High School Education<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 2: 33040, FL Bachelors Degree or Better Education<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td> 0% 50% 100% United States 33050 Florida Orlando-Deltona-Daytona Beach 33040 33043 33001 33036 33051 33042<table><tr><th> Place</th><th> High School Grad or higher</th></tr><tbody><tr><td> United States</td><td> 89%</td></tr><tr><td> 33050</td><td> 89%</td></tr><tr><td> Florida</td><td> 89%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 90%</td></tr><tr><td> 33040</td><td> 91%</td></tr><tr><td> 33043</td><td> 92%</td></tr><tr><td> 33001</td><td> 94%</td></tr><tr><td> 33036</td><td> 97%</td></tr><tr><td> 33051</td><td> 97%</td></tr><tr><td> 33042</td><td> 97%</td></tr></tbody></table> Beach</td><td> 0% 50% 100% 33001 33043 Orlando-Deltona-Daytona Beach 33050 Florida United States 33040 33036 33042 33051<table><tr><th> Place</th><th> Bachelors Degree or higher</th></tr><tbody><tr><td> 33001</td><td> 19%</td></tr><tr><td> 33043</td><td> 29%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 30%</td></tr><tr><td> 33050</td><td> 31%</td></tr><tr><td> Florida</td><td> 32%</td></tr><tr><td> United States</td><td> 34%</td></tr><tr><td> 33040</td><td> 35%</td></tr><tr><td> 33036</td><td> 41%</td></tr><tr><td> 33042</td><td> 42%</td></tr><tr><td> 33051</td><td> 44%</td></tr></tbody></table> Beach</td></tr></tbody></table>
<table><tr><th> Figure 3: Advertisement<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 4: 33040, FL School Dropout Rate<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td></td><td> 0% 10% 20% 33042 33051 33036 33001 33043 33040 Orlando-Deltona-Daytona Beach Florida 33050 United States<table><tr><th> Place</th><th> School Dropout Rate</th></tr><tbody><tr><td> 33042</td><td> 3%</td></tr><tr><td> 33051</td><td> 3%</td></tr><tr><td> 33036</td><td> 3%</td></tr><tr><td> 33001</td><td> 6%</td></tr><tr><td> 33043</td><td> 8%</td></tr><tr><td> 33040</td><td> 9%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 10%</td></tr><tr><td> Florida</td><td> 11%</td></tr><tr><td> 33050</td><td> 11%</td></tr><tr><td> United States</td><td> 11%</td></tr></tbody></table> Beach</td></tr></tbody></table>
<table><tr><th> Figure 5: 33040, FL Education Attainment Breakdown<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 6: Higher Education Attainment (100%=All People with Bachelor or better)<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td> Bachelors Degree or higher High School or GED Some college or Associates Degree Less than High School No schooling 35.3% 7.8% 27.2% 28.6%<table><tr><th> Place</th><th> 33040</th></tr><tbody><tr><td> Bachelors Degree or higher</td><td> 0.353</td></tr><tr><td> High School or GED</td><td> 0.286</td></tr><tr><td> Some college or Associates Degree</td><td> 0.272</td></tr><tr><td> Less than High School</td><td> 0.078</td></tr><tr><td> No schooling</td><td> 0.01</td></tr></tbody></table> No schooling</td><td> Bachelors degree % Masters degree % Associate degree % Professional school degree % Doctorate degree % 16.8% 23.6% 51.2%<table><tr><th> Place</th><th> 33040</th></tr><tbody><tr><td> Bachelors degree %</td><td> 0.512</td></tr><tr><td> Masters degree %</td><td> 0.236</td></tr><tr><td> Associate degree %</td><td> 0.168</td></tr><tr><td> Professional school degree %</td><td> 0.048</td></tr><tr><td> Doctorate degree %</td><td> 0.036</td></tr></tbody></table> Doctorate degree</td></tr></tbody></table>
Figure 7: 33040, FL Bachelors Degrees Field of Study<here is a image 377931e4a21edf85-24ad93d40e2d87d9> Science & Engineering Science and Engineeri… Arts, Humanities, Other Business Education 33040 33042 33043 33051 33050 33001 33036 United States Florida Orlando-Deltona-Dayto… 0% 50% 100%<table><tr><th> Place</th><th> Science & Engineering</th><th> Science and Engineering Related</th><th> Arts, Humanities, Other</th><th> Business</th><th> Education</th></tr><tbody><tr><td> 33040</td><td> 32.1%</td><td> 10%</td><td> 28.9%</td><td> 21%</td><td> 8%</td></tr><tr><td> 33042</td><td> 37.9%</td><td> 7.9%</td><td> 27.9%</td><td> 20.1%</td><td> 6.2%</td></tr><tr><td> 33043</td><td> 40%</td><td> 14.1%</td><td> 20.7%</td><td> 12.2%</td><td> 12.9%</td></tr><tr><td> 33051</td><td> 26.1%</td><td> 23%</td><td> 21%</td><td> 19.9%</td><td> 10.1%</td></tr><tr><td> 33050</td><td> 29.2%</td><td> 9.1%</td><td> 23.8%</td><td> 26.3%</td><td> 11.5%</td></tr><tr><td> 33001</td><td> 66.7%</td><td> 6.1%</td><td> 15.2%</td><td> 12.1%</td><td> 0%</td></tr><tr><td> 33036</td><td> 29.6%</td><td> 6.2%</td><td> 20.6%</td><td> 36.6%</td><td> 7.1%</td></tr><tr><td> United States</td><td> 35.8%</td><td> 9.7%</td><td> 23.7%</td><td> 19.6%</td><td> 11.2%</td></tr><tr><td> Florida</td><td> 32.7%</td><td> 10.7%</td><td> 20.6%</td><td> 23.7%</td><td> 12.3%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 31.6%</td><td> 10.8%</td><td> 21.4%</td><td> 24%</td><td> 12.2%</td></tr></tbody></table> Science and Engineerin…
Figure 8: 33040, FL Bachelors Degree Obtained<here is a image 377931e4a21edf85-24ad93d40e2d87d9> Computers, Mathemat… Biological, Agricultura… Physical and Related S… Psychology Social Sciences Engineering Multidisciplinary Studies Science and Engineering Related Business Education Literature and Languages Liberal Arts and History 1/2 33040 0% 5% 10% 15% 20% 25%<table><tr><th> Place</th><th> Computers, Mathematics and Statistics</th><th> Biological, Agricultural, and Environmental Sciences</th><th> Physical and Related Sciences</th><th> Psychology</th><th> Social Sciences</th><th> Engineering</th><th> Multidisciplinary Studies</th><th> Science and Engineering Related</th><th> Business</th><th> Education</th><th> Literature and Languages</th><th> Liberal Arts and History</th><th> Visual and Performing Arts</th><th> Communications</th><th> Other</th></tr><tbody><tr><td> 33040</td><td> 2.6%</td><td> 5.1%</td><td> 3.5%</td><td> 5.4%</td><td> 9.4%</td><td> 5.7%</td><td> 0.5%</td><td> 10%</td><td> 21%</td><td> 8%</td><td> 5.2%</td><td> 5.4%</td><td> 9%</td><td> 5.1%</td><td> 4.2%</td></tr></tbody></table> 0/0
Figure 9: 33040, FL Education Attainment by Level Comparison (Age 25+)<here is a image 377931e4a21edf85-24ad93d40e2d87d9> No schooling Less than High School High School or GED Some college or Associates Degree Bachelors Degree or higher 33040 33042 33043 33051 33050 33001 33036 United States Florida Orlando-Deltona-Dayto… 0% 50% 100%<table><tr><th> Place</th><th> No schooling</th><th> Less than High School</th><th> High School or GED</th><th> Some college or Associates Degree</th><th> Bachelors Degree or higher</th></tr><tbody><tr><td> 33040</td><td> 1%</td><td> 7.8%</td><td> 28.6%</td><td> 27.2%</td><td> 35.3%</td></tr><tr><td> 33042</td><td> 1.4%</td><td> 1.8%</td><td> 23%</td><td> 32.1%</td><td> 41.7%</td></tr><tr><td> 33043</td><td> 2.9%</td><td> 5.3%</td><td> 26.4%</td><td> 36.7%</td><td> 28.6%</td></tr><tr><td> 33051</td><td> 0%</td><td> 3.2%</td><td> 23.4%</td><td> 29.6%</td><td> 43.8%</td></tr><tr><td> 33050</td><td> 0.9%</td><td> 10.1%</td><td> 29.1%</td><td> 29.1%</td><td> 30.8%</td></tr><tr><td> 33001</td><td> 0%</td><td> 5.7%</td><td> 60.4%</td><td> 15.1%</td><td> 18.7%</td></tr><tr><td> 33036</td><td> 0%</td><td> 3.3%</td><td> 27.6%</td><td> 28.2%</td><td> 40.9%</td></tr><tr><td> United States</td><td> 1.6%</td><td> 9.5%</td><td> 26.5%</td><td> 28.7%</td><td> 33.7%</td></tr><tr><td> Florida</td><td> 1.6%</td><td> 9.3%</td><td> 27.9%</td><td> 29.6%</td><td> 31.5%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 1.5%</td><td> 8.8%</td><td> 28.1%</td><td> 31.5%</td><td> 30%</td></tr></tbody></table> Bachelors Degree or higher
Figure 10: 33040, FL Education Attainment Detailed Comparison (Age 25+)<here is a image 377931e4a21edf85-24ad93d40e2d87d9> No schooling Less than High School High School or GED Some college Not Graduate Associate degree Bachelors degree Masters degree Professional school degree Doctorate degree 33040 0% 10% 20% 30%<table><tr><th> Place</th><th> No schooling</th><th> Less than High School</th><th> High School or GED</th><th> Some college Not Graduate</th><th> Associate degree</th><th> Bachelors degree</th><th> Masters degree</th><th> Professional school degree</th><th> Doctorate degree</th></tr><tbody><tr><td> 33040</td><td> 1%</td><td> 7.8%</td><td> 28.6%</td><td> 20.1%</td><td> 7.1%</td><td> 21.8%</td><td> 10%</td><td> 2%</td><td> 1.5%</td></tr></tbody></table> Doctorate degree
Figure 11: 33040, FL Detailed Education Attainment Breakout by Age Group (Age 18+)<here is a image 377931e4a21edf85-24ad93d40e2d87d9><table><tr><th> Education</th><th> 18 to 24 years</th><th> 25 to 34 years</th><th> 35 to 44 years</th><th> 45 to 64 years</th><th> 65 years and over</th></tr><tbody><tr><td colspan=1> 9th to 12th grade, no diploma</td><td colspan=1>10%</td><td colspan=1>4%</td><td colspan=1>6%</td><td colspan=1>4%</td><td colspan=1>6.4%</td></tr><tr><td colspan=1> Associates degree</td><td colspan=1>6%</td><td colspan=1>10%</td><td colspan=1>6%</td><td colspan=1>7%</td><td colspan=1>6.1%</td></tr><tr><td colspan=1> Bachelors degree</td><td colspan=1>7%</td><td colspan=1>23%</td><td colspan=1>25%</td><td colspan=1>22%</td><td colspan=1>17.0%</td></tr><tr><td colspan=1> Graduate or professional degree</td><td colspan=1>0%</td><td colspan=1>6%</td><td colspan=1>13%</td><td colspan=1>14%</td><td colspan=1>20.3%</td></tr></tbody></table> 1 2
Figure 12: 33040, FL Detailed Education Attainment Breakout by Race (Age 25+)<here is a image 377931e4a21edf85-24ad93d40e2d87d9><table><tr><th> Education</th><th> White</th><th> Black</th><th> American Indian</th><th> Asian</th><th> Native Hawaiian</th><th> Hispanic</th></tr><tbody><tr><td colspan=1> Bachelors degree or higher</td><td colspan=1>39%</td><td colspan=1>19%</td><td colspan=1>0%</td><td colspan=1>24%</td><td colspan=1>0%</td><td colspan=1>20.7%</td></tr><tr><td colspan=1> High school graduate or GED</td><td colspan=1>25%</td><td colspan=1>47%</td><td colspan=1>0%</td><td colspan=1>23%</td><td colspan=1>0%</td><td colspan=1>37.9%</td></tr><tr><td colspan=1> Less than high school diploma</td><td colspan=1>8%</td><td colspan=1>13%</td><td colspan=1>12%</td><td colspan=1>21%</td><td colspan=1>77%</td><td colspan=1>18.4%</td></tr><tr><td colspan=1> Some college or associates degree</td><td colspan=1>28%</td><td colspan=1>22%</td><td colspan=1>89%</td><td colspan=1>32%</td><td colspan=1>23%</td><td colspan=1>23.1%</td></tr></tbody></table>
Figure 13: 33040, FL Detailed Male and Female breakdown of Educational Attainment<here is a image 377931e4a21edf85-24ad93d40e2d87d9><table><tr><th> Education</th><th> Total</th><th> Male</th><th> Female</th></tr><tbody><tr><td colspan=1> Associates Degree</td><td colspan=1>7%</td><td colspan=1>6%</td><td colspan=1>8.0%</td></tr><tr><td colspan=1> Bachelors Degree</td><td colspan=1>22%</td><td colspan=1>21%</td><td colspan=1>23.2%</td></tr><tr><td colspan=1> Doctorate degree</td><td colspan=1>2%</td><td colspan=1>2%</td><td colspan=1>1.4%</td></tr><tr><td colspan=1> High school/GED</td><td colspan=1>29%</td><td colspan=1>30%</td><td colspan=1>27.2%</td></tr><tr><td colspan=1> Less than High School</td><td colspan=1>8%</td><td colspan=1>8%</td><td colspan=1>7.1%</td></tr><tr><td colspan=1> Masters degree</td><td colspan=1>10%</td><td colspan=1>10%</td><td colspan=1>10.4%</td></tr><tr><td colspan=1> No schooling completed</td><td colspan=1>1%</td><td colspan=1>1%</td><td colspan=1>0.8%</td></tr><tr><td colspan=1> Professional school degree</td><td colspan=1>2%</td><td colspan=1>3%</td><td colspan=1>1.1%</td></tr><tr><td colspan=1> Some college-No Degree</td><td colspan=1>20%</td><td colspan=1>20%</td><td colspan=1>20.8%</td></tr><tr><td colspan=1> Total</td><td colspan=1>100%</td><td colspan=1>53%</td><td colspan=1>47.3%</td></tr></tbody></table>
Figure 14: 33040, FL School Enrollment by Aggregate Categories<here is a image 377931e4a21edf85-24ad93d40e2d87d9> Kindergarten Grade 1 to 4 Grade 5 to 8 Grade 9 to 12 College, undergraduate Graduate or prof school 33040 33042 33043 33051 33050 33001 33036 United States Florida Orlando-Deltona-Dayto… 0% 50% 100%<table><tr><th> Place</th><th> Kindergarten</th><th> Grade 1 to 4</th><th> Grade 5 to 8</th><th> Grade 9 to 12</th><th> College, undergraduate</th><th> Graduate or prof school</th></tr><tbody><tr><td> 33040</td><td> 4.8%</td><td> 17.6%</td><td> 26.9%</td><td> 23.4%</td><td> 21%</td><td> 6.3%</td></tr><tr><td> 33042</td><td> 5.6%</td><td> 23.5%</td><td> 20.9%</td><td> 18.3%</td><td> 26.9%</td><td> 4.8%</td></tr><tr><td> 33043</td><td> 7.6%</td><td> 33.2%</td><td> 25.7%</td><td> 14.3%</td><td> 8.4%</td><td> 10.8%</td></tr><tr><td> 33051</td><td> 0%</td><td> 0%</td><td> 50%</td><td> 50%</td><td> 0%</td><td> 0%</td></tr><tr><td> 33050</td><td> 3%</td><td> 19.2%</td><td> 35.8%</td><td> 26.4%</td><td> 11.4%</td><td> 4.3%</td></tr><tr><td> 33001</td><td> 0%</td><td> 0%</td><td> 0%</td><td> 0%</td><td> 0%</td><td> 100%</td></tr><tr><td> 33036</td><td> 11.9%</td><td> 26.5%</td><td> 46.6%</td><td> 9.7%</td><td> 0.5%</td><td> 4.9%</td></tr><tr><td> United States</td><td> 5.3%</td><td> 21.1%</td><td> 22.3%</td><td> 22.6%</td><td> 23%</td><td> 5.8%</td></tr><tr><td> Florida</td><td> 5.2%</td><td> 20.6%</td><td> 22%</td><td> 22.3%</td><td> 23.9%</td><td> 6%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 5.4%</td><td> 21%</td><td> 21.8%</td><td> 22.3%</td><td> 24.2%</td><td> 5.4%</td></tr></tbody></table> Graduate or prof school
<table><tr><th> Figure 15: 33040, FL Overall Public vs. Private School Enrollment<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 16: 33040, FL Public vs. Private K-8 School Enrollment<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td> Public Sc… Private S… 0% 50% 100% 33040 33042 33043 33051 33050 33001 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public School Enrollment</th><th> Private School Enrollment</th></tr><tbody><tr><td> 33040</td><td> 89%</td><td> 11%</td></tr><tr><td> 33042</td><td> 89%</td><td> 11%</td></tr><tr><td> 33043</td><td> 86%</td><td> 14%</td></tr><tr><td> 33051</td><td> 100%</td><td> 0%</td></tr><tr><td> 33050</td><td> 87%</td><td> 13%</td></tr><tr><td> 33001</td><td> 100%</td><td> 0%</td></tr><tr><td> 33036</td><td> 60%</td><td> 40%</td></tr><tr><td> United States</td><td> 83%</td><td> 17%</td></tr><tr><td> Florida</td><td> 81%</td><td> 19%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 81%</td><td> 19%</td></tr></tbody></table> Private Sc…</td><td> Public K-… Private K… 0% 50% 100% 33040 33042 33043 33051 33050 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public K-8 Enrollment</th><th> Private K-8 Enrollment</th></tr><tbody><tr><td> 33040</td><td> 94%</td><td> 6%</td></tr><tr><td> 33042</td><td> 96%</td><td> 4%</td></tr><tr><td> 33043</td><td> 93%</td><td> 7%</td></tr><tr><td> 33051</td><td> 100%</td><td> 0%</td></tr><tr><td> 33050</td><td> 96%</td><td> 5%</td></tr><tr><td> 33036</td><td> 55%</td><td> 45%</td></tr><tr><td> United States</td><td> 88%</td><td> 12%</td></tr><tr><td> Florida</td><td> 85%</td><td> 15%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 85%</td><td> 15%</td></tr></tbody></table> Private K-…</td></tr></tbody></table>
<table><tr><th> Figure 17: 33040, FL Public vs. Private High School Enrollment<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 18: 33040, FL Public vs. Private College Enrollment<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td> Public Hi… Private… 0% 50% 100% 33040 33042 33043 33051 33050 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public High School Enrollment</th><th> Private High School Enrollment</th></tr><tbody><tr><td> 33040</td><td> 95%</td><td> 5%</td></tr><tr><td> 33042</td><td> 100%</td><td> 0%</td></tr><tr><td> 33043</td><td> 100%</td><td> 0%</td></tr><tr><td> 33051</td><td> 100%</td><td> 0%</td></tr><tr><td> 33050</td><td> 90%</td><td> 10%</td></tr><tr><td> 33036</td><td> 100%</td><td> 0%</td></tr><tr><td> United States</td><td> 89%</td><td> 11%</td></tr><tr><td> Florida</td><td> 88%</td><td> 12%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 89%</td><td> 12%</td></tr></tbody></table> Private H…</td><td> Public C… Private C… 0% 50% 100% 33040 33042 33043 33050 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public College Enrollment</th><th> Private College Enrollment</th></tr><tbody><tr><td> 33040</td><td> 76%</td><td> 24%</td></tr><tr><td> 33042</td><td> 78%</td><td> 22%</td></tr><tr><td> 33043</td><td> 76%</td><td> 24%</td></tr><tr><td> 33050</td><td> 81%</td><td> 19%</td></tr><tr><td> 33036</td><td> 100%</td><td> 0%</td></tr><tr><td> United States</td><td> 78%</td><td> 22%</td></tr><tr><td> Florida</td><td> 79%</td><td> 21%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 77%</td><td> 23%</td></tr></tbody></table> Private Co…</td></tr></tbody></table>
<table><tr><th> Figure 19: 33040, FL Public vs. Private Graduate or Professional School Enrollment<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 20: 33040, FL Total Enrolled in Schools<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td> Public Gr… Private… 0% 50% 100% 33040 33042 33043 33050 33001 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public Gradudate or Pro school enrollment</th><th> Private Gradudate or Pro school enrollment</th></tr><tbody><tr><td> 33040</td><td> 68%</td><td> 32%</td></tr><tr><td> 33042</td><td> 44%</td><td> 56%</td></tr><tr><td> 33043</td><td> 50%</td><td> 50%</td></tr><tr><td> 33050</td><td> 40%</td><td> 60%</td></tr><tr><td> 33001</td><td> 100%</td><td> 0%</td></tr><tr><td> 33036</td><td> 0%</td><td> 100%</td></tr><tr><td> United States</td><td> 60%</td><td> 40%</td></tr><tr><td> Florida</td><td> 59%</td><td> 41%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 61%</td><td> 39%</td></tr></tbody></table> Private G…</td><td> 0 5,000 10,000 33001 33051 33036 33043 33042 33050 33040<table><tr><th> Place</th><th> Total Enrolled</th></tr><tbody><tr><td> 33001</td><td> 4</td></tr><tr><td> 33051</td><td> 18</td></tr><tr><td> 33036</td><td> 443</td></tr><tr><td> 33043</td><td> 773</td></tr><tr><td> 33042</td><td> 1,028</td></tr><tr><td> 33050</td><td> 1,505</td></tr><tr><td> 33040</td><td> 6,181</td></tr></tbody></table> ...</td></tr></tbody></table>
<table><tr><th> Figure 21: Advertisement<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th><th> Figure 22: 33040, FL Public vs. Private Preschool<here is a image 377931e4a21edf85-24ad93d40e2d87d9></th></tr><tbody><tr><td></td><td> Public pr… Private p… 0% 50% 100% 33040 33042 33043 33050 33036 United States Florida Orlando-Deltona-Daytona Beach<table><tr><th> Place</th><th> Public preschool enrollment</th><th> Private preschool enrollment</th></tr><tbody><tr><td> 33040</td><td> 87%</td><td> 13%</td></tr><tr><td> 33042</td><td> 88%</td><td> 12%</td></tr><tr><td> 33043</td><td> 72%</td><td> 28%</td></tr><tr><td> 33050</td><td> 10%</td><td> 90%</td></tr><tr><td> 33036</td><td> 100%</td><td> 0%</td></tr><tr><td> United States</td><td> 59%</td><td> 41%</td></tr><tr><td> Florida</td><td> 54%</td><td> 46%</td></tr><tr><td> Orlando-Deltona-Daytona Beach</td><td> 55%</td><td> 45%</td></tr></tbody></table> Private pr…</td></tr></tbody></table>
Figure 23: List of Schools in the 33040, FL Area (2013)<here is a image 377931e4a21edf85-24ad93d40e2d87d9><table><tr><th> School Name</th><th> School District</th><th> School Level</th><th> Grade Range</th><th> Magnet School</th><th> Charter School</th></tr><tbody><tr><td colspan=1> Treasure Village Montessori Charter School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 8</td><td colspan=1> No</td><td colspan=1> Yes</td></tr><tr><td colspan=1> Sugarloaf School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 8</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Stanley Switlik Elementary School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 5</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Sigsbee Charter School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 7</td><td colspan=1> No</td><td colspan=1> Yes</td></tr><tr><td colspan=1> Poinciana Elementary School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 5</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Plantation Key School</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> PK to 8</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Marathon High School</td><td colspan=1> Monroe</td><td colspan=1> Other</td><td colspan=1> 6 to 12</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Keys Center</td><td colspan=1> Monroe</td><td colspan=1> High School</td><td colspan=1> 8 to 12</td><td colspan=1> No</td><td colspan=1> No</td></tr><tr><td colspan=1> Key West Montessori Charter School, Inc</td><td colspan=1> Monroe</td><td colspan=1> Primary School</td><td colspan=1> 1 to 7</td><td colspan=1> No</td><td colspan=1> Yes</td></tr><tr><td colspan=1> Key West High School</td><td colspan=1> Monroe</td><td colspan=1> High School</td><td colspan=1> 9 to 12</td><td colspan=1> No</td><td colspan=1> No</td></tr></tbody></table> 1 2
Figure 24: 33040, FL School Enrollment (2013)<here is a image 377931e4a21edf85-24ad93d40e2d87d9> Enrollment Keys Center Key West Collegiate School Key West Montessori Charter School, Inc Big Pine Academy Treasure Village Montessori Charter School Glynn Archer Elementary School Sigsbee Charter School Plantation Key School Stanley Switlik Elementary School Gerald Adams Elementary School Sugarloaf School Poinciana Elementary School Marathon High School Horace Obryant Middle School Key West High School 0 1000 2000<table><tr><th> School Name</th><th> Enrollment</th></tr><tbody><tr><td> Keys Center</td><td> 15</td></tr><tr><td> Key West Collegiate School</td><td> 46</td></tr><tr><td> Key West Montessori Charter School, Inc</td><td> 115</td></tr><tr><td> Big Pine Academy</td><td> 188</td></tr><tr><td> Treasure Village Montessori Charter School</td><td> 216</td></tr><tr><td> Glynn Archer Elementary School</td><td> 394</td></tr><tr><td> Sigsbee Charter School</td><td> 465</td></tr><tr><td> Plantation Key School</td><td> 470</td></tr><tr><td> Stanley Switlik Elementary School</td><td> 523</td></tr><tr><td> Gerald Adams Elementary School</td><td> 543</td></tr><tr><td> Sugarloaf School</td><td> 574</td></tr><tr><td> Poinciana Elementary School</td><td> 612</td></tr><tr><td> Marathon High School</td><td> 636</td></tr><tr><td> Horace Obryant Middle School</td><td> 638</td></tr><tr><td> Key West High School</td><td> 1,218</td></tr></tbody></table> Enrollment
Figure 25: Student to Teacher Ratios (2013) - Low Scores Are Better<here is a image 377931e4a21edf85-24ad93d40e2d87d9> Student to Teacher Ratio Keys Center Big Pine Academy Sigsbee Charter School Key West Montessori Charter School, Inc Stanley Switlik Elementary School Plantation Key School Gerald Adams Elementary School Key West Collegiate School Treasure Village Montessori Charter School Sugarloaf School Poinciana Elementary School Glynn Archer Elementary School Horace Obryant Middle School Marathon High School Key West High School 0 10 20<table><tr><th> School Name</th><th> Student to Teacher Ratio</th></tr><tbody><tr><td> Keys Center</td><td> 7.5</td></tr><tr><td> Big Pine Academy</td><td> 12.5</td></tr><tr><td> Sigsbee Charter School</td><td> 13.3</td></tr><tr><td> Key West Montessori Charter School, Inc</td><td> 14.4</td></tr><tr><td> Stanley Switlik Elementary School</td><td> 14.5</td></tr><tr><td> Plantation Key School</td><td> 14.7</td></tr><tr><td> Gerald Adams Elementary School</td><td> 15.1</td></tr><tr><td> Key West Collegiate School</td><td> 15.3</td></tr><tr><td> Treasure Village Montessori Charter School</td><td> 15.4</td></tr><tr><td> Sugarloaf School</td><td> 15.5</td></tr><tr><td> Poinciana Elementary School</td><td> 15.7</td></tr><tr><td> Glynn Archer Elementary School</td><td> 15.8</td></tr><tr><td> Horace Obryant Middle School</td><td> 16.4</td></tr><tr><td> Marathon High School</td><td> 18.2</td></tr><tr><td> Key West High School</td><td> 18.5</td></tr></tbody></table> Student to Teacher Ratio
Figure 26: 33040, FL School Racial Mix (2013)<here is a image 377931e4a21edf85-24ad93d40e2d87d9> White Black Hispanic Asian Pacific Islander American Indian Two or More Races Gerald Adams Elementary School Glynn Archer Elementary School Stanley Switlik Elementary School Horace Obryant Middle School Poinciana Elementary School Marathon High School Keys Center Key West High School Sigsbee Charter School Key West Collegiate School Sugarloaf School Plantation Key School Key West Montessori Charter Sch… Treasure Village Montessori Char… Big Pine Academy 0% 50% 100%<table><tr><th> School Name</th><th> White</th><th> Black</th><th> Hispanic</th><th> Asian</th><th> Pacific Islander</th><th> American Indian</th><th> Two or More Races</th></tr><tbody><tr><td> Gerald Adams Elementary School</td><td> 23.4%</td><td> 25.4%</td><td> 48.1%</td><td> 0.2%</td><td> 0%</td><td> 0.2%</td><td> 2.8%</td></tr><tr><td> Glynn Archer Elementary School</td><td> 25.6%</td><td> 21.3%</td><td> 44.9%</td><td> 2%</td><td> 0.5%</td><td> 0%</td><td> 5.6%</td></tr><tr><td> Stanley Switlik Elementary School</td><td> 33.5%</td><td> 7.6%</td><td> 55.6%</td><td> 1.1%</td><td> 0.2%</td><td> 0%</td><td> 1.9%</td></tr><tr><td> Horace Obryant Middle School</td><td> 38.7%</td><td> 19.9%</td><td> 36.8%</td><td> 2%</td><td> 0.3%</td><td> 0%</td><td> 2.2%</td></tr><tr><td> Poinciana Elementary School</td><td> 38.7%</td><td> 14.1%</td><td> 41%</td><td> 2.1%</td><td> 0.2%</td><td> 0.3%</td><td> 3.6%</td></tr><tr><td> Marathon High School</td><td> 45.9%</td><td> 8.3%</td><td> 43.4%</td><td> 1.1%</td><td> 0%</td><td> 0%</td><td> 1.3%</td></tr><tr><td> Keys Center</td><td> 46.7%</td><td> 0%</td><td> 53.3%</td><td> 0%</td><td> 0%</td><td> 0%</td><td> 0%</td></tr><tr><td> Key West High School</td><td> 53.8%</td><td> 14.4%</td><td> 26.2%</td><td> 2.1%</td><td> 0.2%</td><td> 0.4%</td><td> 3%</td></tr><tr><td> Sigsbee Charter School</td><td> 64.1%</td><td> 6.9%</td><td> 21.5%</td><td> 1.3%</td><td> 0.2%</td><td> 0%</td><td> 6%</td></tr><tr><td> Key West Collegiate School</td><td> 65.2%</td><td> 6.5%</td><td> 23.9%</td><td> 0%</td><td> 0%</td><td> 0%</td><td> 4.3%</td></tr><tr><td> Sugarloaf School</td><td> 68.5%</td><td> 3%</td><td> 22.6%</td><td> 1.4%</td><td> 0.7%</td><td> 0.5%</td><td> 3.3%</td></tr><tr><td> Plantation Key School</td><td> 73.6%</td><td> 0.6%</td><td> 21.9%</td><td> 0.9%</td><td> 0%</td><td> 0.6%</td><td> 2.3%</td></tr><tr><td> Key West Montessori Charter School, Inc</td><td> 74.8%</td><td> 4.3%</td><td> 8.7%</td><td> 2.6%</td><td> 0%</td><td> 0%</td><td> 9.6%</td></tr><tr><td> Treasure Village Montessori Charter School</td><td> 76.9%</td><td> 2.3%</td><td> 17.6%</td><td> 2.3%</td><td> 0.5%</td><td> 0.5%</td><td> 0%</td></tr><tr><td> Big Pine Academy</td><td> 82.4%</td><td> 0%</td><td> 13.8%</td><td> 2.1%</td><td> 0%</td><td> 0%</td><td> 1.6%</td></tr></tbody></table> Two or More Races
Cities marked with an asterisk ("*") should resemble a city or town but do not have their own government (i.e. Mayor, City Council, etc.) These places should be recognizable by the local community but their boundaries have no legal status. Technically these include both Census Designated Places (CDP) and Census County Divisions (CCD) which are defined by the Census Bureau along with local authorities. (For more information, see:Census Designated Place or "CDP")and Census County Division "CCD".)
For comparison purposes, the US national average and the state average value are provided. Additionally, the "Combined Statistical Area" or CSA is shown that is closest to the city, county, or zip code shown. A CSA is a large grouping of adjacent metropolitan areas that identified by the Census Bureau based on social and economic ties. (See:Combined Statistical Area) Data sources - Mouse over<here is a image 81d2476066588f4e-267363bb7eb3110b>icon in upper right corner of each chart for information.
| https://www.towncharts.com/Florida/Education/33040-Zipcode-FL-Education-data.html |
Insulin Resistance Syndrome Predicts Coronary Heart Disease Events in Elderly Type 2 Diabetic Men | Diabetes Care | American Diabetes Association
OBJECTIVE—To investigate whether cardiovascular risk factors cluster with hyperinsulinemia in elderly type 2 diabetic subjects and, if so, whether this clusteri
Insulin Resistance Syndrome Predicts Coronary Heart Disease Events in Elderly Type 2 Diabetic Men
Johanna Kuusisto, MD
Johanna Kuusisto, MD
1 Department of Medicine, University of Kuopio, Kuopio, Finland, and the
Päivi Lempiäinen, MD
Leena Mykkänen, MD
Leena Mykkänen, MD
1 Department of Medicine, University of Kuopio, Kuopio, Finland, and the
Markku Laakso, MD
Markku Laakso, MD
1 Department of Medicine, University of Kuopio, Kuopio, Finland, and the
Diabetes Care 2001;24(9):1629–1633
https://doi.org/10.2337/diacare.24.9.1629
OBJECTIVE—To investigate whether cardiovascular risk factors cluster with hyperinsulinemia in elderly type 2 diabetic subjects and, if so, whether this clustering predicts coronary heart disease (CHD) events during a 7-year follow-up.
RESEARCH DESIGN AND METHODS—Clustering of cardiovascular risk factors was analyzed by factor analysis. Cox regression models were used to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) during a 7-year follow-up in 229 type 2 diabetic subjects aged 65–74 years.
RESULTS—There were 70 CHD events (21 in men and 49 in women) during the follow-up period. In diabetic men, components of the insulin resistance syndrome (IRS) loaded on Factor 1 (the insulin resistance factor), which reflected high fasting insulin, obesity (high BMI), central obesity (high waist-to-hip ratio), high total triglycerides, and a short duration of diabetes. Only this IRS factor predicted CHD events in multivariate Cox regression analysis (hazard ratio [HR] 1.71, 95% CI 1.08–2.71, P= 0.022). In diabetic women, components of IRS loaded on two factors, none of which predicted CHD events. In women, only Factor 4, characterized by advanced age, left ventricular hypertrophy on electrocardiogram, high alcohol consumption, high systolic blood pressure, and albuminuria, predicted CHD events in multivariate Cox regression analysis (1.34, 1.03–1.74, P= 0.03).
CONCLUSIONS—IRS is a risk factor for CHD in elderly type 2 diabetic men.
Coronary heart disease (CHD) is two- to fourfold more common in subjects with type 2 diabetes than in nondiabetic subjects (1). Conventional risk factors, such as smoking, hypertension, and hypercholesterolemia also predict CHD events in diabetic subjects (2,3). However, at any given level of a risk factor, diabetic subjects have a higher risk of CHD than nondiabetic subjects (2). This indicates that conventional CHD risk factors cannot explain the excess risk of CHD in type 2 diabetes.
The insulin resistance syndrome (IRS), which is characterized by hyperinsulinemia, glucose intolerance, hypertriglyceridemia, low HDL cholesterol level, elevated blood pressure, and central obesity, accompanies the majority of cases of type 2 diabetes and has been suggested to be one of the links between diabetes and an excess risk of CHD. Until recently, IRS has been difficult to investigate because of the lack of generally accepted criteria for the syndrome. Furthermore, intercorrelated risk factors typical of IRS are not readily studied by conventional statistical methods. Recently, factor analysis and principal components analysis, statistical methods for studies of intercorrelating variables, have been applied to investigate the clustering of cardiovascular risk factors in both nondiabetic and diabetic subjects (4,5,6,7). Clusterings of cardiovascular risk factors typical of IRS have been identified in all of these study populations. Furthermore, we have previously shown in our studies, which were based on different study cohorts, that this clustering, the IRS factor, predicts CHD events in elderly nondiabetic men (6) and in middle-aged patients with type 2 diabetes (7). Most diabetic subjects are elderly and at a particularly high risk of cardiovascular mortality and morbidity. However, the value of IRS as a predictor of CHD in elderly diabetic subjects has not been previously studied. Therefore, we applied factor analysis and principal component analysis to investigate the clustering of cardiovascular risk factors in a population of elderly men and women with type 2 diabetes and studied if this risk factor clustering predicts CHD during a 7-year follow-up.
RESEARCH DESIGN AND METHODS
Baseline study
The baseline study was carried out in Kuopio, which is located in eastern Finland, from 1986 to 1988. The formation and representativeness of the study population have been previously described in detail (8,9). The study population consisted of 229 elderly subjects who had a previous history of type 2 diabetes or newly diagnosed type 2 diabetes at the baseline study. All subjects with normal or impaired glucose tolerance were excluded from statistical analyses.
Weight, height, waist and hip circumference, and blood pressure were measured as previously reported (8). A subject was defined as having hypertension if systolic blood pressure was ≥160 mmHg, diastolic blood pressure was ≥95 mmHg, or the subject was taking drug treatment for hypertension. With respect to alcohol consumption, subjects were classified as alcohol users or nonusers. Smoking status was defined as current smoker.
Chest pain symptoms suggestive of CHD were recorded with the Rose Cardiovascular Questionnaire (10). Electrocardiograms (ECGs) were classified according to the Minnesota Code (11). Verified definite and possible myocardial infarction (MI) were defined according to the World Health Organization (WHO) MONICA project criteria (12), as modified by the FINMONICA Acute Myocardial Infarction (AMI) Register Study Group (13). WHO criteria for definite and possible stroke were used in the ascertainment of a previous stroke (14).
In the classification of subjects without previously known diabetes, the diagnostic criteria of the WHO (1985) were used (15). The criteria for diabetes were fasting venous plasma glucose ≥7.8 mmol/l or 2-h venous plasma glucose ≥11.1 mmol/l in a 75-g oral glucose tolerance test. Previously known diabetes was considered to be present if the diagnosis of diabetes had been made by a physician (15). Insulin-treated subjects whose C-peptide level 6 min after intravenous glucagon (1 mg) stimulation was <0.20 nmol/l were regarded as having type 1 diabetes and excluded from the present study (one male subject). The duration of diabetes was counted from the year of diagnosis; if the diagnosis was made at the baseline study, the duration of diabetes was 0 years.
Blood samples were taken in the morning, after a 12-h overnight fast. All subjects underwent an oral glucose tolerance test (75 g glucose). Plasma glucose and insulin, C-peptide, serum lipids and lipoproteins, urinary albumin (8), and HbA 1c(16) were determined as previously described. The urinary albumin-to-creatinine ratio (ACR) (milligrams per liter–to–millimoles per liter) was used as a measure of albumin excretion.
This study was approved by the Ethics Committee of Kuopio University Hospital. All study subjects gave informed consent.
Follow-up study
The 7-year follow-up study was carried out in 1995. A postal questionnaire was sent to every surviving participant of the original study cohort. The questionnaire contained questions about hospital admissions due to chest pain or symptoms suggestive of MI. Of the 229 original diabetic participants of the baseline study, 140 were alive on 30 June 1995; of these subjects, 130 responded to the postal questionnaire (response rate 93%).
Medical records of those who died during the 7-year follow-up (between the baseline study and 30 June 1995) and of those who reported hospitalization due to symptoms suggestive of MI during the 7-year follow-up were reviewed by two of the authors (J.K. and P.L.). In addition, the medical records of all of the nonrespondents to the postal questionnaire were reviewed (J.K. and P.L.) to verify definite or possible MIs and CHD deaths. Copies of death certificates of those who had died during the 7-year follow-up were obtained from the medical records or from the files of the Central Statistical Office in Finland and were reviewed (J.K. and P.L). Thus, all subjects from the original cohort were evaluated for CHD events. All deaths were coded according to the ICD-9 (17).
CHD death during the follow-up was defined as a death resulting from CHD (ICD-9 codes 410–414). A new nonfatal MI during the 7-year follow-up was defined as follows: 1) a definite or possible MI verified at hospital by the WHO criteria (WHO MONICA project criteria [12], as modified by the FINMONICA AMI Register Study Group [13], based on chest pain symptoms, ECG changes, and enzyme determinations) or 2) a new major Q-QS change on the ECG (progression from no Minnesota Q-QS code to 1.1 or 1.2 or from 1.3 to 1.1) for those who participated in the 3.5-year follow-up. CHD events included CHD death and definite or possible nonfatal MI. If a subject had more than one CHD event during the follow-up, only the first CHD event was included in statistical analyses.
Statistical methods
Data analyses were conducted with the SPSS/PC+ programs. Fasting and 2-h insulin and triglycerides were log-transformed for statistical analyses. The results for continuous variables are given as means ± SE or percentages. Two-way Student’s ttest for independent samples or the χ 2test were used in the assessment of differences between the two groups when appropriate. Univariate and multivariate Cox regression models (18) were used to investigate the association of cardiovascular risk factors with the incidence of CHD events. Factor analysis consisted of extraction of initial components by use of principal-component analysis, rotation of components, which resulted in elucidation of factors, and interpretation of factors with loadings >0.40 ( P< 0.05) and was used to assess the relationship of several intercorrelated variables as previously described in detail (6,7). Principal component analysis identifies a minimum number of components that are transformed (rotated) into interpretable factors. Principal components were rotated using the ortogonal varimax method. Interpretation is based on correlations, known as loadings, between the factors and the original independent variables. Factors represent physiological processes underlying the overall relationship among the original independent variables. The final number of factors was limited to four. Univariate and multivariate Cox regression models were used to investigate the association of these factors, which were identified by factor analysis, with the incidence of CHD events.
RESULTS
Of 229 type 2 diabetic subjects (74 men and 155 women) who had participated in the baseline study, 89 subjects (30 [41%] men and 59 [38%] women) died during the 7-year follow-up. The number of CHD deaths was 43 (19%) in the whole study population (10 [14%] men and 33 [21%] women). CHD events (CHD death or nonfatal MI) occurred in 70 (31%) subjects (21 [28%] men and 49 [32%] women).
The characteristics of the study population at baseline are presented inTable 1. Women were slightly older than men, and fewer women had a previous MI. There was no difference in the duration of diabetes between men and women (5.7 and 5.0 years, respectively). Women were more often hypertensive than men (78.7 and 59.5%, respectively), although the proportion of hypertensive men was also high. There were no statistically significant differences in lipid and lipoprotein levels or in fasting insulin between the sexes, but 2-h insulin was higher in women. Smoking and alcohol consumption were more frequent among men than women. Also, waist-to-hip ratio (WHR) was significantly greater in men than in women.
The association of baseline risk factors with the incidence of CHD events during the 7-year follow-up was assessed by univariate and multivariate Cox regression analyses.Table 2shows the results of univariate Cox regression analyses by sex. In diabetic men, previous MI, BMI, WHR, and low HDL cholesterol levels were associated with the risk of CHD events. In diabetic women, only systolic blood pressure was a statistically significant predictor of CHD events. Both low HDL cholesterol level and high urinary ACR predicted CHD events, with a borderline significance ( P= 0.055 and 0.054) in diabetic women.
Multivariate Cox regression analyses were performed to investigate risk factors that were independently associated with the incidence of CHD events. In men, only previous MI predicted CHD events (hazard ratio [HR] 3.16 [1.09–9.15], P= 0.034). In women, only systolic blood pressure was associated with CHD events (HR 1.01 [1.00–1.02], P= 0.039).
To investigate intercorrelating factors, factor analyses were performed separately for men and women. Varimax rotated factors and their loadings of original variables on these factors by sex are shown inTable 3. In men, components of IRS, such as high fasting insulin level, high BMI, high WHR, high triglycerides, low HDL cholesterol, and a short duration of diabetes had significant (>0.40) loadings on Factor 1. High fasting glucose level and HbA 1cloaded on Factor 2. Age, left ventricular hypertrophy (LVH), and systolic blood pressure loaded on Factor 3. Current smoking, alcohol consumption, elevated total cholesterol, and HDL cholesterol levels loaded on Factor 4. Altogether, these four factors accounted for 47.1% of the total variance.
In women, elevated fasting glucose level, low fasting insulin level, and high HbA 1chad significant loadings on Factor 1 (Table 3). Elevated fasting insulin level, low HDL cholesterol, and high triglycerides loaded on Factor 2. Current smoking, high WHR and BMI, high fasting insulin level, and low total cholesterol level had significant loadings on Factor 3. Advanced age, LVH on ECG, alcohol consumption, high systolic blood pressure, and high urinary ACR loaded on Factor 4. These four factors accounted for 42.6% of the total variance.
Factors assessed by factor analysis were included in Cox regression model to investigate if they predicted CHD events during the 7-year follow-up. In men, only Factor 1 (the IRS factor) was significantly associated with the risk of CHD events in both univariate and multivariate Cox regression models (Table 4). In women, only Factor 4 (the hypertension factor) was significantly associated with the risk of CHD events in univariate and multivariate models; Factors 2 and 3, on which fasting insulin had a significant loading, did not predict CHD events. Finally, we performed factor analysis in the whole study population, including both sexes (data not shown). In this analysis, Factor 1 was characterized by a clustering of high fasting insulin level, high BMI, high levels of triglycerides, and low HDL cholesterol levels, but this IRS factor did not quite reach the conventional level of statistical significance to be a predictor of CHD events (HR in multivariate Cox regression model 1.23 [0.98–1.62], P= 0.066).
CONCLUSIONS
The present study shows that features of IRS, such as hyperinsulinemia, obesity (particularly central obesity), hypertriglyceridemia, and low HDL cholesterol, clustered in elderly type 2 diabetic men, and this IRS factor predicted CHD events during the 7-year follow-up. In elderly type 2 diabetic women, however, fasting insulin and other components of IRS loaded on two separate factors, none of which predicted CHD events.
Type 2 diabetic subjects have two- to fourfold excess risk for CHD compared with nondiabetic subjects. This excess risk has been shown to be independent of conventional risk factors (1,2). IRS, which is very common in subjects with type 2 diabetes, has been suggested to be one of the factors increasing the cardiovascular risk in diabetic patients. Until recently, however, the role of IRS as a risk factor for CHD in type 2 diabetes has remained controversial. This is because hyperinsulinemia, which has been used as a sole indicator of IRS, correlates weakly with insulin sensitivity in diabetic subjects (19) and because interrelated risk factors typical of IRS are not readily studied by conventional statistical methods. Recently, factor analysis and principal component analysis have been used to show that cardiovascular risk factors, including metabolic, inflammatory, and hemostatic risk factors (21), which are typical of the IRS, cluster in various combinations in Finnish type 2 diabetic middle-aged subjects (7), diabetic Japanese-American men (20), and diabetic tribal members of Arizona, Oklahoma, and North and South Dakota (22). The clustering of the components of IRS in the present study is in accordance with our previous study, which was based on a completely different diabetic cohort (7). Also, in the present study, we could identify a factor characterized by hyperinsulinemia, high BMI, high triglycerides, and low HDL cholesterol. Furthermore, high WHR and a short duration of diabetes had high loadings on this factor. This IRS factor predicted CHD events in both of these Finnish diabetic populations, providing evidence that IRS increases CHD risk in middle-aged (7) and elderly type 2 diabetic subjects, particularly in men.
In the present study, IRS predicted CHD events in elderly diabetic men but not in elderly diabetic women. In women, components of IRS were dispersed among two factors, none of which was predictive of CHD, although the number of CHD events was not smaller in women than in men. Our results support the findings of previous studies that suggest that IRS is probably not as important a risk factor in women as it is in men (6). To our knowledge, there are no studies showing that IRS predicts cardiovascular events in nondiabetic or diabetic women. In the present study, Factor 4, characterized by hypertension, LVH, and albuminuria was the only factor that predicted CHD events in women, which is in accordance with the results of our previous study of nondiabetic elderly women (6).
The present study indicates that IRS also predicts CHD events in elderly type 2 diabetic subjects. The mechanisms by which IRS enhances atherothrombosis are largely unknown, but adverse changes, indirectly through cardiovascular risk or directly through hyperinsulinemia, may accelerate atherothrombosis (23). Insulin resistance may also cause cardiovascular disease by some currently unidentified mechanisms. Although the present study cannot reveal mechanisms via which IRS causes CHD, it suggests that neither hypertension nor hyperglycemia is responsible for the link, since neither of these two loaded on the IRS factor in the present study. Although a short duration of diabetes is not a component of IRS, it loaded on the IRS factor, which suggests that insulin resistance is present and affects CHD risk soon after the onset of diabetes. This is not a surprise because previous studies have suggested that insulin resistance already increases cardiovascular risk in prediabetic subjects (24). On the other hand, our study does not exclude the possibility that insulin resistance is also important in subjects with a long history of diabetes. Plasma insulin concentrations are determined by both insulin resistance and insulin secretion. In type 2 diabetic subjects, defects in both of these components coexist and insulin levels may be low, particularly in those with a long history of diabetes, although subjects are insulin resistant.
The present study included only a limited number of diabetic subjects; thus, more studies are needed to confirm our results. However, our finding that the IRS factor but not conventional cardiovascular risk factors predicted CHD events implies that insulin resistance may be a very important risk factor for CHD also in elderly diabetic subjects. If IRS is an important risk factor for CHD in elderly diabetic subjects, as suggested by the present study, it is possible that decreasing insulin resistance by nonpharmacological (weight reduction and physical activity) or pharmacological therapy might decrease cardiovascular mortality and morbidity in these subjects.
In conclusion, our population-based prospective study on elderly diabetic subjects demonstrates that cardiovascular risk factors typical of the IRS cluster and that this clustering predicts CHD events in type 2 diabetic men. Therefore, in addition to classic risk factors, IRS should be considered as a significant contributor to cardiovascular disease in elderly subjects with type 2 diabetes.
Table 1—
Baseline characteristics of the study subjects by sex
. Men . Women .
n 74 155
Age (years) 68.7 ± 0.3 69.7 ± 0.2 *
Duration of clinical diabetes (years) 5.7 ± 0.7 5.0 ± 0.4
Previous MI (%) 24.3 8.4 ‡
LVH on ECG (%) 16.2 26.5
Hypertension (%) 59.5 78.7 †
Current smoker (%) 9.5 1.3 †
Consumer of alcohol (%) 45.9 5.8 ‡
Apolipoprotein c4 allele (%) 35.1 40.1
BMI (kg/m 2 ) 27.7 ± 0.5 29.8 ± 0.4
WHR 1.00 ± 0.01 0.92 ± 0.01 ‡
Systolic BP (mmHg) 156 ± 3 167 ± 2 †
Diastolic BP (mmHg) 84 ± 1 82 ± 1
Total cholesterol (mmol/l) 6.30 ± 0.16 6.53 ± 0.13
HDL cholesterol (mmol/l) 1.07 ± 0.04 1.15 ± 0.03
Triglycerides (mmol/l) 2.31 ± 0.21 2.75 ± 0.29
Fasting plasma glucose (mmol/l) 10.3 ± 0.5 10.0 ± 0.3
2-h plasma glucose (mmol/l) 17.6 ± 0.8 17.8 ± 0.5
HbA1 (%) 7.2 ± 0.2 7.3 ± 0.2
Fasting plasma insulin (mU/l) 20.7 ± 1.4 24.8 ± 1.3
2-h plasma insulin (mU/l) 82.3 ± 9.3 114.0 ± 10.2 *
Urinary ACR (mg/mmol) 8.27 ± 2.29 9.52 ± 1.63
. Men . Women . n 74 155 Age (years) 68.7 ± 0.3 69.7 ± 0.2 * Duration of clinical diabetes (years) 5.7 ± 0.7 5.0 ± 0.4 Previous MI (%) 24.3 8.4 ‡ LVH on ECG (%) 16.2 26.5 Hypertension (%) 59.5 78.7 † Current smoker (%) 9.5 1.3 † Consumer of alcohol (%) 45.9 5.8 ‡ Apolipoprotein c4 allele (%) 35.1 40.1 BMI (kg/m 2 ) 27.7 ± 0.5 29.8 ± 0.4 WHR 1.00 ± 0.01 0.92 ± 0.01 ‡ Systolic BP (mmHg) 156 ± 3 167 ± 2 † Diastolic BP (mmHg) 84 ± 1 82 ± 1 Total cholesterol (mmol/l) 6.30 ± 0.16 6.53 ± 0.13 HDL cholesterol (mmol/l) 1.07 ± 0.04 1.15 ± 0.03 Triglycerides (mmol/l) 2.31 ± 0.21 2.75 ± 0.29 Fasting plasma glucose (mmol/l) 10.3 ± 0.5 10.0 ± 0.3 2-h plasma glucose (mmol/l) 17.6 ± 0.8 17.8 ± 0.5 HbA1 (%) 7.2 ± 0.2 7.3 ± 0.2 Fasting plasma insulin (mU/l) 20.7 ± 1.4 24.8 ± 1.3 2-h plasma insulin (mU/l) 82.3 ± 9.3 114.0 ± 10.2 * Urinary ACR (mg/mmol) 8.27 ± 2.29 9.52 ± 1.63
Data are means ± SE unless otherwise indicated. BP, blood pressure.
*
P< 0.05;
†
P< 0.01;
‡
P< 0.001 (Student’s ttest or χ 2test).
Table 2—
Risk factors of CHD events in elderly diabetic men and women during 7 years of follow-up, univariate Cox regression analysis
. Men . Women . HR . 95% CI . P . HR . 95% CI . P .
Age 1.10 0.93–1.30 0.255 1.02 0.92–1.13 0.697
Previous MI 2.47 1.04–5.86 0.041 1.76 0.75–4.15 0.195
LVH on ECG 1.27 0.42–3.80 0.669 1.20 0.64–2.23 0.570
Current smoker 0.61 0.08–4.56 0.627 0.05 0.02–1.98 0.608
Alcohol consumption 0.75 0.50–1.13 0.164 0.88 0.27–2.83 0.827
BMI 1.16 1.06–1.27 0.001 1.04 0.98–1.09 0.211
WHR (≥1.00)* 2.86 1.15–7.11 0.024 1.20 0.54–2.68 0.657
Hypertension 1.23 0.51–2.96 0.650 1.63 0.76–3.48 0.210
Systolic blood pressure 1.00 0.98–1.02 0.881 1.01 1.00–1.03 0.010
Apolipoprotein e4 allele (no/yes) 0.49 0.18–1.35 0.170 0.79 0.44–1.43 0.441
Total cholesterol (≥6.2 mmol/l) † 0.95 0.40–2.23 0.903 1.04 0.59–1.82 0.894
HDL cholesterol (<1.00 mmol/1) † 2.59 1.07–6.28 0.036 1.74 0.99–3.05 0.055
Triglycerides (2.3 mmol/l) † 1.01 0.41–2.51 0.983 1.14 0.65–2.00 0.647
Fasting glucose 0.99 0.89–1.11 0.910 1.05 0.97–1.13 0.215
2-h glucose 0.98 0.91–1.05 0.526 1.02 0.97–1.06 0.438
Fasting insulin (log) 0.26 0.05–1.48 0.130 0.88 0.27–2.80 0.823
2-h insulin (log) 0.54 0.19–1.49 0.235 0.81 0.39–1.69 0.581
Duration of diabetes 0.92 0.84–1.01 0.075 0.96 0.91–1.02 0.216
HbA 1c 1.05 0.85–1.30 0.668 1.12 0.99–1.26 0.071
ACR (≥8.55 mg/mmol) ‡ 1.71 0.66–4.42 0.268 1.79 0.99–3.22 0.054
. Men . Women . HR . 95% CI . P . HR . 95% CI . P . Age 1.10 0.93–1.30 0.255 1.02 0.92–1.13 0.697 Previous MI 2.47 1.04–5.86 0.041 1.76 0.75–4.15 0.195 LVH on ECG 1.27 0.42–3.80 0.669 1.20 0.64–2.23 0.570 Current smoker 0.61 0.08–4.56 0.627 0.05 0.02–1.98 0.608 Alcohol consumption 0.75 0.50–1.13 0.164 0.88 0.27–2.83 0.827 BMI 1.16 1.06–1.27 0.001 1.04 0.98–1.09 0.211 WHR (≥1.00)* 2.86 1.15–7.11 0.024 1.20 0.54–2.68 0.657 Hypertension 1.23 0.51–2.96 0.650 1.63 0.76–3.48 0.210 Systolic blood pressure 1.00 0.98–1.02 0.881 1.01 1.00–1.03 0.010 Apolipoprotein e4 allele (no/yes) 0.49 0.18–1.35 0.170 0.79 0.44–1.43 0.441 Total cholesterol (≥6.2 mmol/l) † 0.95 0.40–2.23 0.903 1.04 0.59–1.82 0.894 HDL cholesterol (<1.00 mmol/1) † 2.59 1.07–6.28 0.036 1.74 0.99–3.05 0.055 Triglycerides (2.3 mmol/l) † 1.01 0.41–2.51 0.983 1.14 0.65–2.00 0.647 Fasting glucose 0.99 0.89–1.11 0.910 1.05 0.97–1.13 0.215 2-h glucose 0.98 0.91–1.05 0.526 1.02 0.97–1.06 0.438 Fasting insulin (log) 0.26 0.05–1.48 0.130 0.88 0.27–2.80 0.823 2-h insulin (log) 0.54 0.19–1.49 0.235 0.81 0.39–1.69 0.581 Duration of diabetes 0.92 0.84–1.01 0.075 0.96 0.91–1.02 0.216 HbA 1c 1.05 0.85–1.30 0.668 1.12 0.99–1.26 0.071 ACR (≥8.55 mg/mmol) ‡ 1.71 0.66–4.42 0.268 1.79 0.99–3.22 0.054
Of 74 men, 21 experienced a CHD event, and of 155 women, 49 experienced a CHD event by the time of the 7-year follow-up. Cutoff point is the highest WHR quartile (≥1.00);
†
cutoff points based on high risk category classification of the National Cholesterol Education Program and the guidelines of the European Atherosclerosis Society;
‡
cutoff point is the highest ACR quartile (≥8.55 mg/mmol).
Table 3—
Factors and loadings of different variables (factor analysis) in elderly diabetic men and women
. Men . Women . Factor 1 . Factor 2 . Factor 3 . Factor 4 . Factor 1 . Factor 2 . Factor 3 . Factor 4 .
Age 0.234 −0.002 0.587 0.063 −0.392 −0.044 −0.053 0.456
Previous MI 0.156 −0.000 −0.396 −0.105 −0.229 0.129 0.099 0.081
LVH on ECG −0.106 0.024 0.458 −0.065 −0.059 0.000 0.162 0.613
Current smoker −0.117 −0.172 −0.064 0.553 0.149 −0.086 0.434 −0.255
Alcohol consumption −0.058 −0.116 −0.026 0.747 −0.150 −0.326 0.028 0.459
WHR 0.650 0.217 −0.117 0.276 0.204 −0.021 0.459 0.016
BMI 0.796 0.020 −0.263 0.059 −0.110 0.249 0.676 −0.098
Systolic blood pressure 0.008 −0.097 0.699 −0.134 0.065 0.153 −0.204 0.519
Total cholesterol 0.074 0.202 0.367 0.450 0.078 0.260 −0.616 0.028
HDL cholesterol −0.641 0.098 −0.054 0.478 −0.025 −0.777 −0.275 −0.051
Triglycerides (log) 0.721 0.253 0.312 −0.015 0.108 0.864 −0.133 −0.080
Fasting glucose −0.034 0.906 −0.013 −0.040 0.867 0.053 0.147 0.177
Fasting insulin (log) 0.606 −0.379 −0.221 0.060 −0.428 0.478 0.487 −0.136
HbA 1c −0.029 0.920 −0.065 −0.025 0.836 0.069 0.190 0.048
Duration of diabetes −0.425 0.238 −0.124 0.166 0.369 0.119 −0.320 −0.196
ACR 0.079 0.371 0.378 −0.197 0.251 −0.033 −0.205 0.574
Apo e4 −0.106 −0.021 0.003 −0.368 −0.072 0.340 −0.160 0.049
. Men . Women . Factor 1 . Factor 2 . Factor 3 . Factor 4 . Factor 1 . Factor 2 . Factor 3 . Factor 4 . Age 0.234 −0.002 0.587 0.063 −0.392 −0.044 −0.053 0.456 Previous MI 0.156 −0.000 −0.396 −0.105 −0.229 0.129 0.099 0.081 LVH on ECG −0.106 0.024 0.458 −0.065 −0.059 0.000 0.162 0.613 Current smoker −0.117 −0.172 −0.064 0.553 0.149 −0.086 0.434 −0.255 Alcohol consumption −0.058 −0.116 −0.026 0.747 −0.150 −0.326 0.028 0.459 WHR 0.650 0.217 −0.117 0.276 0.204 −0.021 0.459 0.016 BMI 0.796 0.020 −0.263 0.059 −0.110 0.249 0.676 −0.098 Systolic blood pressure 0.008 −0.097 0.699 −0.134 0.065 0.153 −0.204 0.519 Total cholesterol 0.074 0.202 0.367 0.450 0.078 0.260 −0.616 0.028 HDL cholesterol −0.641 0.098 −0.054 0.478 −0.025 −0.777 −0.275 −0.051 Triglycerides (log) 0.721 0.253 0.312 −0.015 0.108 0.864 −0.133 −0.080 Fasting glucose −0.034 0.906 −0.013 −0.040 0.867 0.053 0.147 0.177 Fasting insulin (log) 0.606 −0.379 −0.221 0.060 −0.428 0.478 0.487 −0.136 HbA 1c −0.029 0.920 −0.065 −0.025 0.836 0.069 0.190 0.048 Duration of diabetes −0.425 0.238 −0.124 0.166 0.369 0.119 −0.320 −0.196 ACR 0.079 0.371 0.378 −0.197 0.251 −0.033 −0.205 0.574 Apo e4 −0.106 −0.021 0.003 −0.368 −0.072 0.340 −0.160 0.049
Apo e4, e4 allele of apolipoprotein E.
Table 4—
Association of four factors derived from factor analysis with CHD events in elderly diabetic men and women, per Cox regression analysis
. Men . Women . HR . 95% CI . P . HR . 95% CI . P .
Univariate
Factor 1 1.62 1.03–2.55 0.037 1.09 0.83–1.44 0.539
Factor 2 1.19 0.78–1.81 0.427 1.23 0.91–1.66 0.178
Factor 3 1.01 0.64–1.58 0.982 1.05 0.78–1.41 0.735
Factor 4 1.21 0.77–1.91 0.402 1.31 1.01–1.70 0.038
Multivariate
Factor 1 1.71 1.08–2.71 0.022 1.11 0.84–1.46 0.481
Factor 2 1.27 0.80–2.02 0.306 1.26 0.94–1.71 0.127
Factor 3 1.12 0.70–1.79 0.640 1.07 0.79–1.44 0.677
Factor 4 1.36 0.82–2.25 0.229 1.34 1.03–1.74 0.030
. Men . Women . HR . 95% CI . P . HR . 95% CI . P . Univariate Factor 1 1.62 1.03–2.55 0.037 1.09 0.83–1.44 0.539 Factor 2 1.19 0.78–1.81 0.427 1.23 0.91–1.66 0.178 Factor 3 1.01 0.64–1.58 0.982 1.05 0.78–1.41 0.735 Factor 4 1.21 0.77–1.91 0.402 1.31 1.01–1.70 0.038 Multivariate Factor 1 1.71 1.08–2.71 0.022 1.11 0.84–1.46 0.481 Factor 2 1.27 0.80–2.02 0.306 1.26 0.94–1.71 0.127 Factor 3 1.12 0.70–1.79 0.640 1.07 0.79–1.44 0.677 Factor 4 1.36 0.82–2.25 0.229 1.34 1.03–1.74 0.030
Article Information
This study was supported by grants from the Academy of Finland, the Finnish Heart Foundation, the Aarne and Aili Turunen Foundation, and the Finnish Cultural Foundation of Northern Savo.
References
1.
Pyörälä K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: an epidemiologic view
. Diabete Metab Rev
3
:
463
–524,
1987
2.
Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
Diabetes Care
16
:
434
–444,
1993
3.
Laakso M, Lehto S: Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance.
Atherosclerosis
137 (Suppl.):S65–S73, 1998
4.
Edwards KL, Austin MA, Newman B, Mayer E, Krauss R, Selby J: Multivariate analysis of the insulin resistance syndrome in women.
Arterioscler Thromb
14
:
1940
–1945,
1994
5.
Meigs JB, D’Agostino RB Sr, Wilson PW, Cupples LA, Nathan DM, Singer DE: Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study.
Diabetes
46
:
1594
–1600,
1997
6.
Lempiäinen P, Mykkänen L, Pyörälä K, Laakso M, Kuusisto J: Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men.
Circulation
100
:
123
–128,
1999
7.
Lehto S, Rönnemaa T, Pyörälä K, Laakso M: Cardiovascular risk factors clustering with insulin predict coronary heart disease death in patients with type 2 diabetes.
Diabetologia
43
:
148
–155,
2000
8.
Mykkänen L, Laakso M, Uusitupa M, Pyörälä K: Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes.
Diabetes Care
13
:
1099
–1105,
1990
9.
Mykkänen L, Laakso M, Penttilä I, Pyörälä K: Asymptomatic hyperglycemia and cardiovascular risk factors in the elderly.
Atherosclerosis
88
:
153
–161,
1991
10.
Rose GA, Blackburn H, Gillman RF, Prineas RJ: Cardiovascular Survey Methods . Geneva, World Health Organization, 1982
11.
Prineas RJ, Crow RS, Blackburn H:
The Minnesota Code Manual of Electrocardiographic Findings: Standards and Procedures for Measurement and Classification
. Boston, MA, John Wright, 1982
12.
World Health Organization: MONICA Manual: CVD/MNC . Geneva, World Health Org., 1990
13.
Tuomilehto J, Arstila M, Kaarsalo E, Kankaanpää J, Ketonen M, Kuulasmaa K, Lehto S, Miettinen H, Mustaniemi H, Palomäki P, Puska P, Pyörälä K, Salomaa V, Torppa J, Vuorenmaa T: Acute myocardial infarction (AMI) in Finland: baseline data from the FINMONICA AMI register in 1983–
1985
.
Eur Heart J
13
:
577
–587,
1992
14.
Weinfeld FD: The National Survey of Stroke.
Stroke
12 (Suppl. I):I32–I37, 1981
15.
World Health Organization: WHO Study Group on Diabetes Mellitus . Geneva, World Health Org., 1985 (Tech. Rep. Ser., no. 727)
16.
Kuusisto J, Mykkänen L, Pyörälä K, Laakso M: NIDDM and its metabolic control predict coronary heart disease in elderly subjects.
Diabetes
43
:
960
–967,
1994
17.
International Classification of Diseases: Clinical Modification. Ninth Revision . Ann Arbor, MI, Edwards Bros, 1981
18.
Cox DR: Regression models and life-tables.
J Roy Stat Soc
34
:
187
–201,
1972
19.
Laakso M: How good a marker is insulin level for insulin resistance?
Am J Epidemiol
137
:
959
–965,
1993
20.
Edwards KL, Burchfiel CM, Sharp DS, Curb JD, Rodriguez BL, Fujimoto WY, LaCroix AZ, Vitiello MV, Austin MA: Factors of the insulin resistance syndrome in nondiabetic and diabetic elderly Japanese-American men.
Am J Epidemiol
147
:
441
–447,
1998
21.
Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP: Clustering of procoagulation, inflammation, and fibrinolysis variables wth metabolic factors in insulin resistance syndrome.
Am J Epidemiol
152
:
908
–911,
2000
22.
Gray RS, Fabsitz RR, Cowan LD, Lee ET, Howard BV, Savage PJ: Risk factor clustering in the insulin resistance syndrome: the Strong Heart Study.
Am J Epidemiol
148
:
869
–878,
1998
23.
Laakso M: Insulin resistance and coronary heart disease.
Curr Opin Lipidol
7
:
217
–226,
1996
24.
Haffner SM, Mykkänen L, Festa A, Burke JP, Stern MP: Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state.
Circulation
101
:
975
–80,
2000
Address correspondence and reprint requests to Markku Laakso, MD, Department of Medicine, University of Kuopio, P.O. Box 1777, FIN-70211 Kuopio, Finland. E-mail:[email protected].
Received for publication 22 February 2001 and accepted in revised form 31 May 2001.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Online Ahead of Print Alert
| https://diabetesjournals.org/care/article/24/9/1629/21518/Insulin-Resistance-Syndrome-Predicts-Coronary |
UMLS:C0042940 - FACTA Search
)
253 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
In a mass screening of children ages 6-10 in a rural school division, 203 children were identified as showing a voice deviation. One year later a retesting of 178 of these children showed that 39.9% still showed a voice disorder . Four years later 50 of these children were still available in the same school system; 38% of them still showed a
voice disorder
. Virtually none of these children were referred to the otolaryngologist for an ENT evaluation or to the speech-language pathologist for voice rehabilitation. Results indicate that, for many of these children, the voice disorders do not "clear up" through maturation alone.
...
PMID:A longitudinal study of the prevalence of voice disorders in children from a rural school division. 260 Jan 99
A psychogenic voice disorder co-occurred or evolved with the symptoms and signs of unilateral superior laryngeal nerve paresis. We speculated that the former was a manifestation of a musculoskeletal tension or conversion reaction disorder, whereas the latter was a sequela to a self-limiting inflammatory process. Voice therapy proved effective for alleviating the psychogenic dysphonia after the signs of the neuropathy had resolved, whereas psychotherapy offered strategies for stress management. A multidisciplinary approach to this patient provided for differential diagnosis and efficacious treatment.
...
PMID:A case of superior laryngeal nerve paresis and psychogenic dysphonia. 268 99
Voice disorders are frequently seen in the pediatric population. They can have significant impact on the patient.
Voice disorders
may result from aberrations in the speech mechanism. The salient features of four common voice disorders and their clinical relevance are discussed.
...
PMID:Surgical management of voice disorders. 268 29
Aphonia is the extreme form of a functional voice disorder . 22 female patients with aphonia underwent laryngoscopic and phonic examinations, psychiatric evaluation, psychological testing and biographical history-taking. Results demonstrate a homogeneous clinical picture, but heterogeneous personality structures and conflict situations. All patients are overtaxed by their situation; the conversion reaction is used as a means to express anxiety and maintain self-assertion at the same time.
...
PMID:Functional aphonia. A conversion symptom as defensive mechanism against anxiety. 323 59
Spasmodic dysphonia (SD) is a low-incidence voice disorder of unknown origin. A subgroup of seven patients with SD from our larger pool of 70 report vocal symptoms subsequent to head injury. This article is a case report of the neurodiagnostic findings, including computed tomography, magnetic resonance imaging, auditory brain-stem response, brain electrical activity mapping, and single photon emission computed tomography for three such patients. For each patient, two or more tests revealed positive neurologic findings. Each test, except computed tomography, demonstrated abnormalities in one or more patients. Two principles of clinical management are derived: (1) information regarding head trauma sustained before SD symptom onset is significant; (2) the absence of neuropathology on a single measure of central nervous system function should not be considered conclusive evidence that no neurologic lesions exist.
...
PMID:Spasmodic dysphonia subsequent to head trauma. 349 53
Of 121 consecutive outpatients seen in an ENT clinic who received a diagnosis of functional dysphonia, 71 who were referred to the speech therapy department were interviewed. Sixty one (86%) were women, and the mean age of the group was 47.6 yr. The commonest
voice disorder was huskiness or hoarseness, and only five patients had a pure 'whispering' dysphonia. There was little evidence of major psychiatric disorder in the group: eight patients had a past psychiatric history; two had histrionic personality disorder, and 22 (33%) had clinically diagnosable mood disorders which were mainly anxiety/tension states. This descriptive study formed the background for an investigation of the psychosocial stressors preceding onset of functional dysphonia.
...
PMID:The psychiatric and social characteristics of patients with functional dysphonia. 366 86
The proper treatment of many voice disorder
patients includes modification of voice production. Laryngeal image biofeedback (LIB), a new technique to help selected patients modify vocal fold posture and thereby vocal production is described. The effectiveness of this technique as a learning tool is assessed in 20 subjects.
...
PMID:Laryngeal image biofeedback. 366 46
A vowel [a]-like, synthesized speech wave was perturbated by defined and comparable jitter and shimmer levels. The signal-to-noise ratio was calculated from the speech wave spectra. Noise emerges in those spectral regions in which the harmonics have high amplitudes, that is, at low frequencies and in the formant regions. Jitter created noise levels significantly higher than shimmer. To verify the theoretical findings, the voices of 32 women with functional voice disorders were analyzed for shimmer and jitter. It was found that only jitter is relevant for differentiating between hypo- and hyperfunctional voice disorders. Jitter was reduced in hyperfunctional voice disorder . This is presumed to be an effect of the high vocal fold tension found in the disorder.
...
PMID:Quantitative spectral evaluation of shimmer and jitter. 401 Feb 46
The view held over the last six decades that coniotomy often leads to subglottic stenosis has recently been called into question. In this study 203 electively performed coniotomies were analysed. The operation was found to be much simpler than tracheostomy. No severe intra- or postoperative complications occurred. Six months after decannulation 61 patients operated on were alive and accessible to follow-up examination. No evidence of subglottic stenosis was found. The main disadvantage was a relatively high frequency of
voice disorder .
...
PMID:Five years experience of coniotomy. 404 96
A sample of 19 spasmodic dysphonia (SD) patients was selected from a larger population of such patients to undergo magnetic resonance imaging (MRI), auditory brain stem response (ABR) testing, speech analysis, and extensive physical examination. Six patients had abnormal spin-echo MRI findings, ranging from infarcts within the basal ganglia to demyelinating lesions within the supralateral angles of the lateral ventricles. A weakly positive correlation was noted between the abnormal MRI findings and an abnormal ABR. The lack of a significant correlation between the MRI findings and other predictors of brain stem and midbrain disease, and the current spatial resolution limitations of MRI, suggest that we are visualizing the associated lesions rather than the actual foci of SD. The range of MRI findings is consistent with the concept that SD is a
voice disorder in a heterogeneous patient population.
...
PMID:Magnetic resonance imaging findings and correlations in spasmodic dysphonia patients. 407 38
<< Previous 1 2 3 4 5 6 7 8 9 10 Next >> | http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=UMLS%3AC0042940%7C111111%7C0%7C0%7C109053%7C20%7C30 |
View - Tasmanian Legislation Online
Return to standard view
Statutory Rules
Settled Land Act 1884
Settled Land Act 1884
An Act for facilitating sales, leases, and other disposition of settled land, and for promoting the execution of improvements thereon
[Royal Assent 27 October 1884]
Be it enacted by His Excellency the Governor of Tasmania, by and with the advice and consent of the Legislative Council and House of Assembly, in Parliament assembled, as follows:
PART I - Preliminary
1. Short title: Commencement
[Section 1 Amended by 25 Geo. V No. 78 ]
(1) This Act may be cited as the Settled Land Act 1884 .
(2) This Act shall commence on the first day of January 1885.
PART II - Definitions
2. Definitions
[Section 2 Amended by 25 Geo. V No. 78 ]
(1)
[Section 2 Subsection (1) amended by 2 Geo. V No. 33, s. 15 ]
Any deed, will, agreement for a settlement, or other agreement, Act, or other instrument, whether made or passed before or after, or partly before and partly after, the commencement of this Act, under or by virtue of which any land, or any estate or interest in land, stands for the time being limited to or in trust for any persons by way of succession, or is so limited that no person is presently entitled beneficially in possession or to the receipt of the rents and profits thereof, creates or is for purposes of this Act a settlement, and is in this Act referred to as a settlement, or as the settlement, as the case requires.
(2) An estate or interest in remainder or reversion not disposed of by a settlement, and reverting to the settlor or any person deriving title under him, is, for purposes of this Act, an estate or interest coming to the settlor or such person under or by virtue of the settlement, and comprised in the subject of the settlement.
(3) Land, and any estate or interest therein which is the subject of a settlement, is for purposes of this Act settled land, and is, in relation to the settlement, referred to in this Act as the settled land.
(4) The determination of the question whether land is settled land for purposes of this Act or not is governed by the state of facts and the limitations of the settlement at the time of the settlement taking effect.
(5) The person who is for the time being under a settlement beneficially entitled to possession of settled land for his life is for purposes of this Act the tenant for life of that land and the tenant for life under that settlement.
(6) If, in any case, there are two or more persons so entitled as tenants in common, or as joint tenants, or for other concurrent estates or interests, they together constitute the tenant for life for purposes of this Act.
(7) A person being tenant for life within the foregoing definitions shall be deemed to be such notwithstanding that under the settlement or otherwise the settled land, or his estate or interest therein, is encumbered or charged in any manner or to any extent.
(8) The persons, if any, who are for the time being, under a settlement, trustees with power of sale of settled land, or with power of consent to or approval of the exercise of such a power of sale, or if under a settlement there are no such trustees, then the persons, if any, for the time being, who are by the settlement declared to be trustees thereof for purposes of this Act, are for purposes of this Act trustees of the settlement.
(9) Capital money arising under this Act, and receivable for the trusts and purposes of the settlement, is in this Act referred to as capital money arising under this Act.
(10)
[Section 2 Subsection (10) amended by No. 75 of 1973, s. 2 and Sched. 1 ]
In this Act –
(a) building purposes include the erecting and the improving of, and the adding to, and the repairing of buildings; and a building lease is a lease for any building purposes or purposes connected therewith;
(b) land includes incorporeal hereditaments, also an undivided share in land; income includes rents and profits; and possession includes receipt of income;
(c) rent includes yearly or other rent, and toll, duty, royalty, or other reservation by the hectare, or the tonne, or otherwise; and, in relation to rent, payment includes delivery; and fine includes premium or foregift, and any payment, consideration, or benefit in the nature of a fine, premium, or foregift;
(d) securities include Government debentures and any debentures or securities the principal or interest of which is guaranteed by the Government of Tasmania, Treasury Bills, and shares;
(e) the Court means the Supreme Court or a judge;
(f) timber , unless a contrary intention appears, includes all indigenous and foreign trees, the wood of which is ordinarily used for building or manufacturing purposes, and the bark of such trees, but does not include brushwood, scrub, or underwood;
(g) will includes codicil and other testamentary instrument, and a writing in the nature of a will.
PART III - Sale: Exchange: Partition
3. Power of tenant for life to sell, exchange, or concur in partition
[Section 3 Amended by 25 Geo. V No. 78 ]
A tenant for life –
(a) may sell the settled land, or any part thereof, or any easement, right, or privilege of any kind over or in relation to the same;
(b) may make an exchange of the settled land, or any part thereof, for other land, including an exchange in consideration of money paid for equality of exchange; and
(c) where the settlement comprises an undivided share in land, or, under the settlement, the settled land has come to be held in undivided shares, may concur in making partition of the entirety, including a partition in consideration of money paid for equality of partition.
4. Regulations respecting sale, exchange, and partition
[Section 4 Amended by 25 Geo. V No. 78 ]
(1) Every sale shall be made at the best price that can reasonably be obtained.
(2) Every exchange and every partition shall be made for the best consideration in land, or in land and money, that can reasonably be obtained.
(3) A sale may be made in one lot or in several lots, but before any sale shall take place by private contract, the lot or lots shall be submitted for sale by public auction.
(4) On a sale the tenant for life may fix reserve biddings and buy in at an auction.
(5) A sale, exchange, or partition may be made subject to any stipulations respecting title or evidence of title or other things.
(6) On a sale, exchange, or partition any restriction or reservation with respect to building on or other user of land or with respect to or for the purpose of the more beneficial working thereof, or with respect to any other thing, may be imposed or reserved and made binding, as far as the law permits, by covenant, condition, or otherwise, on the tenant for life and the settled land, or any part thereof, or on the other party and any land sold or given in exchange or on partition to him.
(7) Settled land in Tasmania shall not be given in exchange for land out of Tasmania.
5. Powers of tenant for life in relation to incumbrances
Where on a sale, exchange, or partition there is an incumbrance affecting land sold or given in exchange or on partition, the tenant for life, with the consent of the incumbrancer, may charge that incumbrance on any other part of the settled land, whether already charged therewith or not, in exoneration of the part sold or so given, and, by conveyance of the fee simple, or other estate or interest the subject of the settlement, or by creation of a term of years in the settled land, or otherwise make provision accordingly.
PART IV - Leases
6. Power of tenant for life to lease for ordinary or building purposes
[Section 6 Amended by 25 Geo. V No. 78 ]
A tenant for life may lease the settled land, or any part thereof, or any easement, right, or privilege of any kind over or in relation to the same, for any purpose whatever, whether involving waste or not, for any term not exceeding –
(a) in case of a building lease, ninety-nine years;
(b) in case of any other lease, twenty-one years.
7. Regulations respecting leases generally
(1) Every lease shall be by deed, and be made to take effect in possession not later than twelve months after its date.
(2) Every lease shall reserve the best rent that can reasonably be obtained, regard being had to any fine taken, and to any money laid out or to be laid out for the benefit of the settled land, and generally to the circumstances of the case.
(3) Every lease shall contain a covenant by the lessee for payment of the rent, and a condition of re-entry on the rent not being paid within a time therein specified not exceeding thirty days.
(4) A counterpart of every lease shall be executed by the lessee and delivered to the tenant for life; of which execution and delivery the execution of the lease by the tenant for life shall be sufficient evidence.
(5) A statement, contained in a lease or in an endorsement thereon, signed by the tenant for life, respecting any matter of fact or of calculation under this Act in relation to the lease, shall, in favour of the lessee and of those claiming under him, be sufficient evidence of the matter stated.
8. Regulations respecting building leases
[Section 8 Amended by 25 Geo. V No. 78 ]
(1) Every building lease shall be made partly in consideration of the lessee, or some person by whose direction the lease is granted, or some other person having erected, or agreeing to erect, buildings new or additional, or having improved or repaired, or agreeing to improve or repair, buildings, or having executed or agreeing to execute on the land leased an improvement authorized by this Act, for or in connection with building purposes.
(2) A peppercorn rent, or a nominal or other rent less than the rent ultimately payable, may be made payable for the first five years or any less part of the term.
(3) Where the land is contracted to be leased in lots, the entire amount of rent to be ultimately payable may be apportioned among the lots in any manner; save that –
(a) the annual rent reserved by any lease shall not be less than $1;
(b) the total amount of the rents reserved on all leases for the time being granted shall not be less than the total amount of the rents which, in order that the leases may be in conformity with this Act, ought to be reserved in respect of the whole land for the time being leased; and
(c) the rent reserved by any lease shall not exceed one-fifth part of the full annual value of the land comprised in that lease, with the buildings thereon when completed.
9.
[Section 9 Repealed by 25 Geo. V No. 78 ]
. . . . . . . .
10. Variation of building leases according to circumstances of district
[Section 10 Amended by 25 Geo. V No. 78 ]
(1) Where it is shown to the Court with respect to the district in which any settled land is situate, that it is difficult to make leases or grants for building purposes of land therein, except for a longer term or on other conditions than the term and conditions specified in that behalf in this Act, or except in perpetuity, the Court may, if it thinks fit, authorize generally the tenant for life to make leases or grants of or affecting the settled land in that district, or parts thereof, for any term or in perpetuity, at such rents, secured by condition of re-entry or otherwise, as in the order of the Court expressed, or may, if it thinks fit, authorize the tenant for life to make any such lease or grant in any particular case.
(2) Thereupon the tenant for life, and, subject to any direction in the order of the Court to the contrary, each of his successors in title being a tenant for life, or having the powers of a tenant for life under this Act, may make in any case, or in the particular case, a lease or grant of or affecting the settled land, or part thereof, in conformity with the order.
11. Part of compensation for mining to be set aside
[Section 11 Amended by 25 Geo. V No. 78 ]
Where a mining lease is granted under the
Mining Act 1929
, in respect of any land which is subject to this Act, unless a contrary intention is expressed in the settlement, there shall be set aside, as capital money arising under this Act, part of any compensation received in respect thereof, as follows, namely: Where the tenant for life is impeachable for waste in respect of minerals, three-fourth parts of such compensation, and otherwise one-fourth part thereof, and in every such case the residue of such compensation shall go as rents and profits.
12. Leasing power of tenant for life
The leasing power of a tenant for life extends to the making of –
(a) a lease for giving effect to a contract entered into by any of his predecessors in title for making a lease which, if made by the predecessor, would have been binding on the successors in title;
(b) a lease for giving effect to a covenant of renewal performance whereof could be enforced against the owner for the time being of the settled land; and
(c) a lease for confirming as far as may be of a previous lease, being void or voidable; but so that every lease, as and when confirmed, shall be such a lease as might at the date of the original lease have been lawfully granted under this Act, or otherwise, as the case may require.
13. Power of tenant for life to accept surrender of lease and grant new leases
[Section 13 Amended by 25 Geo. V No. 78 ]
(1) A tenant for life may accept, with or without consideration, a surrender of any lease of settled land, whether made under this Act or not, in respect of the whole land leased, or any part thereof.
(2) On a surrender of a lease in respect of part only of the land leased, the rent may be apportioned.
(3) On a surrender, the tenant for life may make of the land surrendered, or of any part thereof, a new or other lease, or new or other leases in lots.
(4) A new or other lease may comprise additional land, and may reserve any apportioned or other rent.
(5) On a surrender, and the making of a new or other lease, whether for the same or for any extended or other term, and whether or not subject to the same or to any other covenants, provisions, or conditions, the value of the lessee's interest in the lease surrendered may be taken into account in the determination of the amount of the rent to be reserved, and of any fine to be taken, and of the nature of the covenants, provisions, and conditions to be inserted in the new or other lease.
(6) Every new or other lease shall be in conformity with this Act.
PART V - Sales, Leases, and Other Dispositions
14. Power of tenant for life, on sale or grant for building purposes to provide for streets, open spaces, &c., and for use thereof
[Section 14 Amended by 25 Geo. V No. 78 ]
On or in connection with a sale or grant for building purposes, or a building lease, the tenant for life, for the general benefit of the residents on the settled land, or on any part thereof –
(a) may cause or require any parts of the settled land to be appropriated and laid out for streets, roads, paths, squares, gardens, or other open spaces, for the use, gratuitously or on payment, of the public or of individuals, with sewers, drains, watercourses, fencing, paving, or other works necessary or proper in connection therewith;
(b) may provide that the parts so appropriated shall be conveyed to or vested in the trustees of the settlement or other trustees, or any company or public body, on trusts or subject to provisions for securing the continued appropriation thereof to the purposes aforesaid, and the continued repair or maintenance of streets, and other places and works aforesaid, with or without provision for appointment of new trustees when required; and
(c) may execute any general or other deed necessary or proper for giving effect to the provisions of this section, and thereby declare the mode, terms, and conditions of the appropriation, and the manner in which and the persons by whom the benefit thereof is to be enjoyed, and the nature and extent of the privileges and conveniences granted.
15. Moneys erroneously paid in relation to timber
[Section 15 Amended by 25 Geo. V No. 78 ]
(1) Where on a sale the consideration attributable to any timber or fixtures is by mistake paid to a tenant for life or other person not entitled to receive it, then, if such person or the purchaser or the persons deriving title under either of them subsequently pay the aforesaid consideration, with such interest, if any, thereon as the Court may direct, to the trustees of the settlement or other persons entitled thereto or into Court, the Court may, on the application of the purchaser or the persons deriving title under him, declare that the disposition is to take effect as if the whole of the consideration had, at the date thereof, been duly paid to the trustees of the settlement or other persons entitled to receive the same.
(2) The person not entitled to receive the same, to whom the consideration is paid, and his estate and effects, shall remain liable to make good any loss attributable to the mistake.
16. Mortgage for money required for equality of exchange or partition
Where money is required for equality of exchange or partition, the tenant for life may raise the same on mortgage of the settled land, or of any part thereof, by conveyance of the fee simple, or other estate or interest the subject of the settlement, or by creation of a term of years in the settled land, or otherwise, and the money raised shall be capital money arising under this Act.
17. Concurrence in exercise of powers as to undivided share
Where the settled land comprises an undivided share in land, or, under the settlement, the settled land has come to be held in undivided shares, the tenant for life of an undivided share may join or concur, in any manner and to any extent necessary or proper for any purpose of this Act, with any person entitled to or having power or right of disposition of or over another undivided share.
18. Completion of sale, lease, &c., may be by deed: Effect of deed
[Section 18 Amended by 25 Geo. V No. 78 ]
(1) On a sale, exchange, partition, lease, mortgage, or charge, the tenant for life may, as regards land sold, given in exchange, or on partition, leased, mortgaged, or charged, or intended so to be, including leasehold land vested in trustees, or as regards easements or other rights or privileges sold or leased, or intended so to be, convey or create the same by deed, for the estate or interest the subject of the settlement, or for any less estate or interest, to the uses and in the manner requisite for giving effect to the sale, exchange, partition, lease, mortgage, or charge.
(2) Such a deed, to the extent and in the manner to and in which it is expressed or intended to operate and can operate under this Act, is effectual to pass the land conveyed, or the easements, rights, or privileges created, discharged from all the limitations, powers, and provisions of the settlement, and from all estates, interests, and charges subsisting or to arise thereunder, but subject to and with the exception of –
(a) all estates, interests, and charges having priority to the settlement;
(b) all such other, if any, estates, interests, and charges as have been conveyed or created for securing money actually raised at the date of the deed; and
(c) all leases and grants and all grants of easements or other rights or privileges granted or made for value in money or money's worth, or agreed so to be, before the date of the deed, by the tenant for life, or by any of his predecessors in title, or by any trustees for him or them, under the settlement, or under any statutory power, or being otherwise binding on the successors in title of the tenant for life.
PART VI - Investment or Other Application of Capital Trust Money
19. Capital money under Act: How to be invested and applied
[Section 19 Amended by 25 Geo. V No. 78 ]
Capital money arising under this Act, subject to payment of claims properly payable thereout, and to application thereof for any special authorized object for which the same was raised, shall, when received, be invested or otherwise applied wholly in one, or partly in one and partly in another or others, of the following modes, namely:
(a) In investment on Government securities, or on other securities on which the trustees of the settlement are by the settlement or by law authorized to invest trust money of the settlement, with power to vary the investment into or for any other such securities;
(b) In discharge, purchase, or redemption of incumbrances affecting the inheritance of the settled land, or other the whole estate the subject of the settlement, charged on or payable out of the settled land;
(c) In payment for any improvement authorized by this Act;
(d) In payment for equality of exchange or partition of settled land;
(e) In purchase of the reversion or freehold in fee of any part of the settled land, being leasehold land held for years, or life or years determinable on life;
(f) In purchase of land in fee simple or of leasehold land held for sixty years or more unexpired at the time of purchase;
(g) In payment to any person becoming absolutely entitled or empowered to give an absolute discharge;
(h) In payment of costs, charges, and expenses of or incidental to the exercise of any of the powers, or the execution of any of the provisions of this Act;
(i) In any other mode in which money produced by the exercise of a power of sale in the settlement is applicable thereunder.
20. Capital money to be paid either to trustees or into Court
(1) Capital money arising under this Act shall, in order to its being invested or applied as aforesaid, be paid either to the trustees of the settlement or into Court, at the option of the tenant for life, and shall be invested or applied by the trustees, or under the direction of the Court, as the case may be, accordingly.
(2) The investment or other application by the trustees shall be made according to the direction of the tenant for life, and in default thereof, according to the discretion of the trustees, but in the last-mentioned case subject to any consent required or direction given by the settlement with respect to the investment or other application by the trustees of trust money of the settlement; and any investment shall be in the names or under the control of the trustees.
(3) The investment or other application under the direction of the Court shall be made on the application of the tenant for life, or of the trustees.
(4) Any investment or other application shall not during the life of the tenant for life be altered without his consent.
(5) Capital money arising under this Act while remaining uninvested or unapplied, and securities on which an investment of any such capital money is made, shall, for all purposes of disposition, transmission, and devolution, be considered as land, and the same shall be held for and go to the same persons successively, in the same manner and for and on the same estates, interests, and trusts, as the land wherefrom the money arises would, if not disposed of, have been held and have gone under the settlement.
(6) The income of those securities shall be paid or applied as the income of that land, if not disposed of, would have been payable or applicable under the settlement.
(7) Those securities may be converted into money, which shall be capital money arising under this Act.
21. Capital money not to be applied in purchase of land outside Tasmania unless settlement expressly authorizes
Capital money arising under this Act from settled land in Tasmania shall not be applied in the purchase of land out of Tasmania unless the settlement expressly authorizes the same.
22. Land acquired by purchase, exchange, or partition: How to be made subject to settlement
(1) Land acquired by purchase or in exchange or on partition shall be made subject to the settlement in manner directed in this section.
(2) Freehold land shall be conveyed to the uses, on the trusts, and subject to the powers and provisions which, under the settlement, or by reason of the exercise of any power of charging therein contained, are subsisting with respect to the settled land, or as near thereto as circumstances permit, but not so as to increase or multiply charges or powers of charging.
(3) Leasehold land shall be conveyed to and vested in the trustees of the settlement on trusts and subject to powers and provisions corresponding, as nearly as the law and circumstances permit, with the uses, trusts, powers, and provisions to, on, and subject to which freehold land is to be conveyed as aforesaid; so nevertheless that the beneficial interest in land held by lease for years shall not vest absolutely in a person who is by the settlement made by purchase tenant in tail, or in tail male, or in tail female, and who dies under the age of twenty-one years, but shall, on the death of that person under that age, go as freehold land conveyed as aforesaid would go.
(4) Land acquired as aforesaid may be made a substituted security for any charge in respect of money actually raised, and remaining unpaid, from which the settled land, or any part thereof, or any undivided share therein, has theretofore been released on the occasion and in order to the completion of a sale, exchange, or partition.
(5) Where a charge does not affect the whole of the settled land, then the land acquired shall not be subjected thereto, unless the land is acquired either by purchase with money arising from sale of land which was before the sale subject to the charge, or by an exchange or partition of land which, or an undivided share wherein, was before the exchange or partition subject to the charge.
(6) On land being so acquired, any person who, by the direction of the tenant for life, so conveys the land as to subject it to any charge, is not concerned to inquire whether or not it is proper that the land should be subjected to the charge.
(7) [Section 22 Subsection (7) omitted by 25 Geo V No. 78 ] . . . . . . . .
PART VII - Improvements
23. Description of improvements authorized by Act
[Section 23 Amended by 25 Geo. V No. 78 ]
Improvements authorized by this Act are the making or execution on, or in connection with, and for the benefit of settled land, of any of the following works, or of any works for any of the following purposes, and any operation incident to or necessary or proper in the execution of any of those works, or necessary or proper for carrying into effect any of those purposes, or for securing the full benefit of any of those works or purposes, namely:
(a) Drainage, including the straightening, widening, or deepening of drains, streams, and watercourses;
(b) Irrigation; warping;
(c) Drains, pipes, and machinery for supply and distribution of sewage as manure;
(d) Embanking or weiring from a river or lake, or from the sea, or a tidal water;
(e) Groynes; sea walls; defences against water;
(f) Enclosing; straightening of fences; redivision of fields;
(g) Reclamation; dry warping;
(h) Farm roads; private roads; roads or streets in villages or towns;
(i) Clearing; trenching; planting;
(j) Cottages for labourers, farm servants, and artisans, employed on the settled land or not;
(k) Farm-houses, offices, and out-buildings, and other buildings for farm purposes;
(l) Sawmills and other mills, water-wheels, engine-houses, and kilns, which will increase the value of the settled land for agricultural purposes or as woodland or otherwise;
(m) Reservoirs, tanks, conduits, watercourses, pipes, wells, ponds, shafts, dams, weirs, sluices, and other works and machinery for supply and distribution of water for agricultural, manufacturing, or other purposes, or for domestic or other consumption;
(n) Tramways; railways; canals; docks;
(o) Jetties, piers, and landing-places on rivers, lakes, the sea, or tidal waters, for facilitating transport of persons and of agricultural stock and produce, and of manure and other things required for agricultural purposes, and of minerals, and of things required for mining purposes;
(p) Markets and market-places;
(q) Streets, roads, paths, squares, gardens, or other open spaces for the use, gratuitously or on payment, of the public or of individuals, or for dedication to the public, the same being necessary or proper in connection with the conversion of land into building land;
(r) Sewers, drains, watercourses, pipe-making, fencing, paving, brick-making, tile-making, and other works necessary or proper in connection with any of the objects aforesaid;
(s) Reconstruction, enlargement, or improvement of any of those works.
24. Approval by trustees or by Court of scheme for improvement and expenditure thereon
[Section 24 Amended by 25 Geo. V No. 78 ]
(1) Where the tenant for life is desirous that capital money arising under this Act shall be applied in or towards payment for an improvement authorized by this Act, he may submit for approval to the trustees of the settlement, or to the Court, as the case may require, a scheme for the execution of the improvement, showing the proposed expenditure thereon.
(2) Where the capital money to be expended is in the hands of trustees, then, after a scheme is approved by them, the trustees may apply that money in or towards payment for the whole or part of any work or operation comprised in the improvement, on –
(a) a certificate of a competent engineer or able practical surveyor nominated by the trustees, and approved by the Court certifying that the work or operation, or some specified part thereof, has been properly executed, and what amount is properly payable by the trustees in respect thereof, which certificate shall be conclusive in favour of the trustees as an authority and discharge for any payment made by them in pursuance thereof; or
(b) an order of the Court directing or authorizing the trustees to so apply a specified portion of the capital money.
(3) Where the capital money to be expended is in Court, then, after a scheme is approved by the Court, the Court may, if it thinks fit, on a report or certificate of a competent engineer or able practical surveyor, approved by the Court, or on such other evidence as the Court thinks sufficient, make such order and give such directions as it thinks fit for the application of that money, or any part thereof, in or towards payment for the whole or part of any work or operation comprised in the improvement.
25. Concurrence with other person interested in scheme for improvement
The tenant for life may join or concur with any other person interested in executing any improvement authorized by this Act, or in contributing to the cost thereof.
26. Tenant for life to maintain, repair, and insure improvements
(1) The tenant for life, and each of his successors in title having, under the settlement, a limited estate or interest only in the settled land, shall, during such period, if any, as the Court by certificate in any case prescribes, maintain and repair, at his own expense, every improvement executed under the foregoing provisions of this Act, and where a building or work in its nature insurable against damage by fire is comprised in the improvement, shall insure and keep insured the same, at his own expense, in such amount, if any, as the Court by certificate in any case prescribes.
(2) The tenant for life, or any of his successors as aforesaid, shall not cut down or knowingly permit to be cut down, except in proper thinning, any trees planted as an improvement under the foregoing provisions of this Act.
(3) The tenant for life, and each of his successors as aforesaid, shall, if required by the Court, on or without the suggestion of any person having, under the settlement, any estate or interest in the settled land in possession, remainder, or otherwise, report to the Court the state of every improvement executed under this Act, and the fact and particulars of fire insurance, if any.
(4) The Court may vary any certificate made under this section, in such manner or to such extent as circumstances appear to the Court to require, but not so as to increase the liabilities of the tenant for life, or any of his successors as aforesaid.
(5) If the tenant for life, or any of his successors as aforesaid, fails in any respect to comply with the requisitions of this section, or does any act in contravention thereof, any person having, under the settlement, any estate or interest in the settled land in possession, remainder, or reversion, shall have a right of action, in respect of that default or act, against the tenant for life; and the estate of the tenant for life, after his death, shall be liable to make good to the persons entitled under the settlement any damages occasioned by that default or act.
27. Protection as regards waste in execution and repair of improvements
The tenant for life, and each of his successors in title having, under the settlement, a limited estate or interest only in the settled land, and all persons employed by or under contract with the tenant for life, or any such successor, may enter on the settled land, and, without impeachment of waste by any remainderman or reversioner, thereon execute any improvement authorized by this Act, or inspect, maintain, and repair the same, and, for the purposes thereof, on the settled land, do, make, and use all acts, works, and conveniences proper for the execution, maintenance, repair, and use thereof, and get and work freestone, limestone, clay, sand, and other substances, and make tramways and other ways, and burn and make bricks, tiles, and other things, and cut down and use timber and other trees not planted or left standing for shelter or ornament.
PART VIII - Contracts
28. Powers of tenant for life as to contracts regarding settled land
[Section 28 Amended by 25 Geo. V No. 78 ]
(1) A tenant for life –
(a) may contract to make any sale, exchange, partition, mortgage, or charge;
(b) may vary or rescind, with or without consideration, the contract, in the like cases and manner in which, if he were absolute owner of the settled land, he might lawfully vary or rescind the same, but so that the contract as varied be in conformity with this Act; and any such consideration, if paid in money, shall be capital money arising under this Act;
(c) may contract to make any lease; and in making the lease may vary the terms, with or without consideration, but so that the lease be in conformity with this Act;
(d) may accept a surrender of a contract for a lease, in like manner and on the like terms in and on which he might accept a surrender of a lease; and thereupon may make a new or other contract, or new or other contracts, for or relative to a lease or leases, in like manner and on the like terms in and on which he might make a new or other lease where a lease had been surrendered;
(e) may enter into a contract for or relating to the execution of any improvement authorized by this Act, and may vary or rescind the same; and
(f) may, in any other case, enter into a contract to do any act for carrying into effect any of the purposes of this Act, and may vary or rescind the same.
(2) Every contract shall be binding on and shall enure for the benefit of the settled land, and shall be enforceable against and by every successor in title for the time being of the tenant for life, and may be carried into effect by any such successor; but so that it may be varied or rescinded by any such successor, in the like case and manner, if any, as if it had been made by himself.
(3) The Court may, on the application of the tenant for life, or of any such successor, or of any person interested in any contract, give directions respecting the enforcing, carrying into effect, varying, or rescinding thereof.
(4) Any preliminary contract under this Act for or relating to a lease shall not form part of the title or evidence of the title of any person to the lease, or to the benefit thereof.
PART IX - Miscellaneous Provisions
29. Application of Act to money in Court under other Acts
[Section 29 Amended by 25 Geo. V No. 78 ]
[Section 29 Amended by No. 24 of 1993, s. 3 and Sched. 1 ]
Where, under an Act incorporating or applying, wholly or in part, the
Land Acquisition Act 1993
, or under any other Act, money is paid into Court, and is liable to be laid out in the purchase of land to be made subject to a settlement, then in addition to any mode of dealing therewith authorized by the Act under which the money is in Court, that money may be invested or applied as capital money arising under this Act, on the like terms, if any, respecting costs and other things, as nearly as circumstances admit, and (notwithstanding anything in this Act) according to the same procedure, as if the modes of investment or application authorized by this Act were authorized by the Act under which the money is in Court.
30. Application of Act to money in hands of trustees under a settlement
Where, under a settlement, money is in the hands of trustees, and is liable to be laid out in the purchase of land to be made subject to the settlement, then, in addition to such powers of dealing therewith as the trustees have independently of this Act, they may, at the option of the tenant for life, invest or apply the same as capital money arising under this Act.
31. Application of money paid for lease or reversion, &c.
Where capital money arising under this Act is purchase-money paid in respect of a lease for years, or life, or years determinable on life, or in respect of any other estate or interest in land less than the fee simple, or in respect of a reversion dependent on any such lease, estate, or interest, the trustees of the settlement or the Court, as the case may be, and in the case of the Court on the application of any party interested in that money, may, notwithstanding anything in this Act, require and cause the same to be laid out, invested, accumulated, and paid in such manner as, in the judgment of the trustees or of the Court, as the case may be, will give to the parties interested in that money the like benefit therefrom as they might lawfully have had from the lease, estate, interest, or reversion in respect whereof the money was paid, or as near thereto as may be.
32. Cutting and sale of timber by tenant for life, impeachable for waste, and setting aside part of proceeds
(1) Where a tenant for life is impeachable for waste in respect of timber, and there is on the settled land timber fit for cutting, the tenant for life, on obtaining the consent of the trustees of the settlement or an order of the Court, may cut and sell that timber, or any part thereof.
(2) Three-fourth parts of the net proceeds of the sale shall be set aside as and be capital money arising under this Act, and the other fourth part shall go as rents and profits.
33. Proceedings for protection and recovery of land settled or alleged to be settled
The Court may, if it thinks fit, approve of any action, defence, petition to Parliament, Parliamentary opposition, or other proceeding taken or proposed to be taken for protection of settled land, or of any action or proceeding taken or proposed to be taken for recovery of land being or alleged to be subject to a settlement, and may direct that any costs, charges, or expenses incurred or to be incurred in relation thereto, or any part thereof, be paid out of property subject to the settlement.
34. Sale of heirlooms by tenant for life and application of proceeds
(1) Where personal chattels are settled on trust so as to devolve with land until a tenant in tail by purchase is born or attains the age of twenty-one years, or so as otherwise to vest in some person becoming entitled to an estate of freehold of inheritance in the land, a tenant for life of the land may sell the chattels or any of them.
(2) The money arising by the sale shall be capital money arising under this Act, and shall be paid, invested, or applied and otherwise dealt with in like manner in all respects as by this Act directed with respect to other capital money arising under this Act, or may be invested in the purchase of other chattels, of the same or any other nature, which, when purchased, shall be settled and held on the same trusts, and shall devolve in the same manner as the chattels sold.
(3) A sale or purchase of chattels under this section shall not be made without an order of the Court.
PART X - Trustees
35. Appointment of trustees by Court
(1) If at any time there are no trustees of a settlement within the definition of this Act, or where in any other case it is expedient, for purposes of this Act, that new trustees of a settlement be appointed, the Court may, if it thinks fit, on the application of the tenant for life, or of any other person having under the settlement an estate or interest in the settled land, in possession, remainder, or otherwise, or, in the case of an infant, of his testamentary, or other guardian, or next friend, appoint fit persons to be trustees under the settlement for purposes of this Act.
(2) The persons so appointed, and the survivors and survivor of them, while continuing to be trustees or trustee, and, until the appointment of new trustees, the personal representatives or representative for the time being of the last surviving or continuing trustee shall for the purposes of this Act become and be the trustees or trustee of the settlement.
36. Minimum number of trustees
[Section 36 Amended by 25 Geo. V No. 78 ]
(1) Notwithstanding anything in this Act, capital money arising under this Act shall not be paid to fewer than two persons as trustees of a settlement, unless the settlement authorizes the receipt of capital trust money of the settlement by one trustee, or unless the sole trustee is a company authorized by law to act as a trustee.
(2) Subject thereto, the provisions of this Act referring to the trustees of a settlement apply to the surviving or continuing trustees or trustee of the settlement for the time being.
(3) Any company authorized by law to act as a trustee may be appointed as sole trustee of any settlement whenever made, for the purposes of this Act; and any such trustee whenever appointed may lawfully act as trustee of any such settlement.
37. Trustees' receipts
[Section 37 Amended by 25 Geo. V No. 78 ]
The receipt in writing of the trustees of a settlement, or where one trustee is empowered to act, of one trustee, or of the personal representatives of the last surviving or continuing trustee, for any money or securities, paid or transferred to the trustees or representatives, as the case may be, effectually discharges the payer or transferror therefrom, and from being bound to see to the application or being answerable for any loss or misapplication thereof, and, in case of a mortgagee or other person advancing money, from being concerned to see that any money advanced by him is wanted for any purpose of this Act, or that no more than is wanted is raised.
38. Protection of trustees individually
Each person who is for the time being trustee of a settlement is answerable for what he actually receives only, notwithstanding his signing any receipt for conformity, and in respect of his own acts, receipts, and defaults only, and is not answerable in respect of those of any other trustee, or of any banker, broker, or other person, or for the insufficiency or deficiency of any securities, or for any loss not happening through his own wilful default.
39. Protection of trustees generally
The trustees of a settlement, or any of them, are not liable for giving any consent, or for not making, bringing, taking, or doing any such application, action, proceeding, or thing, as they might make, bring, take, or do; and in case of purchase of land with capital money arising under this Act, or of an exchange, partition, or lease, are not liable for adopting any contract made by the tenant for life or bound to inquire as to the propriety of the purchase, exchange, partition, or lease, or answerable as regards any price, consideration, or fine, and are not liable to see to or answerable for the investigation of the title, or answerable for a conveyance of land, if the conveyance purports to convey the land in the proper mode, or liable in respect of purchase-money paid by them by direction of the tenant for life to any person joining in the conveyance as a conveying party, or as giving a receipt for the purchase-money, or in any other character, or in respect of any other money paid by them by direction of the tenant for life on the purchase, exchange, partition, or lease.
40. Trustees' reimbursement
The trustees of a settlement may reimburse themselves or pay and discharge out of the trust property all expenses properly incurred by them.
40A. Power of trustees in certain cases to exercise powers of tenant for life
[Section 40A Inserted by 2 Geo. V No. 33, s. 16 ]
Where no person is tenant for life of, or but for this section would have the powers of a tenant for life in regard to, the settled land, then the trustees of the settlement shall have the powers of a tenant for life in respect of the settled land.
41. Reference of differences to Court
If at any time a difference arises between a tenant for life and the trustees of the settlement, respecting the exercise of any of the powers of this Act, or respecting any matter relating thereto, the Court may, on the application of either party, give such directions respecting the matter in difference, and respecting the costs of the application, as the Court thinks fit.
42. Notice to trustees by tenant for life intending to deal with land
[Section 42 Amended by 25 Geo. V No. 78 ]
(1)
[Section 42 Subsection (1) amended by No. 66 of 2007, Sched. 1, Applied:31 Dec 2008]
A tenant for life, when intending to make a sale, exchange, partition, lease, mortgage, or charge, shall give notice of his intention in that behalf to each of the trustees of the settlement by registered post to the trustees, severally, and shall give like notice to the Australian legal practitioner for the trustees if any such Australian legal practitioner is known to the tenant for life, by registered post, to the Australian legal practitioner at his place of business in Tasmania, every letter under this section being posted not less than one month before the making by the tenant for life of the sale, exchange, partition, lease, mortgage, or charge, or of a contract for the same.
(2) At the date of notice given the number of trustees shall not be less than two, unless a contrary intention is expressed in the settlement, or unless the sole trustee is a company authorized by law to act as a trustee.
(3) A person dealing in good faith with the tenant for life is not concerned to inquire respecting the giving of any such notice as is required by this section.
(4) The notice required by this section may be a notice of a general intention to make a sale, exchange, partition, lease, mortgage, or charge.
(5) The tenant for life, upon request by a trustee of the settlement, shall furnish to him such particulars as may be reasonably required by him, with reference to any sale, exchange, partition, lease, mortgage, or charge effected or in progress or immediately intended.
(6) Any trustee may, by writing under his hand, waive notice, either in any particular case or generally, and may accept less than one month's notice.
PART XI - [Part XI Heading amended by 25 Geo. V No. 78 ] Court: Procedure: Costs
43. Procedural provisions
[Section 43 Amended by 25 Geo. V No. 78 ]
(1) The procedure in respect of all matters within the jurisdiction of the Court under this Act shall be in accordance with the Rules of Court under the Supreme Court Civil Procedure Act 1932 .
(2) Payment of money into Court effectually exonerates therefrom the person making payment.
(3) Every application to the Court shall be by petition or by summons at chambers.
(4) On an application by the trustees of a settlement notice shall be served in the first instance on the tenant for life.
(5) On any application notice shall be served on such persons, if any, as the Court thinks fit.
(6) The Court shall have full power and discretion to make such order as it thinks fit respecting the costs, charges, or expenses of all or any of the parties to any application or proceeding, and may, if it thinks fit, order that all or any of those costs, charges, or expenses be paid out of property subject to the settlement.
(7) [Section 43 Subsection (7) omitted by 25 Geo. V No. 78 ] . . . . . . . .
44. Payment of costs out of settled property
Where the Court directs that any costs, charges, or expenses be paid out of property subject to a settlement, the same shall, subject and according to the directions of the Court, be raised and paid out of capital money arising under this Act, or other money liable to be laid out in the purchase of land to be made subject to the settlement, or out of investments representing such money, or out of income of any such money, or investments, or out of any accumulations of income of land, money, or investments, or by means of a sale of part of the settled land in respect whereof the costs, charges, or expenses are incurred, or of other settled land comprised in the same settlement, and subject to the same limitations, or by means of a mortgage of the settled land or any part thereof, to be made by such person as the Court directs, and either by conveyance of the fee simple or other estate or interest the subject of the settlement, or by creation of a term, or otherwise, or by means of a charge on the settled land or any part thereof, or partly in one of those modes and partly in another or others, or in any such other mode as the Court thinks fit.
PART XII - Restrictions, Savings, and General Provisions
45. Powers of tenant for life not assignable
(1) The powers under this Act of a tenant for life are not capable of assignment or release, and do not pass to a person as being, by operation of law or otherwise, an assignee of a tenant for life, and remain exercisable by the tenant for life after and notwithstanding any assignment, by operation of law or otherwise, of his estate or interest under the settlement.
(2) A contract by a tenant for life not to exercise any of his powers under this Act is void.
(3)
[Section 45 Subsection (3) amended by 25 Geo. V No. 78 ]
This section shall operate without prejudice to the rights of any person being an assignee for value of the estate or interest of the tenant for life; and in that case the assignee's right shall not be affected without his consent, except that, unless the assignee is actually in possession of the settled land or part thereof, his consent shall not be requisite for the making of leases thereof by the tenant for life, provided the leases are made at the best rent that can reasonably be obtained, without fine, and in other respects are in conformity with this Act.
(4) This section extends to assignments made or coming into operation before or after and to acts done before or after the commencement of this Act; and in this section assignment includes assignment by way of mortgage, and any partial or qualified assignment, and any charge or incumbrance; and assignee has a meaning corresponding with that of assignment.
46. Prohibition or limitation against exercise of powers void
(1) If in a settlement, will, assurance, or other instrument executed or made before or after, or partly before and partly after, the commencement of this Act, a provision is inserted purporting or attempting, by way of direction, declaration, or otherwise, to forbid a tenant for life to exercise any power under this Act, or attempting, or tending, or intended, by a limitation, gift, or disposition over of settled land, or by a limitation, gift, or disposition of other real or any personal property, or by the imposition of any condition, or by forfeiture, or in any other manner whatever, to prohibit or prevent him from exercising, or to induce him to abstain from exercising, or to put him into a position inconsistent with his exercising, any power under this Act, that provision, as far as it purports, or attempts, or tends, or is intended to have, or would or might have, the operation aforesaid shall be deemed to be void.
(2) For the purposes of this section an estate or interest limited to continue so long only as a person abstains from exercising any power shall be and take effect as an estate or interest to continue for the period for which it would continue if that person were to abstain from exercising the power, discharged from liability to determination or cessor by or on his exercising the same.
47. Provision against forfeiture
Notwithstanding anything in a settlement, the exercise by the tenant for life of any power under this Act shall not occasion a forfeiture.
48. Tenant for life trustee for all parties interested
A tenant for life shall, in exercising any power under this Act, have regard to the interests of all parties entitled under the settlement, and shall, in relation to the exercise thereof by him, be deemed to be in the position and to have the duties and liabilities of a trustee for those parties.
49. General protection of purchasers, &c.
On a sale, exchange, partition, lease, mortgage, or charge, a purchaser, lessee, mortgagee, or other person dealing in good faith with a tenant for life shall, as against all parties entitled under the settlement, be conclusively taken to have given the best price, consideration, or rent, as the case may require, that could reasonably be obtained by the tenant for life, and to have complied with all the requisitions of this Act.
50. Exercise of powers
(1) [Section 50 Subsection (1) omitted by 25 Geo. V No. 78 ] . . . . . . . .
(2) Where a power of sale, exchange, partition, leasing, mortgaging, charging, or other power is exercised by a tenant for life, or by the trustees of a settlement, he and they may respectively execute, make, and do all deeds, instruments, and things necessary, or proper in that behalf.
(3) Where any provision in this Act refers to sale, purchase, exchange, partition, leasing, or other dealing, or to any power, consent, payment, receipt, deed, assurance, contract, expenses, act, or transaction, the same shall be construed to extend only (unless it is otherwise expressed) to sales, purchases, exchanges, partitions, leasings, dealings, powers, consents, payments, receipts, deeds, assurances, contracts, expenses, acts and transactions under this Act.
51. Saving other powers
(1) Nothing in this Act shall take away, abridge, or prejudicially affect any power for the time being subsisting under a settlement, or by statute or otherwise, exercisable by a tenant for life, or by trustees with his consent, or on his request, or by his direction, or otherwise; and the powers given by this Act are cumulative.
(2) But, in case of conflict between the provisions of a settlement and the provisions of this Act, relative to any matter in respect whereof the tenant for life exercises or contracts or intends to exercise any power under this Act, the provisions of this Act shall prevail; and accordingly, notwithstanding anything in the settlement, the consent of the tenant for life shall, by virtue of this Act, be necessary to the exercise by the trustees of the settlement or other person of any power conferred by the settlement exercisable for any purpose provided for in this Act.
(3) If a question arises, or a doubt is entertained, respecting any matter within this section, the Court may, on the application of the trustees of the settlement, or of the tenant for life, or of any other person interested, give its decision, opinion, advice, or direction thereon.
52. Additional or larger powers by settlement
(1) Nothing in this Act shall preclude a settlor from conferring on the tenant for life, or the trustees of the settlement, any powers additional to or larger than those conferred by this Act.
(2) Any additional or larger powers so conferred shall, as far as may be, notwithstanding anything in this Act, operate and be exercisable in the like manner, and with all the like incidents, effects, and consequences, as if they were conferred by this Act, unless a contrary intention is expressed in the settlement.
PART XIII - Limited Owners Generally
53. Other limited owners who are to have powers of tenant for life
[Section 53 Amended by 25 Geo. V No. 78 ]
(1) Each person as follows shall, when the estate or interest of each of them is in possession, have the powers of a tenant for life under this Act, as if each of them were a tenant for life as defined in this Act, namely:
(a) A tenant in tail;
(b) A tenant in fee simple, with an executory limitation, gift, or disposition over, on failure of his issue, or in any other event;
(c) A person entitled to a base fee, although the reversion is in the Crown, and so that the exercise by him of his powers under this Act shall bind the Crown;
(d) A tenant for years determinable on life, not holding merely under a lease at a rent;
(e) A tenant for the life of another, not holding merely under a lease at a rent;
(f) A tenant for his own or any other life, or for years determinable on life, whose estate is liable to cease in any event during that life, whether by expiration of the estate, or by conditional limitation, or otherwise, or to be defeated by an executory limitation, gift, or disposition over, or is subject to a trust for accumulation of income for payment of debts or other purpose;
(g) A tenant in tail after possibility of issue extinct;
(h) A person entitled to the income of land under a trust or direction for payment thereof to him during his own or any other life, whether subject to expenses of management or not, or until sale of the land, or until forfeiture of his interest therein on bankruptcy or other event.
(2) In every such case, the provisions of this Act referring to a tenant for life, either as conferring powers on him or otherwise, and to a settlement, and to settled land, shall extend to each of the persons aforesaid, and to the instrument under which his estate or interest arises, and to the land therein comprised.
(3) In any such case any reference in this Act to death as regards a tenant for life shall, where necessary, be deemed to refer to the determination by death or otherwise of such estate or interest as last aforesaid.
PART XIV - Infants: Married Women: Lunatics
54. Infant absolutely entitled deemed tenant for life
Where a person who is in his own right seised of or entitled in possession to land, is an infant, then for the purposes of this Act the land is settled land, and the infant shall be deemed tenant for life thereof.
55. Powers of infant tenant for life may be exercised by trustees or by person ordered by Court
Where a tenant for life, or a person having the powers of a tenant for life under this Act, is an infant, or an infant would, if he were of full age, be a tenant for life, or have the powers of a tenant for life under this Act, the powers of a tenant for life under this Act may be exercised on his behalf by the trustees of the settlement, and if there are none, then by such person and in such manner as the Court, on the application of a testamentary or other guardian or next friend of the infant, either generally or in a particular instance, orders.
56. Married woman: How affected by Act
[Section 56 Amended by 25 Geo. V No. 78 ]
(1) The foregoing provisions of this Act shall apply to a married woman of full age, whether or not she is entitled to her estate or interest for her separate use or as her separate property, and she, without her husband, may exercise the powers of a tenant for life under this Act.
(2) A restraint on anticipation in the settlement shall not prevent the exercise by her of any power under this Act.
57.
[Section 57 Repealed by No. 63 of 1963, s. 2 and Sched. 1 ]
. . . . . . . .
PART XV - Repeals
58.
[Section 58 Repealed by 25 Geo. V No. 78 ]
. . . . . . . .
SCHEDULE 1
[Schedule Repealed by 25 Geo. V No. 78 ]
| https://www.legislation.tas.gov.au/view/whole/html/inforce/2013-11-27/act-1884-010 |
(PDF) Association between oral intake magnesium and sarcopenia: a cross-sectional study
PDF | Background Sarcopenia is a common skeletal muscle disorder in the elderly population. The patients with sarcopenia increased the cost of care and... | Find, read and cite all the research you need on ResearchGate
PDF Available
Association between oral intake magnesium and sarcopenia: a cross-sectional study
<here is a image 7563ab3b5a75617e-bb1d1e02075e3998>
October 2022
BMC Geriatrics22(1)
DOI: 10.1186/s12877-022-03522-5
License
CC BY 4.0
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Shih-Wei Yang
Shih-Wei Yang
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Yuan-Yuei Chen
Yuan-Yuei Chen
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Wei-Liang Chen
Abstract and Figures
Background
Sarcopenia is a common skeletal muscle disorder in the elderly population. The patients with sarcopenia increased the cost of care and the risk for hospitalization. Magnesium deficiency might increase reactive oxygen species and protein damage. The purpose of our study was to demonstrate the relation between oral intake magnesium and sarcopenia by European Working Group on Sarcopenia in Older People (EWGSOP) 2 definition.
Methods
Our study included 2532 participants with 1310 males and 1222 females. The multiple logistic regression model was designed to test the cross-sectional protective outcome of oral intake magnesium for sarcopenia.
Results
Oral intake magnesium had a protective outcome with sarcopenia (odd ratio (OR) = 0.997, 95% CI = 0.996, 0.998, P < 0.001). After fully adjusted, the significance persisted with OR = 0.998 (95% CI = 0.996, 0.999, P < 0.001).
Conclusion
Results of the present study showed the dose dependent relationship between oral intake magnesium and sarcopenia. Sufficient oral intake magnesium might prevent patient from sarcopenia.
<here is a image 7f396ecf79843f3e-eeb6bad8c812978e>
Flow chart representing the steps of analysis performed in the study …
Figures - available from: BMC Geriatrics
Yang etal. BMC Geriatrics (2022) 22:816
https://doi.org/10.1186/s12877-022-03522-5
RESEARCH
Association betweenoral intake magnesium
andsarcopenia: across-sectional study
Shih‑Wei Yang 1,2,3, Yuan‑Yuei Chen 2,5 and Wei‑Liang Chen 2,4*
Abstract
Background:Sarcopenia is a common skeletal muscle disorder in the elderly population. The patients with sarcope‑
nia increased the cost of care and the risk for hospitalization. Magnesium deficiency might increase reactive oxygen
species and protein damage. The purpose of our study was to demonstrate the relation between oral intake magne‑
sium and sarcopenia by European Working Group on Sarcopenia in Older People (EWGSOP) 2 definition.
Methods:Our study included 2532 participants with 1310 males and 1222 females. The multiple logistic regression
model was designed to test the cross‑sectional protective outcome of oral intake magnesium for sarcopenia.
Results:Oral intake magnesium had a protective outcome with sarcopenia (odd ratio (OR) =0.997, 95% CI = 0.996,
0.998, P<0.001). After fully adjusted, the significance persisted with OR =0.998 (95% CI = 0.996, 0.999, P< 0.001).
Conclusion:Results of the present study showed the dose dependent relationship between oral intake magnesium
and sarcopenia. Sufficient oral intake magnesium might prevent patient from sarcopenia.
Keywords:Magnesium, Sarcopenia
Introduction
Sarcopenia, one of the primary diseases of the elderly
population, is a common skeletal muscle disorder that
involves the progressive loss of skeletal muscle function
and mass [ 1]. To date, the most widely cited diagnostic
criteria is that proposed by the European Working Group
on Sarcopenia in Older People (EWGSOP) and updated
as EWGSOP2 in 2019 [ 2]. According to EWGSOP2, mus -
cle strength, muscle quantity and physical performance
were measured to evaluate sarcopenia [ 2]. Loss of skeletal
muscle mass and function causes the risk of falls, frac -
tures, physical disability, use of hospital services, poor
quality of life, and death [ 3]. e patients with sarcopenia
increase the risk for hospitalization and the cost of care
during hospitalization [ 4]. In 2000, there was approxi -
mately $18.5 billion ($10.8 billion in men, $7.7 billion in
women) health-care cost in the America due to sarcope -
nia [ 5]. Malnutrition plays a key role in the pathogenesis
of sarcopenia [ 6] [ 7] [ 8]. ere was a growing evidence
base linking nutrition with greater muscle strength and
better physical performance outcomes in patient with
sarcopenia [ 9]. However, these articles paid more atten -
tion on protein [ 10], long-chain polyunsaturated fatty
acids [ 11], vitamin D [ 12], and antioxidant nutrients [ 13 ].
Best to our knowledge, no previous data had discussed
oral intake electrolyte and sarcopenia.
Magnesium is the second most intracellular cation
after potassium in human. Several metabolic pathways
and fundamental cellular activities including peptide and
DNA synthesis, signal transduction, blood glucose con -
trol, stimulus-contraction coupling, stimulus-secretion
coupling, and ion channel translocation related to mag -
nesium [ 14]. Total body magnesium content is mainly
located in bone and soft tissue [ 15]. e recommended
daily intake of magnesium is 320 and 420mg for adult
Open Access
*Correspondence: [email protected]
4 Division of Geriatric Medicine, Department of Family and Community
Medicine, Tri‑Service General Hospital; and School of Medicine, National
Defense Medical Center, Number 325, Section 2, Chang‑gong Rd, Nei‑Hu
District, 114 Taipei, Taiwan
Page 2 of 8
Yang etal. BMC Geriatrics (2022) 22:816
women and men, respectively. Absorption mainly (80–
90%) occurs in the jejunum and colon through passive
and active transport [ 16]. Reabsorption of magnesium
mainly occurred in the thin ascending limb of Henle
(70%) and partially occurred in the proximal tubule and
distal collecting tubule. Hypomagnesemia related to
several clinical manifestations including neuromuscu -
lar and cardiovascular manifestations. Muscle spasms,
muscle cramps, tremors, atrial fibrillation and ventricular
arrhythmias were the specific symptoms of hypomagne -
semia [ 17]. Further, electrolyte and hormone imbalanced
including hypocalcemia, hypokalemia, and hypoparathy -
roidism were also associated with hypomagnesemia.
According to a previous study, magnesium deficiency
might increase reactive oxygen species and lipid and pro -
tein damage and associate with damage of muscle [ 18 ].
e purpose of our study was to demonstrate the relation
between oral intake magnesium and sarcopenia by EWG -
SOP2 definition.
Materials andmethods
Study design andparticipants
We conducted a cross-sectional study using the National
Health and Nutrition Examination Survey (NHANES)
database in 1999-2002 period. e data included over -
all home interviews and laboratory assessments con-
ducted by the National Center for Health Statistics
(NCHS). Institutional Review Board (IRB) approval and
documented consent was obtained from participants.
e exclusion criteria were dysphagia; history of gas -
trointestinal tract disease; inflammatory bowel disease;
history of cancer; participation in resistance training;
participation regularly using steroids, diuretics, hor -
mones, and growth factors; and subjects without com-
plete clinical data, laboratory results, or medical history.
(Fig. 1).
EWGSOP2 guideline
e EWGSOP published a sarcopenia definition in
2010 [ 19]. In early 2018, the Working Group met again
(EWGSOP2) to update the definition of sarcopenia.
In the EWGSOP2, low muscle strength as the primary
parameter of sarcopenia. A sarcopenia diagnosis is con -
firmed by low muscle strength with the presence of low
muscle quantity or quality. Severe sarcopenia was con -
sidered with three components, including low muscle
strength, low muscle quantity/quality and low physical
performance.
Measurement: muscle quality index
e NHANES documentation provided measurement
of the muscle quality index. We listed these methods
and cut points to estimate components of muscle quality
index in Table-S1.
Fig. 1 Flow chart representing the steps of analysis performed in the study
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 3 of 8
Yang etal. BMC Geriatrics (2022) 22:816
Measurement oforal intake magnesium
Total magnesium intake in milligrams per day calcu-
lated from dietary information with 24hours dietary
recalls. Subjects were required to recall all intakes in one
day period prior before the questionnaire. A measuring
guides and a food model booklet was available for partici -
pants to help in reporting food amounts.
Assessment ofCovariables
A computer-aided individual interviewing method was
used for the collection of participants’ information.
Demographic information, including sex, age, race was
assembled. Smoking and drinking status were assessed by
a detailed survey. We also recorded self-reported comor -
bidities, including cancer and cardiovascular disease.
Based on the guidelines of Centers for Disease Control
and Prevention, biochemical analyses in the database
used standard methods.
Statistical analysis
SPSS (Version 18.0 for Windows, SPSS, Inc., Chicago,
IL) was used for all the statistical analyses. Descriptive
information of continuous and categorical covariates is
presented as the mean (standard deviation) and several
observations with percentage (%). Continuous variables
were used Student’s ttests and categorical variables were
used the χ 2 test for the comparison of characteristics and
covariates across subgroups. e odds ratio (OR) with
95% confidence interval (CI) for sarcopenia was esti -
mated by multivariate logistic regression analysis. We
analyzed the association between oral intake magnesium
and muscle quality index using a linear regression model.
e beta coefficient is the degree of change in the muscle
quality index for every 1-unit of change in the oral intake
magnesium. e 2-sided Pvalues less than 0.05 indicated
significant differences. Four extended models were used
for covariate adjustments. Model 1 examined unadjusted
odd ratio (ORs). Model 2 presented ORs after adjusting
sex, age, and race. Model 3 was adjusted for the variables
included in Model 2 + the body mass index (BMI), Albu -
min, total calcium, creatinine, fasting glucose, C-reactive
protein (CRP), daily carbohydrate intake, daily total fat
intake, and daily protein intake. e variables in model
3 + the smoking history, comorbidities and education
level were adjusted for model 4.
Result
Characteristics ofthesubjects
2532 subjects with 1310 males and 1222 females were
included in our study. We separated subjects into two
groups based on the EWGSOP definition of sarcope -
nia. (Table 1) e mean age were 73.14 ± 9.59 years
in the sarcopenic group and 63.90 ± 9.32 yearsinthe
non-sarcopenic group, respectively. It was also observed
that the mean oral intake magnesium amount was higher
for non-sarcopenic group at 276.06 ± 142.04 compared to
235.97 ± 112.61 in the sarcopenic group ( P < 0.001).
Association betweenoral intake magnesium
andsarcopenia
In Table 2, we showed the association between differ-
ent oral intake elements and sarcopenia. After adjusted
all covariates, the association only showed in oral intake
magnesium and potassium.
In Table 3, we performed logistic regression to exam
the association between oral intake magnesium and
sarcopenia. In Model 1, oral intake magnesium was sig -
nificantly associated with sarcopenia (OR = 0.997,95%
confidence interval (CI) = 0.996,0.998, P< 0.001)esig -
nificance persisted after adjusted all covariates in Model
4 (OR = 0.998, 95% CI = 0.996,0.999, P= 0.007).
Sensitivity analysis
Logistic regression was used for sensitivity analysis to
compare the sarcopenic and non-sarcopenic groups and
quartiles of oral intake magnesium. Similar outcomes
were found for the relation between oral intake magne -
sium and sarcopenia in Table 4. In the unadjusted model,
the highest quartile of oral intake magnesium had an
odds ratio of 0.400 to be associated with sarcopenia (95%
CI = 0.282,0.568, P <0.001). e odds ratio of subjects
with the highest quartile of oral intake magnesium would
have sarcopenia was 0.468 (0.274, 0.799) times fewer than
subjects with the lowest quartile of oral intake magne -
sium after fully adjusted.
Correlation betweenoral intake magnesium andmuscle
quality index
In Table 5, the coefficients of oral intake magnesium and
muscle strength, SMI, and gait speed were 0.207, 0.134,
and − 0.137. e linear regression analysis of the relation
of oral intake magnesium and muscle quality index was
showed in Table 6. e association of oral intake mag -
nesium and muscle strength (β = 0.145, 95% CI = 0.118,
0.172), SMI (β = 0.001, 95% CI = 0.001, 0.002), and gait
speed (β = − 0.000365, 95% CI = − 0.000471,− 0.000258)
had statistically significant result ( P<0.001). After fully
adjusted, the association of oral intake magnesium and
muscle strength (β = 0.048, 95% CI = 0.012, 0.083), SMI
(β = − 0.000149, 95% CI =− 000434, 0.000136), and gait
speed (β = − 0.000171, 95% CI =− 0.000338,− 0.000005).
Discussion
In our presented study, the relationship between oral
intake magnesium and the components of sarcopenia
was closely inspected in 2532 adult population. Our
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Yang etal. BMC Geriatrics (2022) 22:816
Table 1 Characteristics of study participants
Characteristics of study participantsSarcopeniaNon-sarcopenia Pvalue
( n = 390)( n =2142)
Age at screening 73.14 (9.59)63.90 (9.32)0.227
Body mass index (kg/m 2 ) 27.89 (4.70)28.79 (5.58)0.421
Creatinine (mg/dL) 0.92 (0.67)0.88 (0.50)0.001
Glucose (mg/dL) 107.81 (43.25)102.39 (36.39)0.001
C-reactive protein (mg/dL) 0.57 (0.98)0.46 (0.75)0.008
Albumin(g/dL) 4.22 (0.31)4.31 (0.28)0.211
Total Calcium (mg/dL) 9.47 (0.44)9.43 (0.40)0.178
Magnesium (mg/dL) 235.97 (112.61)276.06 (142.04) < 0.001
Carbohydrate (gm) 210.63 (94.13)239.32 (114.20)0.002
Total fat (gm) 61.79 (31.69)72.23 (43.07) < 0.001
Protein (gm) 64.26 (28.22)74.22 (37.50) < 0.001
Dietary ber (gm) 14.16 (8.09)16.78 (10.76) < 0.001
Comorbidity 0.92 (0.99)0.60 (0.89)0883
Gender (male) 34.1%54.9% < 0.001
Race/ethnicity
Mexican American 15.1%19.2%0.280
Other Hispanic 4.4%4.2%
Non-Hispanic White 63.1%59.8%
Non-Hispanic Black 14.1%14.6%
Smoking 52.1%43.5%0.008
Drinking 53.5%67.6% < 0.001
Education level past high school 57.8%65.8%0.003
Congestive heart failure 7.4%3.2% < 0.001
Coronary heart disease 9.2%6.8%0.109
Angina 6.9%5.6%0.291
Heart attack 9.0%5.7%0.016
Stroke 0.5%0.7%1.000
Emphysema 6.2%2.4% < 0.001
Table 2 The association between different oral intake elements and sarcopenia
BMI Body mass index,CRP C-reactive protein
Adjusted covariates:
Model 1 = Unadjusted
Model 2 =Adjusted age, sex, race/ethnicity
Model 3 = Model 2 +BMI, Albumin, total calcium, creatinine, fasting glucose, CRP, daily carbohydrate intake, daily total fat intake, and daily protein intake
Model 4 = Model 3 +drinking history, smoking history, comorbidities, and education level
Components of sarcopenia
Oral intake
elements Model 1 P ValueModel 2 P ValueModel 3 P ValueModel 4 P Value
magnesium (mg) 0.997 (0.996‑0.998) < 0.0010.999 (0.998‑1.000)0.0280.997 (0.996‑0.999)0.0030.998 (0.996‑0.999)0.007
Calcium (mg) 1.000 (0.999‑1.000)0.0471.000 (1.000‑1.000)0.8351.000 (1.000‑1.000)0.9881.000 (1.000‑1.000)0.883
Phosphorate (mg) 1.000 (0.999‑1.000) < 0.0011.000 (1.000‑1.000)0.4911.000 (0.999‑1.000)0.3571.000 (0.999‑1.000)0.442
Iron (mg) 0.981 (0.968‑0.996)0.0100.993 (0.979‑1.008)0.3600.992 (0.973‑1.011)0.4150.994 (0.975‑1.014)0.567
Zinc (mg) 0.966 (0.948‑0.985) < 0.0010.992 (0.975‑1.009)0.3350.986 (0.963‑1.010)0.2620.988 (0.966‑1.011)0.305
Copper (mg) 0.925 (0.804‑1.064)0.2761.042 (0.966‑1.125)0.2881.040 (0.962‑1.124)0.3261.046 (0.968‑1.131)0.255
Sodium (mg) 1.000 (1.000‑1.000) < 0.0011.000 (1.000‑1.000)0.8711.000 (1.000‑1.000)0.5331.000 (1.000‑1.000)0.508
Potassium (mg) 1.000 (1.000‑1.000) < 0.0011.000 (1.000‑1.000)0.0471.000 (1.000‑1.000)0.0171.000 (1.000‑1.000)0.034
Yang etal. BMC Geriatrics (2022) 22:816
results demonstrated strong relationships between oral
intake magnesium and sarcopenia. Otherwise, based on
the EWGSOP2, three components of sarcopenia all pre -
sented correlation with oral intake magnesium. To date,
our study was the first article investigating the relation
of oral intake magnesium and sarcopenia in a repre -
sentative sample of the United States adult population.
Due to complicated pathogenesis, the development
of sarcopenia remained controversial in the medi -
cal field. Previous study had mentioned different fac -
tors which associated with sarcopenia [ 20]. One of the
main factors induced sarcopenia was the mitochondrial
dysfunction [ 21]. Mitochondrial oxidative stress and
dysfunction could be induced by intracellular mag -
nesium deficiency [ 22]. Downregulating the electron
transport chain increased the production of reactive
oxygen species [ 23]. Low level of intracellular magne -
sium also suppressed the antioxidant defense system
and reduced proteins such as superoxide dismutase,
catalase, and glutathione [ 24]. Intracellular magnesium
sufficient, in contrast, was found to suppress mitochon -
drial reactive oxygen species and improve mitochon -
drial function [ 25].
Intracellular and extracellular concentration of mag -
nesium had thought to impact the synthesis of DNA and
protein [ 26]. Magnesium regulated the onset of protein
synthesis in activated frog oocytes and its rate in lym -
phocytes. Magnesium determines the onset of protein
synthesis through the phosphatidylinositol-3-OH kinase
Table 3 Result of logistic regression predicting the presence of sarcopenia by oral intake magnesium
BMI Body mass index,CRP C-reactive protein
Adjusted covariates:
Model 1 = Unadjusted
Model 2 =Adjusted age, sex, race/ethnicity
Model 3 = Model 2 +BMI, Albumin, total calcium, creatinine, fasting glucose, CRP, daily carbohydrate intake, daily total fat intake, and daily protein intake
Model 4 = Model 3 +drinking history, smoking history, comorbidities, and education level
Components of sarcopenia
Model 1 P ValueModel 2 P Value Model 3 PValue Model 4 PValue
Oral intake magnesium
(mg) 0.997 (0.996‑0.998) < 0.0010.999 (0.998‑1.000)0.0280.997 (0.996‑0.999)0.0030.998 (0.996‑0.999)0.007
Table 4 Association between quartiles of oral intake
magnesium and sarcopenia
BMI Body mass index,CRP C-reactive protein,CI Condence interval,OR Odds
ratio, QQuartile
Adjusted covariates:
Model 1 = Unadjusted
Model 2 =Adjusted age, sex, race/ethnicity
Model 3 = Model 2 +BMI, Albumin, total calcium, creatinine, fasting glucose,
CRP, daily carbohydrate intake, daily total fat intake, and daily protein intake
Model 4 = Model 3 +drinking history, smoking history, comorbidities, and
education level
Sarcopenia
ModelsQuartiles of oral
intake magnesium OR (95% CI) P Value
Model 1Q2 v.s. Q10.937 (0.701-1.251)0.658
Q3 v.s. Q10.767 (0.568-1.036)0.084
Q4 v.s. Q10.400 (0.282-0.568) < 0.001
Model 2Q2 v.s. Q10.870 (0.635-1.192)0.387
Q3 v.s. Q10.871 (0.628-1.208)0.409
Q4 v.s. Q10.615 (0.421-0.900)0.012
Model 3Q2 v.s. Q10.782 (0.555-1.102)0.160
Q3 v.s. Q10.767 (0.518-1.134)0.183
Q4 v.s. Q10.453 (0.267-0.767)0.003
Model 4 Q2 v.s. Q10.775 (0.548-1.097)0.150
Q3 v.s. Q10.794 (0.534-1.181)0.255
Q4 v.s. Q10.468 (0.274-0.799)0.005
Table 5 Pearson correlation coefficient between oral intake magnesium and muscle quality index
Components of sarcopenia
Average peak force
(Newtons) Skeletal muscle indexGait speed
Correlation P ValueCorrelation PValueCorrelation P
Value
Oral intake magnesium
(mg) 0.207 < 0.001 0.134< 0.001 −0.137< 0.001
(PI-3-K) pathway at mechanistic target of rapamycin
(mTOR) phosphorylation of two translation-regulating
proteins [ 27 , 28]. One study measured intracellular con -
centration of magnesium and the rate of protein and
DNA synthesis [ 29]. At the same magnesium concentra -
tion, the rate of DNA synthesis peaked as protein synthe-
sis. is article provided strong evidence of magnesium
as a regulator of DNA and protein synthesis.
Low magnesium status is also reported to associate
with increasing reactive oxygen species and inflamma -
tion. Several articles had discussed that higher magne-
sium consumption was related to lower serum CRP [ 30 ].
People who takes magnesium at least 50mg/day were
22% less likely to have higher level of plasma CRP com -
pared with those dietary magnesium taking less than
50% of the recommended dietary allowance [ 31]. Magne -
sium supplement is associated with a lower serum CRP
in these studies. One linear regression analysis of 3173
females aged 50–79years found that magnesium sup -
plement was associated with lower serum inflammatory
biomarkers, such as CRP, interlukin-6 (IL-6), and tumor
necrosis factor-α receptor 2 (TNF-α-R2, [ 32]].
Our study has several strengths. We screened the sar -
copenia clearly by using EWGSOP2 guideline. We also
screened other oral intake elements initially in our study.
A large adult sample was included to discuss the protec -
tive outcome of oral intake magnesium for sarcopenia. In
the current study, sufficient oral intake magnesium could
reduce the incidence of sarcopenia. is result is not only
effective, but also economical for preventing from sarco -
penia in the public health system.
However, some limitations in our study should be iden -
tified. First, we used a cross-sectional database in which
the oral intake magnesium was determined at single
measure instead of a long observational period. en,
some information such as participants’ education levels
and medical histories were based on questionnaires. e
recall bias and other unknown bias might distort our
results. ird, total magnesium intake was calculated
from 24hours dietary recalls and measured by guides and
a food model booklet. is method caused inaccuracy of
daily oral intake magnesium. Lastly, the factors of drug
consumption, participants’ cognitive and nutritional sta -
tus were not included our results. us, the confounding
bias could not be estimated.
Conclusion
In our presented study, we identified the protective out-
come of oral intake magnesium with sarcopenia. e
significance especially showed in muscle strength and
gait speed. Otherwise, dose dependent relationship was
observed between oral intake magnesium and sarco -
penia. Our findings suggested that sufficient oral intake
magnesium might prevent patient from sarcopenia. Fur -
ther prospective studies may be warranted to find the
curative effect of oral intake magnesium in the patient
with sarcopenia.
Abbreviations
EWGSOP: European Working Group on Sarcopenia in Older People; NHANES:
National Health and Nutritional Examination Survey; NCHS: National Center
for Health Statistics; DXA: Dual‑energy X‑ray absorptiometry; SMI: Skeletal
muscle index; BMI: Body mass index; CRP: C‑Reactive protein; OR: Odds ratio;
CI: Confidence interval; ROC: Receiver operating characteristic curve; AUROC:
Area under receiver operating characteristic curve; IL‑6: Interlukin‑6; TNF‑α‑R2:
Tumor necrosis factor‑α receptor 2.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s12877‑ 022‑ 03522‑5 .
Additional le1 Supplement Table1. Standard measurement protocol
of muscle quality index in NHANES.
Table 6 Association between oral intake magnesium and muscle quality index
BMI Body mass index,CRP C-reactive protein,CI Condence interval,OR Odds ratio
Adjusted covariates:
Model 1 = Unadjusted
Model 2 =Adjusted age, sex, race/ethnicity
Model 3 = Model 2 +BMI, Albumin, total calcium, creatinine, fasting glucose, CRP, daily carbohydrate intake, daily total fat intake, and daily protein intake
Model 4 = Model 3 +drinking history, smoking history, comorbidities, and education level
Muscle quality index
Average peak force (Newtons)Skeletal muscle indexLow gait speed
ModelsOR (95% CI) PValueOR (95% CI) PValueOR (95% CI) P Value
Model 1 0.145 (0.118‑0.172) < 0.0010.001 (0.001‑0.002) < 0.001 −0.000365( −0.000471‑ −0.000258)< 0.001
Model 2 0.043 (0.020‑0.066) < 0.001 −0.000356 ( − 0.001‑ −0.000032) 0.031 −0.000253 ( −0.000359‑ −0.000147)< 0.001
Model 3 0.060 (0.025‑0.096)0.001 −0.000188 ( − 0.000472‑0.000096) 0.195 −0.000264 ( − 0.000433‑ −0.000096)0.002
Model 4 0.048 (0.012‑0.083)0.009 −0.000149 ( −000434‑0.000136)0.306 −0.000171 ( − 0.000338‑ −0.000005)0.044
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 8
Yang etal. BMC Geriatrics (2022) 22:816
Acknowledgements
Not applicable.
Authors’contributions
Shih‑Wei Yang and Wei‑Liang Chen designed the initial study. Shih‑Wei Yang
also managed and retrieved the data, contributed to primary data analysis
and explanation, and drafted the initial script. Shih‑Wei Yang, Yuan‑Yuei Chen,
and Wei‑Liang Chen decided on the methods of data collection. Shih‑Wei
Yang and Wei‑Liang Chen were both responsible for the decisions of data
analysis. Wei‑Liang Chen conceptualized the study, inspected all sides of the
study, critically reviewed, and revised the initial script, and approved the final
manuscript as submitted. All authors meet the ICMJEcriteria for authorship.
Funding
All authors did not receive any specific grant from funding agencies in the
public, commercial, or not‑for‑profit sectors.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from
the NHANES database, https:// www. cdc. gov/ nchs/ nhanes/ index. htm.
Declarations
Ethics approval and consent to participate
The health data collection protocols were performed by the CDC’s NCHS and
approved by the NCHS IRB (Protocol Number: Protocol #98‑12). All informed
consents had been obtained from the eligible subjects before initiating data
collection and NHANES health examinations. All methods were performed in
accordance with the relevant guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
There is no support, financial or otherwise received from any organization that
may have an interest in the submitted work, and there are no other relation‑
ships or activities that could appear to have influenced the submitted work.
Author details
1 Division of Plastic and Reconstruction Surgery, Department of Surgery, Tri‑service
General Hospital, National Defense Medical Center,Taipei, Taiwan, Republic
of China. 2Division of Family Medicine, Department of Family and Community
Medicine, Tri‑Service General Hospital; and School of Medicine, National Defense
Medical Center, Taipei, Taiwan, Republic of China. 3Department of General
Medicine, Tri‑Service General Hospital; and School of Medicine, National Defense
Medical Center, Taipei, Taiwan, Republic of China. 4Division of Geriatric Medicine,
Department of Family and Community Medicine, Tri‑Service General Hospital;
and School of Medicine, National Defense Medical Center, Number 325, Section 2,
Chang‑gong Rd, Nei‑Hu District, 114 Taipei,Taiwan. 5Department of Pathology,
Tri‑Service General Hospital Songshan Branch; and School of Medicine, National
Defense Medical Center,Taipei, Taiwan, Republic of China.
Received: 24 July 2022 Accepted: 10 October 2022
References
1.Bauer J, Morley JE, Schols A, Ferrucci L, Cruz‑Jentoft AJ, Dent E, et al.
Sarcopenia: a time for action. An SCWD Position Paper J Cachexia
Sarcopenia Muscle. 2019;10(5):956–61.
2.Cruz‑Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al.
Sarcopenia: revised European consensus on definition and diagnosis.
Age Ageing. 2019;48(1):16–31.
3.Santilli V, Bernetti A, Mangone M, Paoloni M. Clinical definition of sarco ‑
penia. Clin Cases Miner Bone Metab. 2014;11(3):177–80.
4.Sousa AS, Guerra RS, Fonseca I, Pichel F, Ferreira S, Amaral TF. Financial impact
of sarcopenia on hospitalization costs. Eur J Clin Nutr. 2016;70(9):1046–51.
5.Dodds RM, Roberts HC, Cooper C, Sayer AA. The epidemiology of
sarcopenia. J Clin Densitom. 2015;18(4):461–6.
6.Bloom I, Shand C, Cooper C, Robinson S, Baird J. Diet quality and sarco ‑
penia in older adults: a systematic review. Nutrients. 2018;10(3).
7.de Sire A, Ferrillo M, Lippi L, Agostini F, de Sire R, Ferrara PE, et al. Sarco ‑
penic dysphagia, malnutrition, and Oral frailty in elderly: a comprehen ‑
sive review. Nutrients. 2022;14(5).
8.Avola M, Mangano GRA, Testa G, Mangano S, Vescio A, Pavone V, et al.
Rehabilitation strategies for patients with femoral neck fractures in
sarcopenia: a narrative review. J Clin Med. 2020;9(10).
9.Robinson S, Cooper C, Aihie SA. Nutrition and sarcopenia: a review of
the evidence and implications for preventive strategies. J Aging Res.
2012;2012:510801.
10.Wolfe RR, Miller SL, Miller KB. Optimal protein intake in the elderly. Clin
Nutr. 2008;27(5):675–84.
11.Calder PC. N‑3 polyunsaturated fatty acids, inflammation, and inflam ‑
matory diseases. Am J Clin Nutr. 2006;83(6 Suppl):1505s–19s.
12.Hamilton B. Vitamin D and human skeletal muscle. Scand J Med Sci
Sports. 2010;20(2):182–90.
13.Semba RD, Ferrucci L, Sun K, Walston J, Varadhan R, Guralnik JM, et al.
Oxidative stress and severe walking disability among older women.
Am J Med. 2007;120(12):1084–9.
14.Gröber U, Schmidt J, Kisters K. Magnesium in prevention and therapy.
Nutrients. 2015;7(9):8199–226.
15.Van Laecke S. Hypomagnesemia and hypermagnesemia. Acta Clin
Belg. 2019;74(1):41–7.
16.de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications
for health and disease. Physiol Rev. 2015;95(1):1–46.
17.Gragossian A, Bashir K, Friede R. Hypomagnesemia. In: StatPearls.
Treasure Island. FL: StatPearls Publishing; 2022.
18.Rock E, Astier C, Lab C, Vignon X, Gueux E, Motta C, et al. Dietary mag ‑
nesium deficiency in rats enhances free radical production in skeletal
muscle. J Nutr. 1995;125(5):1205–10.
19.Cruz‑Jentoft AJ, Baeyens JP, Bauer JM, BoirieY, CederholmT, Landi F,
et al. Sarcopenia: European consensus on definition and diagnosis:
report of the European working group on sarcopenia in older people.
Age Ageing. 2010;39(4):412–23.
20.Dhillon RJ, Hasni S. Pathogenesis and Management of Sarcopenia. Clin
Geriatr Med. 2017;33(1):17–26.
21.Marzetti E, Calvani R, Cesari M, Buford TW, Lorenzi M, Behnke
BJ, et al. Mitochondrial dysfunction and sarcopenia of aging:
from signaling pathways to clinical trials. Int J Biochem Cell Biol.
2013;45(10):2288–301.
22.Rodríguez‑Zavala JS, Moreno‑Sánchez R. Modulation of oxidative
phosphorylation by Mg2 +in rat heart mitochondria. J Biol Chem.
1998;273(14):7850–5.
23.Kramer JH, Misík V, Weglicki WB. Magnesium‑deficiency potenti ‑
ates free radical production associated with postischemic injury
to rat hearts: vitamin E affords protection. Free Radic Biol Med.
1994;16(6):713–23.
24.Shah NC, Liu JP, Iqbal J, Hussain M, Jiang XC, Li Z, et al. Mg deficiency
results in modulation of serum lipids, glutathione, and NO synthase
isozyme activation in cardiovascular tissues: relevance to de novo syn ‑
thesis of ceramide, serum mg and atherogenesis. Int J Clin Exp Med.
2011;4(2):103–18.
25.Liu M, Jeong EM, Liu H, Xie A, So EY, Shi G, et al. Magnesium sup ‑
plementation improves diabetic mitochondrial and cardiac diastolic
function. JCI insight. 2019;4(1).
26.Rubin H. Intracellular free mg (2 +) and MgATP (2‑) in coordinate
control of protein synthesis and cell proliferation. In: Vink R, Adelaide
NM, editors. Magnesium in the central nervous system. AU: University
of Adelaide Press; 2011.
27.Richardson CJ, Schalm SS, Blenis J. PI3‑kinase and TOR: PIKTORing cell
growth. Semin Cell Dev Biol. 2004;15(2):147–59.
28.Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell.
2000;103(2):253–62.
29.Rubin H. Central roles of Mg2 +and MgATP2‑ in the regulation of
protein synthesis and cell proliferation: significance for neoplastic
transformation. Adv Cancer Res. 2005;93:1–58.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
<here is a image 714f4f2e1acc7ea4-54fe2a89d19538d1> Alessandro de Sire
<here is a image 542f85ee437bd970-cc49743460cfbcc3> Martina Ferrillo
<here is a image 9b6d01422c214bca-f90f1c923bbae368> Lorenzo Lippi
<here is a image d591ef712658408a-26f9024f0004fb2e> Mario Migliario
Frailty is a highly prevalent condition in the elderly that has been increasingly considered as a crucial public health issue, due to the strict correlation with a higher risk of fragility fractures, hospitalization, and mortality. Among the age-related diseases, sarcopenia and dysphagia are two common pathological conditions in frail older people and could coexist leading to dehydration and malnutrition in these subjects. “Sarcopenic dysphagia” is a complex condition characterized by deglutition impairment due to the loss of mass and strength of swallowing muscles and might be also related to poor oral health status. Moreover, the aging process is strictly related to poor oral health status due to direct impairment of the immune system and wound healing and physical and cognitive impairment might indirectly influence older people’s ability to carry out adequate oral hygiene. Therefore, poor oral health might affect nutrient intake, leading to malnutrition and, consequently, to frailty. In this scenario, sarcopenia, dysphagia, and oral health are closely linked sharing common pathophysiological pathways, disabling sequelae, and frailty. Thus, the aim of the present comprehensive review is to describe the correlation among sarcopenic dysphagia, malnutrition, and oral frailty, characterizing their phenotypically overlapping features, to propose a comprehensive and effective management of elderly frail subjects.
Clinical Medicine Rehabilitation Strategies for Patients with Femoral Neck Fractures in Sarcopenia: A Narrative Review
Full-text available
Sep 2020
<here is a image f537c6e77cf37383-a891c36e5db8bbc8> Marianna Avola
<here is a image 8f97d6a0a8027da0-5d444d31a530118f> Gianluca Testa
Sebastiano Mangano
<here is a image e03ab41486d4bdc0-a724b9c379dd6239> Giulia Rita Agata Mangano
Sarcopenia is defined as a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. It has been identified as one of the most common comorbidities associated with femoral neck fracture (FNF). The aim of this review was to evaluate the impact of physical therapy on FNF patients' function and rehabilitation. The selected articles were randomized controlled trials (RCTs), published in the last 10 years. Seven full texts were eligible for this review: three examined the impact of conventional rehabilitation and nutritional supplementation, three evaluated the effects of rehabilitation protocols compared to new methods and a study explored the intervention with erythropoietin (EPO) in sarcopenic patients with FNF and its potential effects on postoperative rehabilitation. Physical activity and dietary supplementation are the basic tools of prevention and rehabilitation of sarcopenia in elderly patients after hip surgery. The most effective physical therapy seems to be exercise of progressive resistance. Occupational therapy should be included in sarcopenic patients for its importance in cognitive rehabilitation. Erythropoietin and bisphosphonates could represent medical therapy resources.
Sarcopenia: A Time for Action. An SCWD Position Paper
Sep 2019
<here is a image 1f76f9d3bed3cba9-0caca4e9a972c51c> Juergen M Bauer
John E. Morley
Annemie M.W.J. Schols
Stefan D. Anker
The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.
Sarcopenia: revised European consensus on definition and diagnosis
May 2019
Alfonso J. Cruz-Jentoft
Gϋlistan Bahat
Jϋrgen Bauer
<here is a image 1c3d3375e3709f8f-0154db7c9b950a1a> Antonio Cherubini
In the original version of the above paper there was an error in Table 3, which shows the recommended cut-off points for ASM/height² in women. The cut-off point was given as <6.0 kg/m², but the correct value is <5.5 kg/m². This has now been corrected online. The authors wish to apologise for this error.
Sarcopenia: revised European consensus on definition and diagnosis
Oct 2018
AGE AGEING
Alfonso J. Cruz-Jentoft
<here is a image 8dc2b9d0866ad5be-bbd8845c03e031ec> Gulistan Bahat
<here is a image 1f76f9d3bed3cba9-0caca4e9a972c51c> Juergen M Bauer
| https://www.researchgate.net/publication/364643873_Association_between_oral_intake_magnesium_and_sarcopenia_a_cross-sectional_study |
Peacenvironmentalism | Freepress.org
Remarks at North Carolina Peace Action Event in Raleigh, N.C., August 23, 2014.Thank you for inviting me, and thank you to North Carolina Peace Action, and to John Heuer whom I consider a tireless selfless and inspired peacemaker himself. Can we thank John?It's an honor for me to have a role in honoring the 2014 Student Peacemaker, iMatter Youth North Carolina. I've followed what iMatter has been doing around the country for years, I've sat in on a court case they brought in Washington, D.C., I've shared a stage with them at a public event, I've organized an online petition with them at RootsAction.org, I've written about them and watched them inspire writers like Jeremy Brecher whom I recommend reading. Here is an organization acting in the interests of all future generations of all species and being led -- and led well -- by human kids. Can we give them some applause?
Peacenvironmentalism
Remarks at North Carolina Peace Action Event in Raleigh, N.C., August 23, 2014.
Thank you for inviting me, and thank you to North Carolina Peace Action, and to John Heuer whom I consider a tireless selfless and inspired peacemaker himself. Can we thank John?
It's an honor for me to have a role in honoring the 2014 Student Peacemaker, iMatter Youth North Carolina. I've followed what iMatter has been doing around the country for years, I've sat in on a court case they brought in Washington, D.C., I've shared a stage with them at a public event, I've organized an online petition with them at RootsAction.org, I've written about them and watched them inspire writers like Jeremy Brecher whom I recommend reading. Here is an organization acting in the interests of all future generations of all species and being led -- and led well -- by human kids. Can we give them some applause?
But, perhaps revealing the short-sightedness and self-centeredness of myself as a member of a species that didn't evolve to manage a whole planet, I'm especially happy to be recognizing iMatter Youth North Carolina because my own niece Hallie Turner and my nephew Travis Turner are part of it. They deserve LOTS of applause.
And the full iMatter planning team, I'm told, is represented tonight as well by Zack Kingery, Nora White, and Ari Nicholson. They should have even more applause.
I take complete credit for Hallie and Travis's work, because although I didn't really teach them anything, I did, before they were born, tell my sister she should go to our high school reunion, at which she met the man who became my brother in law. Without that, no Hallie and no Travis.
However, it was my parents -- who I suppose by the same logic (although in this case I of course reject it) get complete credit for anything I do -- it was they who took Hallie to her first rally, at the White House protesting a tar sands pipeline. I'm told that Hallie didn't know what it was all about at first or why the good people were being arrested, instead of the people committing the offenses against our loved ones and our earth being arrested. But by the end of the rally Hallie was right in the thick of it, wouldn't leave until the last person had gone off to jail for justice, and she pronounced the occasion the most important day of her life thus far, or words to that effect.
Perhaps, as it turns out, that was an important day, not just for Hallie but also for iMatter Youth North Carolina, and, who knows, just maybe -- like the day Gandhi was thrown off a train, or the day Bayard Rustin talked Martin Luther King Jr. into giving up his guns, or the day a teacher assigned Thomas Clarkson to write an essay on whether slavery was acceptable -- it will eventually turn out to have been an important day for more of us.
I'm a bit ashamed of two things though, despite all my pride.
One is that we adults leave kids to discover moral action and serious political engagement by accident rather than teaching it to them systematically and universally, as if we don't really think they want meaningful lives, as if we imagine comfortable lives is the complete human ideal. We are asking kids to lead the way on the environment, because we -- I'm speaking collectively of everyone over 30, the people Bob Dylan said not to trust until he was over 30 -- we are not doing it, and the kids are taking us to court, and our government is allowing its fellow leading destroyers of the environment to become voluntary co-defendants (can you imagine volunteering to be sued along with someone else who's facing a law suit? No, wait, sue me too!), and the voluntary co-defendants, including the National Association of Manufacturers, are providing teams of lawyers that probably cost more than the schools Hallie and Travis attend, and the courts are ruling that it is an individual right of non-human entities called corporations to destroy the inhabitability of the planet for everyone, despite the evident logic that says the corporations will cease to exist as well.
Should our kids do as we say or as we do? Neither! They should run in the opposite direction from anything we've touched. There are exceptions, of course. Some of us try a little. But it is an uphill effort to undo the cultural indoctrination that has us saying phrases like "throw this away" as if there really were an away, or labeling the destruction of a forest "economic growth," or worrying about so-called peak oil and how we'll live when the oil runs out, even though we've already found five times what we can safely burn and still be able to live on this beautiful rock.
But kids are different. The need to protect the earth and use clean energy even if it means a few inconveniences or even some serious personal risk, is no more unusual or strange to a kid than half the other stuff they are presented with for the first time, like algebra, or swim meets, or uncles. They haven't spent as many years being told that renewable energy doesn't work. They haven't developed the fine-tuned sense of patriotism that allows us to keep believing renewable energy cannot work even as we hear about it working in other countries. (That's German physics!)
Our young leaders have fewer years of indoctrination into what Martin Luther King Jr. called extreme materialism, militarism, and racism. Adults block the way in the courts, so kids take to the streets, they organize and agitate and educate. And so they must, but they are up against an educational system and an employment system and an entertainment system that often tells them they are powerless, that serious change is impossible, and that the most important thing you can do is vote.
Now, adults telling each other that the most important thing they can do is vote is bad enough, but saying that to kids who aren't old enough to vote is like telling them to do nothing. We need a few percent of our population doing the opposite of nothing, living and breathing dedicated activism. We need creative nonviolent resistance, re-education, redirection of our resources, boycotts, divestments, the creation of sustainable practices as models for others, and the impeding of an established order that is politely and smilingly steering us over a cliff. Rallies organized by iMatter Youth North Carolina look like moves in the right direction to me. So, let's thank them again.
The second thing I'm a little ashamed of is that it is not at all uncommon for a peace organization to arrive at an environmental activist when choosing someone to honor, whereas I have never once heard of the reverse. Hallie and Travis have an uncle who works largely on peace, but they live in a culture where the activism that receives funding and attention and mainstream acceptance, to the limited extent that any does and of course trailing far behind 5Ks against breast cancer and the sort of activism that lacks real opponents, is activism for the environment. But I think there's a problem with what I've just done and what we usually tend to do, that is, with categorizing people as peace activists or environmental activists or clean elections activists or media reform activists or anti-racism activists. As we came to realize a few years back, we all add up to 99% of the population, but those who are really active are divided, in reality as well as in people's perceptions.
Peace and environmentalism should, I think, be combined into the single word peacenvironmentalism, because neither movement is likely to succeed without the other. iMatter wants to live as if our future matters. You can't do that with militarism, with the resources it takes, with the destruction it causes, with the risk that grows greater with each passing day that nuclear weapons will be intentionally or accidentally detonated. If you could really figure out how to nuke another nation while shooting its missiles out of the sky, which of course nobody has figured out, the impact on the atmosphere and climate would severely impact your own nation as well. But that's a fantasy. In a real world scenario, a nuclear weapon is launched on purpose or by mistake, and many more are quickly launched in every direction. This has in fact nearly happened numerous times, and the fact that we pay almost no attention to it anymore makes it more rather than less likely. I imagine you know what happened 50 miles southeast of here on January 24, 1961? That's right, the U.S. military accidentally dropped two nuclear bombs and got very lucky they didn't explode. Nothing to worry about, says comedy news anchor John Oliver, that's why we have TWO Carolinas.
iMatter advocates for an economic shift from fossil fuels to renewable energy and for sustainable jobs. If only there were a couple of trillion dollars a year being wasted on something useless or destructive! And of course there is, worldwide, that unfathomable sum is being spent on preparations for war, half of it by the United States, three quarters of it by the United States and its allies -- and much of that last bit on U.S. weapons. For a fraction of it, starvation and disease could be seriously dealt with, and so could climate change. War kills primarily through taking spending away from where it's needed. For a small fraction of war preparations spending, college could be free here and provided free in some other parts of the world too. Imagine how many more environmental activists we could have if college graduates didn't owe tens of thousands of dollars in exchange for the human right of an education! How do you pay that back without going to work for the destroyers of the earth?
79% of weapons in the Middle East come from the United States, not counting those belonging to the U.S. military. U.S. weapons were on both sides in Libya three years ago and are on both sides in Syria and Iraq. Weapons making is an unsustainable job if ever I saw one. It drains the economy. The same dollars spent on clean energy or infrastructure or education or even tax cuts for non-billionaires produces more jobs than military spending. Militarism fuels more violence, rather than protecting us. The weapons have to be used up, destroyed, or given to local police who will begin to see local people as enemies, so that new weapons can be made. And this process is, by some measures, the biggest destroyer of the environment we have.
The U.S. military burned through about 340,000 barrels of oil each day, as measured in 2006. If the Pentagon were a country, it would rank 38th out of 196 in oil consumption. If you removed the Pentagon from the total oil consumption by the United States, then the United States would still rank first with nobody else anywhere close. But you would have spared the atmosphere the burning of more oil than most countries consume, and would have spared the planet all the mischief the U.S. military manages to fuel with it. No other institution in the United States consumes remotely as much oil as the military.
Each year, the U.S. Environmental Protection Agency spends $622 million trying to figure out how to produce power without oil, while the military spends hundreds of billions of dollars burning oil in wars fought and on bases maintained to control the oil supplies. The million dollars spent to keep each soldier in a foreign occupation for a year could create 20 green energy jobs at $50,000 each.
Wars in recent years have rendered large areas uninhabitable and generated tens of millions of refugees. War "rivals infectious disease as a global cause of morbidity and mortality," according to Jennifer Leaning of Harvard Medical School. Leaning divides war's environmental impact into four areas: "production and testing of nuclear weapons, aerial and naval bombardment of terrain, dispersal and persistence of land mines and buried ordnance, and use or storage of military despoliants, toxins, and waste." A 1993 U.S. State Department report called land mines "the most toxic and widespread pollution facing mankind." Millions of hectares in Europe, North Africa, and Asia are under interdiction. One-third of the land in Libya conceals land mines and unexploded World War II munitions.
The Soviet and U.S. occupations of Afghanistan have destroyed or damaged thousands of villages and sources of water. The Taliban has illegally traded timber to Pakistan, resulting in significant deforestation. U.S. bombs and refugees in need of firewood have added to the damage. Afghanistan’s forests are almost gone. Most of the migratory birds that used to pass through Afghanistan no longer do so. Its air and water have been poisoned with explosives and rocket propellants.
You may not care about politics, the saying goes, but politics cares about you. That goes for war. John Wayne avoided going off to World War II by making movies to glorify other people going. And do you know what happened to him? He made a movie in Utah near a nuclear testing area. Of the 220 people who worked on the film, 91, rather than the 30 that would have been the norm, developed cancer including John Wayne, Susan Hayward, Agnes Moorehead, and director Dick Powell.
We need a different direction. In Connecticut, Peace Action and many other groups have been involved in successfully persuading the state government to set up a commission to work on converting from weapons to peaceful industries. Labor unions and management support it. Environmental and peace groups are part of it. It's very much a work in progress. It was likely stimulated by false stories that the military was being slashed. But whether we can make that a reality or not, the environmental need to shift our resources to green energy is going to grow, and there is no reason North Carolina shouldn't be the second state in the country to do this. You have moral Mondays here. Why not have moral every days of the year?
Major changes look larger before they happen than after. Environmentalism has come on very quickly. The U.S. already had nuclear submarines back when whales were still being used as a source of raw materials, lubricants, and fuels, including in nuclear submarines. Now whales are, almost suddenly, seen as marvelous intelligent creatures to be protected, and the nuclear submarines have begun to look a bit archaic, and the deadly sound pollution that the Navy imposes on the world's oceans looks a bit barbaric.
iMatter's lawsuits seek to protect the public trust for future generations. The ability to care about future generations is, in terms of the imagination required, almost identical to the ability to care about foreign people at a distance in space rather than time. If we can think of our community as including those not yet born, who of course we hope far outnumber the rest of us, we can probably think of it as including the 95% of those alive today who don't happen to be in the United States of America, and vice versa.
But even if environmentalism and peace activism were not a single movement, we'd have to join them and several others together in order to have the sort of Occupy 2.0 coalition we need to effect change. A big chance to do that is coming up around September 21st which is the International Day of Peace and the time when a rally and all sorts of events for the climate will be happening in New York City.
At WorldBeyondWar.org you'll find all sorts of resources for holding your own event for peace and the environment. You'll also find a short two-sentence statement in favor of ending all war, a statement that has been signed in the past few months by people in 81 nations and rising. You can sign it on paper here this evening. We need your help, young and old. But we should be especially glad that time and numbers are on the side of the young around the world, to whom I say along with Shelley:
Rise like Lions after slumber In unvanquishable number, Shake your chains to earth like dew Which in sleep had fallen on you- Ye are many — they are few.
--
| https://freepress.org/article/peacenvironmentalism |
Gondkhed Branch Post Office, Jalgaon 06, Maharashtra
Gondkhed Post Office, Jalgaon
Gondkhed post office is located at Gondkhed, Jalgaon of Maharashtra state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Gondkhed PO is424206. This Postoffice falls under Bhusaval postal division of the Maharashtra postal circle. The related head P.O. for this branch office is Bhusawal head post office and the related sub-post office (S.O.) for this branch office is Jamner post office.
Gondkhed dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Gondkhed.
Types of Post Offices
Post offices are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Gondkhed P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Gondkhed Post Office & Its Pin Code
Branch Office Information
Gondkhed Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Gondkhed Post Office Recruitment
Location Map
Contact Details
About India Post
Gondkhed Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Gondkhed Post Office has the Postal Index Number or Pin Code 424206. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Gondkhed PO Pincode 424 206
The first digit of 424206 Pin Code '4' represents the region, to which this Post Office of Gondkhed belongs to. The first two digits of the Pin Code '42' represent the sub region, i.e, Maharashtra. The first 3 digits '424' represent the post-office revenue district, i.e, Bhusaval. The last 3 digits, i.e, '206' represent the Gondkhed Delivery Branch Office.
Branch Office Information
The Gondkhed Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Bhusaval, which falls under Aurangabad region. The circle name for this PO is Maharashtra and it falls under Jalgaon Taluka and Jalgaon District. The state in which this Dakghar is situated or located is Maharashtra. The related head postoffice is Bhusawal post office and the related sub post office is Jamner post-office. The phone number of Gondkhed post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Bhusaval Postal Region Aurangabad Postal Circle Maharashtra Town / City / Tehsil / Taluka / Mandal Jalgaon District Jalgaon State Maharashtra Related Sub PO Jamner Sub Office Related Head PO Bhusawal Head Post Office
Gondkhed Post Office Services
Traditionally the primary function of Gondkhed post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Gondkhed P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Gondkhed and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Gondkhed Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Gondkhed can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Gondkhed peoples and nearby living people. The premium services provided by Gondkhed Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Gondkhed customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Gondkhed Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Gondkhed postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Gondkhed postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Gondkhed people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Gondkhed post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Gondkhed customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Gondkhed customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Gondkhed postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Gondkhed can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Gondkhed area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Gondkhed postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Gondkhed postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/-and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Disclaimer: All the information in this website is published for general information purpose only. Some schemes and other postal services may not be available in Gondkhed Post Office. Kindly verify for all India post saving schemes and other postal services with official resources.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 09:00 AM or 10:00 AM and the closing time is 06:00 PM or 07:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Gondkhed Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Gondkhed people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Gondkhed Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Gondkhed postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Gondkhed Post Office Recruitment
For latest Gondkhed post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Gondkhed Branch Post Office is located in Gondkhed, Jalgaon.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc. services in Gondkhed Post Office, can be resolved at Gondkhed Branch Post Office. You can send letters to "Postmaster, Gondkhed Branch Post Office, Gondkhed, Jalgaon, Maharashtra, India, Pincode: 424 206". The official website of the Berhampur University Sub Office is www.indiapost.gov.in.
Gondkhed Branch Office
Address: Gondkhed Branch Post Office, Gondkhed, Jalgaon, Maharashtra, India
Pin Code: 424206
Website: www.indiapost.gov.in
About India Post
India Post is a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the India with over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Gondkhed Post Office Summary
Dak Ghar Name Gondkhed Branch Post Office Pincode 424206 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Bhusaval Postal Region Aurangabad Postal Circle Maharashtra Location Gondkhed Town / City / Tehsil / Taluka / Mandal Jalgaon District Jalgaon State Maharashtra Country India Related Sub Office Jamner Sub Office Related Head Office Bhusawal Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
Kasali Post Office
Jamner Post Office
| https://www.postoffices.co.in/maharashtra-mh/gondkhed-jalgaon-06/amp/ |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Publications
Type
Journal Paper
Themes
Assistive & Accessible Technology
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Jamie Danemayer,Cathy Holloway,Youngjun Cho, Nadia Berthouze, Aneesha Singh, William Bhot, Ollie Dixon, Marko Grobelnik, John Shawe-Taylor
Paper highlights: Assistive technology (AT) information networks are insular among stakeholder groups, causing unequal access to information. Participants often cited fragmented international marketplaces as a barrier and valued info-sharing across industries. Current searches produce biased results in marketplaces influenced by commercial interests and high-income contexts. Smart features could facilitate searching, update centralised data sources, and disseminate information more inclusively.
International Journal of Human-Computer Studies; 2023
Abstract
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain.
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Type
Journal Paper
Themes
Assistive & Accessible Technology
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Cite
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Type
Journal Paper
Themes
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Cite
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Share
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
Cite
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
Cite
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
Share
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Cite
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Share
Developing inclusive and resilient systems: COVID-19 and assistive technology
| https://www.disabilityinnovation.com/publications?type=journal-paper+working-paper+editorial+conference-paper+book |
Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence
Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence
Authors:
Jian‑Zhi Gao
Jia Li
Jing‑Li Du
Xiao‑Lei Li
Published online on: January 19, 2016 https://doi.org/10.3892/ol.2016.4130
Pages: 1791-1798
Abstract
The present study aimed to investigate the expression level of HOX transcript antisense RNA (HOTAIR) in hepatocellular carcinoma (HCC) and its association with various clinicopathological characteristics, and to further explore the molecular mechanisms of HOTAIR function in HCC. Quantitative reverse transcription‑polymerase chain reaction (RT‑PCR) was used to detect the expression level of HOTAIR in 60 paired fresh HCC samples and adjacent normal liver tissue samples. The association between HOTAIR expression and clinicopathological parameters was analyzed. Lentivirus‑mediated HOTAIR‑specific small hairpin RNA vectors were transfected into HepG2 cells. Cell proliferation and invasion in vitro were examined by MTT and Transwell assays, respectively. A xenograft model was used to analyze the tumorigenesis of liver cancer cells in vivo. In addition, semi‑quantitative RT‑PCR was used to detect the expression level of Wnt/β-catenin signaling molecules under the condition of HOTAIR inhibition. The results revealed that the expression level of HOTAIR in HCC tissues was higher than that in adjacent non‑cancerous tissues. HOTAIR expression was significantly associated with poor tumor differentiation (P=0.002), metastasis (P=0.002) and early recurrence (P=0.001). In vitro, the inhibition of HOTAIR in liver cancer cells resulted in the suppression of cell proliferation and invasion. HOTAIR depletion significantly inhibited the rate of growth of liver cancer cells in vivo. Furthermore, the expression levels of Wnt and β‑catenin were downregulated when HOTAIR expression was suppressed. In conclusion, HOTAIR is important in the progression and recurrence of HCC, partly through the regulation of the Wnt/β‑catenin signaling pathway. Targeting HOTAIR may be a novel therapeutic strategy for HCC.
Introduction
Hepatocellular carcinoma (HCC) is the fifth most
frequent cancer worldwide and is also the third leading cause of
cancer-related mortality (
1
). The
World Health Organization has estimated that almost 56,400 new
cases of HCC occur globally per year (
2
), and the incidence is markedly higher in
men than in women. The highest liver cancer rates are observed in
developing countries, particularly in East Asia and Malaysia, South
Africa and Sub-Saharan Africa, whereas rates are lower in Europe,
North and South America, Australia and New Zealand (
3
). HCC may be induced by a number of risk
factors, including chronic infection with hepatitis B virus (HBV)
or hepatitis C virus (HCV), hepatic cirrhosis, alcoholic liver
disease and exposure to aflatoxins (
4
).
Despite recent advances in surgical treatments and
chemoradiotherapy, aggressive metastasis and early recurrence still
result in a high mortality rate among HCC patients (
5
). To date, a number of molecular markers
and signaling pathways have been identified to be associated with
HCC oncogenesis, progression, recurrence and survival, including
tumor protein P53 (TP53), K-ras mutation (
6
,
7
), HBx,
Notch 1, Glypican-3 and osteopontin overexpression (
7
–
10
),
Wnt/β-catenin and the phosphoinositide 3-kinase/protein kinase
B/mammalian target of rapamycin signaling pathways (
11
,
12
).
However, the exact mechanism of HCC has not been fully established.
Therefore, a better understanding of the molecular mechanisms
underlying HCC may contribute to the development of novel
strategies for prediction, diagnosis and therapy.
Long non-coding RNAs (lncRNAs) are
non-protein-coding transcripts of >200 nucleotides (
13
). A recent study found that the human
genome consists of at least four times more lncRNA sequences than
coding RNA sequences (
14
). The
majority of lncRNAs demonstrated to be functional are involved in
the regulation of gene transcription, post-transcriptional
regulation and epigenetic regulation, such as genomic imprinting
and X-inactivation (
15
–
17
), and are closely associated with
numerous human diseases, including cancer (
18
,
19
). The
lncRNA HOX transcript antisense RNA (HOTAIR), a human gene located
on chromosome 12, is expressed from the HOXC locus and is important
in the transcriptional regulation of various genes (
20
). The 5′ end of HOTAIR interacts with and
induces the genome-wide retargeting of Polycomb Repressive Complex
2 (PRC2), which combines with HOTAIR to silence the transcription
of the HOXC locus, and promotes metastasis of breast cancer by
silencing multiple metastasis suppressor genes (
21
). The 3′ end of HOTAIR interacts with
lysine-specific histone demethylase 1A (
22
). Furthermore, recent studies have
reported that HOTAIR is highly expressed and associated with poor
prognosis in a number of types of cancer, including breast cancer,
epithelial ovarian cancer, pancreatic cancer, colorectal cancer,
non-small-cell lung cancer and endometrial carcinoma (
21
,
23
–
27
).
The objective of the current study was to
investigate the expression of HOTAIR in HCC and to further explore
its clinical significance and molecular mechanisms. Paired fresh
HCC samples and adjacent normal tissues were used to examine the
expression level of HOTAIR and analyze the association between
HOTAIR expression and clinicopathological characteristics.
Furthermore, a lentivirus-mediated RNA interference method was
utilized to investigate the role and molecular mechanism of HOTAIR
in HCC progression.
Materials and methods
Patients and tissue samples
The patients enrolled in the study were diagnosed
with primary HCC and underwent partial liver resection between
January and September 2012 at Chinese People's Liberation Army
(PLA) General Hospital (Beijing, China). A total of 60 paired
samples of HCC and non-cancerous tissue were obtained from the
resected tumors and adjacent normal liver tissues of the patients,
and were immediately frozen in liquid nitrogen and stored at −80°C
until use. This study was approved by the ethics committee of
Chinese PLA General Hospital (LREC 2012/40) and the protocol was
conducted with the prior written informed consent of all patients.
All samples were confirmed independently by two pathologists, and
the clinicopathological characteristics were documented and are
described in detail in
Table I
.
<table><tbody><tr><td></td><td> Table I. Association between HOTAIR expression
and clinicopathological parameters in hepatocellular carcinoma
patients (n=60).</td></tr></tbody></table>
Table I.
Association between HOTAIR expression
and clinicopathological parameters in hepatocellular carcinoma
patients (n=60).
<table><tr><th rowspan=1 colspan=2> HOTAIR expression,
n</th></tr><tr><th rowspan=1 colspan=1> Characteristic</th><th rowspan=1 colspan=1> n</th><th rowspan=1 colspan=1> High (n=36)</th><th rowspan=1 colspan=1> Low (n=24)</th><th rowspan=1 colspan=1> χ 2</th><th rowspan=1 colspan=1> P-value</th></tr><tbody><tr><td rowspan=1 colspan=1> Gender</td><td rowspan=1 colspan=1> 0.082</td><td rowspan=1 colspan=1> 0.775</td></tr><tr><td rowspan=1 colspan=1> Male</td><td rowspan=1 colspan=1> 42</td><td rowspan=1 colspan=1> 25</td><td rowspan=1 colspan=1> 17</td></tr><tr><td rowspan=1 colspan=1> Female</td><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1> 10</td><td rowspan=1 colspan=1> 8</td></tr><tr><td rowspan=1 colspan=1> Age (years)</td><td rowspan=1 colspan=1> 0.866</td><td rowspan=1 colspan=1> 0.352</td></tr><tr><td rowspan=1 colspan=1> <50</td><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1> 10</td><td rowspan=1 colspan=1> 12</td></tr><tr><td rowspan=1 colspan=1> ≥50</td><td rowspan=1 colspan=1> 38</td><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1> 16</td></tr><tr><td rowspan=1 colspan=1> Tumor size
(cm)</td><td rowspan=1 colspan=1> 0.431</td><td rowspan=1 colspan=1> 0.512</td></tr><tr><td rowspan=1 colspan=1> ≤5</td><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 10</td></tr><tr><td rowspan=1 colspan=1> >5</td><td rowspan=1 colspan=1> 38</td><td rowspan=1 colspan=1> 24</td><td rowspan=1 colspan=1> 14</td></tr><tr><td rowspan=1 colspan=1> Tumor number</td><td rowspan=1 colspan=1> 3.386</td><td rowspan=1 colspan=1> 0.066</td></tr><tr><td rowspan=1 colspan=1> Solitary</td><td rowspan=1 colspan=1> 42</td><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1> 20</td></tr><tr><td rowspan=1 colspan=1> Multiple</td><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1> 14</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1> Serum α-fetoprotein
(µg/l)</td><td rowspan=1 colspan=1> 2.188</td><td rowspan=1 colspan=1> 0.139</td></tr><tr><td rowspan=1 colspan=1> <400</td><td rowspan=1 colspan=1> 32</td><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1> 10</td></tr><tr><td rowspan=1 colspan=1> ≥400</td><td rowspan=1 colspan=1> 28</td><td rowspan=1 colspan=1> 14</td><td rowspan=1 colspan=1> 14</td></tr><tr><td rowspan=1 colspan=1> Peritumoral
tissue</td><td rowspan=1 colspan=1> 3.103</td><td rowspan=1 colspan=1> 0.078</td></tr><tr><td rowspan=1 colspan=1> Non-cirrhotic</td><td rowspan=1 colspan=1> 2</td><td rowspan=1 colspan=1> 0</td><td rowspan=1 colspan=1> 2</td></tr><tr><td rowspan=1 colspan=1> Cirrhotic</td><td rowspan=1 colspan=1> 58</td><td rowspan=1 colspan=1> 36</td><td rowspan=1 colspan=1> 22</td></tr><tr><td rowspan=1 colspan=1> Tumor
differentiation</td><td rowspan=1 colspan=1> 12.198</td><td rowspan=1 colspan=1> 0.002 a</td></tr><tr><td rowspan=1 colspan=1> Well</td><td rowspan=1 colspan=1> 6</td><td rowspan=1 colspan=1> 0</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> Moderate</td><td rowspan=1 colspan=1> 28</td><td rowspan=1 colspan=1> 16</td><td rowspan=1 colspan=1> 12</td></tr><tr><td rowspan=1 colspan=1> Poor</td><td rowspan=1 colspan=1> 26</td><td rowspan=1 colspan=1> 20</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> TNM stage</td><td rowspan=1 colspan=1> 6.389</td><td rowspan=1 colspan=1> 0.094</td></tr><tr><td rowspan=1 colspan=1> I</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 4</td><td rowspan=1 colspan=1> 8</td></tr><tr><td rowspan=1 colspan=1> II</td><td rowspan=1 colspan=1> 6</td><td rowspan=1 colspan=1> 4</td><td rowspan=1 colspan=1> 2</td></tr><tr><td rowspan=1 colspan=1> III</td><td rowspan=1 colspan=1> 30</td><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1> 12</td></tr><tr><td rowspan=1 colspan=1> IV</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 10</td><td rowspan=1 colspan=1> 2</td></tr><tr><td rowspan=1 colspan=1> Vessel embolus</td><td rowspan=1 colspan=1> 3.403</td><td rowspan=1 colspan=1> 0.065</td></tr><tr><td rowspan=1 colspan=1> Negative</td><td rowspan=1 colspan=1> 48</td><td rowspan=1 colspan=1> 26</td><td rowspan=1 colspan=1> 22</td></tr><tr><td rowspan=1 colspan=1> Positive</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 10</td><td rowspan=1 colspan=1> 2</td></tr><tr><td rowspan=1 colspan=1> Metastasis</td><td rowspan=1 colspan=1> 10.000</td><td rowspan=1 colspan=1> 0.002 a</td></tr><tr><td rowspan=1 colspan=1> Negative</td><td rowspan=1 colspan=1> 48</td><td rowspan=1 colspan=1> 24</td><td rowspan=1 colspan=1> 24</td></tr><tr><td rowspan=1 colspan=1> Positive</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1> 0</td></tr><tr><td rowspan=1 colspan=1> Early recurrence
(<2 years)</td><td rowspan=1 colspan=1> 11.250</td><td rowspan=1 colspan=1> 0.001 a</td></tr><tr><td rowspan=1 colspan=1> Negative</td><td rowspan=1 colspan=1> 40</td><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1> 22</td></tr><tr><td rowspan=1 colspan=1> Positive</td><td rowspan=1 colspan=1> 20</td><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1> 2</td></tr></tbody></table>
{ label (or @symbol) needed
for fn[@id='tfn1-ol-0-0-4130'] }HOTAIR, HOX transcript
antisense RNA; TNM, tumor-node-metastasis.
a Statistically significant.
RNA extraction, reverse transcription
(RT) and quantitative (q) polymerase chain reaction (PCR)
Total RNA from frozen HCC and paired non-cancerous
tissues or cell lines were extracted with the Ultrapure RNA Kit
(CWBio, Co., Ltd., Beijing, China) according to the manufacturer's
instructions. cDNA was synthesized by reverse transcribing the
total RNA using a HiFi-MMLV cDNA Kit (CWBio, Co., Ltd.). The
expression level of HOTAIR was detected by qPCR using the Ultra
SYBR Mixture with ROX (CWBio, Co., Ltd.) and ABI7500 system
(Applied Biosystems Life Technologies, Foster City, CA, USA).
Template cDNA (2 µl) was mixed with 25µl 2X UltraSYBR Mixture with
ROX, 2 µl primers and RNase-free water. β-actin was used as an
internal control and HOTAIR values were normalized to β-actin. The
primer sequences (Invitrogen; Thermo Fisher Scientific, Waltham,
MA, USA) used were as follows: HOTAIR forward,
5′-GCAGTAGAAAAATAGACATAGGAGA-3′, and reverse,
5′-ATAGCAGGAGGAAGTTCAGGCATTG-3′; β-actin forward,
5′-ACTTAGTTGCGTTACACCCTT-3′, and reverse, 5′-GTCACCTTCACCGTTCCA-3′.
HOTAIR cDNA was amplified under the following conditions: Initital
denaturation at 95°C for 5 min followed by 30 cycles of
denaturation at 95°C for 30 sec and primer annealing at 55°C for 30
sec, with a final extension step at 72°C for 60 sec. Expression
levels were calculated using the 2
−ΔΔCT
method (
28
) and were normalized to that of the
housekeeping β-actin gene.
HOTAIR siRNA lentiviral expression
vector
The RNA interference sequence for human HOTAIR (Gene
ID, 100124700) was obtained from a previous article (
21
). The small interfering RNA (siRNA)
sequences were as follows: HOTAIR, 5′-UAACAAGACCAGAGAGCUGUU-3′;
negative control (NC), 5′-TTCTCCGAACGTGTCACGT-3′. The
oligonucleotides encoding short hairpin RNA (shRNA) were then
constructed and synthesized by Shanghai GenePharma Co., Ltd.
(Shanghai, China) and annealed into double strands by Annealing
Buffer for RNA Oligos (Beyotime Institute of Biotechnology, Haimen,
China). Following digestion with
BamHI
and
EcoRI
restriction endonucleases (TransGen Biotech, Inc., Beijing, China),
the double stranded DNA molecules were inserted into pGCSi-neo-GFP
lentiviral vector (lentiviral plasmid and packaging vectors were
provided by Dr Xiao-Lei Li from the Department of Molecular Biology
of Chinese PLA General Hospital). All of the constructed plasmids
were confirmed by DNA sequencing.
pGCSi-neo-GFP-HOTAIR-shRNA/NC-shRNA plasmid DNAs, along with
packaging vectors, were transiently transfected into HEK293T
(American Type Culture Collection, Manassas, VA, USA) cells using
Lipofectamine 2000 (Invitrogen; Thermo Fisher Scientific) according
to the manufacturer's instructions. At 48 h after transfection,
supernatants containing lentivirus were collected and purified by
ultracentrifugation at 70,000 × g at 4°C for 2 h. The titer of the
lentivirus was detected using Lentivirus-Associated HIV p24 ELISA
Kit (Cell Biolabs, Inc., San Diego, CA, USA).
Cell culture and lentiviral
infection
Human liver cancer HepG2 cells were purchased from
the American Type Culture Collection and maintained in the research
center from the Department of Gastroenterology in Chinese PLA
General Hospital. Cells were maintained in Dulbecco's modified
Eagle's medium (DMEM; Gibco; Thermo Fisher Scientific) supplemented
with 10% fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific)
and penicillin-streptomycin (MP Biomedicals, Santa Ana, CA, USA) at
37°C in an atmosphere of 5% CO
2
. For transfection,
well-cultured cells were seeded into a 6-well plate at a density of
1×105 cells/well for 24 h. Subsequently, lentivirus containing
shRNA targeting HOTAIR or NC shRNA was added into the medium and
incubated for 24 h. After replacing the culture medium of each
well, cells were incubated for a further 48 h. qPCR was performed
to detect the interference efficiency of the HOTAIR shRNA.
MTT assay
For cell proliferation assays, HepG2 cells stably
transfected with HOTAIR shRNA or NC shRNA were digested with 0.25%
trypsin (Boster Inc., Wuhan, China), seeded into 96-well plates at
a density of 1,000 cells/well in a final volume of 100 µl, and
maintained in DMEM supplemented with 10% FBS. At different time
points (24 h, 48 h, 72 h, 4 days, 5 days, 6 days or 7 days after
plating), 10 µl MTT solution (Sigma-Aldrich, St. Louis, MO, USA)
was added to each well, and cells were incubated for an additional
4 h at 37°C. The blue formazan crystals were dissolved in 100 µl
dimethyl sulfoxide (Origen Bioedical, Austin, TX, USA), and the
absorbance was measured at 490 nm using a microplate reader
(ELx800; BioTek Instuments, Inc., Winooski, VT, USA).
Transwell assay
A Transwell assay was performed to assess the
invasiveness of HepG2 cells by using chambers with an 8.0 µm
transparent polyethylene terephthalate membrane in 24-well plates
(Corning Incorporated, Corning, New York, NY, USA). Cells (2×105
per chamber) were seeded into the upper chambers in 200 µl
serum-free DMEM, and 500 µl of DMEM with 10% FBS was added to each
lower chamber. Three duplicate wells were performed for each group.
After 12 h, the unfiltered cells at the top surface of the membrane
were gently removed with cotton swabs. The cells that had passed
through the filters were fixed in methanol for 15 min and stained
with hematoxylin (OriGene China, Beijing, China) for 20 min,
air-dried and photographed (Olympus Stream Image Analysis Software;
Olympus Corporation, Tokyo, Japan). The invasive cells were counted
under a microscope (magnification, ×200; CX31; Olympus Corporation)
in five randomly selected visual fields.
Xenograft model
To examine the ability of tumor formation
in
vivo
, the cell lines stably transfected with HOTAIR shRNA or NC
shRNA were injected into nude mice. Ten four-week-old BALB/c male
nude mice were purchased from the Vital River Laboratories
(Beijing, China) and randomly assigned to two groups. All nude mice
were bred and maintained at the the Vital River Laboratories
(Beijing, China) under specific pathogen-free conditions. The
research program, objective and animal use protocol were reviewed
and approved by the Animal Ethical and Welfare Committee of
Tsinghua University. Cell suspension (100 µl) containing 1×107
HepG2-HOTAIR-shRNA or HepG2-NC-shRNA cells was injected
subcutaneously into the back of each nude mouse. The tumor size and
weight of the mice were measured every 4 days from the 8th day
following injection. On the 28th day following injection, all mice
in the two groups were sacrificed by cervical dislocation and the
primary tumors were removed from each mouse. Tumor size and tumor
weight were measured and recorded. The tumor volume was calculated
according to the following formula: Tumor volume = length ×
width
2
× π/6 (
29
).
Semi-quantitative RT-PCR
Semi-quantitative RT-PCR was performed to assess the
mRNA expression levels of Wnt and β-catenin in tumor tissues from
nude mice. The methods for RNA extraction and RT were performed
using the aforementioned method. 2X Taq MasterMix (CWBio, Co.,
Ltd.) was used to amplify the cDNA. The PCR cycling parameters (30
cycles) were as follows: Predenaturation (95°C, 5 min),
denaturation (95°C, 30 sec), annealing (55°C, 30 sec) and extension
(72°C, 60 sec). GAPDH was used as an internal control. The RNA
primers (Invitrogen; Thermo Fisher Scientific) used in the PCR were
as follows: Wnt forward, 5′-GGAGTTGTATTTGCCATCACCAGGG-3′, and
reverse, 5′-ATGCGCGGGCAAATTTGATCCCATA-3′; β-catenin forward,
5′-ACAAGCCACAAGATTACAAGAAACGG-3′, and reverse,
5′-CCACCAGAGTGAAAAGAACGATAGCT-3′; GAPDH forward,
5′-TGGAGTCTACTGGCGTCTT-3′, and reverse,
5′-TGTCATATTTCTCGTGGTTCA-3′. The PCR products were assessed by 1.5%
agarose gel electrophoresis. Expression levels were calculated
using the 2
−ΔΔCT
method (
28
) and were normalized to that of the
housekeeping β-actin gene
Statistical analysis
All statistical analyses were performed using SPSS
version 20.0 statistical software package (IBM SPSS, Armonk, NY,
USA) or GraphPad Prism version 5.0 (GraphPad Software, Inc., La
Jolla, CA, USA). A χ
2
test was used to assess the
association between HOTAIR expression level or tumor recurrence and
clinicopathological characteristics. Comparisons of quantitative
data between two groups were analyzed by an independent-samples
t
-test. Spearman's correlation test was used to analyze the
correlation between HOTAIR expression level and clinicopathological
factors. All experiments were repeated independently three times
and data are presented as the mean ± standard deviation. P<0.05
was considered to indicate statistical significance.
Results
Increased expression of HOTAIR in
HCC
To examine the expression level of the lncRNA HOTAIR
in HCC and its association with clinical progression of HCC, HOTAIR
expression was detected in 60 paired fresh HCC tissues and adjacent
non-cancerous tissues using qPCR. The results revealed that HOTAIR
expression was increased at least 2-fold relative to that in
non-cancerous samples in 36 (60%) HCC samples; the mean expression
level of HOTAIR in HCC samples was 5.7-fold higher than the mean
level in the adjacent non-cancerous tissue samples (P=0.014,
t-test;
Fig. 1A
).
<table><tbody><tr><td></td><td> Figure 1.(A) Expression of HOTAIR in 60 paired
HCC and adjacent non-HCC tissues detected by quantitative PCR. Bars
represent mean ± standard deviation; *P<0.05 vs. NC (Student's
t-test). (B) Interference efficiency of HOTAIR in HepG2
cells. **P<0.01 vs. NC (Student's t-test). (C) Effect of
HOTAIR silence on cell proliferation assessed my MTT assay. HepG2
cells treated with siHOTAIR exhibited a marked inhibition in cell
growth compared with cell treated with siNC; **P<0.01 vs. NC
(Student's t-test). (C) Transwell invasion assays were
applied to assess for cell invasion ability, revealing that
downregulation of HOTAIR inhibits invasion in HepG2 liver cancer
cells (crystal violet staining; magnification, ×200); bars
represent mean ± standard deviation; *P<0.05 vs. NC (Student's
t-test). HCC, hepatocellular carcinoma; HOTAIR, HOX
transcript antisense RNA; OD, optical density; NC, negative
control.</td></tr></tbody></table>
Correlation between HOTAIR expression
and clinicopathological parameters of HCC
The association between HOTAIR expression and the
clinicopathological characteristics of patients with HCC was
assessed (
Table I
). Significant
associations were identified between the HOTAIR expression and a
number of clinicopathological parameters that represent higher
tumor burdens, including poor tumor differentiation (P=0.002),
metastasis (P=0.002) and early recurrence (within 2 years;
P=0.001). Statistical analyses revealed no association between
HOTAIR expression and tumor size, tumor number, serum α-fetoprotein
level, cirrhosis, tumor-node-metastasis (TNM) stage (
30
) or the presence of vessel emboli.
Spearman's rank correlation coefficient analysis revealed that a
high expression level of HOTAIR was strongly correlated with tumor
differentiation (r=0.391, P=0.002), TNM stage (r=0.293, P=0.023),
metastasis (r=0.408, P=0.001) and early recurrence (r=0.433,
P=0.001) (
Table II
). Taken together,
these observations indicated that increased HOTAIR expression is
associated with HCC progression and early recurrence.
<table><tbody><tr><td></td><td> Table II. Spearman rank correlation coefficient
analysis between HOTAIR expression level and clinicopathological
factors.</td></tr></tbody></table>
Table II.
Spearman rank correlation coefficient
analysis between HOTAIR expression level and clinicopathological
factors.
<table><tr><th rowspan=1 colspan=2> Relative HOTAIR
expression</th></tr><tr><th rowspan=1 colspan=1> Characteristic</th><th rowspan=1 colspan=1> Correlation
coefficient</th><th rowspan=1 colspan=1> P-value</th></tr><tbody><tr><td rowspan=1 colspan=1> Tumor size
(cm)</td><td rowspan=1 colspan=1> 0.085</td><td rowspan=1 colspan=1> 0.520</td></tr><tr><td rowspan=1 colspan=1> Tumor number</td><td rowspan=1 colspan=1> 0.238</td><td rowspan=1 colspan=1> 0.068</td></tr><tr><td rowspan=1 colspan=1> Serum α-fetoprotein
(µg/l)</td><td rowspan=1 colspan=1> −0.191</td><td rowspan=1 colspan=1> 0.144</td></tr><tr><td rowspan=1 colspan=1> Peritumoral tissue
cirrhosis</td><td rowspan=1 colspan=1> 0.227</td><td rowspan=1 colspan=1> 0.081</td></tr><tr><td rowspan=1 colspan=1> Tumor
differentiation</td><td rowspan=1 colspan=1> 0.391</td><td rowspan=1 colspan=1> 0.002 a</td></tr><tr><td rowspan=1 colspan=1> TNM stage</td><td rowspan=1 colspan=1> 0.293</td><td rowspan=1 colspan=1> 0.023 a</td></tr><tr><td rowspan=1 colspan=1> Vessel embolus</td><td rowspan=1 colspan=1> 0.238</td><td rowspan=1 colspan=1> 0.067</td></tr><tr><td rowspan=1 colspan=1> Metastasis</td><td rowspan=1 colspan=1> 0.408</td><td rowspan=1 colspan=1> 0.001 a</td></tr><tr><td rowspan=1 colspan=1> Early recurrence
(<2 years)</td><td rowspan=1 colspan=1> 0.433</td><td rowspan=1 colspan=1> 0.001 a</td></tr></tbody></table>
{ label (or @symbol) needed
for fn[@id='tfn3-ol-0-0-4130'] }TNM,
tumor-node-metastasis.
a Statistically significant.
Downregulation of HOTAIR inhibits
proliferation of HepG2 cells
As the clinical data indicated that the expression
level of HOTAIR was closely associated with human HCC progression,
the effect of HOTAIR on the proliferation of liver cancer cells was
investigated. The constructed lentiviral vectors designated
siHOTAIR and siNC were transfected into HepG2 liver cancer cells,
and the interference efficiency was detected by qPCR following
transfection for 72 h. As shown in
Fig.
1B
, the expression level of HOTAIR was significantly
downregulated by 95% in siHOTAIR cells compared with NC cells
(P<0.001).
An MTT assay was performed to examine the effect of
HOTAIR on liver cancer cell proliferation. The results revealed
that the cell proliferative ability of siHOTAIR stably transfected
cells was markedly inhibited compared to the NC cells (
Fig. 1C
). These data indicate that HOTAIR is
important in liver cancer cell proliferation
in vitro
.
Inhibition of HOTAIR reduces
invasiveness of HepG2 cells
A Transwell assay was used to assess the effect of
HOTAIR on the invasive ability of liver cancer cells. The results
revealed that the number of cells that passed through the filters
was significantly decreased in the siHOTAIR group compared with
that of siNC group (
Fig. 1D
).
Statistical analysis indicated that the difference between two
groups was significant (P=0.049). This finding demonstrated that
increased expression of HOTAIR may enhance liver cancer cell
invasiveness
in vitro
.
HOTAIR expression regulates the
tumorigenicity of HepG2 cells
To further determine whether HOTAIR expression could
promote HCC progression and enhance the tumorigenicity of liver
cancer cells, an
in vivo
tumor model was used. Using a shRNA
lentiviral knockdown system, two stable cell lines, HepG2-siHOTAIR
and HepG2-siNC, were generated and injected subcutaneously into the
backs of nude mice (n=5 per group). Tumor volumes were measured
every 4 days until the 28th day following injection. As shown in
Fig. 2A
, tumors from HepG2-siNC cells
grew faster than tumors formed from siHOTAIR cells. In addition,
the mean tumor weight in HepG2-siHOTAIR group was significantly
lower compared with that from the HepG2-siNC group (
Fig. 2B
). Four mice from each group were
photographed and tumor size in the siHOTAIR group was observed to
be markedly smaller than that in the NC group (
Fig. 2C
). These
in vivo
results were
consistent with the findings of the
in vitro
experiments,
and suggested that HOTAIR regulates liver cancer cell
proliferation, invasion and the tumorigenic ability, and may play
an important role in HCC progression.
<table><tbody><tr><td></td><td> Figure 2.Expression of HOTAIR regulates
tumorigenicity of liver cancer cells in xenograft models. (A) Tumor
growth curves in nude mice from two groups. Tumors in the siHOTAIR
group grew markedly slower than siNC group (*P<0.05). (B) The
mean tumor weights were markedly reduced in siHOTAIR group vs. siNC
group (**P<0.01). (C) Four mice with primary tumors from each
group were photographed prior to sacrifice. HOTAIR, HOX transcript
antisense RNA; NC, negative control.</td></tr></tbody></table>
HOTAIR regulates Wnt/β-catenin mRNA
expression
Tumor models of the nude mice from the two groups (5
per group) were used to detect the mRNA expression levels of Wnt
and β-catenin under the condition of HOTAIR inhibition using
semi-quantitative RT-PCR. The interference efficiency of HOTAIR in
these tumor models was confirmed by qPCR (
Fig. 3A
). As shown in
Fig. 3B
, in the siHOTAIR group, the
expression levels of Wnt and β-catenin were markedly reduced
compared with those of the NC group. These data indicate that
HOTAIR may regulate Wnt/β-catenin expression alone or in
combination with other molecules by an unknown mechanism that
merits further study.
<table><tbody><tr><td></td><td> Figure 3.(A) Relative expression levels of
HOTAIR in primary tumors from nude mice detected by quantitative
PCR. (B) The expression level of Wnt and β-catenin were examined in
primary tumors by semi-quantitative PCR. HOTAIR, HOX transcript
antisense RNA; NC, negative control; PCR, polymerase chain
reaction.</td></tr></tbody></table>
Discussion
HCC is a significant health problem worldwide, with
high rates of incidence and mortality (
2
). Accumulative, long-term interactions
between environmental and genetic factors lead to the occurrence
and progression of HCC (
31
).
Although a number of tumor suppressor genes and oncogenes,
including
KRAS
,
PTEN
and
TP53
, have been
identified to be involved in HCC progression (
6
,
7
,
32
), the molecular mechanism of HCC is not
completely understood. In recent years, the focus of tumor research
has expanded to investigate the potential tumor suppressive or
oncogenic functions of lncRNAs (
33
,
34
).
HOTAIR is an oncogenic lncRNA that has been found to
interact with PRC2 to epigenetically regulate chromatin state and
multiple target genes (
21
).
Recently, accumulating evidence has demonstrated that HOTAIR is
dysregulated in various types of cancer. Gupta
et al
(
21
) reported that HOTAIR is highly
expressed in metastatic breast cancer and its high expression in
primary breast tumors is a significant predictor of subsequent
metastasis and mortality (
21
). In a
similar manner, increased HOTAIR expression may also indicate poor
prognosis and promote metastasis in non-small cell lung cancer
(
25
), epithelial ovarian cancer
(
27
) and colon cancer (
23
).
In the current study, the expression level of HOTAIR
in HCC tissues versus adjacent non-cancerous tissues was examined
by quantitative RT-PCR, and its clinical implications were
investigated. The results revealed that HOTAIR expression was at
least 2-fold higher in 60% of HCC samples, and the extent of the
increase ranged from 2- to 46-fold (mean, 5.7-fold). With regard to
clinicopathological significance, HOTAIR expression levels were
closely associated with tumor differentiation (P=0.002), metastasis
(P=0.002) and early recurrence (P=0.001). Furthermore, a Spearman's
rank correlation coefficient analysis revealed that high HOTAIR
expression was linked to poor tumor differentiation (r=0.391,
P=0.002) and advanced TNM stage (r=0.293, P=0.023) and predicted a
greater tendency for metastasis (r=0.408, P=0.001) and early
recurrence (r=0.433, P=0.001). From these data, we hypothesize that
HOTAIR participates in the development and progression of HCC. As
certain clinicopathological characteristics, including tumor
differentiation, TNM stage, metastasis and recurrence, always
indicate poor prognosis, HOTAIR may be a predictor of poor
prognosis in HCC patients, warranting further research.
Previous reports have suggested that HOTAIR may
regulate cell proliferation, migration and invasion in a variety of
tumor cell types (
35
–
37
). In endometrial carcinoma, the
overexpression of HOTAIR increases the malignant potential of tumor
cells
in vitro
and
in vivo
(
24
). The knockdown of HOTAIR lncRNA
suppresses tumor invasion in gastric cancer cells and reverses the
epithelial-mesenchymal transition (
38
). To explore the biological function of
HOTAIR in HCC progression, a lentivirus-mediated shRNA expression
system capable of interfering with HOTAIR expression in HepG2 cells
was developed in the present study. The data demonstrated that
knockdown of HOTAIR significantly suppressed the proliferation and
invasion of HepG2 cells
in vitro
, and effectively reduced
the oncogenicity of liver cancer cells HepG2
in vivo
. Taken
together, these data indicate that high levels of HOTAIR may
promote the progression of liver cancer cells; this mechanism
remains to be explored.
The Wnt/β-catenin signaling pathway is a group of
signal transduction pathways, which was first identified for its
role in carcinogenesis and has been demonstrated to promote tumor
development in multiple types of human cancer. Ge
et al
(
39
) found that HOTAIR is able to
directly reduce the expression of Wnt inhibitory factor 1,
activating the Wnt/β-catenin signaling pathway; this clarified one
of the molecular mechanisms underlying progression and metastasis
in esophageal squamous cell carcinoma, and may represent a novel
therapeutic target in these patients (
39
). The present study examined the
expression of Wnt and β-catenin in neoplasms of the nude mice from
two groups. The results revealed that the mRNA expression level of
Wnt and β-catenin were repressed when HOTAIR was silenced. Emerging
evidence has demonstrated that the Wnt/β-catenin signaling pathway
plays a key role during HCC genesis and development, and may be a
therapeutic target in human HCC (
40
,
41
). We
hypothesize that HOTAIR may influence carcinogenesis partially
through activating and cooperating with the Wnt/β-catenin signaling
molecules in HCC. However, further research is necessary to clarify
the exact mechanism of HOTAIR in HCC.
In conclusion, the present study demonstrated that
HOTAIR expression is upregulated in the majority of HCC tissues,
and is closely associated with tumor differentiation, metastasis
and early recurrence in HCC patients. Furthermore, the
overexpression of HOTAIR promotes HCC progression partly by
activating the Wnt/β-catenin signaling pathway. Thus,
downregulating HOTAIR by interference may serve as a promising
therapeutic strategy for the treatment of HCC.
Acknowledgements
The authors would like to thank their colleagues
from the Department of Molecular Biology and the Department of
Gastroenterology of Chinese PLA General Hospital for their
technical support.
References
<table><tbody><tr><td rowspan=1 colspan=1> 1</td><td rowspan=1 colspan=1>El-Serag HB and Rudolph KL: Hepatocellular
carcinoma: Epidemiology and molecular carcinogenesis.
Gastroenterology. 132:2557–2576. 2007.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 2</td><td rowspan=1 colspan=1>Bosch FX, Ribes J, Diaz M and Cléries R:
Primary liver cancer: Worldwide incidence and trends.
Gastroenterology. 127(5 Suppl 1): S5–S16. 2004.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 3</td><td rowspan=1 colspan=1>Turdean S, Gurzu S, Turcu M, Voidazan S
and Sin A: Current data in clinicopathological characteristics of
primary hepatic tumors. Rom J Morphol Embryol. 53(Suppl 3):
719–724. 2012.PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 4</td><td rowspan=1 colspan=1>Severi T, van Malenstein H, Verslype C and
van Pelt JF: Tumor initiation and progression in hepatocellular
carcinoma: Risk factors, classification and therapeutic targets.
Acta pharmacol Sin. 31:1409–1420. 2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 5</td><td rowspan=1 colspan=1>Tang ZY: Hepatocellular carcinoma
surgery-review of the past and prospects for the 21st century. J
Surg Oncol. 91:95–96. 2005.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 6</td><td rowspan=1 colspan=1>Qi LN, Bai T, Chen ZS, Wu FX, Chen YY, De
Xiang B, Peng T, Han ZG and Li LQ: The p53 mutation spectrum in
hepatocellular carcinoma from Guangxi, China: Role of chronic
hepatitis B virus infection and aflatoxin B1 exposure. Liver Int.
35:999–1009. 2015.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 7</td><td rowspan=1 colspan=1>Ye H, Zhang C, Wang BJ, Tan XH, Zhang WP,
Teng Y and Yang X: Synergistic function of Kras mutation and HBx in
initiation and progression of hepatocellular carcinoma in mice.
Oncogene. 33:5133–5138. 2014.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 8</td><td rowspan=1 colspan=1>Li J, Gao JZ, Du JL and Wei LX: Prognostic
and clinicopathological significance of glypican-3 overexpression
in hepatocellular carcinoma: A meta-analysis. World J
Gastroenterol. 20:6336–6344. 2014.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 9</td><td rowspan=1 colspan=1>Sun Q, Wang R, Wang Y, et al: Notch1 is a
potential therapeutic target for the treatment of human hepatitis B
virus X protein-associated hepatocellular carcinoma. Oncol Rep.
31:933–939. 2014.PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 10</td><td rowspan=1 colspan=1>Zhang CH, Xu GL, Jia WD, Ge YS, Li JS, Ma
JL and Ren WH: Prognostic significance of osteopontin in
hepatocellular carcinoma: A meta-analysis. Int J Cancer.
130:2685–2692. 2012.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 11</td><td rowspan=1 colspan=1>Xie L, Jiang H and Wu F: Role of
Wnt/β-catenin signaling pathway in promoting tumorigenesis of
hepatocellular carcinoma. Nan Fang Yi Ke Da Xue Xue Bao.
34:913–917. 2014.(In Chinese).PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 12</td><td rowspan=1 colspan=1>Janku F, Kaseb AO, Tsimberidou AM, Wolff
RA and Kurzrock R: Identification of novel therapeutic targets in
the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using
targeted next generation sequencing. Oncotarget. 5:3012–3022. 2014.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 13</td><td rowspan=1 colspan=1>Perkel JM: Visiting ‘noncodarnia’.
Biotechniques. 54:301, 303–304. 2013.</td></tr><tr><td rowspan=1 colspan=1> 14</td><td rowspan=1 colspan=1>Kapranov P, Cheng J, Dike S, Nix DA,
Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermüller J,
Hofacker IL, et al: RNA maps reveal new RNA classes and a possible
function for pervasive transcription. Science. 316:1484–1488. 2007.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 15</td><td rowspan=1 colspan=1>Hung T and Chang HY: Long noncoding RNA in
genome regulation: Prospects and mechanisms. RNA Biol. 7:582–585.
2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 16</td><td rowspan=1 colspan=1>Koerner MV, Pauler FM, Huang R and Barlow
DP: The function of non-coding RNAs in genomic imprinting.
Development. 136:1771–1783. 2009.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 17</td><td rowspan=1 colspan=1>Costanzi C and Pehrson JR: Histone
macroH2A1 is concentrated in the inactive X chromosome of female
mammals. Nature. 393:599–601. 1998.View
Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 18</td><td rowspan=1 colspan=1>Fu X, Ravindranath L, Tran N, Petrovics G
and Srivastava S: Regulation of apoptosis by a prostate-specific
and prostate cancer-associated noncoding gene, PCGEM1. DNA Cell
Biol. 25:135–141. 2006.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 19</td><td rowspan=1 colspan=1>Reis EM, Nakaya HI, Louro R, Canavez FC,
Flatschart AV, Almeida GT, Egidio CM, Paquola AC, Machado AA, Festa
F, et al: Antisense intronic non-coding RNA levels correlate to the
degree of tumor differentiation in prostate cancer. Oncogene.
23:6684–6692. 2004.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 20</td><td rowspan=1 colspan=1>Rinn JL, Kertesz M, Wang JK, Squazzo SL,
Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E and
Chang HY: Functional demarcation of active and silent chromatin
domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323.
2007.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 21</td><td rowspan=1 colspan=1>Gupta RA, Shah N, Wang KC, Kim J, Horlings
HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al: Long
non-coding RNA HOTAIR reprograms chromatin state to promote cancer
metastasis. Nature. 464:1071–1076. 2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 22</td><td rowspan=1 colspan=1>Tsai MC, Manor O, Wan Y, Mosammaparast N,
Wang JK, Lan F, Shi Y, Segal E and Chang HY: Long noncoding RNA as
modular scaffold of histone modification complexes. Science.
329:689–693. 2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 23</td><td rowspan=1 colspan=1>Wu ZH, Wang XL, Tang HM, Jiang T, Chen J,
Lu S, Qiu GQ, Peng ZH and Yan DW: Long non-coding RNA HOTAIR is a
powerful predictor of metastasis and poor prognosis and is
associated with epithelial-mesenchymal transition in colon cancer.
Oncol Rep. 32:395–402. 2014.PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 24</td><td rowspan=1 colspan=1>Huang J, Ke P, Guo L, Wang W, Tan H, Liang
Y and Yao S: Lentivirus-mediated RNA interference targeting the
long noncoding RNA HOTAIR inhibits proliferation and invasion of
endometrial carcinoma cells in vitro and in vivo. Int J Gynecol
Cancer. 24:635–642. 2014.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 25</td><td rowspan=1 colspan=1>Liu XH, Liu ZL, Sun M, Liu J, Wang ZX and
De W: The long non-coding RNA HOTAIR indicates a poor prognosis and
promotes metastasis in non-small cell lung cancer. BMC Cancer.
13:4642013.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 26</td><td rowspan=1 colspan=1>Kim K, Jutooru I, Chadalapaka G, Johnson
G, Frank J, Burghardt R, Kim S and Safe S: HOTAIR is a negative
prognostic factor and exhibits pro-oncogenic activity in pancreatic
cancer. Oncogene. 32:1616–1625. 2013.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 27</td><td rowspan=1 colspan=1>Qiu JJ, Lin YY, Ye LC, Ding JX, Feng WW,
Jin HY, Zhang Y, Li Q and Hua KQ: Overexpression of long non-coding
RNA HOTAIR predicts poor patient prognosis and promotes tumor
metastasis in epithelial ovarian cancer. Gynecol Oncol.
134:121–128. 2014.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 28</td><td rowspan=1 colspan=1>Livak KJ and Schmittgen TD: Analysis of
relative gene expression data using real-time quantitative PCR and
the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 29</td><td rowspan=1 colspan=1>Shao R, Bao S, Bai X, Blanchette C,
Anderson RM, Dang T, Gishizky ML, Marks JR and Wang XF: Acquired
expression of periostin by human breast cancers promotes tumor
angiogenesis through up-regulation of vascular endothelial growth
factor receptor 2 expression. Mol Cell Biol. 24:3992–4003. 2004.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 30</td><td rowspan=1 colspan=1>Edge SB and Compton CC: The American Joint
Committee on Cancer: The 7th edition of the AJCC cancer staging
manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 31</td><td rowspan=1 colspan=1>Farazi PA and DePinho RA: Hepatocellular
carcinoma pathogenesis: From genes to environment. Nat Rev Cancer.
6:674–687. 2006.View
Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 32</td><td rowspan=1 colspan=1>Hu TH, Wang CC, Huang CC, Chen CL, Hung
CH, Chen CH, Wang JH, Lu SN, Lee CM, Changchien CS and Tai MH:
Down-regulation of tumor suppressor gene PTEN, overexpression of
p53, plus high proliferating cell nuclear antigen index predict
poor patient outcome of hepatocellular carcinoma after resection.
Oncol Rep. 18:1417–1426. 2007.PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 33</td><td rowspan=1 colspan=1>Niland CN, Merry CR and Khalil AM:
Emerging roles for long non-coding RNAs in cancer and neurological
disorders. Front Genet. 3:252012.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 34</td><td rowspan=1 colspan=1>Spizzo R, Almeida MI, Colombatti A and
Calin GA: Long non-coding RNAs and cancer: A new frontier of
translational research? Oncogene. 31:4577–4587. 2012.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 35</td><td rowspan=1 colspan=1>Li X, Wu Z, Mei Q, Li X, Guo M, Fu X and
Han W: Long non-coding RNA HOTAIR, a driver of malignancy, predicts
negative prognosis and exhibits oncogenic activity in oesophageal
squamous cell carcinoma. Br J Cancer. 109:2266–2278. 2013.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 36</td><td rowspan=1 colspan=1>Gupta RA, Shah N, Wang KC, et al: Long
non-coding RNA HOTAIR reprograms chromatin state to promote cancer
metastasis. Nature. 464:1071–1076. 2010.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 37</td><td rowspan=1 colspan=1>Geng YJ, Xie SL, Li Q, Ma J and Wang GY:
Large intervening non-coding RNA HOTAIR is associated with
hepatocellular carcinoma progression. J Int Med Res. 39:2119–2128.
2011.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 38</td><td rowspan=1 colspan=1>Xu ZY, Yu QM, Du YA, Yang LT, Dong RZ,
Huang L, Yu PF and Cheng XD: Knockdown of long non-coding RNA
HOTAIR suppresses tumor invasion and reverses
epithelial-mesenchymal transition in gastric cancer. Int J Biol
Sci. 9:587–597. 2013.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 39</td><td rowspan=1 colspan=1>Ge XS, Ma HJ, Zheng XH, Ruan HL, Liao XY,
Xue WQ, Chen YB, Zhang Y and Jia WH: HOTAIR, a prognostic factor in
esophageal squamous cell carcinoma, inhibits WIF-1 expression and
activates Wnt pathway. Cancer Sci. 104:1675–1682. 2013.View Article:Google Scholar:PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 40</td><td rowspan=1 colspan=1>Qu B, Liu BR, Du YJ, Chen J, Cheng YQ, Xu
W and Wang XH: Wnt/β-catenin signaling pathway may regulate the
expression of angiogenic growth factors in hepatocellular
carcinoma. Oncol Lett. 7:1175–1178. 2014.PubMed/NCBI</td></tr><tr><td rowspan=1 colspan=1> 41</td><td rowspan=1 colspan=1>Dahmani R, Just PA and Perret C: The
Wnt/β-catenin pathway as a therapeutic target in human
hepatocellular carcinoma. Clin Res Hepatol Gastroenterol.
35:709–713. 2011.View Article:Google Scholar:PubMed/NCBI</td></tr></tbody></table>
| https://www.spandidos-publications.com/10.3892/ol.2016.4130 |
The Modern Inquisition by Hugo Dewar 1953
The Modern Inquisition. Hugo Dewar 1953
Chapter II: The Heads are Harvested
All these trials aroused, to put it mildly, very grave doubts in the minds of observers abroad. But what was to follow surpassed all previous human experience, not excluding that of the witchcraft trials of the Middle Ages. In a series of world-staggering trials, practically the entire Old Guard of the Russian Revolution publicly confessed to all the crimes in the Soviet calendar, and were duly despatched from this world by a bullet in the back of the neck in the cellars of the Lubianka, or else, in a few instances, hidden away in secret prisons from which they have never since emerged. At the same time, nearly the whole of the General Staff and many minor officers were tried in secret, condemned as traitors and shot, while hundreds of thousands of real or alleged opponents of the regime were executed without trial or exiled to remote regions of the country under conditions amounting for most of them to slow death from starvation and disease.
In 1934 a faint light of hope appeared on the Soviet horizon. The worst period of forced collectivisation was past; the last harvest had mercifully been excellent; the speeches at the party congress of that year appeared to give grounds for the belief that the terrible tension of the previous years would at last be relaxed.
A single shot shattered all these hopes and gave the starting signal for a new wave of ferocious repression worse than anything that had gone before. A certain Leonid Nikolayev, in circumstances never clarified and for reasons never divulged by the authorities (although Nikolayev left a letter stating the reasons for his action), shot down and killed the party boss of the Leningrad district, Sergei Mironovich Kirov.
An examination of this affair does not lie within the scope of this book. [1]Suffice it to say that the ‘realists’ in Russia utilised this assassination as the pretext for a final settling of accounts with all who had ever at any time had even the remotest connection with any opposition inside the party.
The Dewey Commission set up in Mexico to sift the evidence of the first two of the Moscow Trials (1936 and 1937), submitted it to an exhaustive and devastating analysis, see The Case of Leon Trotskyand Not Guilty(Secker and Warburg, 1937 and 1938 respectively), and demonstrated with irrefutable logic that in their confessions the accused contradicted themselves and one another, that certain key statements in these confessions were false, and came to the conclusion:
(1) That the conduct of the Moscow Trials was such as to convince any unprejudiced person that no effort was made to ascertain the truth.
(2) While confessions are necessarily entitled to the most serious consideration, the confessions themselves contain such inherent improbabilities as to convince the commission that they do not represent the truth, irrespective of any means used to obtain them.
In view of this very thorough investigation by the Dewey Commission, it is not here necessary to recapitulate the abundant evidence proving the bogus nature of the confessions. Our notice of these Moscow Trials will therefore be confined to two aspects: their purpose and the technique employed to obtain confessions.
The purpose of these two trials, and also the one that followed in 1938, was very simple. They destroyed all those within the party who had at any time in the past belonged to an opposition. They not only destroyed them physically, but they also sought to annihilate them morally; to deny their past services in the revolutionary cause, transform them into traitors, and render them for ever anathema to the mass of the Russian people. At the same time they constituted the ostensible motive for a purge, both at home and abroad, of the administrative apparatus and the armed forces, thus removing all who did not belong to the new generation of parvenus typified in the person of AY Vyshinsky, who, during the days of revolution, had been on the other side of the barricade — and as far away on the other side as possible. This process halted only with the fall and trial of Yagoda, chief of the GPU, accompanied by a cleansing of the police apparatus itself, thus silencing — by death or the threat of death — all those who knew too much about the inner mechanics of the purge.
This does not mean to say that all of the purged were innocent of any hostility towards Stalin. Many nursed in secret a passionate desire for a change in the regime. Stalin could not but know how much he was hated, and that was enough for him. This was treachery! Vengeful, almost (one hesitates over the qualification) pathologically suspicious, Stalin smelled treason everywhere; and, once launched, the purge acquired a momentum of its own, independent of its author, impossible to stop till at last it bogged down of itself in the blood and filth churned up in its path.
From a study of the trial records themselves we can obtain a glimpse into their shadowy background.
The chief accused in the 1936 trial had already been in prison for a long time before they appeared in the dock. Yevdokimov was asked by Vyshinsky: ‘Do you admit that the assassination of Comrade Kirov was prepared with your assistance?’ Yevdokimov admits it. Vyshinsky continues: ‘At the trial in Leningrad, on 15-16 January 1935, you emphatically asserted that you had nothing to do with that murder.’ So — he had been in GPU hands since before January 1935. Among others figuring in this trial of 1935 were Kamenev, Zinoviev and Bakayev. They had all been sentenced to long terms of imprisonment for ‘moral complicity’ in the killing of Kirov. Now they all figured in this new trial in 1936. Thus they had all been in prison, at the disposal of the investigators, for a long time before they once again faced their judges.
The official report also gives us an indication of the length of interrogation necessary before the accused can be made to confess. V Olberg confessed ‘during examination on 21 February of this year’ (that is, 1936). But there is no date in the report indicating that any of the other accused confessed before July. It is reasonable to assume that had they confessed earlier, the report would have said so. It gives dates ranging from 3 July to 10 August, when ‘detailed evidence’, that is, when the required admissions were made by some of the principal accused (no dates are given for Fritz David and Berman-Yurin, who, like another accused, Olberg, rouse the very strong suspicion of being government agents). Thus we have a period of time from 21 February to 10 August: more than five months between the first confession and the last.
During these five months (at least) the accused were subject to interrogation. Again the trial record itself helps us to understand that these men (apart from Olberg, Fritz David and Berman-Yurin) did not give way easily. We quote from the report ( Trial I): ‘After obdurate denials, the accused Zinoviev, convicted by the testimony of a number of other accused, had to admit that ...’ (p 31) (No date is given for Zinoviev’s first break, but from the text it is obviously after many of the others.)
After persistent denials of his participation ... the accused Bakayev, under the weight of evidence brought against him, testified... (p 33)
Comrade Vyshinsky reminds Kamenev that he admitted this only after Reingold had given his evidence; that at the preliminary investigation he did not admit this until he had been implicated by others. (p 57)
Gradually a picture of part of what takes place behind the scenes begins to form. Olberg confesses first, a long time before any of the others; his confession is shown to others, or they are confronted with him in person to hear his accusations; still others ‘confess’, perhaps at first only partially but at last they are completely broken; and finally the most obdurate fall into line ‘under the weight of evidence’.
Now, we already have a slight idea of the nature of the preliminary interrogation from the evidence of Monkhouse in the Metro-Vickers Trial. He admitted that he lost his nerve after only forty-eight hours of questioning. Only forty-eight hours! — but ‘under such conditions it was enough’ — he said in court. For these later victims, however, it was not a question of two days, but of at least five months. Vyshinsky sought to excuse the very long periods of each interrogation session to which the British engineers were subjected, on the grounds that the British government itself was urging that the case be speeded up. The investigation of Nordwall and Monkhouse would normally have taken weeks and they would have been questioned for only two or three hours at a time, he said. But what power on earth was there to prevent the investigators in the case of Zinoviev and Kamenev et aliifrom continuing each interrogation for more than two or three hours, for as long as the prisoners retained consciousness? And then reviving them, to continue the torture. What power on earth was there to stop them from keeping up this pressure day after day, week after week, and month after month?
The reports of the public trials, particularly the first (1936), are far from being verbatim, and appear to have been edited with some care. Still it is clear that of all the accused, Smirnov, even in court, was more difficult to hold in line than the others. It is not therefore without significance that before his turn comes for cross-examination by Vyshinsky the ‘witness’ Safonova is brought into court. We put ‘witness’ in quotes because ‘her case has been set aside for separate trial’ ( Trial I, p 76), although she is manifestly just as much one of the accused as any of those actually in the dock.
After Safonova had affirmed that Smirnov said ‘Stalin must be assassinated, Stalin would be assassinated’, Vyshinsky turns to Smirnov and asks: ‘What were your relations with Safonova?’
Smirnov: ‘Good.’
Vyshinsky: ‘And more.’
Smirnov: We were intimately related.
Vyshinsky: ‘You were husband and wife.’
Smirnov: ‘Yes.’
Was Smirnov’s wife brought into court simply to report alleged conversations, or conversations about conversations, which added nothing to what other accused had already confessed? And why was her case ‘set aside for separate trial'? And why was she never tried in public after all?
Is it altogether unwarranted to suggest that some sort of bargain is here in question? We affirm nothing at this point, but the reader is asked to bear this incident in mind when reading later testimony regarding the methods employed at the preliminary investigations. Let us for the time being content ourselves with quoting the words of the 67-year-old accused Fyedotov in the Industrial Party Trial: ‘If at the present time I none the less beg... for leniency, it is not for myself... but for my family.’
It must also be noted that many others allegedly involved with the accused at this trial were also ‘reserved’. ‘The cases of Gertik, Grinberg, Y Gaven, Karev, Kuzmichev, Konstant, Matorin, Paul Olberg, Radin, Faivilovich, D Schmidt and Esterman, in view of the fact that investigation is still proceeding, have been set aside for separate trial.’ ( Trial I, p 39 — my emphasis) What becomes of them? No one knows — or rather no one tells. They do not figure in the next great trial in 1937, or the next in 1938. Who are they, what were they? Just names, outlandish names. But nearly all of them were leading figures in the early Bolshevik movement, and men who had for years worked hand-in-glove with Stalin. The GPU has power, however, to deal with them ‘administratively’ — and it uses this power. Since men can be shot without trial, it rests with the preliminary investigation whether they ever appear at a public trial — or any trial at all. On the other hand, men are ostensibly condemned to death and yet later they reappear in public life. Ramzin, for a well-known example. His case might well be cited to men under interrogation as an example of the fact that the regime is not vindictive, is prepared to rehabilitate those who aid it by making a clean breast of their sins.
Listen to the evidence on Smirnov’s attitude during the preliminary investigations:
At first he denied everything: he denied the existence of a Trotskyite organisation, he denied the existence of a centre, he denied his part in the centre, he denied connection with Trotsky, he denied that he gave any secret instructions, even those which he gave in 1936, and we know that this great conspirator managed to organise the communication of criminal instructions to his adherents even while he was in isolation. He denied everything. The whole of his examination of 20 May consisted of the word: ‘I deny that, again I deny, I deny.'... On 21 July, you, Smirnov, gave somewhat different evidence... When confronted with Mrachkovsky you continued to deny... I want to remind you that at the confrontation with Safonova during the preliminary investigation, which, in the main, reproduced what we saw in this court... he says ‘I do not remember.’ ... But on 13 August he was compelled to admit that this conversation did take place in 1932... ( Trial I, pp 158-60, my emphasis)
Note in the above the phrase ‘even while he was in isolation’: the prosecution could not ignore the awkward fact that Smirnov had been in prison from January 1933 until his last trial in 1936.
The 1936 trial of Zinoviev and Kamenev is their third. Twice before, in January and July 1935, they have been tried in connection with the Kirov affair, in conditions of almost complete secrecy. Clearly they were not at that time ripe for a public propaganda trial. At this, their third and last appearance in court, prospective members of the cast of other performances are mentioned. In addition to the list of names of those whose ‘cases are reserved’, others crop up during the court questioning. Since the accused only repeat in court what they have confessed behind the scenes, the mention of these names comes as no shock to the prosecuting authorities.
There is therefore nothing haphazard about all this. The second and third Moscow Trials are already in process of rehearsal before the first is launched. It is not enough for the accused to confess his own guilt: he must have had accomplices. Who were they? We get a hint of this aspect of the matter from the following:
Ter-Vaganyan explains to the court that Smirnov is afraid of telling the court the whole truth because he would then have to name a number of persons who were associated with terrorism. ( Trial I, p 109)
Smirnov’s reluctance to go the whole hog is thus explained in part by his desire not to implicate others. Ter-Vaganyan then offers him a way out of the dilemma; he suggests that Smirnov should admit connection with the ‘Gruzian [that is, Georgian — author] deviationists’: ‘In particular, Smirnov does not want to say that beginning with 1928 he maintained systematic connections with Gruzian deviationists.’ Thus aided, Smirnov remembers that in 1929 he ‘met Okudjava’. No danger here, because Okudjava had already been sentenced in secret trial (if ‘trial’ is the right word) and shot, together with seven other prominent Georgian leaders.
While Smirnov is allowed this easy way out, not so for the others of lesser calibre. On 21 August 1936, Comrade Vyshinsky makes the following statement:
At the preceding sessions some of the accused (Kamenev, Zinoviev and Reingold) in their testimony referred to Tomsky, Bukharin, Rykov, Uglanov, Radek, Pyatakov, Serebriakov and Sokolnikov as being to a greater or lesser degree involved in the criminal counter-revolutionary activities... ( Trial I, p 115)
I consider it necessary to inform the court that yesterday I gave orders to institute an investigation of these statements of the accused in regard to Tomsky, Rykov, Bukharin, Uglanov, Radek and Pyatakov, and that in accordance with the results of this investigation the office of the State Attorney will institute legal proceedings in this matter. In regard to Serebriakov and Sokolnikov, the investigating authorities are already in possession of material convicting these persons of counter-revolutionary crimes...
It goes without saying that the mere mention by the accused of these men is sufficient to condemn them. The prosecutor bears this statement out — an investigation will be instituted, but its findings are already known — for the ‘State Attorney will institute legal proceedings in this matter’. All the men whose names are mentioned know this. One of them, Tomsky, commits suicide rather than be forced to dishonour his name by public ‘repentance’. In the words of an exiled Oppositionist, ‘he throws his corpse in the face of Stalin’. Two are already ‘convicted'; they are due to appear at the following trial, which will serve only to publicise the conviction already decided upon.
The trial of the next batch of victims does not take place until January 1937. Among the accused are such famous figures as Radek, Sokolnikov, Serebriakov and Pyatakov. These men must have been under interrogation at least since the date of Vyshinsky’s statement on 21 August, that is, for five months. The trial report also in this case gives us evidence that the accused here too took some time to condition. Shestov says: ‘I did not surrender on the first day of my detention. For five weeks I denied everything, for five weeks they kept confronting me with one fact after another... (Report of the Court Proceedings in The Case of the Anti-Soviet Trotskyite Centre(Moscow, 1937), p 562; hereafter referred to as Trial II) Muralov declares: ‘And I said to myself almost after [sic] eight months, that I must submit...’ ( Trial II, p 233) Norkin holds out for two months and then yields. Why? asks Vyshinsky. ‘Because there is a limit to everything’, replies Norkin. The reply is not good enough; it has a double meaning; Vyshinsky is suspicious. Isn’t that precisely what the accused intended to convey? ‘Perhaps pressure was brought to bear on you?’, he asks. Norkin still refuses a direct answer. ‘I was questioned, exposed, there were confrontations.’ Vyshinsky persists: ‘You were confronted with evidence, facts?’ Norkin: ‘There were confrontations.’ ( Trial II, p 288) How revealing is Norkin’s refusal to accommodate Vyshinsky.
From this material we are in a position to gain a vague impression of the general circumstances of the accused during the preliminary investigation. Many are (at least as far as the three great Moscow Trials are concerned) proclaimed guilty even before the preliminary investigation is completed. They are all questioned for long periods of time (we shall later show how long each session can last). Those who prove obstinate are confronted with other accused who have yielded, or they are shown their depositions. Finally even the most obdurate are convinced that further resistance is useless.
But these preliminary investigations have a kind of ‘chain-reaction’ effect. It is not only a question of the men who formerly played a leading part in Soviet life, and whose destruction has already been planned. So many others are in addition inevitably involved, their families, their friends, their colleagues, and these in turn are compelled to involve others. So many investigators working on so many suspects, and all of them goaded to fulfil their ‘norm’. The Frankenstein monster thus created begins to run amok. There is no end to the nightmare. Yet eventually there must be an end, if the entire administrative machinery is not to fall apart. So finally the signal for a halt is given. In the third and last great trial Henry Yagoda, the Grand Inquisitor, is himself put in the dock! At the same time large numbers of his investigators are thrown into jail, side by side with the men whom they have put to the question! Finally — the truth is out! — GPU men themselves are tried on the charge of — having extorted false confessions!
On 2 August 1938, Pravda(no 211) reported a three-day trial of GPU men in Yaroslavl. BK Yurchak, former District Prosecutor, together with his assistants, is accused of ‘abusing his position’, using it to ‘sanction unmotivated arrests of citizens’, forcing them to confess that ‘accidental mistakes’ committed during the course of their work were ‘sabotage, wrecking, counter-revolutionary crimes’. Do we read aright? There is no doubt about it. Again on 22 October 1938, Pravda(no 292) reports the trial of GPU man Busorgin, and his assistant, Nikigorovsky, for ‘sanctioning illegal arrests’, holding ‘innocent workers’ for from three to five months. These GPU officials are sent for trial by none other than Vyshinsky, who affects great moral indignation at this state of affairs! What! — innocent men forced to confess to imaginary crimes! Who ever heard of such monstrous proceedings! Away with these ‘enemies of the people’ who have ‘penetrated into the leading district organs’ — that is, into the GPU itself! Vyshinsky did not know that such things were possible! If only he had known about it when he was prosecuting at the Moscow Trials!
Still another trial of scapegoat inquisitors, reported by Pravda(8 February 1939), results in the death sentence for Shlipniev, former deputy-chief of the Thirty-Ninth Militia Department, and in sentences of ten, seven, five and three years’ imprisonment for four others; all accused of ‘manufacturing’ cases and using false witnesses. Similar trials in various parts of the country marked the turn of the tide. These miscreants had been discovered as a result of complaints to the Public Prosecutor! So many crimes, so many victims, so many cries for justice unheard for so many years. And at last the great Leader deigns to hear, Vyshinsky gets his instructions — and a handful of underlings are sacrificed. All is well; justice has been done.
In the last great Moscow Trial Stalin makes a final clearance of his rivals; the remaining famous personalities of the Russian Revolution are removed for ever from the political scene — and from life.
Once again all the defendants are seen to have been in the hands of the interrogators for a long time. We shall cite only the following statement of Bukharin as typical for them all, including, of course, even those who played the role of agents of the prosecution among the accused: ‘I have been in prison for over a year, and I therefore do not know what is going on in the world.’ ( Trial III, p 767)
The most illuminating incident during the course of this trial was when the accused Krestinsky tried to retract his confession.
Krestinsky made the usual confession before the trial, but as soon as he got into open court he withdrew it and pleaded not guilty. Vyshinsky asks him if he always tells the truth and he replies with one word — no. Upon this Vyshinsky retorts — to this man accused of treason and on trial for his life — that ‘there is no need to get excited’. One can well appreciate that Krestinsky was in a state of the highest nervous tension. The following exchange then takes place:
Vyshinsky: ‘Consequently, Bessonov is not telling the truth?’
Krestinsky: ‘No.’
Vyshinsky: ‘But you do not always tell the truth. Is that not so?’
Krestinsky: ‘I did not always tell the truth during the investigation.’
Vyshinsky: ‘But at other times you always tell the truth?’
Krestinsky: ‘The truth!’
Vyshinsky: ‘Why this lack of respect for the investigation, why during the investigation did you tell untruths? Explain!’
Krestinsky: (No answer.)
The process of accusation and denial continues. Then once more Vyshinsky asks: ‘But what about your admission?’ Krestinsky replies: ‘ During the investigation I gave false evidence.’ [my emphasis] The State Prosecutor tries very hard to bring him back to a confirmation of his confession, but Krestinsky stubbornly persists in his denials. At one point he says that he does not feel well but that he has ‘only to take a pill’ and he will be able to continue. Further questioning takes place.
Vyshinsky: ‘You remember that I directly asked you whether you had any declarations or complaints to make against the investigator. Was that not so?’
Krestinsky: ‘It was.’
Vyshinsky: ‘Did you answer me?’
Krestinsky: ‘Yes.’
Vyshinsky: ‘Did I ask whether you had any complaints, or not?’
Krestinsky: ‘Yes, and I answered that I had no complaints.’
Vyshinsky: ‘If you were asked whether you had any complaints, you should have answered that you had.’
Krestinsky: ‘ I had, in the sense that I did not speak voluntarily.’ ( Trial III, pp 47-66 — my emphasis)
The afternoon and evening session of 2 March concluded with Krestinsky still denying his guilt. But at the evening session of the next day Krestinsky yields and says: ‘I fully confirm the testimony I gave in the preliminary investigation.’ ( Trial III, p 157)
What happened to make Krestinsky give way again?
* * *
As indicated in the Foreword to this book, most of the defendants in the three great Moscow Trials had long records of devoted service to the Russian revolutionary movement. The charges against them were so incompatible with all that was known of their past, and the notion of them as men whom the threat of torture and death could not turn from the path of what they held to be their duty as revolutionaries was so generally accepted, that many observers explained their confessions by their devotion to ‘the Cause’. Krestinsky’s attitude helps us to estimate the validity of this theory.
Krestinsky first of all makes a complete confession during the preliminary investigation; then he retracts it in court; then he retracts his retraction. His denial of guilt in court is quite categorical. Four times the president of the court asks him if he pleads guilty; four times he gives him the opportunity to fall into line with all the other accused, but he remains firm:
I plead not guilty. I am not a Trotskyite. I was never a member of the bloc of Rights and Trotskyites, of whose existence I was not aware. Nor have I committed any of the crimes with which I personally am charged, in particular I plead not guilty to the charge of having had connections with the German intelligence service... I have never been a Trotskyite. I have never belonged to the bloc of Rights and Trotskyites and have not committed a single crime. ( Trial III, p 36)
He alone of all the accused had the courage to make this point-blank denial of the charges made against him. What caused him to lose courage again? His final plea gives us the answer.
He begins his plea by evoking his revolutionary past:
I am one of those who have the longest records of active participation in political life. I began my revolutionary career as an 18-year-old youth, in 1901... The first stage in my revolutionary activities, 1901-06, was connected with the first revolution of 1905. I worked in practically every town of the North-Western Territory, was several times arrested... was deported... I removed to St Petersburg, where I established connections with Lenin, Nadezhda Konstantinovna Krupskaya [Lenin’s wife — author] and Mikhail Ivanovich Kalinin. At that time I worked on the Zvezda( Izvestia), and on Pravda.
And so on, up to 1921, when he says that he linked up with Trotsky in the ‘illegal Trotskyite work which he was then commencing’.
Having emphasised his complete loyalty to Lenin and Stalin he refers the beginning of his downfall to his agreement with Trotsky’s views in 1921; [2]views which were then freely expressed, published by the party press, but which he now calls ‘illegal’. However, in course of time this inner-party battle of ideas assumed ‘a purely conspiratorial’ character, eventually involving ‘terrorism, wrecking and diversion’. Then comes the key to his strange behaviour in pleading not guilty at the outset of the trial. ‘I consider it necessary’, he says, ‘to stress the fact that I had absolutely no knowledge of the terrorists’ acts enumerated in the second section of the indictment, and that I learnt about them only when I was handed a copy of the indictment.’ ( Trial III, p 734) He continues:
The fact is that in the days just preceding the trialI was under the painful impression caused by the gruesome facts that I had learnt from the indictment, and especially from its second section... It seemed to me easier to die than to give the world the idea that I was even a remote accessory to the murder of Gorky,about which I actually knew nothing. ( Trial III, p 736 — author’s emphasis)
Thus Krestinsky did not know the full charges against him until a few days before the opening of the trial (this gives a further insight into the preliminary staging), although he had been nine months in prison. At the end of the trial, in excuse for pleading not guilty, he said that it was the shock of learning that he was charged with being an accessory to the murder (so-called) of Maxim Gorky that made him deny everything he had previously admitted.
It seemed to him ‘easier to die’ than admit this charge. But this excuse is obviously not in accord with the words he used when pleading not guilty: for he did not then once mention the name of Gorky; instead he made a point of denying ‘ in particular’ the charge of being a German agent. Had his retraction really been due to a feeling of revulsion on learning that he was to be implicated in the death of Gorky, he would have denied ‘ in particular’ this charge and not a quite different one. So in reality it was the charge of treason to socialism and of counter-revolutionary activity that he found so hard to admit. Although Krestinsky says that he admitted ‘at the first interrogation’ his ‘connections with the German Military Intelligence Service’, it took a further four months before he could be made to accept the prosecution’s interpretation of these ‘connections’. The reason why he made this initial deposition with relative ease is clear: it meant no more than that he was Ambassador in Berlin when the 1922 Rapallo Treaty was signed between Germany and Russia. Secret military clauses of this treaty provided for exchange of information and cooperation between the two countries in building up their armed forces.
Since 1923 [Krestinsky testified during the trial] the agreement with Seeckt was carried out mainly in Moscow, and sometimes in Berlin. But, of course, as I was the person who concluded this agreement, inasmuch as I carried it out at times, and inasmuch as I was a member of the organisation on behalf of which this agreement was concluded [that is, a member of the government! — author], I naturally bear full political responsibility also for those acts which were committed in Moscow. This agreement did not remain unchanged: in 1926 the Reichswehr raised the question of repudiating this agreement. ( Trial III, p 263)
Note here that he speaks of bearing full ‘political responsibility’, not ‘criminal responsibility'; also that he refers to ‘the Reichswehr’ not the ‘military intelligence service’. The change in 1926 probably is a reference to the new Treaty of Berlin of 24 April 1926.
The whole rickety structure of lies and half-truths which compose the confessions has a certain foundation in fact, but as we can see from Krestinsky’s ‘connections’ with German intelligence, any actual historical event mentioned in the course of the trial is given a completely false interpretation, and is sometimes so camouflaged that it cannot be recognised for what it really was except by the leading participants in the trial. Seen in retrospect, the policy of aiding Germany to rebuild her war potential was wrong. Up to 1933 the main enemy had been France, with England a step behind; but after Hitler took power it became clear to Stalin, although not immediately, that the main danger was Germany. Krestinsky accepts ‘political responsibility’ for supporting and carrying out this earlier policy, but he cannot be charged with treason on this account, so official ‘connections’ must be transformed into espionage. After four months of conditioning to acceptance of this, Krestinsky agrees. Will he stand up in court and say exactly what these ‘connections’ were — that they belonged to the secret agreement with Germany whereby she evaded the provisions of the Versailles Treaty? Will he tell the workers of the world that Russia helped to build up the military strength of Germany — now Nazi Germany? No, that he cannot do. He is persuaded to accept the false version, and take the blame on his own shoulders. And then there comes another five months’ waiting for the trial. And at the last moment comes an addition to the charges by implicating him in Gorky’s death. To this man, who up to that moment has tried to retain the illusion that he remains a political figure, with a past worthy of some respect, and that he is not to be treated as a common criminal, this additional charge inserted at the penultimate moment comes as a tremendous shock. It reveals his opponents as even more unscrupulous than he had imagined them to be. This single breach of faith brings back the doubts overcome by four months of ‘conditioning’. That Gorky’s quite natural death was thus dragged into the affair is not in itself important — for who can take this seriously? — but all this repellent penny-dreadful nonsense about poisoning causes him to review his confession. For the first time he admits to himself that he may have been motivated by the desire to save his life. The courage that it took four months to break down momentarily returns to him. No, ‘easier to die’ than admit to it. And, of course, it was not complicity in Gorky’s death that he found easier to die for than admit: for, let us once again repeat, he did not even mention this when he pleaded not guilty at the opening of the trial.
But his new-found courage lasted a short time only. Hear his last words:
I beg you to bear in mind that I did not take a direct part in the most acute forms of struggle — terrorism, diversion and wrecking — and did not specifically know about these actions. I beg you to remember my former really revolutionary work, to believe me when I say that during these nine months I have undergone a radical change, and, by sparing my life, to give me the opportunity to expiate my crimes in any way, even if only partially. ( Trial III, p 736 — author’s emphasis)
It could hardly be put more plainly. Krestinsky is pleading for his life. In the final analysis it is the instinct to survive that motivates his submission, however much he may have rationalised. During the night following his categorical retraction of his entire confession, his inquisitors have once again placed the alternative brutally before him.
This basic aspect of the matter is important, because if one accepts the Darkness at Noonexplanation of the confessions, according to which these revolutionaries sacrifice themselves in the larger interests of the Party and the Cause, then the confessions of others who had no such motives would remain a mystery. But already, long before the trial of the Bolshevik ‘Old Guard’, we had confessions whose essence was similar, given by persons with no allegiance to the Communist Party. And since these trials we have had Protestant and Catholic leaders and British and American employees of business firms all making confessions. Therefore for all of them there must be some common factor compelling their submission.
Just as it is clear that the ‘Russian soul’ has nothing to do with the matter, so it is clear that the ‘Marxist soul’ offers no solution to the problem.
It is not, of course, suggested by this that the Darkness at Noontheory in no way contributes towards understanding of the confessions. On the contrary, it raises an extremely important aspect of the technique employed: the ‘psychological approach’. During the preliminary investigation it is the task of the examiners to aid the accused to rationalise his motives for submission. According to the psychological make-up of the person concerned, the arguments employed will be more or less subtle, will combine physical with moral pressure in differing proportions. Something of this can be deduced from the case of a man like Bukharin, who would never admit to himself that he was motivated by the fear of death and whose resistance would only be strengthened by the bald threat of it. He gives the following reasons for his confession:
I shall now speak of myself, of the reasons for my repentance. Of course, it must be admitted that incriminating evidence plays a very important part. For three months I refused to say anything. Then I began to testify. Why? Because while in prison I made a revaluation of my entire past. For when you ask yourself: ‘If you must die, what are you dying for?’ — an absolutely black vacuity suddenly rises before you with startling vividness. There was nothing to die for, if one wanted to die unrepented. And, on the contrary, everything positive that glistens in the Soviet Union acquires new dimensions in a man’s mind. This in the end disarmed me completely and led me to bend my knees before the party and the country. And when you ask yourself: ‘Very well, suppose you do not die; suppose by some miracle you remain alive, again what for! Isolated from everybody, an enemy of the people, in an inhuman position, completely isolated from everything that constitutes the essence of life...’ And at once the same reply arises. And at such moments, Citizen Judges, everything personal, all the personal incrustation, all the rancour, pride, and a number of other things, fall away, disappear. And, in addition, when the reverberations of the broad international struggle reach your ear, all this in its entirety does its work, and the result is the complete internal moral victory of the USSR over its kneeling opponents... ( Trial III, p 777)
In considering this statement we may leave aside the reference to ‘incriminating evidence’, since there was none apart from the confessions themselves; he almost seems to be saying; let us have done with the formalities and get to the real issue. Bukharin here is seeking to explain the apparently inexplicable in terms that may leave something of his past reputation unsullied. Here it is not the propaganda needs of the immediate moment that concern him so much as the verdict of History. He had lived for a Cause and now he wanted to persuade posterity that he was dying for a Cause — or what remained of it: ‘everything positive that glistens in the Soviet Union’. Again the spectre of the ultimate and irrevocable — Death. The choice had been put before him: die in the dark alone or perform one last service, and perhaps not the last, perhaps there is a chance of rehabilitation; in any case there will be an opportunity, within certain limits, of defending yourself, of explaining why you are doing what you are doing. And he did defend himself, so well that he at times made Vyshinsky look like a not particularly gifted pupil.
He categorically denied that he was ‘connected with foreign intelligence services’, categorically denied complicity in the assassinations real or alleged, and categorically denied participating in the alleged conspiracy to murder Lenin. But still he accepted the role of a counter-revolutionary, because he had been convinced when he threw in his lot with Stalin years before that that was the only thing to do to save the country and the revolution; and because in spite of all vacillations and doubtings he ultimately returned to this conviction — since what else was there with all possible alternative leadership destroyed? — and because, finally, the ‘reverberations of the broad international struggle’ had reached his ear through his inquisitors — after a year without any knowledge of what was going on in the world. Be sure that his informants had coloured the picture to suit their aims. War threatened and the masses must be rallied to the only leadership there was; the leadership of which he had been a part, all whose crimes he shared, and whose positive achievements he could not deny without stripping himself of everything — the self within, the part that History would respect, not the outer man that the politically uninitiated would revile a short time and then forget. Yes, he convinced himself of this. But it took him and the investigators three months to do it; and did the fear of death play absolutely no part in his final yielding? Not just death itself, the physical end, but the uselessness of it, the senselessness of it. ‘Only a miracle’, he said, could avert it; clearly the thought of this miracle was ever present in his mind. For three months he could tell himself with truth that he would rather die than do this thing; and the mere threat of death would only have stiffened his resistance. But he was offered life, one chance in a million perhaps, but a chance.
War is coming, comrade, and all will be needed. Only a full confession will show whether you are truly devoted, whether it is possible to trust you. ‘Everything personal, all the personal incrustation, all the rancour, pride, and a number of other things’ must be cast aside... Yes, his inquisitors would help him to rationalise...
Against Bukharin’s case set that of Friedman. Ignace Reiss, the secret Soviet agent abroad who broke with Stalin and was shortly afterwards assassinated in Switzerland, tells the story of this man:
A case better known than the others is that of the aged Friedman, an old Chekist whom Stalin, for some reason, was bent on including in the Zinoviev trial... But old Friedman remained adamant. The story is that his last words were: ‘You can shoot old Friedman only once, but no one can make a whore out of him.’
Thus men of fundamentally differing mental and physical calibre, although their devotion to the Party and the Cause be equally profound, will choose opposite paths. In general it may be said that the more purely intellectual the character of the accused, the less difficult it is to persuade him to confess. But for the investigators each accused required for a trial is a separate problem, demanding individual treatment. However, while the ‘psychological approach’ is an essential element of the technique, this understanding must not be permitted to obscure the fact that this moulding of the individual psychology is only possible in certain conditions. Without these essential conditions the confessional trial is not possible; it is therefore their sum total of all the circumstances that makes confessions possible, and not one element of them alone.
* * *
It would be a mistake to underestimate the propaganda value of these displays. However fantastically remote from reality they may appear to most of us in the West, they are yet effective, even if only temporarily, for the peasant masses for whose benefit they are primarily staged. No study of ‘mass persuasion’ can ignore them, for in this process they have undoubtedly been of immense value. Even in the West there are those — otherwise normally intelligent persons — who shake their heads and knowingly remark that ‘there is no smoke without fire’.
There is another angle worth considering. Even for those in the country concerned who do not wholly credit the ‘evidence’ of these trials, there is still a considerable satisfaction to be obtained from the fall of those who once sat in the seats of the mighty. The worker on the bottom rung of the Soviet social ladder derives some compensation from the fact that those at the top are even less secure than he, that they can be plunged overnight to depths beneath even him. [3]The more culturally immature a people, the more effective is the appeal to the basest instincts, to envy, unreasoning spite and personal malice; and the stage managers of these political demonstrations know how to play on all the stops. For the time being at any rate, millions of politically uneducated workers and peasants are persuaded that these ‘agents of the enemy’ are the sole cause of all their misfortunes. Attention is temporarily diverted from the evils of the system itself to individuals. If there are grave shortages of food, clothing, houses; if the promises of an easier and happier life do not materialise — it is all the fault of these saboteurs, these enemies of the people. Glass in butter, potatoes allowed to rot, grain not sown, jerry-built dwellings, mining disasters and train wrecks, wages not paid out at the right time, high prices and shoddy goods — it is all due to sabotage, behind which lurks the foreign enemy awaiting the appropriate moment to strike.
So one must work still harder, tighten one’s belt in order to ensure the defence of the Fatherland.
If those responsible for the trials had not found them effective in this respect, they would not have exported them abroad.
In the trials that have taken place of recent years outside Russia the same essential propaganda purpose is evident. The Russian government finds it expedient to maintain the ‘interventionist atmosphere’ of the early years of the Russian Revolution, however much world conditions may have altered. This constitutes one of the strongest psychological props of the regime. And those who frame Soviet policy — are they not also infected by the interventionist phobia? We have already briefly noted that the confessions of the accused always tally with the diplomatic manoeuvres of the Russian government; let us now examine this side of the question in more detail.
In the Industrial Party Trial of 1930 and the Menshevik Trial of 1931 the accused were chiefly in league with French imperialism; after 1935, when the Popular Front was in full swing, the accused forgot all about France and confessed themselves agents of the Gestapo, Japanese and, to lesser extent, British imperialism. England for long played a more or less secondary role in Soviet diplomatic considerations, and the USA no role at all; but today the accused in the satellite countries are all primarily agents of US or British imperialism. In the Moscow Trials the arch instigator of intervention was Trotsky, who had allegedly been an agent of German imperialism since 1921, and of British imperialism since 1926 — but nothing was said about France, which had loomed so prominent in previous trials. In the trials in satellite countries, Tito has taken the place of Trotsky; it is in agreement and collusion with Tito, arch-agent of imperialism, that the accused admit to having conspired. In 1936-38 Japan and Poland are also involved with Germany in interventionist plots, just as today France, Belgium and even Sweden stand behind the USA and Great Britain in the organisation of espionage against the People’s democracies and their protector, the Soviet Union.
The fact that all countries maintain intelligence services is not disputed. What strikes one as peculiar, however, is that in their confessions the defendants never admit to being in the pay of countries that are considered ‘friendly’ to Russia at the given time. This is most strikingly brought out by the single fact that never at any time has anyone confessed to being an agent in the pay of Italy. Italy had never been regarded as a serious threat to Russian security and relations between the two countries, in spite of Fascism in Italy, have never been strained. (In September 1933 the two countries signed a pact of non-aggression.)
Thus no one confesses to being a spy for Germany and Japan when England and France are regarded as the main enemies; and this in spite of the fact that at later trials the majority of the leading men in governmental, administrative and army circles are alleged to have all been in the pay of Germany and Japan long before these earlier trials took place. Conversely, no one confesses to having been a spy of England and France when the Comintern, on instructions from the Kremlin, is pursuing the policy of a United Front against the Axis Powers. Nor does the fact that hundreds are executed for allegedly seeking an agreement with Germany and Japan prevent the Soviet government from concluding an agreement with these countries scarcely a year after the last batch of ‘German and Japanese agents’ have been executed. (The later excuse that the Nazi-Soviet Pact was entered upon merely to gain time is demonstrably pure humbug.)
While, therefore, what the accused have to say about external aid is dictated by diplomatic considerations of the moment, their selection is sometimes determined by the requirements of the domestic situation. Thus we have batches of industrial technicians and specialists, Mensheviks (or, rather, former Mensheviks), foreign and native technicians, and finally high-ranking members of the Communist Party itself together with GPU men.
In Russia the process of suppressing opposition went on over a number of years, gradually widening its scope to embrace more and more social categories. In the satellites this destructive process, clearing the ground for the construction of the totalitarian states, is being telescoped into a much shorter period, for the driving force behind this is Soviet Russia. So in quick succession we have seen the Catholic and Protestant churches, foreign specialists, the Agrarian opposition parties, the Social Democrats, and Communist Party members themselves, all involved in confessional trials in the comparatively short space of six years.
An early and little remembered attempt to export the technique of the Moscow Trial to Europe took place in Spain in 1938. This is of particular interest because it was a dress rehearsal, as it were, of the later, successful export of these trials to Eastern Europe. It furnishes additional strong evidence in support of the view that these trials are not concerned with bringing criminals to justice, but are organised in order to provide scapegoats and a platform for propaganda and to give a legal covering for the physical suppression of opponents. Moreover, by noting the circumstances that prevented this Spanish trial from blossoming into a confession trial proper, we shall assist our understanding of those trials that were successful.
Russia’s policy in Spain during the Civil War was in essence no different from that pursued in Eastern Europe after the Second World War. She hoped to see emerge from the fires of war a government that would be her puppet; she was not content that gratitude for military aid against Franco should forge a bond of friendship between her and Spain; she wanted to make sure that her own satraps should be in control of any government resulting from a victory of the Loyalist forces. To ensure that it was felt necessary, even before the Civil War had ended, to destroy the parties and personalities within the Spanish workers’ movement that were hostile to the Communist Party. As hopelessly unrealistic as this aim of dominating Spain through the Russian-controlled Communist Party may seem, the Barcelona trial in 1938, and the circumstances surrounding it, so strongly resemble postwar experience in Eastern Europe that there can be no doubt that such an ambition existed, and was not so unlikely of realisation as it may seem.
As early as December 1936, Pravda(17 December 1936) exposed this aim by stating that ‘so far as Catalonia is concerned the cleaning up of the Trotskyist and Anarcho-Syndicalist elements has already begun and it will be carried out with the same degree of energy as in the USSR’. The ‘Trotskyist’ elements referred to were the Partido Obrero de Unificación Marxista(Workers Party of Marxist Unity), commonly known by its initials, POUM. Its main strength was in Catalonia, the most industrialised part of Spain, and during the first months of the Civil War it had achieved a large following, representing the most serious challenge to the Communist Party. The POUM, whose leaders were mostly ex-members of the Spanish Communist Party, although in some respects the weakest party opposing the Stalinists, was at the same time the greatest potential danger to their plans. Unlike the Socialists and Republicans, it had no illusions about Russian policy, and it refused to soften its criticism of this policy. Soviet military aid increased the influence of the Spanish Communists, who had been a negligible handful at the outset of the Civil War. Seeking an alliance with the Socialists and Republicans, it toned down its social demands in order to create the impression of moderation. Manoeuvring on the basis of the popular desire for unity in the interests of the common struggle against Franco, the Communists in Catalonia succeeded in uniting with the Socialists to form the Partido Socialista Unificado de Cataluña(PSUC). In spite of the numerical superiority of the Socialists in this new party, it was soon apparent that the Communists were in full control. This particular manoeuvre is now familiar to us from similar experiences in Eastern Europe.
The next step was to gain control of the armed police by placing Communists in all key positions. At the same time a propaganda campaign against the anarchists and the POUMists — and particularly against the latter — was waged, and the POUM was eventually forced out of the Barcelona Generalidad. In June 1937, six months after the Pravdadirective had been given, the leaders of the POUM were arrested as ‘agents of General Franco’. Nin, however, was not among those officially arrested. He, like many others, had been seized by secret agents acting on Russian instructions, taken to a private prison, and murdered. His body was picked up in a Madrid gutter some time afterwards.
The leaders of POUM were not brought to trial until sixteen months after their arrest. But in spite of this long delay they had not been broken and did not make any confessions. A very lively interest in their fate had been aroused in the working-class movement abroad, and a widespread campaign was being waged on their behalf. The exigencies of the Civil War made the Spanish authorities susceptible to pressure of this nature, and, although Prieto had been manoeuvred and strong-armed out of office, the Stalinists were still not completely master of the situation. The POUM leaders’ place of detention was known; they could not in the circumstances be kept incommunicado.In an ‘unofficial’ secret Spanish prison men could be interrogated: as was the case with the Belgian ex-Communist Kopp, questioned twenty-seven times for a total of one hundred and thirty-five hours in an unsuccessful effort to make him ‘confess’. But these prisoners, held officially by a government containing men still hesitant to go as far as the Communists urged, although conscious of their dependence upon Russian support, could not be subjected to such methods. Nor, even if they had been so treated, is it likely that they would all have been broken, since they could not be isolated from the outside world and were well aware of the efforts being made outside on their behalf.
The considerable volume of protests aroused by the arrest of these men and the charges brought against them made the authorities reluctant to bring the case to court. Anxious as they were to please their Russian ‘advisers’, the manufactured ‘evidence’ purporting to show that the accused were Franco agents was a little too much even for them, and this main charge in the indictment was dropped. But heavy prison sentences were none the less passed on the defendants — for seeking to overthrow the existing Loyalist government by force. The moderate Socialists and Republicans who lent themselves to this Communist manoeuvre apparently saw no inconsistency in thus allying themselves with the exponents par excellence ofthe armed coup d'état.Nor did they have the slightest inkling of the fact that, should the Communists’ policy prove successful, they themselves would have eventually been in the dock, charged with attempting to overthrow the regime by armed force!
Unfortunately, as postwar events in Eastern Europe have demonstrated, the Socialist and Liberal movements never studied Russian methods in Spain. Had they done so they would have been better equipped to fight for survival.
Notes
1.See the author’s Assassins at Large, Wingate, 1951. [On the MIA at http://www.marxists.org/archive/dewar/assassins/index.htm — MIA.]
2.At the Tenth Party Congress (March 1921) Trotsky’s views on the role of the trade unions were supported by, among others, Bukharin, Krestinsky, Serebriakov, Pyatakov, Sokolnikov — all tried and convicted in the Moscow Trials (see Isaac Deutscher’s Soviet Trade Unions(Chatham House, 1950), p 42 and following).
| https://www.marxists.org/archive/dewar/modern-inquisition/ch02.htm |
Full article: Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
Annual seasonal influenza vaccination (SIV) is recommended for people with diabetes, but vaccine coverage remains low. We estimated the probabilities of stopping or starting SIV, their correlates, ...
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
ABSTRACT
Formulae display: on ? Mathematical formulae have been encoded as MathML and are displayed in this HTML version using MathJax in order to improve their display. Uncheck the box to turn MathJax off. This feature requires Javascript. Click on a formula to zoom.
Annual seasonal influenza vaccination (SIV) is recommended for people with diabetes, but vaccine coverage remains low. We estimated the probabilities of stopping or starting SIV, their correlates, and the expected time spent in the vaccinated state over 10 seasons for different patient profiles. We set up a retrospective cohort study of patients with diabetes in 2006 (n = 16,026), identified in a representative sample of beneficiaries of the French National Health Insurance Fund. We followed them up over 10 seasons (2005/06–2015/16). We used a Markov model to estimate transition probabilities and a proportional hazards model to study covariates. Between two consecutive seasons, the probabilities of starting (0.17) or stopping (0.09) SIV were lower than those of remaining vaccinated (0.91) or unvaccinated (0.83). Men, older patients, those with type 1 diabetes, treated diabetes or more comorbidities, frequent contacts with doctors, and with any hospital stay for diabetes or influenza during the last year were more likely to start and/or less likely to stop SIV. The mean expected number of seasons with SIV uptake over 10 seasons (range: 2.6–7.9) was lowest for women <65 years with untreated diabetes and highest for men ≥65 years with type 1 diabetes. Contacts with doctors and some clinical events may play a key role in SIV adoption. Healthcare workers have a crucial role in reducing missed opportunities for SIV. The existence of empirical patient profiles with different patterns of SIV uptake should encourage their use of tailored educational approaches about SIV to address patients’ vaccine hesitancy.
KEYWORDS:
Administrative claims
cohort studies
influenza vaccines
Markov model
transition probability
Introduction
Because people with diabetes are at increased risk of severe complications linked to seasonal influenza, Citation 1 Mertz D , Kim TH , Johnstone J , Lam -P-P , Science M , Kuster SP , Fadel SA , Tran D , Fernandez E , Bhatnagar N , et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis . BMJ. 2013 ;347: f5061 . doi: 10.1136/bmj.f5061 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]the World Health Organization (WHO) and many national guidelines Citation 2 World Health Organization. Fact sheet on influenza (Seasonal) ; 2018 [accessed 2020 Feb 21]. http://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal) . [Google Scholar] , Citation 3 Rizzo C , Rezza G , Ricciardi W. Strategies in recommending influenza vaccination in Europe and US . Hum Vaccines Immunother. 2018 ;14: 693 – 98 . doi: 10.1080/21645515.2017.1367463 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]recommend they receive annual seasonal influenza vaccination (SIV). The SIV rate in this population is nonetheless far below WHO’s target of 75% in most Western countries, Citation 4 Loerbroks A , Stock C , Bosch JA , Litaker DG , Apfelbacher CJ . Influenza vaccination coverage among high-risk groups in 11 European countries . Eur J Public Health. 2012 ;22: 562 – 68 . doi: 10.1093/eurpub/ckr094 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]including France (about 30% among those <65 years and 60% among those ≥ 65 years). Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar] , Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar]Vaccine hesitancy among people with diabetes may contribute significantly to suboptimal vaccination coverage, Citation 7 Verger P , Bocquier A , Vergélys C , Ward J , Peretti-Watel P . Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey . BMC Public Health. 2018 ;18: 569 . doi: 10.1186/s12889-018-5441-6 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]as observed in other population groups, such as parents. Citation 8-11 Bianco A , Mascaro V , Zucco R , Pavia M . Parent perspectives on childhood vaccination: how to deal with vaccine hesitancy and refusal? Vaccine. 2019 ;37: 984 – 90 . doi: 10.1016/j.vaccine.2018.12.062 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] Dubé È , Farrands A , Lemaitre T , Boulianne N , Sauvageau C , Boucher FD , Tapiero B , Quach C , Ouakki M , Gosselin V , et al. Overview of knowledge, attitudes, beliefs, vaccine hesitancy and vaccine acceptance among mothers of infants in Quebec, Canada . Hum Vaccines Immunother. 2019 ;15: 113 – 20 . doi: 10.1080/21645515.2018.1509647 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar] Napolitano F , D’Alessandro A , Angelillo IF . Investigating Italian parents’ vaccine hesitancy: A cross-sectional survey . Hum Vaccines Immunother. 2018 ;14: 1558 – 65 . doi: 10.1080/21645515.2018.1463943 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar] Bocquier A , Fressard L , Cortaredona S , Zaytseva A , Ward J , Gautier A , Peretti-Watel P , Verger P . Social differentiation of vaccine hesitancy among French parents and the mediating role of trust and commitment to health: A nationwide cross-sectional study . Vaccine. 2018 ;36: 7666 – 73 . doi: 10.1016/j.vaccine.2018.10.085 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]The complexity of the vaccination pathway in France – despite efforts to simplify it – may also contribute to this situation. Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]
SIV must be repeated annually because immunity from vaccination wanes over time and because of the constant evolution of influenza viruses. Citation 2 World Health Organization. Fact sheet on influenza (Seasonal) ; 2018 [accessed 2020 Feb 21]. http://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal) . [Google Scholar]Each season, the decision to be vaccinated or not is ultimately the patient’s choice. Quantifying behavior changes (starting or stopping SIV) and understanding their determinants are both key to improving public health programs and patient education. Nonetheless, few longitudinal studies have explored the course of SIV behaviors over several consecutive years Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar] , Citation 12-14 Jiménez-Garcia R , Lopez-de-Andres A , Hernandez-Barrera V , Gómez-Campelo P , San Andrés-Rebollo FJ , de Burgos-lunar C , Cárdenas-Valladolid J , Abánades-Herranz JC , Salinero-Fort MA . Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study . Vaccine. 2017 ;35: 101 – 08 . doi: 10.1016/j.vaccine.2016.11.039 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] Caille-Brillet AL , Raude J , Lapidus N , De Lamballerie X , Carrat F , Setbon M . Trends in influenza vaccination behaviours–results from the CoPanFlu cohort, France, 2006 to 2011 . Euro Surveill. 2013 ;18: 20628 . doi: 10.2807/1560-7917.ES2013.18.45.20628 . [Crossref] , [PubMed] , [Google Scholar] Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar]to obtain chronological information about the clinical events preceding and explaining SIV behavior changes.
Multistate Markov (MSM) models, because they allow the analysis of transitions from one health state to another, are particularly appropriate for analyzing sequences of health events. These models make it possible to estimate transition probabilities, namely, the probability of remaining in the same state or of moving to another, and to identify factors affecting these transitions. Citation 15 Kalbfleisch JD , Lawless JF . The analysis of panel data under a Markov Assumption . J Am Stat Assoc. 1985 ;80: 863 . doi: 10.1080/01621459.1985.10478195 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]We used this approach to understand the dynamics of SIV behavior changes and identify clinical profiles predictive of this behavior over 10 years.
Our objectives were: 1) to estimate SIV transition probabilities (see above); 2) to quantify associations between these transitions and sociodemographic, clinical, and healthcare utilization characteristics; and 3) to assess the total time spent in the vaccinated state over the 10-season study period according to patients’ characteristics. This third objective seeks to determine easily identifiable demographic-clinical profiles to help clinicians tailor SIV promotion strategies to their patients.
Materials and methods
Study design and data source
We conducted the study in the Permanent Sample of Beneficiaries (Echantillon Généraliste des Bénéficiaires, EGB). The EGB, set up in 2005, is a permanent, representative, and open national random sample of 1/97th of the people affiliated with one of the three major national health insurance funds in France (salaried workers, agricultural workers and farmers, and self-employed workers); these cover nearly 95% of the French population. Citation 16 Tuppin P , de Roquefeuil L , Weill A , Ricordeau P , Merlière Y . French national health insurance information system and the permanent beneficiaries sample . Rev Epidemiol Sante Publique. 2010 ;58: 286 – 90 . doi: 10.1016/j.respe.2010.04.005 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]In August 2017 (time of extraction), the database included 804,089 beneficiaries. For this study, we extracted data for salaried workers (including those who are retired) and their covered family members (i.e., children and non-working spouses), who are covered by the French National Health Insurance Fund (NHIF) and account for about 86% of the French population. Citation 16 Tuppin P , de Roquefeuil L , Weill A , Ricordeau P , Merlière Y . French national health insurance information system and the permanent beneficiaries sample . Rev Epidemiol Sante Publique. 2010 ;58: 286 – 90 . doi: 10.1016/j.respe.2010.04.005 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]Accessible data were age, sex, long-term illness (LTI) status, and reimbursement claims – for consultations with private healthcare professionals, medical procedures, and drugs purchased in the community (classified by Anatomical Therapeutic Chemical (ATC) codes). At their doctors’ requests, the NHIF grants LTI status to beneficiaries with long-term and costly diseases; this status exempts them from copayments for any medical care associated with that disease, regardless of their income level. Citation 17 Cortaredona S , Pambrun E , Verdoux H , Verger P . Comparison of pharmacy-based and diagnosis-based comorbidity measures from medical administrative data . Pharmacoepidemiol Drug Saf. 2017 ;26: 402 – 11 . doi: 10.1002/pds.v26.4 . [Crossref] , [PubMed] , [Google Scholar]Data regarding the diagnoses associated with admissions since 2006 to a French public or private hospital, excluding military and psychiatric hospitals, are also available for all individuals in the EGB.
The study analyzed reimbursement data from the National System of Health Data (Système National des Données de Santé), in accordance with the General Conditions of Use of the Portal and the Data (Conditions Générales d’Utilization du Portail et des Données) (version 3.0). Because the study was performed in accordance with Article L1461–1 (paragraph III.6) of the French Public Health Code (Code de la santé publique) for public health purposes with fully anonymized data, there were no further requirements for ethical approval, consent to participate, or data protection agency approval.
Study population
The study population comprised patients identified with diabetes (all types) in 2006, residing in mainland France, and with at least two years of follow-up over the study period. To identify them, we used an NHIF algorithm Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]based on LTI status, hospitalization diagnoses and reimbursement claims for antidiabetic drugs or hemoglobin A1c (HbA1c) assays (Supplementary Table 1). Those who died or withdrew from the NHIF during the follow-up period were censored at the start of the year of the event.
Outcome: SIV uptake
For each individual and each SIV season n/n + 1 (temporal statistical units in our analyses), we constructed a binary variable “SIV uptake” (yes, no), based on SIV deliveries (ATC codes J07BB02, J07BB03, J07CA, excluding A/H1N1 pandemic vaccines, Supplementary Table 2) recorded between September 1 of year n and March 31 of year n + 1. Each SIV delivered in a community pharmacy is recorded in the NHIF database. SIV dispensing was considered a proxy for SIV uptake.
Clinical characteristics of cohort members
Cohort members without diabetes in 2005 according to the algorithm mentioned above were considered “patients with newly identified diabetes”. Furthermore, we categorized each patient, each year, according to the characteristics and treatment of her/his diabetes, from data on LTI status and reimbursement claims. Specifically, the reimbursements were those for antidiabetic drugs recorded during the six months before the start of the season under consideration (n/n + 1): type 1 diabetes (LTI status for type 1 diabetes: E10 according to the 10th International Classification of Diseases, ICD-10, and/or treated by insulin at inclusion); other types not treated by antidiabetic drugs or insulin; other types treated by antidiabetic drugs and/or insulin.
To measure comorbidities, we calculated an individual chronic condition score (ICC) for each year of follow-up, based on drug deliveries (excluding antidiabetic drugs). This methodology has previously been published and used in several articles. Citation 17 Cortaredona S , Pambrun E , Verdoux H , Verger P . Comparison of pharmacy-based and diagnosis-based comorbidity measures from medical administrative data . Pharmacoepidemiol Drug Saf. 2017 ;26: 402 – 11 . doi: 10.1002/pds.v26.4 . [Crossref] , [PubMed] , [Google Scholar] , Citation 18 Huber CA , Szucs TD , Rapold R , Reich O . Identifying patients with chronic conditions using pharmacy data in Switzerland: an updated mapping approach to the classification of medications . BMC Public Health. 2013 ;13: 1030 . doi: 10.1186/1471-2458-13-1030 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
We also extracted, for each cohort member, the number of hospital stays each year (between September 1 of year n, and August 31 of year n + 1), for diabetes, diabetes complications, influenza, and influenza complications, and the numbers of visits – separately – with general practitioners (GPs), pulmonologists, endocrinologists, and cardiologists. GPs usually manage most patients with type 2 diabetes Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar]and refer patients to specialists when they face difficulties or complications. We also extracted information about patients’ changes of GP during follow-up.
Statistical analysis
For objective 1, we used an MSM model and estimated, based on transition intensity (i.e., the instantaneous risks of moving from one state to another), the transition probability P r s ( t ): namely, the probability of remaining in the same state r or moving from state r to another state s within a given period of time t (here, a 1-year period: from season n-1/n to season n/n + 1). Citation 15 Kalbfleisch JD , Lawless JF . The analysis of panel data under a Markov Assumption . J Am Stat Assoc. 1985 ;80: 863 . doi: 10.1080/01621459.1985.10478195 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]Each season, we considered two states (vaccinated against seasonal influenza, or not), which generates four kinds of transitions (Figure 1): remaining vaccinated, remaining unvaccinated, starting vaccination, and stopping vaccination. Given the Markov property of our MSM model, the future SIV state is independent of the past state, given the present state and the covariate values. In other words, the probability of SIV the next season depends only on the current state (SIV or no SIV) and the covariate values.
All authors
A. Bocquier , S. Cortaredona , L. Fressard , F. Galtier & P. Verger
https://doi.org/10.1080/21645515.2020.1729628
Published online:
25 March 2020
Figure 1.A graphical representation of the two-state Markov model of seasonal influenza vaccination uptake and of the four kind of transitions
Abbreviation: SIV, seasonal influenza vaccination. a : transition “SIV uptake to SIV uptake” ( i.e ., remaining vaccinated) b : transition “no SIV uptake to no SIV uptake” ( i.e ., remaining unvaccinated) c : transition “SIV uptake to no SIV uptake” ( i.e ., stopping vaccination) d : transition “no SIV uptake to SIV uptake” ( i.e ., starting vaccination).
Figure 1.A graphical representation of the two-state Markov model of seasonal influenza vaccination uptake and of the four kind of transitions
Abbreviation: SIV, seasonal influenza vaccination. a : transition “SIV uptake to SIV uptake” ( i.e ., remaining vaccinated) b : transition “no SIV uptake to no SIV uptake” ( i.e ., remaining unvaccinated) c : transition “SIV uptake to no SIV uptake” ( i.e ., stopping vaccination) d : transition “no SIV uptake to SIV uptake” ( i.e ., starting vaccination).
As the A(H1N1) pandemic season (2009/10) had a major impact on SIV coverage rates, Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]we could not use a standard MSM model that would assume constant transition intensities over time. We implemented a time-inhomogeneous model with piecewise-constant intensities that makes it possible to take into account specific points in time when an identifiable event (here the 2009 pandemic) may imply a change in intensities of transition for all subjects. Citation 19 Jackson CH . Multi-state models for panel data: the MSM package for R . J Stat Software. 2011 : 38 . doi: 10.18637/jss.v038.i08 . [Crossref] , [Google Scholar]
For objective 2, we used a proportional hazards model to model transition intensities as a function of constant (sex, age at inclusion) and time-varying covariates (type of diabetes, ICC score, hospital stays for diabetes/influenza, and healthcare utilization):
q r s z t = q r s 0 e x p β r s T z t
where q r sis the transition intensity from state r to state s; z ( t )is the vector of covariates at time t, and βis the vector of regression coefficients, which can be interpreted as a hazard ratio (HR). This model makes it possible to test the effect of covariates on transition intensities, even if some patients have multiple transitions from one state to another. Citation 16 Tuppin P , de Roquefeuil L , Weill A , Ricordeau P , Merlière Y . French national health insurance information system and the permanent beneficiaries sample . Rev Epidemiol Sante Publique. 2010 ;58: 286 – 90 . doi: 10.1016/j.respe.2010.04.005 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
For objective 3, we used the transition intensities and covariate coefficient estimates to calculate the total time spent in the “SIV uptake” state over 10 SIV seasons. Given the initial state (SIV/no SIV uptake) and a set of three covariates (age, gender, and type of diabetes and its treatment), we were able to estimate the expected (i.e., predicted by the MSM model) number of seasons with SIV uptake over the next 10 seasonal campaigns for different patient profiles. We selected these three covariates because they were strongly associated with SIV uptake and are easily available to physicians in routine practice.
The goodness of fit of the model was assessed by the likelihood-ratio (LR) test and a graphical comparison of the predicted and observed prevalence rates of each state at each seasonal campaign. As most patients were lost during follow-up because of death, we also tested an empty (without covariates) three state model with “death” as an absorbing state to take the probability of dying during follow-up into account. This model yielded to similar results (results available upon request).
Descriptive statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA). The MSM was fitted with R 3.5.0 software, and the MSM package version 1.6.6 developed by Jackson. Citation 19 Jackson CH . Multi-state models for panel data: the MSM package for R . J Stat Software. 2011 : 38 . doi: 10.18637/jss.v038.i08 . [Crossref] , [Google Scholar]
Results
Study population characteristics ( Table 1 )
Of the 17,259 patients identified with diabetes in 2006, we included in the cohort 16,206 patients (94%) with at least two years of follow-up over the study period. Mean age at inclusion was 65 ± 14 years, and 46% were women. Fewer than 10% were patients with diabetes newly identified at inclusion, and 10% had type 1 diabetes. The average duration of follow-up was 8.6 ± 2.4 years (see details in Supplementary Table 3). Over the follow-up period, 27% of the initial cohort died and 4% were lost to follow-up. SIV uptake rates were estimated at 51% in 2006/2007 and 57% in 2015/2016.
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
All authors
A. Bocquier , S. Cortaredona , L. Fressard , F. Galtier & P. Verger
https://doi.org/10.1080/21645515.2020.1729628
25 March 2020
Table 1.Study cohort characteristics during the first and last season n/n + 1of follow-up (EGB, France, 2006/07–2015/16, n = 16,026)
Objective 1: transition probability estimates
Over the study period, 75% of the patients had stable SIV behaviors (i.e., never vaccinated, always vaccinated, or had only one SIV transition) (Figure 2). Between two consecutive seasons, the probability of starting SIV (0.17, 95% confidence interval – CI – 0.17, 0.18) was significantly higher than the probability of stopping it (0.09, 95% CI 0.09, 0.10). The probability of remaining vaccinated (0.91, 95% CI 0.90, 0.91) was significantly higher than the probability of remaining nonvaccinated (0.83, 95% CI 0.82, 0.83). The goodness of fit of our model was satisfactory (Supplementary Figure 1).
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
All authors
A. Bocquier , S. Cortaredona , L. Fressard , F. Galtier & P. Verger
https://doi.org/10.1080/21645515.2020.1729628
Published online:
25 March 2020
Figure 2.Proportion of the study population according to the number of SIV uptake transitions over the 10-year follow-up period (EGB, France, 2006/07–2015/16, n = 16,026)
Abbreviations: SIV, seasonal influenza vaccination. a Transition “SIV uptake to no SIV uptake” or transition “no SIV uptake to SIV uptake”.
Figure 2.Proportion of the study population according to the number of SIV uptake transitions over the 10-year follow-up period (EGB, France, 2006/07–2015/16, n = 16,026)
Abbreviations: SIV, seasonal influenza vaccination. a Transition “SIV uptake to no SIV uptake” or transition “no SIV uptake to SIV uptake”.
Objective 2: factors associated with starting or stopping SIV (
)
Compared with patients who remained nonvaccinated, the probability of starting SIV was higher for men and increased with age. It was also higher for patients with newly identified diabetes in 2006, type 1 diabetes, more comorbidities, or hospitalized for diabetes or influenza since the previous SIV season. Patients with frequent contacts with GPs or at least one contact with a pulmonologist and those who had changed GP since the previous season were also more likely to start SIV.
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
All authors
A. Bocquier , S. Cortaredona , L. Fressard , F. Galtier & P. Verger
https://doi.org/10.1080/21645515.2020.1729628
25 March 2020
Table 2.Demographic and clinical characteristics associated with each SIV uptake transition – Hazard ratios and 95% confidence intervals – Two-state Markov model estimates (EGB, France, 2006/07–2015/16, n = 16,026)
Compared with patients who remained vaccinated, the probability of stopping SIV was lower for men and decreased with age. It was also lower for patients with type 1 diabetes or another type of diabetes treated by insulin and/or antidiabetic drugs. Changing GP increased the probability of stopping, as well as starting, SIV, and contacts with endocrinologists and cardiologists reduced the probability of stopping SIV.
Objective 3: expected time spent in the “SIV uptake” state, according to patient profiles
For patients not vaccinated at the beginning of the period, the group with the lowest expected number of seasons with SIV uptake over the 10-season period (Figure 3a) (mean = 2.6 seasons) was that of women younger than 65 years with untreated diabetes, and the group with the most vaccinated seasons (mean = 5.7) was that of men aged 65 years or older with type 1 diabetes.
Seasonal influenza vaccination among people with diabetes: influence of patients’ characteristics and healthcare use on behavioral changes
All authors
A. Bocquier , S. Cortaredona , L. Fressard , F. Galtier & P. Verger
https://doi.org/10.1080/21645515.2020.1729628
Figure 3.Box-plot diagrams 1for the expected number of seasons with SIV uptake over 10 SIV seasons according to demographic-clinical profiles 2among patients with no SIV uptake at the beginning of the period (Figure 3a) and among patients with SIV uptake at the beginning of the period (Figure 3b) – Two-state Markov model estimates 3(EGB, France, 2006/07–2015/16, n = 16,026).
Abbreviations: F, female; Other noT, other types of diabetes without any treatment; Other T, other type of diabetes treated by insulin and/or antidiabetic drugs; M, men; SIV, seasonal influenza vaccination; T1, type 1 diabetes.
1The box extends from the 25th percentile to the 75th percentile. The line in the middle is the median (i.e., the 50th percentile). The diamond inside the box is the mean. The whiskers, those two lines at either end, extend from the box as far as the minimum and maximum values, up to 1.5 times the interquartile range (i.e., the distance from the 25th percentile to the 50th).
2Profiles are ranked in ascending order of the expected (i.e., predicted by the MSM model) number of seasons with SIV uptake for patients not vaccinated at the beginning of the period.
3For each profile, all remaining covariates (individual chronic condition score, hospital stays for diabetes/influenza, healthcare use) are set to their mean values.
Reading Figure 3a: for a woman not vaccinated at the beginning of the period and younger than 65 years with untreated diabetes, the expected number of seasons with SIV uptake over the next 10 SIV seasons was estimated at 2.6.
Reading Figure 3b: for a woman vaccinated at the beginning of the period and younger than 65 years with untreated diabetes, the expected number of seasons with SIV uptake over the next 10 SIV seasons was estimated at 3.6
Figure 3.Box-plot diagrams 1for the expected number of seasons with SIV uptake over 10 SIV seasons according to demographic-clinical profiles 2among patients with no SIV uptake at the beginning of the period (Figure 3a) and among patients with SIV uptake at the beginning of the period (Figure 3b) – Two-state Markov model estimates 3(EGB, France, 2006/07–2015/16, n = 16,026).
Abbreviations: F, female; Other noT, other types of diabetes without any treatment; Other T, other type of diabetes treated by insulin and/or antidiabetic drugs; M, men; SIV, seasonal influenza vaccination; T1, type 1 diabetes.
1The box extends from the 25th percentile to the 75th percentile. The line in the middle is the median (i.e., the 50th percentile). The diamond inside the box is the mean. The whiskers, those two lines at either end, extend from the box as far as the minimum and maximum values, up to 1.5 times the interquartile range (i.e., the distance from the 25th percentile to the 50th).
2Profiles are ranked in ascending order of the expected (i.e., predicted by the MSM model) number of seasons with SIV uptake for patients not vaccinated at the beginning of the period.
3For each profile, all remaining covariates (individual chronic condition score, hospital stays for diabetes/influenza, healthcare use) are set to their mean values.
Reading Figure 3a: for a woman not vaccinated at the beginning of the period and younger than 65 years with untreated diabetes, the expected number of seasons with SIV uptake over the next 10 SIV seasons was estimated at 2.6.
Reading Figure 3b: for a woman vaccinated at the beginning of the period and younger than 65 years with untreated diabetes, the expected number of seasons with SIV uptake over the next 10 SIV seasons was estimated at 3.6
For patients vaccinated at the beginning of the period, the expected number of seasons with SIV uptake was higher for all profiles, but their ranking remained similar (Figure 3b).
Discussion
Among this cohort of patients with diabetes followed up over 10 seasons, the probability of remaining vaccinated or nonvaccinated was far higher than the probability of moving from one state to the other. The probability that a nonvaccinated patient would start SIV during the next season was higher (0.17) than the probability of a vaccinated patient stopping (0.09). Men, older patients, those with type 1 diabetes, treated diabetes or more comorbidities, frequent contacts with GPs or pulmonologists, or with any hospital stay for diabetes or influenza during the previous year were all more likely to start and/or less likely to stop SIV. Changing GP was associated with starting SIV among those non-vaccinated, and stopping it among those who had previously been vaccinated. The mean expected number of seasons with SIV uptake depended on initial SIV state and patients’ demographic and clinical profiles.
Our results demonstrate, consistently with previous findings, that people with diabetes have mainly stable SIV behaviors. Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar] , Citation 7 Verger P , Bocquier A , Vergélys C , Ward J , Peretti-Watel P . Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey . BMC Public Health. 2018 ;18: 569 . doi: 10.1186/s12889-018-5441-6 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] , Citation 14 Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar]The finding that the probability of remaining vaccinated (0.91) was significantly higher than that of remaining unvaccinated (0.83) is somewhat encouraging, even though the order of magnitude of these probabilities did not differ notably. Nonetheless, the probabilities of behavioral shifts were non-negligible in each group and higher for starting to vaccinate than for stopping it. Our results ( Table 2) confirm that both modifiable (medical care) and nonmodifiable factors (aging and clinical deterioration) were associated with increased SIV uptake rates. Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar] , Citation 12 Jiménez-Garcia R , Lopez-de-Andres A , Hernandez-Barrera V , Gómez-Campelo P , San Andrés-Rebollo FJ , de Burgos-lunar C , Cárdenas-Valladolid J , Abánades-Herranz JC , Salinero-Fort MA . Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study . Vaccine. 2017 ;35: 101 – 08 . doi: 10.1016/j.vaccine.2016.11.039 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] , Citation 14 Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar] , Citation 20 Achtymichuk KA , Johnson JA , Al Sayah F , Eurich DT . Characteristics and health behaviors of diabetic patients receiving influenza vaccination . Vaccine. 2015 ;33: 3549 – 55 . doi: 10.1016/j.vaccine.2015.05.047 . [Crossref] , [PubMed] , [Google Scholar]This finding is both intuitive and fortunate and helps to lighten, in part, the dark picture of low SIV coverage in patients with diabetes: low coverage involves, above all, patients with the least serious forms of disease. Our results suggest that any clinical encounter with patients with diabetes, both vaccinated and nonvaccinated, should be taken as a new opportunity to make them aware of the importance of SIV, especially when their diabetes is becoming more severe. Our results also suggest that this is already the case, to some extent, as we found a higher probability of starting SIV among patients hospitalized for either influenza (+35%) or diabetes (+12%).
These results and their clinical implications are important for doctors. First, the probability of starting SIV rose with contacts with GPs and especially with pulmonologists in the last year. These findings confirm the key role of doctors in promoting SIV among at-risk patients. Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar] , Citation 12 Jiménez-Garcia R , Lopez-de-Andres A , Hernandez-Barrera V , Gómez-Campelo P , San Andrés-Rebollo FJ , de Burgos-lunar C , Cárdenas-Valladolid J , Abánades-Herranz JC , Salinero-Fort MA . Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study . Vaccine. 2017 ;35: 101 – 08 . doi: 10.1016/j.vaccine.2016.11.039 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] , Citation 21 Nagata JM , Hernández-Ramos I , Kurup AS , Albrecht D , Vivas-Torrealba C , Franco-Paredes C . Social determinants of health and seasonal influenza vaccination in adults ≥65 years: a systematic review of qualitative and quantitative data . BMC Public Health. 2013 ;13: 388 . doi: 10.1186/1471-2458-13-388 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]Previous studies have shown that patients trust their physicians strongly Citation 7 Verger P , Bocquier A , Vergélys C , Ward J , Peretti-Watel P . Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey . BMC Public Health. 2018 ;18: 569 . doi: 10.1186/s12889-018-5441-6 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]and that these professionals can play an important role in improving patients’ knowledge and decision-making process about SIV. Citation 22 Napolitano F , Della Polla G , Angelillo IF . Knowledge, attitudes, and behaviors of parents towards recommended adult vaccinations: an explanatory survey in the geographic area of Naples, Italy . Int J Environ Res Public Health. 2019 ;16: 2070 . doi: 10.3390/ijerph16122070 . [Crossref] , [PubMed] , [Google Scholar] , Citation 23 Teo LM , Smith HE , Lwin MO , Tang WE . Attitudes and perception of influenza vaccines among older people in Singapore: A qualitative study . Vaccine. 2019 ;37: 6665 – 72 . doi: 10.1016/j.vaccine.2019.09.037 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]The absence of any similar effect for endocrinologists and cardiologists, however, suggests that these specialists might be missing some opportunities to promote SIV. Citation 24 Davis MM , Wortley PM , Ndiaye SM , Cowan AE , Osta AD , Clark SJ . Influenza vaccine for high-risk non-elderly adults: a national survey of subspecialists . Hum Vaccine. 2008 ;4: 229 – 33 . doi: 10.4161/hv.4.3.5516 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]In particular, it is surprising that medical contacts with endocrinologists are not associated with an increase in SIV uptake, as endocrinologists work with patients on behavioral changes in their daily practice, particularly concerning diet or physical activity. Endocrinologists and cardiologists might have a lower perception of the severity of influenza than pulmonologists because the association between influenza-induced complications of diabetes or cardiovascular diseases might appear less frequent, direct or severe than in patients with chronic respiratory diseases. Citation 24 Davis MM , Wortley PM , Ndiaye SM , Cowan AE , Osta AD , Clark SJ . Influenza vaccine for high-risk non-elderly adults: a national survey of subspecialists . Hum Vaccine. 2008 ;4: 229 – 33 . doi: 10.4161/hv.4.3.5516 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]These specialists may also have the perception that patients will receive SIV elsewhere, a common explanation for missed vaccination among some specialists. Citation 24 Davis MM , Wortley PM , Ndiaye SM , Cowan AE , Osta AD , Clark SJ . Influenza vaccine for high-risk non-elderly adults: a national survey of subspecialists . Hum Vaccine. 2008 ;4: 229 – 33 . doi: 10.4161/hv.4.3.5516 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]Increasing awareness among endocrinologists and cardiologists of the benefits of SIV for people with diabetes (e.g., through guidelines and initial and continuing medical education) is an important goal.
Second, doctors must be aware that some specific events (e.g., intensification of treatment and hospitalization for diabetes or influenza) may present favorable opportunities for encouraging SIV uptake. These events may increase patients’ perception of their own vulnerability toward influenza or of the severity of the disease – both strong facilitators of the adoption of SIV. Citation 7 Verger P , Bocquier A , Vergélys C , Ward J , Peretti-Watel P . Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey . BMC Public Health. 2018 ;18: 569 . doi: 10.1186/s12889-018-5441-6 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]Moreover, they provide a good practical opportunity to meet caregivers involved in therapeutic education programs, provided that these include education about SIV.
Third, our results also suggest that the first visits of new patients may be a critical period for doctors to review their prevention needs (as shown for medications Citation 25 Schuling J , Gebben H , Veehof LJG , Haaijer-Ruskamp FM . Deprescribing medication in very elderly patients with multimorbidity: the view of Dutch GPs. A qualitative study . BMC Fam Pract. 2012 ;13: 56 . doi: 10.1186/1471-2296-13-56 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]) and promote SIV. We also found, however, that changing GPs may be correlated with stopping SIV as well. Lack of additional data on GPs’ characteristics makes this finding difficult to interpret. Changing GPs might reflect a change in a patient’s commitment to health or attitudes toward healthcare, and doctors should be particularly attentive to these new patients.
Fourth, our results highlight the existence of profiles of patients with contrasting propensities for regular vaccination. For example, we estimated that a woman with diabetes younger than 65 years and with no pharmacological treatment for this disease will be vaccinated only about 3 times over the next 10 seasons (vs around 7 times for a woman 65 years or older with type 1 diabetes). While clinicians should systematically assess whether or not their patients have been vaccinated against the flu, they should also bear these profiles in mind to help them to identify those at high risk of irregular or no SIV uptake. This would help them to anticipate the need to spend more effort and time to focus on them, to understand their motives for potential hesitancy/reluctance, and to propose tailored approaches to address these motives and encourage SIV, as recommended for addressing vaccine hesitancy. Citation 26 Dubé E , Gagnon D , MacDonald NE . SAGE working group on vaccine hesitancy. Strategies intended to address vaccine hesitancy: review of published reviews . Vaccine. 2015 ;33: 4191 – 203 . doi: 10.1016/j.vaccine.2015.04.041 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
These results have also several implications for policymakers. According to the Community Guide’s categories of interventions to increase appropriate vaccination, Citation 27 The Community Guide. What works. Increasing appropriate vaccination. Evidence-base intervention for your community ; 2017 [accessed 2020 Feb 21]. https://www.thecommunityguide.org/sites/default/files/assets/What-Works-Factsheet-Vaccination.pdf . [Google Scholar]strategies to improve SIV rates in target populations should rely on: increasing community demand for SIV (e.g., media campaigns, patient reminders); enhancing access to SIV (e.g., in France, free vaccine, vaccination by nurses since 2008, and by community pharmacists – nationwide implementation starting in 2019); and using provider- or system-based interventions (e.g., pay-for-performance for GPs, where performances includes SIV indicators). Applying these recommendations at the national level has remained insufficient in many countries, and SIV rates have remained far lower than the targets of both WHO and individual nations. Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]Further efforts are required. One method, implied by our results, may involve training to enhance the educational skills of physicians and other healthcare workers’ educational skills; it should also provide them with guidance and tools for adapting SIV educational efforts to different patient profiles. No “one size fits all” intervention is likely to exist, and tailored interventions adapted to patients’ characteristics, attitudes, and perceptions may be more effective in fostering SIV. Citation 26 Dubé E , Gagnon D , MacDonald NE . SAGE working group on vaccine hesitancy. Strategies intended to address vaccine hesitancy: review of published reviews . Vaccine. 2015 ;33: 4191 – 203 . doi: 10.1016/j.vaccine.2015.04.041 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]For example, providing communication training to healthcare workers, together with tailored information sheets and patient education websites, should be evaluated for increasing SIV uptake, as it has been shown to be an effective strategy for increasing uptake for HPV vaccine. Citation 28 Dempsey AF , Pyrznawoski J , Lockhart S , Barnard J , Campagna EJ , Garrett K , Fisher A , Dickinson LM , O’Leary ST . Effect of a health care professional communication training intervention on adolescent human papillomavirus vaccination: a cluster randomized clinical trial . JAMA Pediatr. 2018 ; e180016 . doi: 10.1001/jamapediatrics.2018.0016 . [Crossref] , [PubMed] , [Google Scholar]As healthcare workers are also prone to vaccine hesitancy, Citation 29 Verger P , Collange F , Fressard L , Bocquier A , Gautier A , Pulcini C , Raude J , Peretti-Watel P . Prevalence and correlates of vaccine hesitancy among general practitioners: a cross-sectional telephone survey in France, April to July 2014 . Euro Surveill. 2016 ;21: 30406 . doi: 10.2807/1560-7917.ES.2016.21.47.30406 . [Crossref] , [PubMed] , [Google Scholar] , Citation 30 Wilson R , Zaytseva A , Bocquier A , Nokri A , Fressard L , Chamboredon P , Carbonaro C , Bernardi S , Dubé E , Verger P . Vaccine hesitancy and self-vaccination behaviors among nurses in southeastern France . Vaccine. 2020 ;38:1144–1151. doi: 10.1016/j.vaccine.2019.11.0118 . [Crossref] , [Google Scholar]and SIV coverage remains suboptimal among them in many countries, Citation 29–32 Verger P , Collange F , Fressard L , Bocquier A , Gautier A , Pulcini C , Raude J , Peretti-Watel P . Prevalence and correlates of vaccine hesitancy among general practitioners: a cross-sectional telephone survey in France, April to July 2014 . Euro Surveill. 2016 ;21: 30406 . doi: 10.2807/1560-7917.ES.2016.21.47.30406 . [Crossref] , [PubMed] , [Google Scholar] Wilson R , Zaytseva A , Bocquier A , Nokri A , Fressard L , Chamboredon P , Carbonaro C , Bernardi S , Dubé E , Verger P . Vaccine hesitancy and self-vaccination behaviors among nurses in southeastern France . Vaccine. 2020 ;38:1144–1151. doi: 10.1016/j.vaccine.2019.11.0118 . [Crossref] , [Google Scholar] Boey L , Bral C , Roelants M , De Schryver A , Godderis L , Hoppenbrouwers K , Vandermeulen C . Attitudes, believes, determinants and organisational barriers behind the low seasonal influenza vaccination uptake in healthcare workers – A cross-sectional survey . Vaccine. 2018 ;36: 3351 – 58 . doi: 10.1016/j.vaccine.2018.04.044 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] Napolitano F , Bianco A , D’Alessandro A , Papadopoli R , Angelillo IF . Healthcare workers’ knowledge, beliefs, and coverage regarding vaccinations in critical care units in Italy . Vaccine. 2019 ;37: 6900 – 06 . doi: 10.1016/j.vaccine.2019.09.053 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]health authorities should also promote and evaluate multicomponent interventions to promote SIV among healthcare professionals.
The strengths of this study include its large sample size, and the use of a combination of different criteria to identify patients with diabetes with various clinical features (Supplementary Table 1). Another strength of our study is its 10-year follow-up period, which is, with our previous article based on the same cohort, Citation 14 Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar]the longest of the studies of SIV behavior over several consecutive seasons. From a statistical standpoint, our study is the first to use an MSM model to estimate transition probabilities for SIV behaviors. Moreover, although several previous studies have examined the factors associated with being vaccinated (or not), Citation 6 Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar] , Citation 12 Jiménez-Garcia R , Lopez-de-Andres A , Hernandez-Barrera V , Gómez-Campelo P , San Andrés-Rebollo FJ , de Burgos-lunar C , Cárdenas-Valladolid J , Abánades-Herranz JC , Salinero-Fort MA . Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study . Vaccine. 2017 ;35: 101 – 08 . doi: 10.1016/j.vaccine.2016.11.039 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] , Citation 14 Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar] , Citation 20 Achtymichuk KA , Johnson JA , Al Sayah F , Eurich DT . Characteristics and health behaviors of diabetic patients receiving influenza vaccination . Vaccine. 2015 ;33: 3549 – 55 . doi: 10.1016/j.vaccine.2015.05.047 . [Crossref] , [PubMed] , [Google Scholar]our approach is the first one to explore associations between shifts in SIV behaviors and several demographic and clinical characteristics. This is essential for identifying opportunities (critical periods and events) to promote SIV. Our model provided a good prediction of SIV rates over the 10-year follow-up period (Supplementary Figure 1), confirming that the Markovian approach is well adapted to modeling SIV state transitions. Moreover, our time-inhomogeneous model with piecewise-constant intensities allowed us to adjust for some variations of the probabilities of SIV uptake during the follow-up period, especially those, now well documented, induced by the 2009 A(H1N1) campaign in France. Citation 5 Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]
We also acknowledge some limitations. First, vaccinations that took place during occupational medicine visits or at vaccination centers or some nursing homes that buy vaccines for their residents (fewer than 20% of all nursing homes Citation 33 Agence technique de l’information sur l’hospitalisation. Les coûts en établissement d’hébergement pour personnes âgées dépendantes. Lyon (France) : ATIH; 2013 . [Google Scholar]) are not recorded in the French NHIF databases. However, these limitations are unlikely to affect our results substantially as the vast majority of vaccinations in France are administered by private healthcare workers and are thus recorded in these databases. Citation 34 Institut de veille sanitaire. Mesure de la couverture vaccinale en France. Bilan des outils et méthodes en l’an 2000. Saint-Maurice, France : Institut de veille sanitaire ; 2001 . [Google Scholar]Second, as SIV behavior may vary by social characteristics, Citation 35 Rey D , Fressard L , Cortaredona S , Bocquier A , Gautier A , Peretti-Watel P , Verger P . Vaccine hesitancy in the French population in 2016, and its association with vaccine uptake and perceived vaccine risk–benefit balance . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.17.17-00816 . [Crossref] , [PubMed] , [Google Scholar]our results cannot be extrapolated to population categories (e.g., farmers, tradespeople, self-employed individuals) that could not be included in this study because they were first included in the EGB only in 2011. Nonetheless, salaried workers (including those who are retired, and their covered spouses and children) account for 86% of the French population. Third, our study is observational and retrospective and thus cannot draw definitive conclusions about causality. Notwithstanding this limitation, our statistical approach is respectful of the chronological succession of events and therefore more robust because it also limits confounding by reverse causality. That is, SIV may be associated with a significant decrease in risk for hospital admission due to stroke, heart failure, and influenza or pneumonia, Citation 36 Goeijenbier M , van Sloten TT , Slobbe L , Mathieu C , van Genderen P , Beyer WEP , Osterhaus ADME . Benefits of flu vaccination for persons with diabetes mellitus: a review . Vaccine. 2017 ;35: 5095 – 101 . doi: 10.1016/j.vaccine.2017.07.095 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]and an approach that fails to take the order of events into account might easily confound the association between hospitalization for diabetes or its complications and the probability of SIV uptake. Finally, several socioeconomic characteristics (e.g., educational level) and cognitive factors (e.g., beliefs about SIV efficacy and safety) may be associated with changes in SIV behaviors but could not be included in the analysis because they are not recorded in the NHIF databases.
While several trials have assessed the effectiveness of interventions to increase SIV rates (especially among older people), further research is needed to determine how best to target these interventions to specific populations, depending on patient characteristics. Citation 37 Thomas RE , Lorenzetti DL . Interventions to increase influenza vaccination rates of those 60 years and older in the community . Cochrane Database Syst Rev. 2018 . doi: 10.1002/14651858.CD005188.pub4 . [Crossref] , [Google Scholar]Further research is also needed to assess the effectiveness of interventions on SIV vaccination that have showed promising results for other vaccines and population groups (e.g., motivational interviewing and web-based tailored educational tools Citation 25 Schuling J , Gebben H , Veehof LJG , Haaijer-Ruskamp FM . Deprescribing medication in very elderly patients with multimorbidity: the view of Dutch GPs. A qualitative study . BMC Fam Pract. 2012 ;13: 56 . doi: 10.1186/1471-2296-13-56 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar] , Citation 38 Lemaitre T , Carrier N , Farrands A , Gosselin V , Petit G , Gagneur A . Impact of a vaccination promotion intervention using motivational interview techniques on long-term vaccine coverage: the PromoVac strategy . Hum Vaccines Immunother. 2019 ;15: 732 – 39 . doi: 10.1080/21645515.2018.1549451 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar] , Citation 39 Pot M , Paulussen TG , Ruiter RA , Eekhout I , de Melker HE , Spoelstra ME , van Keulen HM . Effectiveness of a web-based tailored intervention with virtual assistants promoting the acceptability of HPV vaccination among mothers of invited girls: randomized controlled trial . J Med Internet Res. 2017 ;19: e312 . doi: 10.2196/jmir.7449 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]).
Table 1.Study cohort characteristics during the first and last season n/n + 1of follow-up (EGB, France, 2006/07–2015/16, n = 16,026)
2006/07 (n = 16,206) 2015/16 (n = 11,277) a % b % b Average duration of follow-up in years (min = 2; max = 10) – mean (SD) 8.6 (2.4) Sociodemographic characteristics Age (years) on December 31 of year n – mean (SD) 64.5 (13.5) 70.3 (12.7) Women 46.2 47.1 Clinical characteristics Patients with newly identified diabetes c 8.9 NA Type and treatment of diabetes Type 1 diabetes d 9.5 9.8 Other type diabetes treated by insulin and/or antidiabetic drugs 76.1 81.8 Other type diabetes without any treatment 14.4 8.5 Weighted individual chronic condition score e – mean (SD) 0.8 (0.5) 0.9 (0.5) Hospitalized for diabetes or its complications between September 1 of year n-1 and August 31 of year n 6.2 4.3 Hospitalized for influenza or its complications between September 1 of year n-1 and August 31 of year n 0.6 1.3 Healthcare use Number of consultations between September 1 of year n-1 and August 31 of year n , with – mean (SD) General practitioner 8.6 (7.1) 7.8 (6.3) Pulmonologist 0.0 (0.3) 0.1 (0.6) Endocrinologist 0.3 (1.2) 0.4 (1.2) Cardiologist 0.5 (1.4) 0.5 (1.4) Change of general practitioner between September 1 of year n-1 and August 31 of year n 4.0 10.2 SIV uptake rate 50.8 57.1
Abbreviations: NA, not applicable; SD, standard deviation; SIV, seasonal influenza vaccination.
aAmong all patients included in the cohort, 4334 (26.7%) died during follow-up and 595 were lost to follow-up (3.7%).
bOtherwise stated.
cPatients with newly identified diabetes were those not detected as having had diabetes the year before inclusion.
dPeople with type 1 diabetes were those with long-term illness status for type 1 diabetes (E10 according to the ICD-10) and treated by insulin at inclusion.
eThe individual chronic condition score (ICC) was calculated as a weighted sum of 21 chronic conditions. Weights account for the severity of each condition in the score calculation (ICC range in study cohort: min = 0; max = 3.7).
Table 2.Demographic and clinical characteristics associated with each SIV uptake transition – Hazard ratios and 95% confidence intervals – Two-state Markov model estimates (EGB, France, 2006/07–2015/16, n = 16,026)
No SIV → SIV (ref. No SIV → No SIV) SIV → No SIV (ref. SIV → SIV) aHR [95% CI] Sociodemographic characteristics Men (ref. Women) 1.09 [1.04;1.14] 0.84 [0.80;0.88] Age at inclusion (ref. ≤ 55 years) 56–64 1.32 [1.24;1.41] 0.67 [0.62;0.72] 65–84 1.39 [1.30;1.48] 0.44 [0.41;0.47] ≥ 85 1.57 [1.40;1.76] 0.47 [0.43;0.53] Clinical characteristics Patients with newly identified diabetes in 2006 a (ref. No) 1.28 [1.09;1.50] 0.97 [0.71;1.32] Type and treatment of diabetes at season n-1/n (ref. Other type diabetes without any treatment) Other type diabetes treated by insulin and/or antidiabetic drugs 1.08 [1.00;1.17] 0.71 [0.65;0.79] Type 1 diabetes b 1.32 [1.19;1.47] 0.73 [0.64;0.83] Weighted individual chronic condition score c at season n-1/n (ref. Min-Q1) Q1-median 1.39 [1.30;1.49] 0.92 [0.85;0.99] Median-Q3 1.55 [1.45;1.67] 0.94 [0.87;1.01] Q3-Max 1.87 [1.74;2.02] 0.98 [0.91;1.06] Hospitalized for diabetes or its complications during year n-1 1.12 [1.02;1.24] 1.04 [0.94;1.16] Hospitalized for influenza or its complications between during year n-1 1.35 [1.06;1.72] 1.23 [0.96;1.58] Healthcare use Number of consultations with general practitioner > median during year n-1 (ref. No) 1.29 [1.23;1.36] 0.99 [0.94;1.05] Consultation during year n-1 (ref. No) with: Pulmonologist 1.41 [1.24;1.60] 0.94 [0.81;1.08] Endocrinologist 1.00 [0.93;1.07] 0.90 [0.84;0.97] Cardiologist 1.02 [0.96;1.08] 0.80 [0.75;0.85] Change of general practitioner at season n/n-1 (ref. No) 1.11 [1.02;1.21] 1.14 [1.04;1.25] A(H1N1) pandemic season (ref. before pandemic) Year of pandemic (2009/2010) 1.37 [1.28;1.47] 0.84 [0.76;0.93] Year following pandemic (2010/2011) 0.57 [0.51;0.62] 1.76 [1.64;1.90] After 2010/2011 0.76 [0.72;0.81] 1.11 [1.04;1.18]
Abbreviations: aHR [95% CI], adjusted hazard ratio [95% confidence interval]; SIV, seasonal influenza vaccination.
aPatients with newly identified diabetes were those not detected as having diabetes the year before inclusion.
bPeople with type 1 diabetes were those with long-term illness status for type 1 diabetes (E10 according to the ICD-10) and treated by insulin at inclusion.
cThe individual chronic condition score (ICC) was calculated as a weighted sum of 21 chronic conditions. Weights account for the severity of each condition in the score calculation (ICC range in study cohort: min = 0; max = 3.7).
Supplemental material
Acknowledgments
We thank Florence Garry (National Health Insurance Fund, Cnam-TS) and Professor Jean-Luc Pasquié (CHU Montpellier) for their help in defining the algorithms to identify the study population, Daniel Levy-Bruhl (French Public Health Agency) for his contribution to the study design, and Jo Ann Cahn for her help in editing the manuscript.
Disclosure of potential conflicts of interest
The authors declare that they have no competing interests.
Supplementary material
Supplemental data for this article can be accessed on thepublisher’s website.
Additional information
Funding
This study was conducted with the financial support of the Institut de Recherche en Santé Publique (IReSP) as part of its 2014 general call for research projects [convention no. AAP-2015-03] and of the Agence Nationale de la Recherche (ANR) as part of its generic call for projects 2015 [convention n° ANR-15-CE36-0008-01]. This study was also supported by the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, the National Research Agency under the program « Investissements d’avenir », reference [ANR-10-IAHU-03], the Région Provence Alpes Côte d’Azur and European funding FEDER PRIMI.
References
Mertz D , Kim TH , Johnstone J , Lam -P-P , Science M , Kuster SP , Fadel SA , Tran D , Fernandez E , Bhatnagar N , et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis . BMJ. 2013 ;347: f5061 . doi: 10.1136/bmj.f5061 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
World Health Organization. Fact sheet on influenza (Seasonal) ; 2018 [accessed 2020 Feb 21]. http://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal) . [Google Scholar]
Rizzo C , Rezza G , Ricciardi W. Strategies in recommending influenza vaccination in Europe and US . Hum Vaccines Immunother. 2018 ;14: 693 – 98 . doi: 10.1080/21645515.2017.1367463 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Loerbroks A , Stock C , Bosch JA , Litaker DG , Apfelbacher CJ . Influenza vaccination coverage among high-risk groups in 11 European countries . Eur J Public Health. 2012 ;22: 562 – 68 . doi: 10.1093/eurpub/ckr094 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Verger P , Fressard L , Cortaredona S , Lévy-Bruhl D , Loulergue P , Galtier F , Bocquier A . Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: impact of recommendations and 2009 influenza A(H1N1) pandemic . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.48.1700801 . [Crossref] , [Google Scholar]
Verger P , Cortaredona S , Pulcini C , Casanova L , Peretti-Watel P , Launay O . Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France . Clin Microbiol Infect. 2015 ;21: 930.e1-9 . doi: 10.1016/j.cmi.2015.06.017 . [Crossref] , [PubMed] , [Google Scholar]
Verger P , Bocquier A , Vergélys C , Ward J , Peretti-Watel P . Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey . BMC Public Health. 2018 ;18: 569 . doi: 10.1186/s12889-018-5441-6 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Bianco A , Mascaro V , Zucco R , Pavia M . Parent perspectives on childhood vaccination: how to deal with vaccine hesitancy and refusal? Vaccine. 2019 ;37: 984 – 90 . doi: 10.1016/j.vaccine.2018.12.062 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Dubé È , Farrands A , Lemaitre T , Boulianne N , Sauvageau C , Boucher FD , Tapiero B , Quach C , Ouakki M , Gosselin V , et al. Overview of knowledge, attitudes, beliefs, vaccine hesitancy and vaccine acceptance among mothers of infants in Quebec, Canada . Hum Vaccines Immunother. 2019 ;15: 113 – 20 . doi: 10.1080/21645515.2018.1509647 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Napolitano F , D’Alessandro A , Angelillo IF . Investigating Italian parents’ vaccine hesitancy: A cross-sectional survey . Hum Vaccines Immunother. 2018 ;14: 1558 – 65 . doi: 10.1080/21645515.2018.1463943 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Bocquier A , Fressard L , Cortaredona S , Zaytseva A , Ward J , Gautier A , Peretti-Watel P , Verger P . Social differentiation of vaccine hesitancy among French parents and the mediating role of trust and commitment to health: A nationwide cross-sectional study . Vaccine. 2018 ;36: 7666 – 73 . doi: 10.1016/j.vaccine.2018.10.085 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Jiménez-Garcia R , Lopez-de-Andres A , Hernandez-Barrera V , Gómez-Campelo P , San Andrés-Rebollo FJ , de Burgos-lunar C , Cárdenas-Valladolid J , Abánades-Herranz JC , Salinero-Fort MA . Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study . Vaccine. 2017 ;35: 101 – 08 . doi: 10.1016/j.vaccine.2016.11.039 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Caille-Brillet AL , Raude J , Lapidus N , De Lamballerie X , Carrat F , Setbon M . Trends in influenza vaccination behaviours–results from the CoPanFlu cohort, France, 2006 to 2011 . Euro Surveill. 2013 ;18: 20628 . doi: 10.2807/1560-7917.ES2013.18.45.20628 . [Crossref] , [PubMed] , [Google Scholar]
Bocquier A , Cortaredona S , Fressard L , Loulergue P , Raude J , Sultan A , Galtier F , Verger P . Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006–2015 . BMC Public Health. 2019 ;19: 918 . doi: 10.1186/s12889-019-7209-z . [Crossref] , [PubMed] , [Google Scholar]
Kalbfleisch JD , Lawless JF . The analysis of panel data under a Markov Assumption . J Am Stat Assoc. 1985 ;80: 863 . doi: 10.1080/01621459.1985.10478195 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Tuppin P , de Roquefeuil L , Weill A , Ricordeau P , Merlière Y . French national health insurance information system and the permanent beneficiaries sample . Rev Epidemiol Sante Publique. 2010 ;58: 286 – 90 . doi: 10.1016/j.respe.2010.04.005 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Cortaredona S , Pambrun E , Verdoux H , Verger P . Comparison of pharmacy-based and diagnosis-based comorbidity measures from medical administrative data . Pharmacoepidemiol Drug Saf. 2017 ;26: 402 – 11 . doi: 10.1002/pds.v26.4 . [Crossref] , [PubMed] , [Google Scholar]
Huber CA , Szucs TD , Rapold R , Reich O . Identifying patients with chronic conditions using pharmacy data in Switzerland: an updated mapping approach to the classification of medications . BMC Public Health. 2013 ;13: 1030 . doi: 10.1186/1471-2458-13-1030 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Jackson CH . Multi-state models for panel data: the MSM package for R . J Stat Software. 2011 : 38 . doi: 10.18637/jss.v038.i08 . [Crossref] , [Google Scholar]
Achtymichuk KA , Johnson JA , Al Sayah F , Eurich DT . Characteristics and health behaviors of diabetic patients receiving influenza vaccination . Vaccine. 2015 ;33: 3549 – 55 . doi: 10.1016/j.vaccine.2015.05.047 . [Crossref] , [PubMed] , [Google Scholar]
Nagata JM , Hernández-Ramos I , Kurup AS , Albrecht D , Vivas-Torrealba C , Franco-Paredes C . Social determinants of health and seasonal influenza vaccination in adults ≥65 years: a systematic review of qualitative and quantitative data . BMC Public Health. 2013 ;13: 388 . doi: 10.1186/1471-2458-13-388 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Napolitano F , Della Polla G , Angelillo IF . Knowledge, attitudes, and behaviors of parents towards recommended adult vaccinations: an explanatory survey in the geographic area of Naples, Italy . Int J Environ Res Public Health. 2019 ;16: 2070 . doi: 10.3390/ijerph16122070 . [Crossref] , [PubMed] , [Google Scholar]
Teo LM , Smith HE , Lwin MO , Tang WE . Attitudes and perception of influenza vaccines among older people in Singapore: A qualitative study . Vaccine. 2019 ;37: 6665 – 72 . doi: 10.1016/j.vaccine.2019.09.037 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Davis MM , Wortley PM , Ndiaye SM , Cowan AE , Osta AD , Clark SJ . Influenza vaccine for high-risk non-elderly adults: a national survey of subspecialists . Hum Vaccine. 2008 ;4: 229 – 33 . doi: 10.4161/hv.4.3.5516 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Schuling J , Gebben H , Veehof LJG , Haaijer-Ruskamp FM . Deprescribing medication in very elderly patients with multimorbidity: the view of Dutch GPs. A qualitative study . BMC Fam Pract. 2012 ;13: 56 . doi: 10.1186/1471-2296-13-56 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Dubé E , Gagnon D , MacDonald NE . SAGE working group on vaccine hesitancy. Strategies intended to address vaccine hesitancy: review of published reviews . Vaccine. 2015 ;33: 4191 – 203 . doi: 10.1016/j.vaccine.2015.04.041 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
The Community Guide. What works. Increasing appropriate vaccination. Evidence-base intervention for your community ; 2017 [accessed 2020 Feb 21]. https://www.thecommunityguide.org/sites/default/files/assets/What-Works-Factsheet-Vaccination.pdf . [Google Scholar]
Dempsey AF , Pyrznawoski J , Lockhart S , Barnard J , Campagna EJ , Garrett K , Fisher A , Dickinson LM , O’Leary ST . Effect of a health care professional communication training intervention on adolescent human papillomavirus vaccination: a cluster randomized clinical trial . JAMA Pediatr. 2018 ; e180016 . doi: 10.1001/jamapediatrics.2018.0016 . [Crossref] , [PubMed] , [Google Scholar]
Verger P , Collange F , Fressard L , Bocquier A , Gautier A , Pulcini C , Raude J , Peretti-Watel P . Prevalence and correlates of vaccine hesitancy among general practitioners: a cross-sectional telephone survey in France, April to July 2014 . Euro Surveill. 2016 ;21: 30406 . doi: 10.2807/1560-7917.ES.2016.21.47.30406 . [Crossref] , [PubMed] , [Google Scholar]
Wilson R , Zaytseva A , Bocquier A , Nokri A , Fressard L , Chamboredon P , Carbonaro C , Bernardi S , Dubé E , Verger P . Vaccine hesitancy and self-vaccination behaviors among nurses in southeastern France . Vaccine. 2020 ;38:1144–1151. doi: 10.1016/j.vaccine.2019.11.0118 . [Crossref] , [Google Scholar]
Boey L , Bral C , Roelants M , De Schryver A , Godderis L , Hoppenbrouwers K , Vandermeulen C . Attitudes, believes, determinants and organisational barriers behind the low seasonal influenza vaccination uptake in healthcare workers – A cross-sectional survey . Vaccine. 2018 ;36: 3351 – 58 . doi: 10.1016/j.vaccine.2018.04.044 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Napolitano F , Bianco A , D’Alessandro A , Papadopoli R , Angelillo IF . Healthcare workers’ knowledge, beliefs, and coverage regarding vaccinations in critical care units in Italy . Vaccine. 2019 ;37: 6900 – 06 . doi: 10.1016/j.vaccine.2019.09.053 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Agence technique de l’information sur l’hospitalisation. Les coûts en établissement d’hébergement pour personnes âgées dépendantes. Lyon (France) : ATIH; 2013 . [Google Scholar]
Institut de veille sanitaire. Mesure de la couverture vaccinale en France. Bilan des outils et méthodes en l’an 2000. Saint-Maurice, France : Institut de veille sanitaire ; 2001 . [Google Scholar]
Rey D , Fressard L , Cortaredona S , Bocquier A , Gautier A , Peretti-Watel P , Verger P . Vaccine hesitancy in the French population in 2016, and its association with vaccine uptake and perceived vaccine risk–benefit balance . Euro Surveill. 2018 ;23. doi: 10.2807/1560-7917.ES.2018.23.17.17-00816 . [Crossref] , [PubMed] , [Google Scholar]
Goeijenbier M , van Sloten TT , Slobbe L , Mathieu C , van Genderen P , Beyer WEP , Osterhaus ADME . Benefits of flu vaccination for persons with diabetes mellitus: a review . Vaccine. 2017 ;35: 5095 – 101 . doi: 10.1016/j.vaccine.2017.07.095 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
Thomas RE , Lorenzetti DL . Interventions to increase influenza vaccination rates of those 60 years and older in the community . Cochrane Database Syst Rev. 2018 . doi: 10.1002/14651858.CD005188.pub4 . [Crossref] , [Google Scholar]
Lemaitre T , Carrier N , Farrands A , Gosselin V , Petit G , Gagneur A . Impact of a vaccination promotion intervention using motivational interview techniques on long-term vaccine coverage: the PromoVac strategy . Hum Vaccines Immunother. 2019 ;15: 732 – 39 . doi: 10.1080/21645515.2018.1549451 . [Taylor & Francis Online] , [Web of Science ®] , [Google Scholar]
Pot M , Paulussen TG , Ruiter RA , Eekhout I , de Melker HE , Spoelstra ME , van Keulen HM . Effectiveness of a web-based tailored intervention with virtual assistants promoting the acceptability of HPV vaccination among mothers of invited girls: randomized controlled trial . J Med Internet Res. 2017 ;19: e312 . doi: 10.2196/jmir.7449 . [Crossref] , [PubMed] , [Web of Science ®] , [Google Scholar]
For more information please visit ourPermissions help page.
| https://www.informahealthcare.com/doi/full/10.1080/21645515.2020.1729628?aria-labelledby=full-article&needAccess=true&role=tab&scroll=top |
EWG's Food Scores | Bumble Bee Chunk Light Tuna in Vegetable Oil
Check out the food score for Bumble Bee Chunk Light Tuna in Vegetable Oil from EWG's Food Scores! EWG's Food Scores rates more than 80,000 foods in a simple, searchable online format to empower you to shop smarter and eat healthier.
Bumble Bee Chunk Light Tuna in Vegetable Oil
Lower scores accompany better foods.
Image source: Kwikee
EWG Overall Score Breakdown
The product score is based on weighted scores for nutrition, ingredient and processing concerns. Generally, nutrition counts most, ingredient concerns next and degree of processing least. The weighted scores are added together to determine the final score.Read more about scores here.
EWG Overall Score Breakdown
EWG scored on three factors: nutrition, ingredient concerns, and the degree of processing.Read the full scoring methodology.
Lower concern
N
I
P
Higher concern
Lower concern
Higher concern
N Nutrition Concern
I Ingredient Concern
P Processing Concern
Nutrition Concern Details
Considers calories, saturated fat, trans fat, sugar, sodium, protein, fiber and fruit, vegetable and nut content to differentiate between healthful and less healthful foods. For more information on nutrition concerns,read our full methodology.
Contains ingredients that may contribute small amounts of unhealthy artificial trans fats: Soy Bean Oil [read more]
Per gram, high in protein [read more]
The nutrition factors used for scoring Bumble Bee Chunk Light Tuna in Vegetable Oil
Positive factors
Fruit, vegetable, bean or nut content
Protein content
Fiber content
Omega-3 fatty acids
Negative factors
Calorie density
Sugar/low-calorie sweetener content
Sodium content
Ingredient Concern Details
Considers food additives, pesticides, hormones, antibiotics and contaminants like mercury and BPA, which can affect human health and the environment. For more information on ingredient concerns,read methodology.
This product is not certified organic [read more]
Manufacturer likely used the toxic chemical BPA in can lining [read more]
This product has some contamination concerns:
Bisphenol A (BPA) Contamination from the can liner This contaminant is of moderate concern in food. Learn why.
Processing Concern Details
Estimates how much the food has been processed. Considers many factors, chief among them, modification of individual ingredients from whole foods and number of artificial ingredients. For more information on processing concerns,read our full methodology.
Product has been classified as having moderate processing concerns
Products with moderate and high processing concerns generally have more artificial ingredients, more ingredients that have been significantly modified from whole foods, and more ingredients overall.
EWG's Top Findings
This product is not certified organic [read more]
This product is not certified organic
Products bearing the USDA certified organic seal must contain at least 95 percent organic ingredient, and must be produced without the use of synthetic pesticides and fertilizers and free of genetically engineered ingredients.
Manufacturer likely used the toxic chemical BPA in can lining [read more]
Manufacturer likely used the toxic chemical BPA...
BPA, an endocrine disrupting chemical, is used to line the inside of nearly every canned food sold in the United States. Research shows that BPA readily leaches from the cans into the food. For more information visit: https://www.ewg.org/key-issues/toxics/bpa
Contains ingredients that may contribute small amounts of unhealthy artificial trans fats: Soy Bean Oil [read more]
Contains ingredients that may contribute small ...
Both refined oils and fully hydrogenated oils contain small amounts of unhealthy artificial trans fats and contribute to the total intake of trans fat in the diet (Biofortis 2014). Artificial trans fats are generated in refined oils when they are processed at high temperatures from the crude oil into a bland, odorless, colorless oil (Greyt 1999). A 2012 study conducted by FDA scientists estimated that refined oil contributes an average 0.6 grams of trans fat a day (Doell 2012). The World Health Organization recommends limits on trans fat of less than 1 to 2 grams a day—in this context, it’s easy to see that 0.6 grams is not an insignificant contribution. In the case of fully hydrogenated oils, they should theoretically be free of trans fat, but since no hydrogenation process is 100 percent efficient, trans fats are often found in fully hydrogenated oils at low levels (FDA 2013). The United States Department of Agriculture National Nutrition Database has tested refined, partially hydrogenated and fully hydrogenated oils and found trans fats in all of them (USDA 2013).
Textbooks for food scientists reveal that the mono and di-glycerides and other emulsifiers are often made from hydrogenated fats (Hasenhuettl and Hartel 2008) and at temperatures above 220°C (Sikorski and Kolakowka 2011). Emulsifiers produced from hydrogenated fats “contain measurable concentrations" of trans fats (Hasenhuettl and Hartel 2008).
Unfortunately, due to lack of label disclosure and the trans fat labeling loophole, only the food scientists will ever know just how much trans fat these refined oils and emulsifiers are contributing to foods and the American diet.
Does not contain artificial or industrial ingredients [read more]
Does not contain artificial or industrial ingre...
Per gram, high in protein [read more]
Per gram, high in protein
Protein is a source of amino acids that are required for the proper growth, maintenance and repair of tissues. It also provides the building blocks for important enzymes and hormones. Protein provides calories and if eaten in excess will be stored as fat. Protein is found in high amounts in beans, nuts, eggs, seafood and meat. Protein is essential to health, but eating too much also carries an environmental and health cost. Learn more: http://www.ewg.org/meateatersguide/
Product has been classified as having moderate processing concerns
EWG Food Reports
EWG's Guide to BPA
US Seafood Advice Flawed on Mercury, Omega-3s
EWG's Good Food On A Tight Budget
EWG's 2014 Shopper's Guide to Avoiding GE Food
Why GE Foods are not "Natural"
Ingredient List
From the Package
INGREDIENTS: LIGHT TUNA, SOYBEAN OIL, VEGETABLE BROTH, SALT
* Older Product
Products remain in the database for two years after their label information is recorded in stores. A product with label information last recorded more than a year ago is marked with an * identifying it as an older product.
* Discontinued Product
Product Images
Please note that EWG obtains the displayed images of products from third parties and that the product's manufacturer or packager may change the product's packaging at any point in time. Therefore, EWG assumes no responsibility for the accuracy of images presented.
Other Information
This product contains the following ingredient(s) that may be genetically engineered or derived from GE crops: Soy Bean Oil [read more]
This product contains the following ingredient(...
Nutrition Facts
2.0 servings per containerServing Sizeabout 1/4 cup 28.0 g 56.0 g (1x) 84.0 g 112.0 g (2x) 168.0 g (3x) 224.0 g (4x) Amount Per 56 g Calories 70 % Daily Value (based on a 2,000 calorie diet and adult bodyweight) Update the values for someone: -age- 1-3 years 4-8 years 9-13 years 14-18 years 19-30 years 31-50 years 51-70 years over 70 years -gender/life stage- male female pregnant female lactating female goQUICK FACTS: 4.0 4.0 % Total Fat 2 g Sugars 0 g 20.0 20.0 % Protein 11 gAVOID TOO MUCH: Trans Fat 0.0g 9.0 9.0 % Cholesterol 25 mg 7.0 7.0 % Sodium 180 mg Added Sugar Ingredients: none listedNUTRIENTS: 6.0 6.0 % Vitamin D 0.0 0.0 % Vitamin A 0.0 0.0 % Vitamin C 2.0 2.0 % Calcium 2.0 2.0 % Iron 20.0 20.0 % Niacin 6.0 6.0 % Vitamin B6 20.0 20.0 % Vitamin B12 50.0 50.0 % Selenium 3.0 3.0 % Potassium 105 mg† Institute of Medicine. 2010. "Dietary Reference Intakes Tables and Application." Accessed April 8, 2014:link
| https://www.ewg.org/foodscores/products/086600007106-BumbleBeeChunkLightTunainVegetableOil/ |
State v. Rowe, 30129 - Missouri - Case Law - VLEX 929627998
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
State v. Rowe, 30129
<table><tbody><tr><td> Court</td><td> United States State Supreme Court of Missouri</td></tr><tr><td> Writing for the Court</td><td> DAVIS</td></tr><tr><td> Citation</td><td> 24 S.W.2d 1032,324 Mo. 863</td></tr><tr><td> Parties</td><td> The State v. Oscar Rowe, Appellant</td></tr><tr><td> Docket Number</td><td> 30129</td></tr><tr><td> Decision Date</td><td> 19 February 1930</td></tr></tbody></table>
24 S.W.2d 1032
324 Mo. 863
The State
v.
Oscar Rowe, Appellant
No. 30129
Supreme Court of Missouri
February 19, 1930
[24 S.W.2d 1033]
Appeal from Jackson Circuit Court; Hon. Clarence A. Burney, Judge.
Affirmed.
Fred W. Coon, Horace Guffinand Forest W. Hannafor appellant.
(1) The court erred in admitting evidence tending to show the defendant guilty of other crimes separate and distinct from the one charged. State v. Fenley,275 S.W. 44; State v. Davis,292 S.W. 433; State v. Tunnell,296 S.W. 427; State v. Kurtz,295 S.W. 749; State v. Preslar,290 S.W. 144; State v. Eckstein,5 S.W.2d 648. (2) The conduct and argument of the prosecuting attorney inflamed the jury and prejudiced them against the defendant, requiring the reversal of this case. State v. Byrd,278 Mo. 426, 213 S.W. 37; State v. Campbell,278 S.W. 1052; State v. Cox,268 S.W. 87; State v. Guerringer,265 Mo. 408,178 S.W. 68; State v. Mathis, 18 S.W.2d 10. (3) The court erred in instructing the jury on the State's side of the case and wholly ignoring the defense. State v. Glass,300 S.W. 694; State v. Slusher,301 Mo. 285,256 S.W. 819; State v. Cantrell,234 S.W. 801. (4) Defendant was not given the fair and impartial trial to which every citizen is entitled under our Constitution and laws. State v. Bunton,280 S.W. 1042; State v. Dixon,253 S.W. 748; State v. Guerringer,265 Mo. 408,178 S.W. 68.
Stratton Shartel, Attorney-General, and Ray Weightman, Assistant Attorney-General, for respondent.
(1) The demurrer was properly overruled. The State proved the giving of the corn whiskey to Arch Duncan, the prosecuting witness, by a co-conspirator or employee of the defendant; that defendant owned the soft-drink parlor where the transaction took place; that defendant procured the whiskey that was given away; that he was the father of the general scheme, and that that scheme was carried out under his instructions and general supervision. (2) Complaint is made of the action of the trial court in overruling objections to parts of the opening statement of the prosecuting attorney. The record shows that the State proved all the facts the prosecuting attorney referred to and included in his opening statement, and that the opening statement was not argumentative. The prosecuting attorney was warned by the court to confine himself to just those facts he expected to prove.This was proper. State v. Moon,283 S.W. 468; State v. Brown,247 Mo. 730. (3) It is difficult to formulate a general rule defining the limit to which prosecuting attorneys may go in their arguments to juries, and analogous cases afford little aid in this regard. The extent of the prejudice aroused in the minds of the jury by remarks must therefore be measured by the facts in each particular case. State v. Brown, supra. The trial court ruled out the question and answers concerning the chloral procured by the defendant for use in the whiskey to be given away. However, the jury heard it and when the prosecuting attorney, in his argument, made reference to "giving them this poisonous whiskey until they became so stupid they could not stand up," we confess he bordered upon prejudicial and improper argument outside of the record. State v. Guerringer,265 Mo. 408,178 S.W. 65; State v. Nicholson, 7 S.W.2d 375; State v. Mathis, 18 S.W.2d 8. It is proper for the State's attorney to refer to evidence and deduce theories tending to confirm the main issues. State v. Conrad, 14 S.W.2d 608. However, determining whether argument is improper is largely within the discretion of the trial court. State v. Marshall,317 Mo. 413; State v. White,299 Mo. 612,253 S.W. 724; State v. Hart,292 Mo. 98,237 S.W. 473. (4) Appellant complains of Instruction 5 for the reason that it was covered in Instruction 8. Respondent concedes that Instruction 5 was repeated in the first paragraph of Instruction 8; however, we do not confess that the duplication of said instruction was prejudicial to the rights and interests of this defendant. (5) Appellant charges the court with error in failing to give an instruction cautioning the jury as to the credit and the weight and value to be given to the testimony of any witness offered on behalf of the State who, himself and themselves, were co-conspirators, or who were acting in concert with others in the commission of the crime charged. Defendant offered no instruction on this point. Where the main instruction fully covers the law of the case, the defendant is under the duty of requesting additional instruction on all collateral issues relating to his defense. State v. Gurnee,309 Mo. 16,274 S.W. 58; State v. Hubbard,295 S.W. 790; State v. Robinett,312 Mo. 641,281 S.W. 29; State v. Hadlock,316 Mo. 7,289 S.W. 945; State v. Sandoe,316 Mo. 65,289 S.W. 890. (6) Testimony of the prosecuting witness, as to statements made by persons claimed to have been acting for the defendant in the commission of crime was admissible. State v. Pollnow, 14 S.W.2d 574; State v. Pugh,296 S.W. 138. (7) The record discloses that no instruction on the defense of alibi was requested by the defense. Failure to instruct on collateral matter is not error unless the instruction was requested. State v. Aurentz,315 Mo. 242; State v. Silvey,296 S.W. 128; State v. Hadlock,316 Mo. 1; State v. English,308 Mo. 695.
Davis, C. Henwoodand Cooley, CC., concur.
OPINION
DAVIS [24 S.W.2d 1034]
[324 Mo. 867] The grand jury of Jackson County returned an indictment in the circuit court charging defendant with the offense of giving to Arch Duncan corn whiskey. On a trial, the defendant was found guilty by the verdict of the jury, and his punishment assessed at five years' imprisonment in the penitentiary. He appealed from the judgment entered on the verdict.
The evidence adduced on behalf of the State warrants the finding that on November 5, 1928, and prior thereto and thereafter, defendant was the lessee and in possession of premises located at and known as 602 Main Street in Kansas City. The lease to defendant designated the use of the premises as a soft-drink parlor and a cigar store. The evidence tends to show that defendant operated on the ground floor a restaurant in the front and a gambling establishment in the rear. On the second floor he operated a house of prostitution and Pete Rafferty was his manager. On the premises he sold whiskey. One police officer, a witness for defendant, said the place was what the officers knew as a den of thieves. On said day defendant was a precinct captain for the Republican party and was a worker relative to the election of November 6, 1928, commonly called the Presidential election.
Some time during the summer of 1928 defendant spoke of getting the Democratic voters drunk to prevent their voting. On October 7, 1928, at 602 Main Street, in speaking of election day, he said in the presence of one Keller: "Well, we have got it all arranged: we are going to have a good liquor party; we will get these voters drunk."
On the morning of November 5, 1928, defendant, one Keller, one James Grant and others were present at 602 Main Street. About nine o'clock that morning defendant and Keller, as Keller testified, went to the police garage, where defendant obtained about [324 Mo. 868] twenty-five gallons of whiskey, and, in defendant's automobile, they transported it to 602 Main Street. At the direction of defendant, around noon, Grant went to the police garage and returned with some gallons of whiskey. About one o'clock that afternoon, defendant, Grant and their associates, together with four police detectives, to-wit, officers Morley, King, Red Perrin and one other, whose name could not be remembered, again went to the police garage for whiskey. Three cars were used in thus going, a truck, defendant's car and the officers' car. The truck was driven by an employee of defendant, and it was used to transport whiskey from the police garage to 602 Main Street. In all, sixty-five gallons of corn whiskey were transported by defendant and his associates and employees from the police garage to 602 Main Street on November 5, 1928.
Later that afternoon defendant said that "he wanted to give this whiskey to Al Smith voters so as to get them drunk and keep them from voting." Pursuant thereto, he told his associates and scouts to go out and get all the men wearing Al Smith buttons and bring them in to 602 Main Street. Among the men thus accosted were Arch Duncan and his brother. They were invited into 602 Main Street. Defendant and his associates poured the whiskey from the containers procured from the police garage into quart bottles and served it in tin cups and glasses. Defendant was there and gave it to his confederates to distribute. A band was provided to lure men in and it was playing. The announced lure to the men was whiskey, and, upon this failing to entice them, music was mentioned. When Duncan entered about fifty men were present. Duncan was tendered a drink and he took it and tasted it; but, as it had a queer taste, he refused to drink more. Others in the place were given whiskey. When the men in the room reached a certain stage of intoxication, they were dragged to the basement. Defendant's associates would lift the heads of the drunken men in the basement and pour whiskey down their throats. Some two hundred men were in the basement in all stages of intoxication. Some were pitifully drunk and lying on the floor. The valuables of those lured into the place were taken and retained. Around two o'clock A. M. on November 6, 1928, the police wagons arrived. The wagons were used to convey the drunken men found in the basement to the holdover. No charges were preferred against them. They were there detained until about six-thirty P. M. on the evening of November 6, 1928, when they were released.
The evidence further tends to show that, after the men were lured into 602 Main Street, [24 S.W.2d 1035] they were prevented from departing...
| https://case-law.vlex.com/vid/state-v-rowe-30129-929627998 |
N OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-19:49:32.563 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-19:52:32.571 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-19:56:02.579 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-19:59:32.591 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:02:32.599 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:06:01.169 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:09:21.177 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:12:55.185 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:16:15.201 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:19:49.205 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:23:09.213 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:26:43.225 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:30:03.233 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:33:38.245 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:36:57.280 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN
16/161-20:40:32.280 CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN OPEN CLOSED CLOSED OPEN OPEN OPEN OPEN OPEN CLOSED OPEN OPEN OPEN OPEN OPEN OPEN CLOSED OPEN | https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20170816T224731/anc/eng/usm4/sci_anc_usm416_160_161.drf |
GS-9820 in Lymphoid Malignancies - Clinical Trials Registry - ICH GCP
This study is to determine the appropriate dosing regimen of GS-9820 in subjects with lymphoid malignancies. This is a Phase 1b, open-label, dose-escalation and...
A Phase 1b Study Evaluating GS-9820 in Subjects With Lymphoid Malignancies
A Phase 1b Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GS-9820 in Subjects With Lymphoid Malignancies
This study is to determine the appropriate dosing regimen of GS-9820 in subjects with lymphoid malignancies.
This is a Phase 1b, open-label, dose-escalation and expansion study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of GS-9820.
Study Overview
Status
Completed
Conditions
Lymphoid Malignancies
Intervention / Treatment
Drug: GS-9820
Study Type
Interventional
Enrollment (Actual)
39
Phase
Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
Netherlands
Amsterdam, Netherlands, 1105 AZ
Academic Medical Center
Amsterdam, Netherlands, 1081 HV
VU Medical Center (VUmc)
Nieuwegein, Netherlands, 3435 CM
St. Antonius Hospital
Rotterdam, Netherlands, 3075 EA
Erasmus MC - Daniel den Hoed Cancer Center
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
Previously treated recurrent B-cell iNHL, DLBCL, MCL, HL or CLL
Measurable lymphadenopathy
Requires therapy
Exclusion Criteria:
Recent history of a major non-lymphoid malignancy
Evidence of ongoing infection
Concurrent participation in another therapeutic clinical trial
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
Primary Purpose: Treatment
Allocation: N/A
Interventional Model: Single Group Assignment
Masking: None (Open Label)
1
Arms and Interventions
<table><tr><th> Participant Group / Arm</th><th> Intervention / Treatment</th></tr><tbody><tr><td> Experimental: GS-9820 Participants will be sequentially enrolled at progressively higher dose levels to receive GS-9820 administered twice a day.
Escalation will proceed to the maximum tolerated dose (MTD), defined as the highest tested dose associated with a rate of dose-limiting toxicities (DLT) of < 33% during the first 4 weeks of therapy.</td><td> Drug: GS-9820 GS-9820 tablets containing 200 mg of GS-9820 administered orally Other Names: CAL-120</td></tr></tbody></table>
What is the study measuring?
Primary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Maximum tolerated dose (MTD) Time Frame: Up to 4 weeks</td><td> MTD will be assessed to determine the appropriate dosing regimens for use in future clinical trials of GS-9820 in subjects with lymphoid malignancies.</td><td> Up to 4 weeks</td></tr></tbody></table>
Secondary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Overall safety Time Frame: Up to 5 years</td><td> Overall safety will be assessed by overall safety profile, enumeration and description of any dose-limiting toxicities, serious adverse events, or adverse events leading to discontinuation of study drug.</td><td> Up to 5 years</td></tr><tr><td> Pharmacokinetic parameters of GS-9820 as measured by Cmax, Tmax, Ctrough, and AUC Time Frame: Baseline to Day 29</td><td> Cmax is defined as the maximum concentration of drug Tmax is defined as the time of Cmax Ctrough is defined as the trough concentration AUC is defined as the area under the plasma concentration versus time curve</td><td> Baseline to Day 29</td></tr><tr><td> Pharmacodynamics to measure changes in the phosphatidylinositol 3-kinase (P13K) delta pathway activation and changes in plasma concentration of disease-associated chemokines and cytokines Time Frame: Baseline to Day 29</td><td></td><td> Baseline to Day 29</td></tr><tr><td> Tumor control Time Frame: Up to 5 years</td><td> Tumor control as assessed by overall response rate (ORR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), percent change in lymph node area, lymph node response rate, splenomegaly response rate, ALC response rate, hepatomegaly response rate, platelet response rate, hemoglobin response rate, and neutrophil response rate.</td><td> Up to 5 years</td></tr><tr><td> Patient well-being assessed using changes in baseline in HRQL (health related quality of life questionnaire) domain and symptom scores based on the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) Time Frame: Up to 5 years</td><td></td><td> Up to 5 years</td></tr><tr><td> Drug exposure Time Frame: Up to 5 years</td><td> Drug administration for GS-9820 as assessed by prescribing records and GS-9820 compliance as assessed by quantification of used and unused drug.</td><td> Up to 5 years</td></tr></tbody></table>
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Gilead Sciences
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
November 1, 2012
Primary Completion (Actual)
May 1, 2016
Study Completion (Actual)
May 1, 2016
Study Registration Dates
First Submitted
October 8, 2012
First Submitted That Met QC Criteria
October 11, 2012
First Posted (Estimate)
October 12, 2012
Study Record Updates
Last Update Posted (Estimate)
May 17, 2016
Last Update Submitted That Met QC Criteria
May 16, 2016
Last Verified
May 1, 2016
2012-000360-19 (EudraCT Number)
| https://ichgcp.net/clinical-trials-registry/NCT01705847 |
Antisera | Download Table
Download Table | Antisera from publication: Nerve Growth Factor and Neurotrophin-3 Differentially Regulate the Proliferation and Survival of Developing Rat Brain Oligodendrocytes | There is increasing evidence that the neurotrophins, particularly nerve growth factor (NGF) and neurotrophin-3 (NT-3), play a role in the regulation of glial development in the CNS. Recent studies have shown that the proliferation of optic nerve-derived O2A progenitors (OLPs)... | Nerve Growth Factor, Neurotrophin 3 and Oligodendrocytes | ResearchGate, the professional network for scientists.
Table 2
- uploaded by Rick I Cohen
Antisera
Source publication
Nerve Growth Factor and Neurotrophin-3 Differentially Regulate the Proliferation and Survival of Developing Rat Brain Oligodendrocytes
Article
Full-text available
Rick I Cohen
Ronen Marmur
William T. Norton
[...]
John A. Kessler
There is increasing evidence that the neurotrophins, particularly nerve growth factor (NGF) and neurotrophin-3 (NT-3), play a role in the regulation of glial development in the CNS. Recent studies have shown that the proliferation of optic nerve-derived O2A progenitors (OLPs) is potentiated by NT-3 in combination with platelet-derived growth factor...
Context in source publication
Context 1
... cells were then washed three times with PBS containing 10 mM L-glycine and blocked for 30 min in PBS containing 5% calf serum and 5% lamb serum (blocking solution). The cells were washed twice in PBS and then incubated for 90 min with rabbit polyclonal antibodies against neurotrophin receptors, diluted in blocking solution as follows: anti- TrkA-R, 1:200; anti-TrkA-out, 1:200; anti-TrkB-out, 1:200; anti-TrkC- out, 1:200; anti-p75, 1:250 (see
Table 2
for specificities and references). Similar procedures were carried out with preimmune serum (all 1:200) from rabbits used to generate the anti-TrkA-out, anti-TrkB-out, and anti-TrkC-out antibodies. ...
Jeannette Oldeweme
[...]
Sylvia Mechsner
D Soppet
[...]
L G Presta
[41]
Cohen et al., 1996;
Dario Tascio
Ronald Jabs
Anne Boehlen
Christian Steinhäuser
NG2 glia represents a distinct type of macroglial cells in the CNS and is unique among glia because they receive synaptic input from neurons. They are abundantly present in white and gray matter. While the majority of white matter NG2 glia differentiates into oligodendrocytes, the physiological impact of gray matter NG2 glia and their synaptic input are still ill defined. Here, we asked whether dysfunctional NG2 glia affect neuronal signaling and behavior. We generated mice with inducible deletion of the K+ channel Kir4.1 in NG2 glia and performed comparative electrophysiological, immunohistochemical, molecular and behavioral analyses. Kir4.1 was deleted at postnatal day 23–26 (recombination efficiency about 75%) and mice were investigated 3–8 weeks later. Notably, these mice with dysfunctional NG2 glia demonstrated improved spatial memory as revealed by testing new object location recognition while working and social memory remained unaffected. Focussing on the hippocampus, we found that loss of Kir4.1 potentiated synaptic depolarizations of NG2 glia and stimulated the expression of myelin basic protein while proliferation and differentiation of hippocampal NG2 glia remained largely unaffected. Mice with targeted deletion of the K+ channel in NG2 glia showed impaired long‐term potentiation at CA3‐CA1 synapses, which could be fully rescued by extracellular application of a TrkB receptor agonist. Our data demonstrate that proper NG2 glia function is important for normal brain function and behavior. Main Points NG2 glia lacking Kir4.1 are depolarized and show larger and prolonged mPSPs and ePSCs. Hippocampal LTP is impaired while MBP expression is enhanced in these NG2 glia‐specific Kir4.1 ko mice. These mice show better new object location recognition.
... increased proliferartion of these cells (Pansri et al., 2021). Administration of BDNF promotes OL differentiation after cuprizone-induced demyelination similar to neurotrophin-3 (NT-3) (VonDran et al., 2011;
Cohen et al., 1996)
. NT-3 administration in an SCI led to OPC proliferation and remyelination, as well as OL differentiation (Thomas et al., 2014;Zhu et al., 2012). ...
... Interaction of neurotrophins with their receptor could be regarded as the mechanism of such effects. Both BNDF and NT-3 activate TrkC receptors and MAPK phosphorylation in a phase-dependent manner (VonDran et al., 2011;
Cohen et al., 1996)
. BNDF also affect OPC proliferation through binding to TrkB receptors, as shown in Fig. 2 Islam et al., 2009). ...
The regenerative potential of glial progenitor cells and reactive astrocytes in CNS injuries
Article
Jul 2022
NEUROSCI BIOBEHAV R
Nasim Kiaie
Armita Mahdavi Gorabi
Reid Loveless
Yong Teng
Amirhossein Sahebkar
Cell therapeutic approaches focusing on the regeneration of damaged tissue have been a popular topic among researchers in recent years. In particular, self-repair scarring from the central nervous system (CNS) can significantly complicate the treatment of an injured patient. In CNS regeneration schemes, either glial progenitor cells or reactive glial cells have key roles to play. In this review, the contribution and underlying mechanisms of these progenitor/reactive glial cells during CNS regeneration are discussed, as well as their role in CNS-related diseases.
View
... In the visual pathway, NGF receptors are found in retinal ganglion cells and Muller cells 66 and in the visual cortex, 74 as well as oligodendrocytes of the optic nerve.
75
The possibility of cells in the optic nerve being receptive to exogenous NGF as a therapy has been tested in several experimental and clinical studies. Several early studies confirmed the neuroprotective effect of NGF on neurons in the optic nerve. ...
Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions
Article
Feb 2021
Semin Ophthalmol
Levi N Kanu
Joseph B Ciolino
Nerve growth factor (NGF), the prototypical neurotrophin first discovered in the 1950s, has recently garnered increased interest as a therapeutic agent promoting neuronal health and regeneration. After gaining orphan drug status within the last decade, NGF-related research and drug development has accelerated. The purpose of this article is to review the preclinical and clinical evidence of NGF in various applications, including central and peripheral nervous system, skin, and ophthalmic disorders. We focus on the ophthalmic applications including not only the FDA-approved indication of neurotrophic keratitis but also retinal disease and glaucoma. NGF represents a promising therapy whose therapeutic profile is evolving. The challenges related to this therapy are reviewed, along with possible solutions and future directions.
... No reuse allowed without permission. Regarding remyelination, oligodendrocytes express TrkC and exhibit both enhanced survival in culture and upregulation of myelin associated genes following NT3 application [119]
[120]
[121] . A number of studies have shown beneficial effects of NT3 on remyelination following spinal cord injury 59 , such as increased myelination of regenerating neurons elongating into NT3 secreting fibroblast grafts 122 . ...
An Adeno-Associated Viral vector encoding Neurotrophin 3 injected into affected forelimb muscles modestly improves sensorimotor function after contusive mid-cervical spinal cord injury
Preprint
Feb 2021
Jared Drew Sydney-Smith
Vanessa Megaro
Aline Barroso Spejo
Lawrence David Falcon Moon
Traumatic spinal cord injury (SCI) in humans occurs most frequently in the cervical spine where it can cause substantial sensorimotor impairments to upper limb function. The altered input to spinal circuits below the lesion leads to maladaptive reorganisation which often leads to hyperreflexia in proprioceptive circuits. Neurotrophin 3 (NT3) is growth factor essential for the development of proprioceptive neurons. We have previously shown that following bilateral corticospinal tract axotomy, intramuscular delivery of an Adeno-Associated Viral vector encoding NT3 (AAV-NT3) induces proprioceptive circuit reorganisation linked to functional recovery. To assess its therapeutic effects following a clinically relevant bilateral C5-C6 contusion in rats, AAV-NT3 was injected intramuscularly into the dominant limb 24 hours after injury and forelimb function was assessed over 13 weeks. The injury generated hyperreflexia of a distal forelimb proprioceptive circuit. There was also loss of fine motor skills during reach-and-grasp and walking on a horizontal ladder. Ex vivo magnetic resonance imaging (MRI) revealed atrophy of the spinal cord and white matter disruption throughout the lesion site together with extensive loss of grey matter. Unexpectedly, animals treated with AAV-NT3 had a slightly smaller lesion in the regions close to the epicentre compared to PBS treated animals. Rats treated with AAV-NT3 showed subtly better performance on the horizontal ladder and transient benefits on reach-and-grasp. AAV-NT3 did not normalise hyperreflexia in a treated muscle. The treatment increased the amount of NT3 in treated muscles but, unexpectedly, serum levels were only elevated in a small subset of animals. These results show that this dose and delivery of AAV-NT3 may generate subtle improvements in locomotion but additional treatments will be required to overcome the widespread sensorimotor deficits caused by contusion injury.
View
... Neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5, are endogenous growth factors that act through pro-survival tyrosine kinases receptors (Trks) and/or the pan-neurotrophin receptor p75 (p75 NTR ), exerting an important role in the pathophysiology of MS (Gold et al., 2006). More specifically, administration of BDNF and NT-3 is associated with an increase in the neuronal survival in experimental autoimmune encephalomyelitis-induced demyelination (Mo et al., 2010;Yan et al., 1992), while administration of NGF is associated with an increase in the survival of mature OLs
(Cohen et al., 1996)
. ...
The beneficial role of the synthetic microneurotrophin BNN20 in a focal demyelination model
Article
Feb 2021
J NEUROSCI RES
Ilias Kalafatakis
Alexandros Patellis
Ioannis Charalampopoulos
Achille Gravanis
Domna Karagogeos
BNN20, a C17‐spiroepoxy derivative of the neurosteroid dehydroepiandrosterone, has been shown to exhibit strong neuroprotective properties but its role in glial populations has not been assessed. Our aim was to investigate the effect of BNN20 on glial populations by using in vitro and in vivo approaches, taking advantage of the well‐established lysophosphatidylcholine (LPC)‐induced focal demyelination mouse model. Our in vivo studies, performed in male mice, showed that BNN20 treatment leads to an increased number of mature oligodendrocytes (OLs) in this model. It diminishes astrocytic accumulation during the demyelination phase leading to a faster remyelination process, while it does not affect oligodendrocyte precursor cell recruitment or microglia/macrophage accumulation. Additionally, our in vitro studies showed that BNN20 acts directly to OLs and enhances their maturation even after they were treated with LPC. This beneficial effect of BNN20 is mediated, primarily, through the neurotrophin receptor TrkA. In addition, BNN20 reduces microglial activation and their transition to their pro‐inflammatory state upon lipopolysaccharides stimulation in vitro. Taken together our results suggest that BNN20 could serve as an important molecule to develop blood–brain barrier‐permeable synthetic agonists of neurotrophin receptors that could reduce inflammation, protect and increase the number of functional OLs by promoting their differentiation/maturation.
... The oligodendrocyte lineage proliferation, differentiation and survival, however, can be influenced also by neuregulins, NT-3 and NGF, further validating their role in synaptic plasticity [140,
141]
. Apart from their role in myelin and ECM homeostasis, novel interest is shown in the electrical signaling between oligodendrocytes and neurons. OPCs express a variety of neurotransmitter receptors, such as AMPAR, NMDAR, GABA, and acetylcholine (Ach) receptors [142] and voltage-gated channels (i.e., sodium, potassium, and calcium channels) that could in principle modulate the surrounding neuronal activity [138]. ...
Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease
Article
Full-text available
Feb 2020
INT J MOL SCI
Ciro De Luca
Anna Maria Colangelo
Assunta Virtuoso
Lilia Alberghina
Michele Papa
The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
... Variation in levels of TrkB expression amongst oligodendroglia likely accounts for these differing observations. Both full-length and truncated TrkB isoforms are readily detectable in basal forebrain oligodendrocytes, while lower levels of full-length TrkB are expressed in oligodendrocytes from the cortex [19,26,
29]
. This suggests that BDNF potentially exerts diverse influences upon oligodendroglia, which are highly contextual to specific CNS regions. ...
Brain-Derived Neurotrophic Factor in Central Nervous System Myelination: A New Mechanism to Promote Myelin Plasticity and Repair
Article
Full-text available
Dec 2018
INT J MOL SCI
Jessica L. Fletcher
Simon S. Murray
Junhua Xiao
Brain-derived neurotrophic factor (BDNF) plays vitally important roles in neural development and plasticity in both health and disease. Recent studies using mutant mice to selectively manipulate BDNF signalling in desired cell types, in combination with animal models of demyelinating disease, have demonstrated that BDNF not only potentiates normal central nervous system myelination in development but enhances recovery after myelin injury. However, the precise mechanisms by which BDNF enhances myelination in development and repair are unclear. Here, we review some of the recent progress made in understanding the influence BDNF exerts upon the myelinating process during development and after injury, and discuss the cellular and molecular mechanisms underlying its effects. In doing so, we raise new questions for future research.
... 53 Development, proliferation, migration, and differentiation into myelinating oligodendrocytes depend on various regulatory factors and are in part controlled by NGF, BDNF, and NT-3. 10,
38,
136,208 However, these effects seem to be predominantly mediated by Trk receptors. 38,49,101,114 Using immunohistology, p75 NTR is not detected in oligodendrocytes in the normal adult rodent CNS. ...
... 10,38,136,208 However, these effects seem to be predominantly mediated by Trk receptors.
38,
49,101,114 Using immunohistology, p75 NTR is not detected in oligodendrocytes in the normal adult rodent CNS. 39,143 Similarly, it is expressed by only few oligodendrocytes in the healthy adult human brain. ...
p75 Neurotrophin Receptor: A Double-Edged Sword in Pathology and Regeneration of the Central Nervous System
Article
Jun 2018
VET PATHOL
Kathrin Becker
Armend Cana
Wolfgang Baumgärtner
Ingo Spitzbarth
The low-affinity nerve growth factor receptor p75NTR is a major neurotrophin receptor involved in manifold and pleiotropic functions in the developing and adult central nervous system (CNS). Although known for decades, its entire functions are far from being fully elucidated. Depending on the complex interactions with other receptors and on the cellular context, p75NTR is capable of performing contradictory tasks such as mediating cell death as well as cell survival. In parallel, as a prototype marker for certain differentiation stages of Schwann cells and related CNS aldynoglial cells, p75NTR has recently gained increasing notice as a marker for cells with proposed regenerative potential in CNS diseases, such as demyelinating disease and traumatic CNS injury. Besides its pivotal role as a marker for transplantation candidate cells, recent studies in canine neuroinflammatory CNS conditions also highlight a spontaneous endogenous occurrence of p75NTR-positive glia, which potentially play a role in Schwann cell–mediated CNS remyelination. The aim of the present communication is to review the pleiotropic functions of p75NTR in the CNS with a special emphasis on its role as an immunohistochemical marker in neuropathology. Following a brief illustration of the expression of p75NTR in neurogenesis and in developed neuronal populations, the implications of p75NTR expression in astrocytes, oligodendrocytes, and microglia are addressed. A special focus is put on the role of p75NTR as a cell marker for specific differentiation stages of Schwann cells and a regeneration-promoting CNS population, collectively referred to as aldynoglia.
... 99 Nerve growth factor can bind TrkA or p75 neurotropin receptor and, depending on downstream interactions with other signaling pathways, can either encourage survival or induce cell death of OLs.
100
Furthermore, because neuronal activity can regulate regional secretion of neurotrophins, neurotrophins could also have crucial roles in deciding whether or when OLs myelinate certain axons. 101 ...
The Healthy and Diseased Microenvironments Regulate Oligodendrocyte Properties: Implications for Regenerative Medicine
Article
Full-text available
Oct 2017
Am J Pathol
Prisca Sabine Leferink
Vivi Majella Heine
| https://www.researchgate.net/figure/Antisera_tbl2_14389216 |
IJERPH | Free Full-Text | Effects of a Web-Based Parent& ndash;Child Physical Activity Program on Mental Health in Parents of Children with ASD
Parents of children with ASD experience a higher incidence of mental health difficulties, including stress, depression, and anxiety, than parents of children without ASD. According to studies related to ASD, parent–child physical activity programs are an effective approach to encourage both parents and their children with ASD to exercise together, thus improving the mental health of parents due to this interactive family activity. The purpose of the present study was to explore the effects of this web-based parent–child physical activity program on the mental health of parents of children with ASD. A total of 94 parent–child pairs consented to participate in this study, and 75 parent–child pairs completed the study. Three instruments—DASS-21, PSI-4-SF, and WHOQOL-26—were used to measure mental health, parental stress, and quality of life, respectively. A randomized controlled trial design was implemented to examine the effectiveness of the 10-week web-based parent–child physical activity program on improving the mental health of parents of children with ASD. The results showed that after the 10-week parent–child physical activity program, there were significant differences in overall DASS-21 and PSI-4-SF for the experimental group, compared with control group (p < 0.05), which indicated that the parent–child physical activity program has a positive influence on mental health in parents of children with ASD. One sub-area of WHOQOL-26 between the experimental and control groups across pre-/post-testing intervals also showed greater reductions in the item of psychological health (p < 0.05). In conclusion, the findings demonstrated the efficacy of the web-based parent–child physical activity program for improving mental health in parents of children with ASD.
Effects of a Web-Based Parent–Child Physical Activity Program on Mental Health in Parents of Children with ASD
School of Physical Education, Shenzhen University, Shenzhen 518060, China
2
Department of Physical Education, Institute of KEEP Collaborative Innovation, Shenzhen University, Shenzhen 518060, China
3
Department of Sports Science, Hefei Normal University, Hefei 230061, China
4
Department of Kinesiology, Texas A&M University, Texarkana, TX 75503, USA
5
School of Sports Social Science, Shandong Sport University, Jinan 250102, China
6
College of Sport Arts, Guangzhou Sport University, Guangzhou 510500, China
7
College of Health Sciences and Technology, Rochester Institute of Technology, Rochester, NY 14623, USA
*
Authors to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2021 , 18 (24), 12913; https://doi.org/10.3390/ijerph182412913
Received: 24 October 2021 / Revised: 1 December 2021 / Accepted: 3 December 2021 / Published: 7 December 2021
(This article belongs to the Special Issue Physical Activity and Physical Fitness in Treating Depression and Boosting Mental Health )
Versions Notes
Abstract
Parents of children with ASD experience a higher incidence of mental health difficulties, including stress, depression, and anxiety, than parents of children without ASD. According to studies related to ASD, parent–child physical activity programs are an effective approach to encourage both parents and their children with ASD to exercise together, thus improving the mental health of parents due to this interactive family activity. The purpose of the present study was to explore the effects of this web-based parent–child physical activity program on the mental health of parents of children with ASD. A total of 94 parent–child pairs consented to participate in this study, and 75 parent–child pairs completed the study. Three instruments—DASS-21, PSI-4-SF, and WHOQOL-26—were used to measure mental health, parental stress, and quality of life, respectively. A randomized controlled trial design was implemented to examine the effectiveness of the 10-week web-based parent–child physical activity program on improving the mental health of parents of children with ASD. The results showed that after the 10-week parent–child physical activity program, there were significant differences in overall DASS-21 and PSI-4-SF for the experimental group, compared with control group (
p
< 0.05), which indicated that the parent–child physical activity program has a positive influence on mental health in parents of children with ASD. One sub-area of WHOQOL-26 between the experimental and control groups across pre-/post-testing intervals also showed greater reductions in the item of psychological health (
p
< 0.05). In conclusion, the findings demonstrated the efficacy of the web-based parent–child physical activity program for improving mental health in parents of children with ASD.
Keywords:
mental health
;
depression
;
anxiety
;
autism
;
parent–child dyadic approach
;
web-based physical activity
;
social interaction
;
quality of life
1. Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and restricted or repetitive behaviors [ 1 ]. The prevalence of ASD has experienced rapid growth over the past decade [ 2 ], and the situation has also been serious in other countries, making it a global public health problem. The pervasive impairments always appear in early childhood and endure across the child’s lifespan, seriously influencing physical and mental health and the quality of life of families with children with ASD [ 3 ].
The parents of children with ASD also experience mental health challenges, which refer to their thoughts, emotional regulation, and behaviors reflecting the psychological or biological processes underpinning their mental functioning [ 4 ]. It has been found that parents of children with ASD experience higher incidence of mental health difficulties—such as stress, depression, anxiety, and parental distress—than parents of children who are typically developing or with other types of disabilities [ 5 , 6 , 7 , 8 , 9 ].
Studies have reported that mental health deficits in such parents are considerably high, due to fears, insecurities, and worries about their children’s life, and there exists an association between the stress and anxiety levels of parents and overall ASD severity [ 10 , 11 ]. In addition to the core impairments of ASD, co-morbid difficulties, such as depression, disruptive behavior, hyperactivity disorder, and sleep disorder, have also been found to be associated with higher stress and anxiety in parents [ 12 , 13 ]. Therefore, the challenges relating to caring for children with ASD can lead to difficulties for parents, in terms of meeting their own healthy psychological state and quality of life [ 14 , 15 , 16 ]. Furthermore, their poor mental health may have negative effects on supporting and caring for their children with ASD [ 17 ]. Additionally, the parents of children with ASD face more difficulties in China, such as delayed diagnosis, limited early interventions (as the associated research started relatively late), and the majority of parents have to be responsible for the treatments by themselves, with insufficient training, guidance, and support [ 18 , 19 ], which may add to their psychological burden. These parents are always at high risk for caregiver syndrome, which poses a great risk to the health-related quality of life of parents, as well as the whole family [ 20 ].
The mental health problems of parents of children with ASD might be severely magnified during the COVID-19 pandemic. Therefore, these parents may require more mental health support and assistance [ 21 ]. With increased attention on children with ASD, many physical activities, as alternative treatments, have been shown to be effective for the remediation of behaviors of children with ASD. Some researchers have begun to focus on the psychological health of parents of children with ASD over the past decade, and evidence has shown that some interventions have a certain effect on improving mental health, such as cognitive behavioral therapy [ 22 , 23 ], expressive writing [ 24 ], mindfulness training [ 25 ], and relaxation therapy [ 26 ]. Although there are currently few studies that have been conducted directly on parents of children with ASD, the studies related to this area are still limited, especially studies using randomized controlled trials as intervention.
Physical activity, as an essential component of a healthy lifestyle, has become an increasingly important issue in health promotion, and many studies have demonstrated that physical activity interventions can be used as an effective treatment for improving mental health [
27
,
28
,
29
]; evidence has shown that children with ASD are still less physically active than those who are developing typically, due to their disabilities. It is also well known that the levels of physical activity of parents of children with ASD are low, indicating that there is a clear need to promote physical activity within the family unit [
30
].
As mentioned above, improving the mental health and wellbeing of the parents enhances the potential of the child with ASD to achieve a better quality of life [
31
,
32
], and parental involvement in treatments has been reported for its strengths and effectiveness [
33
]. The parent and child co-participation in physical activity is important for family interpersonal dynamics, including increased parent–child communication, enjoyment of physical activity, and improvement in their mental health [
34
]. In addition, during the COVID-19 pandemic, web-based activities, meetings, and gaming through the internet have become a popular support approach and is more beneficial and convenient for children with ASD and their parents in a family-based environment.
Parent–child physical activities could be a useful approach to involve both parents and their children with ASD to exercise together, and the fun and joyful time during parent–child physical activity not only brings family together, but also motivates inactive children with ASD to get actively involved and allows both the children and parents to cope with stress [
35
,
36
]. To date, there has been a lack of studies on the mental health issues of parents of children with ASD using parent–child dyadic web-based interventions. Therefore, the current study explores the effects of a web-based parent–child physical activity program on the mental health of parents of children with ASD.
2. Materials and Methods
2.1. Participants
Children with an average age of 6 years old were recruited through special schools, autism treatment centers, and community clinics in Beijing and Jinan, China in 2020. One of their parents (average age of 33.6 years old) was paired to participate in this intervention. Written informed consent was obtained from their parents before participating in this study. Ethics approval was granted by the Institutional Review Board of the University of the first author. The inclusion criteria for selecting participants were as follows: (a) availability of one parent and one child, (b) children’s age was between three and ten years old, and (c) children were diagnosed with ASD based on DSM-V criteria. A total of 94 parent–child pairs (comprising one parent and one child per pair) consented to participate in and completed the baseline survey. Forty-seven pairs of participants were randomly assigned to the experimental group, in which a web-based parent–child physical activity program was implemented as the intervention group. The other forty-seven parent–child pairs participated in regular activities as the control group.
Figure 1
presents a flowchart of the participant selection process.
Figure 1. Participant selection process flow diagram.
During the study, eight parent–child pairs withdrew from the program, six parent–child pairs were absent for more than two sessions, and five pairs were absent from the post-test. Therefore, a total of 75 participants ( n = 75) completed the study. An independent sample t -test was conducted to compare the baseline data between the experimental group and control group. There were no significant differences between the two groups in terms of the demographic variables of participants, as listed in Table 1 ( p > 0.05).
Table 1. Demographic data of the participants.
Table 1 also details the demographic characteristics of parents of children with ASD. There were 22 fathers and 53 mothers involved in the program. Most of families participating in the study had only one child. Among the parents, 50 out of 75 participants were housewives/househusbands.
2.2. Instruments
Mental health: The Depression Anxiety and Stress Scale (DASS-21), as a measure of mental health, is commonly used in current research. The scale is a 21-item, self-reported, norm-referenced measurement designed to investigate the severity of common depression, stress, and anxiety symptoms, [
37
] and Chinese versions have been shown to have excellent psychometric properties across normative and clinical samples and, importantly, with parents of youth with ASD [
38
,
39
]. Moreover, the response to treatment can be also measured. The scale has three sub-scales (depression, stress, and anxiety), with seven items in each sub-scale. In our sample, the Cronbach’s alpha for pre- and post-tests were 0.944 and 0.927.
Parenting stress: The Parenting Stress Index-Fourth Edition-Short Form (PSI-4-SF) is an abbreviated and improved version of PSI [ 40 ], which is one of the most commonly used measures of parenting stress in both clinical and research fields [ 41 ]. The PSI-4-SF is a 36-item, self-reported measure with three domains: Parental distress, parent–child dysfunctional interaction, and child difficulty. It has been used to measure the parenting stress of parents in high-risk populations [ 42 , 43 ], and to measure treatment effectiveness [ 44 ]. PSI-SF has been translated into different languages. The Cronbach’s alpha for pre- and post-tests were 0.885 and 0.892.
Quality of Life: The World Health Organization Quality of Life Assessment-26 (WHOQOL-26) is a short version of the WHOQOL-100 scales [ 45 ]. It is a widely used, reliable international instrument that consists of five sub-scales to measure the satisfaction of participants with different aspects of their life. It comprises four dimensions of QOL (physical, psychological, environmental, and social domains), and each item adopts a five-point assessment. The Cronbach’s alpha for pre- and post-tests were 0.861 and 0.877.
2.3. Intervention Procedures
A randomized controlled trial design was implemented to examine the effectiveness of the 10-week web-based parent–child physical activity program on mental health in parents of children with ASD. We adopted a pre-/post-test approach to monitor the progressive changes at two intervals on mental health throughout the 10-week intervention. Baseline data were collected one week before the intervention began, and the post-test was conducted one week after the 10-week program.
The intervention was a web-based parent–child physical activity program developed through the online curriculum from Youth Sport, which includes various physical educational programs based on the international physical activity guidelines and recommendations. The program involved the parents and children with ASD to participating together, and the current intervention was a structured physical activity program lasting 10 weeks, twice a week, for a total of 20 sessions, and each session lasted approximately 60 min. Each session was comprised of four parts: (a) warm-up activities; (b) parent–child exercises; (c) play-based exercises; and (d) cool-down and reward activities. There were three five-minute intervals for each session. All the parent–child pairs completed the same routine exercises under the guidance of trainers who were physical education teachers that were responsible for providing instructions, resolving difficulties, and facilitated practice for the parent–child dyad.
During the 10-week intervention program, all families in the experimental group received parent–child exercise training through a web-based curriculum. The curriculum consisted of teaching videos, live exercises, video games, and workshops. Each parent–child pair had a login account for the online curriculum, and the information was sent to the parents before the intervention. Furthermore, there was a chat group in WeChat, in which the parents could communicate and discuss how to better interact with their children and promote parent–child exercises. During the program, the control group participated in their family’s regular activities as normal. After the 10-week web-based parent–child physical activity program ended, the control group was given the same opportunity to participate in the parent–child physical activity program for ethical consideration.
The content of the parent–child physical activity program was designed especially for children with ASD and their parents, based on the impairment and characteristics of children with ASD [
46
]. Moreover, the program incorporated teaching videos with instructions and demonstrations, guiding the parents to engage in physical activities with their children. Meanwhile, each session contained a number of structured game elements, such as points, a level system, ranking, and a scoreboard for tracking progress [
36
]. To encourage the participants and make the role modeling effective, live courses were also implemented in the intervention. The participants could see other parent–child pairs through the online courses and interact with them through Zoom or Tencent Live.
Table 2
describes the contents of the online parent–child physical activity program.
Table 2. Parent–child physical activity intervention program.
2.4. Data Collection and Analysis
In the current study, data was collected using a quantitative method to examine the effects of the online parent–child physical activity program on the mental health of parents of children with ASD, conducted both before (pre-test) and after (post-test) the intervention. The repeated measure MANOVA was used to analyze the main effect and interaction effect. The changes in overall and subdomains of DASS-21, PSI-4-SF, and WHOQOL-26 data were also analyzed to determine the differences between pre- and post-tests regarding mental health, parenting stress, and quality of life. The statistical analyses were conducted according to the P value, effect size, and sample power, and significance was two-tailed at p < 0.05.
3. Results
3.1. Effects of the Web-Based Parent–Child Physical Activity Program on Mental Health
3.1.1. Effects of the Online Parent–Child Physical Activity Program on DASS-21
The Depression Anxiety and Stress Scale (DASS-21) was employed to evaluate the mental health of parents of children with ASD. As shown in
Table 3
, there were significant differences in terms of time: F = 147.937,
p
< 0.01, and time x group interaction: F = 106.032,
p
< 0.01. The results of the multivariate tests showed that the time factor had significant effects (
p
< 0.01) on DASS-21 over time, and the interaction between testing intervals (pre-test and post-test) and groups (experimental and control groups) also showed a statistically significant difference (
p
< 0.01). The mean scores of overall DASS-21 were similar between the two groups at baseline (
p
> 0.05) and indicated that there was no significant difference between the experimental group and the control group before the intervention. After the 10-week parent–child physical activity program, there were significant differences in the item of mental health between the experimental group and control group (
p
< 0.05). When compared with the control group itself, a significant improvement (
p
< 0.01) was found in overall DASS-21 for the experimental group. These results indicated that the parent–child physical activity program had a positive influence on the mental health of parents of children with ASD.
Table 3. Multivariate Tests.
We also evaluated whether the online physical activity program demonstrated an effect in the three sub-areas of DASS-21 between the experimental and control groups over time. Before the intervention, no statistically significant differences were found between the experimental group and control group, in terms of stress, anxiety, and depression. After the 10-week web-based physical activity program, greater changes were observed in the items of stress, anxiety, and depression for the experimental group over time, compared with control group (
p
< 0.05), as shown in
Table 4
. These results showed that the program significantly reduced the scores in the sub-areas of DASS-21.
Table 4. Comparison of DASS-21 across two intervals between two groups.
As shown in Table 5 , the results revealed that significant differences were observed in both the control group ( p < 0.05) and the experimental group ( p < 0.01). Figure 2 a–c illustrated the trend of reduction in stress, anxiety, and depression for the two groups, respectively. The experimental group had a more noticeable reduction of stress, anxiety, and depression compared to the control group, which indicated that the program had a positive influence on the mental health of parents of children with ASD.
Figure 2. ( a – c ) Impact of parent–child physical activity program on sub-scales of stress, anxiety, and depression in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 5. Pre-/post-comparison of DASS-21 for two groups.
3.1.2. Effects of Online Parent–Child Physical Activity Program on PSI-4-SF
The Parenting Stress Index-Fourth Edition-Short Form (PSI-4-SF) was also conducted to assess whether there were possible changes in mental health of the participants. As shown in Table 6 , there were significant differences in terms of time: F = 137.995b, p < 0.01, and time × group interaction: F = 57.741b, p < 0.01. The results of the multivariate tests showed that the time factor had significant effects ( p < 0.01) on PSI-4-SF over time, and the interaction between testing intervals (pre-test and post-test) and groups (experimental and control groups) also showed a statistically significant difference ( p < 0.01)
Table 6. Multivariate Test.
As reported in Table 7 , there were no significant differences in the overall PSI-4-SF score between the two groups in the pre-test ( p < 0.05), while there were significant differences between the two groups in overall PSI-4-SF scores ( p < 0.05) after the 10-week parent–child physical activity program, and even more significant changes were found in the experimental group, compared with the control group.
Table 7. Comparison of PSI-4-SF across two intervals between two groups.
As reported in Table 8 , the results revealed that there were significant differences from pre- to post-test in the experimental group ( p < 0.01), but no significant differences were observed across the two measures (before/after) in the control group. Therefore, the results indicated that the web-based physical activity program had a positive effect on relieving parenting stress of parents of children with ASD, and it reduced the overall scores in PSI-4-SF.
Table 8. Pre/post comparison of PSI-4-SF for two groups.
As shown in Figure 3 a–c, a significant reduction was found in parent–child dysfunctional interaction for the experimental group compared with the control group, which had a statistically significant effect ( p < 0.01). These results also showed that there were significant differences in parental distress, parent–child dysfunctional interaction, and child difficulty for the experimental group across time (i.e., from pre- to post-test).
Figure 3. ( a–c ) Impact of parent–child physical activity program on sub-scales of parental distress, parent–child dysfunctional interaction, and child difficulty in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
3.2. Effects of Parent–Child Physical Activity Intervention Program on Quality of Life
To determine the effects of intervention on quality of life on parents of children with ASD, the WHO Quality of Life Assessment-26 (QOL-26) was employed to examine the comparison outcomes. There were significant differences in terms of time: F = 48.608b, p < 0.01, and time × group interaction: F = 0.063b, p > 0.01, as reported in Table 9 . The results of the multivariate tests showed that the time factor had a significant effect ( p < 0.01) on QOL-26 over time, and the interaction between testing intervals (pre-test and post-test) and groups (experimental and control groups) showed no statistically significant difference ( p > 0.01)
Table 9. Multivariate Tests.
As reported in Table 10 , before the intervention, there were no significant differences between the two groups ( p > 0.05); furthermore, after the 10-week intervention, no significant differences were observed in overall QOL-26 between the experimental and control groups ( p > 0.05).
Table 10. Between-group comparison for WHOQOL-26 across two intervals.
As shown in Table 11 , a paired samples t -test was conducted to determine whether a significant difference existed at two time points for the within-group comparison. The results revealed that there were significant differences from pre- to post-test in the experimental and control groups ( p < 0.01).
Table 11. Pre/post comparison of WHOQOL-26 for two groups.
We also evaluated whether the program demonstrated influences in the four sub-areas of the WHOQOL-26 between the experimental and control groups across pre/post testing intervals.
Figure 4
a–d display the trends in the sub-scales of WHOQOL-26 for the experimental group and control group. As shown in
Figure 4
a–d, a greater reduction was observed in the item of psychological health for the experimental group over time, compared with control group (
p
< 0.05). These findings demonstrated that the parent–child physical activity program significantly improved the psychological health sub-scale of WHOQOL-26 after the 10-week intervention.
Figure 4. ( a–d ) Impact of parent–child physical activity program on sub-scales of physical health, psychological health, social relationships, and environment in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
4. Discussion
We investigated the effects of a 10-week web-based parent–child physical activity program on the mental health of parents of children with ASD. To our knowledge, this study may be the first randomized controlled trial involving a parent–child dyadic physical activity program intervention specifically designed to address the mental health of parents of children with ASD in a web-based context. The results of the present study provide evidence that web-based parent–child physical activity is effective in enhancing the mental health of parents of children with ASD, and also confirmed the potential effects of web-based parent–child physical activity as a functional and effective approach for parents of children with ASD.
Empirical evidence has shown that raising a child with ASD can be a stressful experience for parents, and parents raising children with ASD tend to experience even higher levels of stress and mental health difficulties than parents of children without ASD [
5
,
9
,
47
]. The mental health of parents includes their thoughts, emotional regulation, and behaviors, which reflect the psychological or biological processes underpinning their mental functioning. Based on previous studies, parental involvement during interventions in children with ASD is critical and essential for children’s development and improvement. From the existing literature in the field, however, most of the studies have focused on children as the main subjects, and the research evidence on involving parents of children in the rehabilitation process has been limited, whereas parents and their child with ASD, as a dyadic group participating in activities together during the intervention, requires further investigation. Therefore, the present study addresses the limitations of previous studies, in terms of the lack of focus on improving the mental health of parents of children with ASD.
The study examined the changes in mental health of parents of children with ASD through the DASS-21, PSI-4-SF, and WHOQOL-26 instruments after a 10-week online parent–child physical activity intervention. Our findings confirmed the significant differences in DASS-21 and PSI-4-SF for the experimental group, when compared with the control group across time, and the significant reduction in overall scores in DASS-21 and PSI-4-SF after the intervention. There was no significant difference in overall WHOQOL-26 scores between the two groups, which may be because the QOL reflects multi-dimensional aspects of life, and the intervention program promotes only several dimensions with a 10-week duration. We speculate that a longer intervention may be helpful to improve other aspects of QOL and achieve significant changes in overall QOL.
Among the three sub-scales of DASS-21 and the PSI-4-SF, they all had statistically significant differences in terms of the stress, anxiety, and depression after the intervention, indicating the positive influence on relieving the stress of parents of children with ASD through participating in the parent–child physical activity program. One possible explanation for the effectiveness of the intervention is the nature of this web-based family-centered program to provide great opportunities for the parent and child to interact with each other, and the step-by-step structured approach easily engages parents and their children in the physical activity sessions together. The evidence obtained clearly indicated that using a family-centered parent–child program targets the core symptoms of children with ASD and has a dramatic impact on children’s weakness to interact and communicate with others, including their parents, which might be major reasons resulting in the psychological anxiety and depression of the parents.
The results of this study confirmed that the parent–child physical activity program can be viewed as a natural environment for building relationships between parents and their children with ASD. The constructed activity program involves co-participation physical activities that naturally engage the parent–child pair, which is crucial for the family to increase parent–child communication, time spent together, and enjoyment of physical activity. During each session, the parents have great opportunities to experience interactions with their children through different kinds of activities that were not impossible before. Such enjoyable experiences greatly increase dyadic shared pleasure, as well as parental self-efficacy and motivation when interacting with their children, while reducing parenting stress and enhancing mental health for both parents and their children.
It has been shown that the mental health of a family unit and family members has a significant positive correlation with their communication and interaction [
48
], and it may explain the effectiveness of the current intervention in improving the mental health of parents of children with ASD through increased interaction and communication during participation in the parent–child physical activity program. Specifically, the program provides a family-based activity environment with warm, interactive, and cohesive styles that promote the shared participation of parents and children with ASD. Parents can influence their children’s physical activity participation through role-modeling (being active themselves), material support (financial, logistic, co-participation), and encouragement [
49
]. Parental role-modeling and support for physical activity benefit children with ASD and can encourage children to be more active in their interactions with others [
50
]. After constant repetition and practice, it may create a constructive interaction environment, which leads to a virtuous cycle. When the parents see their children’s progress, it inevitably leads to reduced psychological pressure. Therefore, we believe that structured parent–child dyadic physical activity can lead to a natural environment that promotes the relationship between parents and their children within a parent–child family context.
Another possibility for the improvement of mental health through the intervention was the essential characteristics of web-based technology supporting the physical activity program. During the COVID-19 lockdown, web-based programs have become popular and necessary, providing an engaging way to easily involve children with ASD and parents in physical activity programs. The web-based parent–child physical activity program provided more opportunities to cope with stress through the use of different kinds of modern scientific and technological innovations, such as video games, an online gym, and a live course, which all provide a rich communicative platform including a chatroom, instant messenger, bulletin boards, art activities, contests, and more, in order to support the interaction and socialization of the participants. With this advanced technology, the significant results of the present study might serve as good practical experience for those special schools and rehabilitation centers where most of the physical activity programs are conducted in the institution, which typically target children with ASD only, without involving their family members. In particular, the web-based parent–child program can assist those parents who are struggling between work and family, and who face greater difficulty in attending school-based parent–child exercise programs. Hence, there is a need to develop a set of web-based parent–child exercise programs for parents and children, allowing them to get active in a convenient setting, as a home-based environment (as a treatment setting) is more comfortable for parents and their children. Therefore, it could be implemented with more joy for the family members.
Many previous studies have indicated the importance of peer support and group practice [
51
,
52
]; as such, we scheduled two sessions of group exercises and live courses, conducted online through Zoom and Tencent Live. The participants also had opportunities to watch other children and families practicing and performing. We believe that this setting may be beneficial to the parents of children with ASD, as Zoom provides them with opportunities to communicate with other parents who are going through similar experiences and difficulties. Through interaction and communication with other parents, these parents could release their stress and improve their mental health. Our findings confirm that family-centered, collaborative, and web-based parent–child physical activity approaches can establish better parent–child relationships for communication, reduce parental stress and improve mental health, and eventually improve the quality of life of families that have children with ASD.
There are some limitations and future directions that we need to consider in future studies. First, the follow-up period was relatively short, and the changes in mental health may be unstable. It is necessary to observe the effects of the parent–child physical activity program on the mental health of parents of children with ASD over a longer period of intervention. Second, although we demonstrated, in the current study, that the parent–child physical activity program had a positive influence on the mental health of parents of children with ASD, it may be worthwhile to further explore whether there is a relationship between the effectiveness of the program and other family members, such as their siblings and other people who live with them. The potential contributions of the parent–child physical activity program toward parental mental health, health-related fitness, and family well-being will be another important direction for future research.
5. Conclusions
The findings of the present study were in line with the results of previous studies, and the results of the present study demonstrated that the web-based structured parent–child physical activity program can significantly improve the mental health of the parents of children with ASD. The program strongly demonstrated a positive influence on the overall DASS-21 and PSF-4-SF scores, and significantly enhanced the sub-scales of three instruments in the areas of depression, anxiety, stress, parental distress, parent–child dysfunctional interaction, child difficulty, and psychological health. The findings of the present study also indicated that addressing the mental health of parents with children with ASD is necessary. We believe that the described web-based family program can be adopted by schools and rehabilitation centers as an alternative approach to enhance parent–child relationships, as well as to improve the mental health of parents of children with ASD.
Author Contributions
Conceptualization, M.Z and S.C.; methodology, M.Z., S.C. and X.D.; software, Y.Y., L.L.; validation, M.Z., S.C., Y.Y., X.D. and Y.W.; formal analysis, M.Z., S.C., Y.Y., X.D. and Y.W; investigation, M.Z.,Y.Y., L.L.; resources, M.Z., Y.Y., L.L; data curation, M.Z., Y.Y., L.L., S.C.; writing—original draft preparation, M.Z., S.C; writing—review and editing, M.Z., S.C., X.D. and Y.W; visualization, M.Z., Y.Y.; supervision, M.Z.; project administration, M.Z., Y.Y., L.L.; funding acquisition, M.Z. All authors have read and agreed to the published version of the manuscript.
Funding
Guangdong Planning Office of Philosophy and Social Science (General Project in 2021, No. GD21CTY02) and Shenzhen University Young Teachers Research initiation project (No. 20210402).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Sports Science Ethics Committee of Shandong Sport University. The code is 20200025.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding or first author.
Conflicts of Interest
The authors declare no conflict of interest.
References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders , 5th ed.; American Psychiatric Association: Washington, DC, USA, 2013. [ Google Scholar ]
CDC Centers for Disease Control and Prevention. Available online: https://www.cdc.gov/ncbddd/autism/data.html (accessed on 5 October 2021).
Khanna, R.; Madhavan, S.S.; Smith, M.J.; Patrick, J.H.; Tworek, C.; Becker-Cottrill, B. Assessment of Health-Related Quality of Life Among Primary Caregivers of Children with Autism Spectrum Disorders. J. Autism Dev. Disord. 2011 , 41 , 1214–1227. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Aktar, E.; Qu, J.; Lawrence, P.J.; Tollenaar, M.S.; Elzinga, B.M.; Bögels, S.M. Fetal and Infant Outcomes in the Offspring of Parents with Perinatal Mental Disorders: Earliest Influences. Front. Psychiatry 2019 , 10 , 391. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hayes, S.A.; Watson, S.L. The Impact of Parenting Stress: A Meta-Analysis of Studies Comparing the Experience of Par-enting Stress in Parents of Children with and without Autism Spectrum Disorder. J. Autism Dev. Disord. 2013 , 43 , 629–642. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Mugno, D.; Ruta, L.; D’Arrigo, V.G.; Mazzone, L. Impairment of quality of life in parents of children and adolescents with pervasive developmental disorder. Health Qual. Life Outcomes 2007 , 5 , 22–30. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Bitsika, V.; Sharpley, C.F. Stress, Anxiety and Depression Among Parents of Children with Autism Spectrum Disorder. Aust. J. Guid. Couns. 2004 , 14 , 151–161. [ Google Scholar ] [ CrossRef ]
Kuusikko-Gauffin, S.; Pollock-Wurman, R.; Mattila, M.-L.; Jussila, K.; Ebeling, H.; Pauls, D.; Moilanen, I. Social Anxiety in Parents of High-Functioning Children with Autism and Asperger Syndrome. J. Autism Dev. Disord. 2012 , 43 , 521–529. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cheung, K.; Theule, J. Parental Psychopathology in Families of Children with ADHD: A Meta-analysis. J. Child. Fam. Stud. 2016 , 25 , 3451–3461. [ Google Scholar ] [ CrossRef ]
Hastings, R.P.; Johnson, E. Stress in UK Families Conducting Intensive Home-Based Behavioral Intervention for Their Young Child with Autism. J. Autism Dev. Disord. 2001 , 31 , 327–336. [ Google Scholar ] [ CrossRef ]
Rivard, M.; Terroux, A.; Parent-Boursier, C.; Mercier, C. Determinants of Stress in Parents of Children with Autism Spectrum Disorders. J. Autism Dev. Disord. 2014 , 44 , 1609–1620. [ Google Scholar ] [ CrossRef ]
Osborne, L.A.; Reed, P. The Relationship between Parenting Stress and Behavior Problems of Children with Autistic Spectrum Disorders. Except. Child. 2009 , 76 , 54–73. [ Google Scholar ] [ CrossRef ]
Hastings, R.P. Child behaviour problems and partner mental health as correlates of stress in mothers and fathers of children with autism. J. Intellect. Disabil. Res. 2003 , 47 , 231–237. [ Google Scholar ] [ CrossRef ]
Hoffman, C.; Sweeney, D.; Hodge, D.; Lopez-Wagner, M. Parenting stress and closeness: Mothers of typically developing children and mothers of children with autism. Focus Autism Dev. Disabil. 2009 , 24 , 178–187. [ Google Scholar ] [ CrossRef ]
Myers, B.J.; Mackintosh, V.H.; Goin-Kochel, R.P. My greatest joy and my greatest heart ache: Parents’ own words on how having a child in the autism spectrum has affected their lives and their families’ lives. Res. Autism Spectr. Disord. 2009 , 3 , 670–684. [ Google Scholar ] [ CrossRef ]
Woodgate, R.L.; Ateah, C.; Secco, L. Living in a world of our own: The experience of parents who have a child with autism. Qual. Health Res. 2008 , 18 , 1075–1083. [ Google Scholar ] [ CrossRef ]
Karst, J.S.; Van Hecke, A.V. Parent and Family Impact of Autism Spectrum Disorders: A Review and Proposed Model for Intervention Evaluation. Clin. Child. Fam. Psychol. Rev. 2012 , 15 , 247–277. [ Google Scholar ] [ CrossRef ]
Sun, X.; Allison, C.; Auyeung, B.; Baron-Cohen, S.; Brayne, C. A review of healthcare service and education provision of Autism Spectrum Condition in mainland China. Res. Dev. Disabil. 2012 , 34 , 469–479. [ Google Scholar ] [ CrossRef ]
Sun, X.; Allison, C.; Auyeung, B.; Matthews, F.E.; Murray, S.; Baron-Cohen, S.; Brayne, C. Service provision for autism in mainland China: A service providers’ perspective. Res. Dev. Disabil. 2013 , 34 , 440–451. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Catalano, D.; Holloway, L.; Mpofu, E. Mental health interventions for parent carers of children with autistic spec-trum disorder: Practice guidelines from a critical interpretive synthesis (CIS) systematic review. Int. J. Environ. Res. Public Health 2018 , 15 , 341. [ Google Scholar ] [ CrossRef ][ Green Version ]
Colizzi, M.; Sironi, E.; Antonini, F.; Ciceri, M.L.; Bovo, C.; Zoccante, L. Psychosocial and Be-havioral Impact of COVID-19 in Autism Spectrum Disorder: An Online Parent Survey. Brain Sci. 2020 , 10 , 341. [ Google Scholar ] [ CrossRef ]
Feinberg, E.; Augustyn, M.; Fitzgerald, E.; Sandler, J.; Suarez, Z.F.-C.; Chen, N.; Silverstein, M. Improving maternal mental health after a child’s diagnosis of autism spectrum disorder: Results from a randomized clinical trial. J. Am. Med. Assoc. Pediatr. 2014 , 168 , 40–46. [ Google Scholar ] [ CrossRef ][ Green Version ]
Kenney, J. Solution Focused Brief Intervention for Caregivers of Children with Autism Spectrum Disorder: A Single Subject Design. Ph.D. Thesis, Walden University, Minneapolis, MN, USA, 2010. [ Google Scholar ]
Campbell, N.B. Emotional Disclosure Through Writing: An Intervention to Facilitate Adjustment to Having a Child with Autism. Ph.D. Thesis. 2003. Retrieved from ProQuest Information & Learning database on. Available online: https://psycnet.apa.org/record/2003 (accessed on 15 September 2021).
Ferraioli, S.J.; Harris, S.L. Comparative Effects of Mindfulness and Skills-Based Parent Training Programs for Parents of Children with Autism: Feasibility and Preliminary Outcome Data. Mindfulness 2013 , 4 , 89–101. [ Google Scholar ] [ CrossRef ]
Gika, D.M.; Artemiadis, A.K.; Alexopoulos, E.C.; Darviri, C.; Papanikolaou, K.; Chrousos, G.P. Use of a relaxation tech-nique by mothers of children with autism: A case-series study. Psychol. Rep. 2012 , 111 , 797–804. [ Google Scholar ] [ CrossRef ] [ PubMed ]
World Health Organization. World Health Organization: Global recommendations on physical activity for health. Available online: https://www.who.int/publications/i/item/9789241599979 (accessed on 15 October 2021).
Wafa, S.W.W.b.S.S.T.; bin Shahril, M.R.; bte Ahmad, A.; Zainuddin, L.R.B.; Aung, M.M.T.; Yusoff, N.A.B.M. Association between physical activity and health-related quality of life in children: A cross-sectional study. Health Qual. Life Outcomes 2016 , 14 , 71. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Czosnek, L.; Lederman, O.; Cormie, P.; Zopf, E.M.; Stubbs, B.; Rosenbaum, S. Health benefits, safety and cost of physical activity interventions for mental health conditions: A meta-review to inform translation efforts. Ment. Health Phys. Act. 2019 , 16 , 140–151. [ Google Scholar ] [ CrossRef ][ Green Version ]
Rhodes, R.E.; Lim, C. Promoting Parent and Child Physical Activity Together: Elicitation of Potential Intervention Targets and Preferences. Health Educ. Behav. 2018 , 45 , 112–123. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Jellett, R.; Wood, C.E.; Giallo, R.; Seymour, M. Family functioning and behaviour problems in children with Autism Spectrum Disorders: The mediating role of parent mental health. Clin. Psychol. 2015 , 19 , 39–48. [ Google Scholar ] [ CrossRef ]
Ooi, K.L.; Ong, Y.S.; Jacob, S.A.; Khan, T.M. A meta-synthesis on parenting a child with autism. Neuropsychiatr. Dis. Treat. 2016 , 12 , 745–762. [ Google Scholar ] [ PubMed ][ Green Version ]
American Heart Association. Heart Diseases and Stroke Statistics ; Centers for Disease Control and Prevention: Atlanta, GA, USA, 2018. Available online: https://www.cdc.gov/healthyyouth/protective/parent_engagement.htm (accessed on 15 October 2021).
Thompson, J.L.; Jago, R.; Brockman, R.; Cartwright, K.; Page, A.S.; Fox, K.R. Physically active families—de-bunking the myth? A qualitative study of family participation in physical activity. Child. Care Health Dev. 2010 , 36 , 265–274. [ Google Scholar ] [ CrossRef ]
Morgan, P.J.; Lubans, D.R.; Callister, R.; Okely, A.D.; Burrows, T.L.; Fletcher, R.; Collins, C.E. The ‘Healthy dads, healthy Kids’ randomized controlled trial: Efficacy of a healthy lifestyle program for overweight fathers and their children. Int. J. Obes. 2011 , 35 , 436–447. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Wong, R.S.M.; Yu, E.Y.T.; Wong, T.W.-L.; Fung, C.S.C.; Choi, C.S.Y.; Or, C.K.L.; Liu, K.S.N.; Wong, C.K.H.; Ip, P.; Lam, C.L.K. Development and pilot evaluation of a mobile app on parent-child exercises to improve physical activity and psychosocial outcomes of Hong Kong Chinese children. BMC Public Health 2020 , 20 , 1544. [ Google Scholar ] [ CrossRef ]
Lovibond, S.H.; Lovibond, P.F. Manual for the Depression Anxiety Stress Scales ; Sydney Psychology Foundation Australia: Sydney, Australia, 1995. [ Google Scholar ]
Eapen, V.; Črnčec, R.; Walter, A.; Tay, K.P. Conceptualisation and Development of a Quality of Life Measure for Parents of Children with Autism Spectrum Disorder. Autism Res. Treat. 2014 , 2014 . [ Google Scholar ] [ CrossRef ][ Green Version ]
Rezendes, D.L.; Scarpa, A. Associations between Parental Anxiety/Depression and Child Behavior Problems Related to Autism Spectrum Disorders: The Roles of Parenting Stress and Parenting Self-Efficacy. Autism Res. Treat. 2011 , 1–10. [ Google Scholar ] [ CrossRef ][ Green Version ]
Loyd, B.H.; Abidin, R.R. Revision of the Parenting Stress Index. J. Pediatr. Psychol. 1985 , 10 , 169–177. [ Google Scholar ] [ CrossRef ]
Rivas, G.R.; Arruabarrena, I.; de Paúl, J. Parenting Stress Index-Short Form: Psychometric properties of the Spanish version in mothers of children aged 0 to 8 years. Psychosoc. Interv. 2020 , 30 , 27–34. [ Google Scholar ] [ CrossRef ]
Crum, K.I.; Moreland, A.D. Parental Stress and Children’s Social and Behavioral Outcomes: The Role of Abuse Potential over Time. J. Child. Fam. Stud. 2017 , 26 , 3067–3078. [ Google Scholar ] [ CrossRef ]
Mackler, J.S.; Kelleher, R.T.; Shanahan, L.; Calkins, S.D.; Keane, S.P.; O’Brien, M. Parenting Stress, Parental Reactions, and Externalizing Behavior from Ages 4 to 10. J. Marriage Fam. 2015 , 77 , 388–406. [ Google Scholar ] [ CrossRef ]
Reyno, S.M.; McGrath, P.J. Predictors of parent training efficacy for child externalizing behavior problems—a meta-analytic review. J. Child. Psychol. Psychiatry 2006 , 47 , 99–111. [ Google Scholar ] [ CrossRef ]
The WHOQOL Group. Development of the World Health Organization WHOQOL-BREF Quality of Life Assessment. Psychol. Med. 1998 , 28 , 551–558. [ Google Scholar ] [ CrossRef ][ Green Version ]
Zhao, M.; Chen, S. The Effects of Structured Physical Activity Program on Social Interaction and Communication for Children with Autism. Biomed. Res. Int. 2018 , 1825046. [ Google Scholar ] [ CrossRef ]
Baker-Ericzén, M.J.; Brookman-Frazee, L.; Stahmer, A. Stress Levels and Adaptability in Parents of Toddlers with and without Autism Spectrum Disorders. Res. Pract. Pers. Sev. Disabil. 2005 , 30 , 194–204. [ Google Scholar ] [ CrossRef ][ Green Version ]
Johnson, W.L.; Friedland, L.; Schrider, P.; Valente, A.; Sheridan, S. The Virtual Cultural Awareness Trainer (VCAT): Joint Knowledge Online’s (JKO’s) Solution to the Individual Operational Culture and Language Training Gap. Available online: https://alelo.com/wp-content/uploads/2014/06 (accessed on 15 October 2021).
Garriguet, D.; Colley, R.; Bushnik, T. Parent-Child association in physical activity and sedentary behaviour. Health Rep. 2017 , 28 , 3–11. [ Google Scholar ]
Arnell, S.; Jerlinder, K.; Lundqvist, L.-O. Parents’ perceptions and concerns about physical activity participation among adolescents with autism spectrum disorder. Autism 2020 , 24 , 2243–2255. [ Google Scholar ] [ CrossRef ]
Mandell, D.S.; Salzer, M.S. Who joins support groups among parents of children with autism? Autism 2007 , 11 , 111–122. [ Google Scholar ] [ CrossRef ][ Green Version ]
Rosqvist, H.B. Knowing what to do: Exploring meanings of development and peer support aimed at people with autism. Int. J. Incl. Educ. 2018 , 23 , 174–187. [ Google Scholar ] [ CrossRef ][ Green Version ]
Figure 1. Participant selection process flow diagram.
Figure 2. ( a – c ) Impact of parent–child physical activity program on sub-scales of stress, anxiety, and depression in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Figure 3. ( a–c ) Impact of parent–child physical activity program on sub-scales of parental distress, parent–child dysfunctional interaction, and child difficulty in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Figure 4. ( a–d ) Impact of parent–child physical activity program on sub-scales of physical health, psychological health, social relationships, and environment in the two groups. Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 1. Demographic data of the participants.
Variables Experimental Group Control Group Total F/t/ 𝝌 2 p -Value Participant—children Age, y, mean (SD) 6.0 (1.7) 5.8 (1.5) 5.9 (1.6) 0.357 0.722 Gender, n, M/F Participant—parents Age, y, mean (SD) 33.8 (3.9) 33.4 (4.2) 33.6 (4.0) 0.417 0.678 Gender, n, M/F 11/26 11/27 22/53 0.006 0.941 Number of children in the family −0.129 0.898 One child 22 24 46 Two children 16 13 29 Parent education level 0.457 0.796 Secondary education 7 9 16 University education 27 25 52 Post-graduate and above 3 4 7 Parent employment 0.829 0.661 Employed 12 13 25 Housewives/househusbands 25 25 50
Table 2. Parent–child physical activity intervention program.
Parts Time (min) Content Way Warm-up activities 10 Parent–child warm-up exercises (make up their own moves to music); Walking Lunges; Arm Circles or Swings. Teaching video Parent–child exercises 20 Jumping jack; Side Hops; Parent–child yoga; Play ball exercises and games with their teachers. Live course and teaching video Play-based exercises 20 Interactive exercise through video games (Run-ning; Tennis; Fruit Slice). Motion sensing game Cool-down and reward activities 10 Stretching and relaxation exercises; High five and clap; Sing goodbye songs together. Live course and teaching video
Table 3. Multivariate Tests.
Index Effect Pillai’s Trace F Hypothesis df Error df Sig. Partial η 2 Sample Power Overall DASS-21 Time 0.670 147.937 1.000 73.000 0.000 0.670 1.000 Time X group 0.592 106.032 1.000 73.000 0.000 0.592 1.000 Stress Time 0.576 99.023 1.000 73.000 0.000 0.576 1.000 Time X group 0.482 67.826 1.000 73.000 0.000 0.482 1.000 Anxiety Time 0.475 66.023 1.000 73.000 0.000 0.475 1.000 Time X group 0.419 52.538 1.000 73.000 0.000 0.419 1.000 Depression Time 0.533 83.165 1.000 73.000 0.000 0.533 1.000 Time X group 0.442 57.821 1.000 73.000 0.000 0.442 1.000
Table 4. Comparison of DASS-21 across two intervals between two groups.
Variables Control Group Experimental Group t df p -Value d Sample Power Pre-Test Overall DASS-21 42.11 ± 9.96 42.55 ± 10.92 −0.184 73 0.854 0.043 0.054 DASS-21 depression 14.38 ± 3.49 14.66 ± 3.74 −0.334 73 0.739 0.077 0.063 DASS-21 anxiety 13.11 ± 3.65 13.13 ± 3.92 −0.027 73 0.979 0.005 0.050 DASS-21 stress 14.62 ± 3.59 14.76 ± 3.92 −0.163 73 0.871 0.037 0.053 Post-Test Overall DASS-21 41.51 ± 9.23 # 35.39 ± 9.11 ** ## 2.889 73 0.005 0.667 0.814 DASS-21 depression 14.14 ± 3.27 12.08 ± 3.21 ** ## 2.750 73 0.008 0.636 0.775 DASS-21 anxiety 13 ± 3.32 11.24 ± 3.27 * ## 2.319 73 0.023 0.534 0.626 DASS-21 stress 14.38 ± 3.34 # 12.08 ± 3.49 ** ## 2.912 73 0.005 0.673 0.821
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 5. Pre-/post-comparison of DASS-21 for two groups.
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # . denotes p < 0.05, ## denotes p < 0.01.
Table 6. Multivariate Test.
Index Effect Pillai’s Trace F Hypothesis df Error df Sig. Partial η 2 Sample Power Overall PSI-4-SF Time 0.654 137.995 1.000 73.000 0.000 0.654 1.000 Time X group 0.442 57.741 1.000 73.000 0.000 0.442 1.000 Parental Distress Time 0.427 54.444 1.000 73.000 0.000 0.427 1.000 Time X group 0.202 18.452 1.000 73.000 0.000 0.202 0.989 Dysfunctional Interaction Time 0.507 74.937 1.000 73.000 0.000 0.507 1.000 Time X group 0.445 58.548 1.000 73.000 0.000 0.419 1.000 Difficult Child Time 0.422 53.361 1.000 73.000 0.000 0.422 1.000 Time X group 0.049 3.740 1.000 73.000 0.057 0.049 0.48
Table 7. Comparison of PSI-4-SF across two intervals between two groups.
Variables Control Group Experimental Group t df p -Value Effect Size Sample Power Pre-Test Overall PSI-4-SF 127.95 ± 6.61 128.24 ± 6.6 −0.191 73 0.849 0.044 0.054 Parental Distress 43.97 ± 3.26 44.21 ± 3.37 −0.310 73 0.757 0.072 0.061 Parent–Child Dysfunctional Interaction 40.41 ± 3.19 40.55 ± 3.28 −0.197 73 0.844 0.043 0.054 Difficult Child 43.57 ± 3.24 43.47 ± 3.24 0.125 73 0.901 0.031 0.052 Post-Test Overall PSI-4-SF 126.41 ± 5.62 121.05 ± 5.69 ** ## 4.095 73 0.000 0.946 0.982 Parental Distress 43.49 ± 2.78 42.37 ± 3.27 ## 1.595 73 0.115 0.369 0.352 Parent–Child Dysfunctional Interaction 40.16 ± 3.01 36.61 ± 2.93 ** ## 5.185 73 0.000 1.195 0.999 Difficult Child 42.76 ± 3.2 42.08 ± 3.13 ## 0.927 73 0.357 0.215 0.151
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 8. Pre/post comparison of PSI-4-SF for two groups.
Pre-Test Post-Test Difference t df p -Value d Sample Power Control Group 127.95 ± 6.61 126.41 ± 5.62 1.541 4.800 36 0.100 0.789 0.996 Experimental Group 128.24 ± 6.6 121.05 ± 5.69 ** ## 7.184 10.839 37 0.000 1.758 1.000
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 9. Multivariate Tests.
Index Effect Pillai’s Trace F Hypothesis df Error df Sig. Partial η 2 Sample Power Overall QOL-26 Time 0.400 48.608 1.000 73.000 0.000 0.400 1.000 Time X group 0.001 0.063 1.000 73.000 0.802 0.001 0.057 Physical Health Time 0.052 4.042 1.000 73.000 0.048 0.052 0.510 Time X group 0.002 0.142 1.000 73.000 0.708 0.002 0.066 Psychological Health Time 0.128 10.727 1.000 73.000 0.002 0.128 0.898 Time X group 0.000 0.008 1.000 73.000 0.931 0.000 0.051 Social Relationships Time 0.097 7.810 1.000 73.000 0.007 0.097 0.788 Time X group 0.004 0.274 1.000 73.000 0.603 0.004 0.081 Environment Time 0.455 60.904 1.000 73.000 0.000 0.455 1.000 Time X group 0.062 4.824 1.000 73.000 0.031 0.062 0.582
Table 10. Between-group comparison for WHOQOL-26 across two intervals.
Variables Control Group Experimental Group t df p -Value Effect Size Sample Power Pre-test Overall QOL-26 40.83 ± 2.86 40.58 ± 2.74 0.376 73 0.708 0.087 0.067 Physical Health 10.92 ± 1.05 10.95 ± 1.19 −0.110 73 0.913 0.027 0.051 Psychological Health 10.86 ± 1.49 11.04 ± 1.45 −0.501 73 0.618 0.122 0.082 Social Relationships 9.15 ± 1.94 9.09 ± 2.01 0.144 73 0.886 0.030 0.052 Environment 9.89 ± 1.35 9.51 ± 1.16 1.295 73 0.199 0.302 0.252 Post-test Overall QOL-26 41.87 ± 2.84 ## 41.55 ± 2.93 ## 0.473 73 0.637 0.109 0.076 Physical Health 11.01 ± 1 11.08 ± 1.22 −0.275 73 0.784 0.063 0.058 Psychological Health 10.41 ± 1.27 # 9.8 ± 1.12 ## * 2.179 73 0.033 0.510 0.585 Social Relationships 9.37 ± 1.87 # 9.4 ± 1.81 −0.080 73 0.936 0.016 0.051 Environment 11.08 ± 1.33 # 11.26 ± 1.6 # −0.535 73 0.594 0.122 0.082
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Table 11. Pre/post comparison of WHOQOL-26 for two groups.
Pre-Test Post-Test Difference t df p -Value d Sample Power Control Group 40.83 ± 2.86 41.87 ± 2.84 ## −1.041 −8.310 36 0.000 1.366 1.000 Experimental Group 40.58 ± 2.74 41.55 ± 2.93 ## −0.969 −3.770 37 0.001 0.612 0.961
Note. Compared with the control group, * denotes p < 0.05, ** denotes p < 0.01. Compared with pre-test, # denotes p < 0.05, ## denotes p < 0.01.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).
MDPI and ACS Style
Zhao, M.; You, Y.; Chen, S.; Li, L.; Du, X.; Wang, Y. Effects of a Web-Based Parent–Child Physical Activity Program on Mental Health in Parents of Children with ASD. Int. J. Environ. Res. Public Health 2021, 18, 12913.
https://doi.org/10.3390/ijerph182412913
AMA Style
Zhao M, You Y, Chen S, Li L, Du X, Wang Y. Effects of a Web-Based Parent–Child Physical Activity Program on Mental Health in Parents of Children with ASD. International Journal of Environmental Research and Public Health. 2021; 18(24):12913.
https://doi.org/10.3390/ijerph182412913
Chicago/Turabian Style
Zhao, Mengxian, Yonghao You, Shihui Chen, Linlin Li, Xiru Du, and Yongtai Wang. 2021. "Effects of a Web-Based Parent–Child Physical Activity Program on Mental Health in Parents of Children with ASD" International Journal of Environmental Research and Public Health18, no. 24: 12913.
https://doi.org/10.3390/ijerph182412913
Article Metrics
Zhao, Mengxian, Yonghao You, Shihui Chen, Linlin Li, Xiru Du, and Yongtai Wang. 2021. "Effects of a Web-Based Parent–Child Physical Activity Program on Mental Health in Parents of Children with ASD" International Journal of Environmental Research and Public Health18, no. 24: 12913.
https://doi.org/10.3390/ijerph182412913
| https://www.mdpi.com/1660-4601/18/24/12913/htm |
U.S. Census Bureau QuickFacts: United States; New Jersey; Hunterdon County, New Jersey; Middlesex County, New Jersey; Hudson County, New Jersey; Somerset County, New Jersey
Frequently requested statistics for: United States; New Jersey; Hunterdon County, New Jersey; Middlesex County, New Jersey; Hudson County, New Jersey; Somerset County, New Jersey
U.S. Census Bureau QuickFacts: United States; New Jersey; Hunterdon County, New Jersey; Middlesex County, New Jersey; Hudson County, New Jersey; Somerset County, New Jersey
Please note that new Connecticut county level geographies are not availabe within the map.
An official website of the United States government
Here's how you know Official websites use .gov
A .gov
website belongs to an official government
organization in the United States. Secure .gov websites use HTTPS
A lock
( Lock A locked padlock
) or https://
means you’ve safely connected to
the .gov website. Share sensitive information only on official,
secure websites.
QuickFacts
United States; New Jersey; Hunterdon County, New Jersey; Middlesex County, New Jersey; Hudson County, New Jersey; Somerset County, New Jersey
QuickFacts provides statistics for all states and counties, and for cities and towns with a
population of 5,000 or more
.
6
Table
Map
United States New Jersey Hunterdon County, New Jersey Middlesex County, New Jersey Hudson County, New Jersey Somerset County, New Jersey
What's New & FAQs
What's New? (data release dates)
Facts Updated for Places and Minor Civil Divisions on 5/18/23 Population Estimates, July 1, 2022 (V2022) Population Estimates base, April 1, 2020 (V2022) Population, Percent Change - April 1, 2020 (estimates base) to July 1, 2022, (V2022)
Facts Updated for U.S., States, and Counties on 5/18/23 Housing Units, July 1, 2022 (V2022)
Fact updated for U.S., States, and Counties on 5/11/23 Building permits, 2022
Facts updated for U.S., States, Puerto Rico, Counties, and Municipios on 4/27/23 Total employer establishments, 2021 Total employment, 2021 Total annual payroll, 2021 ($1,000) Total employment, percent change, 2020-2021
Facts updated for Counties and Municipios on 3/30/23 Population estimates, July 1, 2022, (V2022) Population estimates base, April 1, 2020, (V2022) Population, percent change - April 1, 2020 (estimates base) to July 1, 2022, (V2022)
Facts updated for U.S., States, and Puerto Rico on 12/22/22 Population estimates, July 1, 2022, (V2022) Population estimates base, April 1, 2020, (V2022) Population, percent change - April 1, 2020 (estimates base) to July 1, 2022, (V2022)
Fact updated for Counties on 12/15/22 Persons in poverty, percent, 2021
Facts updated for U.S., States, Puerto Rico, Counties, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 12/8/22 Veterans, 2017-2021 Foreign born persons, percent, 2017-2021 Owner-occupied housing unit rate, 2017-2021 Median value of owner-occupied housing units, 2017-2021 Median selected monthly owner costs -with a mortgage, 2017-2021 Median selected monthly owner costs -without a mortgage, 2017-2021 Median gross rent, 2017-2021 Households, 2017-2021 Persons per household, 2017-2021 Living in same house 1 year ago, percent of persons age 1 year+, 2017-2021 Language other than English spoken at home, percent of persons age 5 years+, 2017-2021 Households with a computer, percent. 2017-2021 Households with a broadband Internet subscription, percent, 2017-2021 High school graduate or higher, percent of persons age 25 years+, 2017-2021 Bachelor's degree or higher, percent of persons age 25 years+, 2017-2021 With a disability, under age 65 years, percent, 2017-2021 In civilian labor force, total, percent of population age 16 years+, 2017-2021 In civilian labor force, female, percent of population age 16 years+, 2017-2021 Mean travel time to work (minutes), workers age 16 years+, 2017-2021 Median household income (in 2019 dollars), 2017-2021 Per capita income in past 12 months (in 2019 dollars), 2017-2021
Facts updated for Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 12/8/22 Persons without health insurance, under age 65 years, percent, 2017-2021 Persons in poverty, percent, 2017-2021
Facts updated for Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 12/8/22 Persons under 5 years, percent, 2017-2021 Persons under 18 years, percent, 2017-2021 Persons 65 years and over, percent, 2017-2021 Female persons, percent, 2017-2021
Facts updated for Puerto Rico, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 12/8/22 White alone, percent, 2017-2021 Black or African American alone, percent, 2017-2021 American Indian and Alaska Native alone, percent, 2017-2021 Asian alone, percent, 2017-2021 Native Hawaiian and Other Pacific Islander alone, percent, 2017-2021 Two or More Races, percent, 2017-2021 Hispanic or Latino, percent, 2017-2021 White alone, not Hispanic or Latino, percent, 2017-2021
Facts updated for States and Puerto Rico on 9/15/22 Persons without health insurance, under age 65 years, percent, 2021 Persons in poverty, percent, 2021
Facts updated for the U.S on 9/13/22 Persons without health insurance, under age 65 years, percent, 2021 Persons in poverty, percent, 2021
Fact updated for States and Counties on 8/11/22 Persons without health insurance, under age 65 years, percent, 2020
Facts updated for U.S., States, and Counties (Source: Population Estimates) on 6/30/22 Persons under 5 years, percent, July 1, 2021, (V2021) Persons under 18 years, percent, July 1, 2021, (V2021) Persons 65 years and over, percent, July 1, 2021, (V2021) Female persons, percent, July 1, 2021, (V2021) White alone, percent, July 1, 2021, (V2021) Black or African American alone, percent, July 1, 2021, (V2021) American Indian and Alaska Native alone, percent, July 1, 2021, (V2021) Asian alone, percent, July 1, 2021, (V2021) Native Hawaiian and Other Pacific Islander alone, percent, July 1, 2021, (V2021) Two or More Races, percent, July 1, 2021, (V2021) Hispanic or Latino, percent, July 1, 2021, (V2021) White alone, not Hispanic or Latino, percent, July 1, 2021, (V2021)
Facts updated for Puerto Rico and Municipios (Source: Population Estimates) on 6/30/22 Persons under 5 years, percent, July 1, 2021, (V2021) Persons under 18 years, percent, July 1, 2021, (V2021) Persons 65 years and over, percent, July 1, 2021, (V2021) Female persons, percent, July 1, 2021, (V2021)
Facts updated for U.S., States, and Counties on 6/30/22 Total nonemployer establishments, 2019
Facts updated for U.S., States, Puerto Rico, Counties, Municipios, Places, and Minor Civil Divisions on 6/23/22 Total accommodation and food services sales, 2017 ($1,000) Total health care and social assistance receipts/revenue, 2017 ($1,000) Total transportation and warehousing receipts/revenue, 2017 ($1,000) Total retail sales, 2017 ($1,000) Total retail sales per capita, 2017
Facts updated for U.S., States, Counties, Places, and Minor Civil Divisions on 6/23/22 All employer firms, Reference year 2017 Men-owned employer firms, Reference year 2017 Women-owned employer firms, Reference year 2017 Minority-owned employer firms, Reference year 2017 Nonminority-owned employer firms, Reference year 2017 Veteran-owned employer firms, Reference year 2017 Nonveteran-owned employer firms, Reference year 2017
Facts updated for U.S., States, Puerto Rico, Counties, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 6/23/22 Population per square miles, 2020 Land area in square miles, 2020
Facts Updated for Places and Minor Civil Divisions on 5/26/22 Population Estimates, July 1, 2021 (V2021) Population Estimates base, April 1, 2020 (V2021) Population, Percent Change - April 1, 2020 (estimates base) to July 1, 2021, (V2021)
Facts Updated for U.S., States, and Counties on 5/26/22 Housing Units, July 1, 2021 (V2021)
Fact updated for U.S., States, and Counties on 5/12/22 Building permits, 2021
Facts updated for U.S., States, Puerto Rico, Counties, and Municipios on 4/28/22 Total employer establishments, 2020 Total employment, 2020 Total annual payroll, 2020 ($1,000) Total employment, percent change, 2019-2020
Facts updated for Counties and Municipios on 3/24/22 Population estimates, July 1, 2021, (V2021) Population estimates base, April 1, 2020, (V2021) Population, percent change - April 1, 2020 (estimates base) to July 1, 2021, (V2021)
Facts updated for U.S., States, Puerto Rico, Counties, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 3/17/22 Veterans, 2016-2020 Foreign born persons, percent, 2016-2020 Owner-occupied housing unit rate, 2016-2020 Median value of owner-occupied housing units, 2016-2020 Median selected monthly owner costs -with a mortgage, 2016-2020 Median selected monthly owner costs -without a mortgage, 2016-2020 Median gross rent, 2016-2020 Households, 2016-2020 Persons per household, 2016-2020 Living in same house 1 year ago, percent of persons age 1 year+, 2016-2020 Language other than English spoken at home, percent of persons age 5 years+, 2016-2020 Households with a computer, percent. 2016-2020 Households with a broadband Internet subscription, percent, 2016-2020 High school graduate or higher, percent of persons age 25 years+, 2016-2020 Bachelor's degree or higher, percent of persons age 25 years+, 2016-2020 With a disability, under age 65 years, percent, 2016-2020 In civilian labor force, total, percent of population age 16 years+, 2016-2020 In civilian labor force, female, percent of population age 16 years+, 2016-2020 Mean travel time to work (minutes), workers age 16 years+, 2016-2020 Median household income (in 2020 dollars), 2016-2020 Per capita income in past 12 months (in 2020 dollars), 2016-2020
Facts updated for Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 3/17/22 Persons without health insurance, under age 65 years, percent, 2016-2020 Persons in poverty, percent, 2016-2020
Facts updated for Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 3/17/22 Persons under 5 years, percent, 2016-2020 Persons under 18 years, percent, 2016-2020 Persons 65 years and over, percent, 2016-2020 Female persons, percent, 2016-2020
Facts updated for Puerto Rico, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 3/17/22 White alone, percent, 2016-2020 Black or African American alone, percent, 2016-2020 American Indian and Alaska Native alone, percent, 2016-2020 Asian alone, percent, 2016-2020 Native Hawaiian and Other Pacific Islander alone, percent, 2016-2020 Two or More Races, percent, 2016-2020 Hispanic or Latino, percent, 2016-2020 White alone, not Hispanic or Latino, percent, 2016-2020
Facts updated for U.S., States, and Puerto Rico on 12/21/21 Population estimates, July 1, 2021, (V2021) Population estimates base, April 1, 2020, (V2021) Population, percent change - April 1, 2020 (estimates base) to July 1, 2021, (V2021)
Fact updated for States and Counties on 12/16/21 Persons in poverty, percent, 2020
Facts updated for the U.S on 9/14/21 Persons without health insurance, under age 65 years, percent, 2020 Persons in poverty, percent, 2020
Facts updated for Counties, Municipios, Places, Zona Urbanas, Comunidades, and Minor Civil Divisions on 8/12/21 Population, Census, April 1, 2020
Fact updated for Counties on 6/24/21 Persons without health insurance, under age 65 years, percent, 2019
Facts updated for U.S., States, and Puerto Rico on 5/18/21 Population, Census, April 1, 2020
Fact updated for U.S., States, and Counties on 5/18/21 Building permits, 2020
Facts updated for U.S., States, Puerto Rico, Counties, and Municipios on 4/22/21 Total employer establishments, 2019 Total employment, 2019 Total annual payroll, 2019 Total employment, percent change, 2018-2019
Why can't I find my ZIP Code?
QuickFacts does not contain data for Postal ZIP Codes. Only States, Counties, Places, and Minor Civil Divisions ( MCDs
) for Puerto Rico and the United States with populations above 5000. When you search via a ZIP code QuickFacts provides a list of near matches for the geographic types contained within the application. These near matches are created from US Census Bureau ZIP Code Tabulation Areas ( ZCTAs )
which are generalized area representations of United States Postal Service (USPS) ZIP Code service areas.
Explore Census Data for ZCTAs data and surveys
.
What is QuickFacts?
QuickFacts is an easy to use application that provides tables, maps, and charts of frequently requested statistics from many Census Bureau censuses, surveys, and programs. Profiles are available for the nation, all 50 states plus the District of Columbia and Puerto Rico, and all counties. Cities and towns with a population of 5,000 or more are also included.
What are the recommended browsers?
IE11+, Chrome, Firefox and Safari (Safari on MAC only)
How do I begin?
QuickFacts begins in TABLE view with data shown for the UNITED STATES. You can change to MAP view, CHART view, or the DASHBOARD view, that shows all three views at once.
How do I “Enter state, county, city, town, or ZIP code?”
Begin typing the name of the geography or ZIP code. After the second character, a list of choices will appear on the drop down. Locate and select your area by single-clicking the mouse or by using the up and down arrows and then pressing the Enter/Return key. The Enter/Return key may also be used if only one geography appears or your highlighted selection is at the top of the list. This becomes one of your selected geographies and is added to the TABLE in the first data column, moving UNITED STATES to the second data column.
How do I “SELECT A FACT?”
Simply click on SELECT A FACT to show the dropdown list, which is grouped by topic. Scroll down to highlight the FACT you want and click on the FACT to select it. In addition, you can double click on the row of the FACT in the TABLE.
How do I narrow the results?
In TABLE view, click ALL TOPICS and select the topic you want. The table view will show only facts within that topic. To view all facts again, select ALL TOPICS. In MAP view, you can further narrow results down to counties, county subdivisions, or places by selecting a geography color-coded circle and a small pop-up window appears with further area selections to view. For example, if your selected geography is a city, and you chose a city in that state on the map, you will have the option to Add this geography to your table, view at the United States level or view the counties in that state. In CHART view, you can toggle between all geographies at the same level as your selected area or those you have selected by using the ‘Show selected locations' checkbox. In DASHBOARD view, you can narrow down only what facts are showing by using the ALL TOPICS dropdown, as indicated above.
In TABLE view, how many geographies can I see?
TABLE view allows six geographies in the table. To add additional geographies use the search box. As you add geographies, they are added to the TABLE in the first data column, moving other geographies to the next column to the right. If there are more than one geography present, you may delete any geography by clicking the
icon. An orange circle on the TABLE icon indicates the total number of geographies currently selected. This is visible throughout the application above the data views.
In MAP view, how many geographies can I see? Can I zoom in and see data?
There are 3 additional controls in addition to the zoom in/out and full screen controls: Left Border Slide-out - Allows the user to quickly move to and remove their selected geographies. Switch Control in the upper right corner - Turns on the ability to select geographies across state boundaries. Toggle Button in the upper right corner - Toggles view between Townships and Places.
Clicking on a geography opens an info window. Within the info window you can: Add or remove a geography to your selection. View the current selected fact's value and footnote notations.
The new switch and toggle button are present on the map only when needed. All new controls will be pointed out to the user with a "NEW!" tooltip when first presented to the user. Hovering over the new control will give the user a description of the control's function as well as its current status if applicable.
Changing geography level is accomplished by zooming in/out. The progression as you zoom in is: States, Counties, Places & Townships. When zoomed into Places & Townships level a toggle button will be available within the upper right map controls to swap between the two.
When you select the MAP view icon, you are given a choice from your selected geographies to view one on the map. Once you click on a geography, you will see your selected geography outlined in red and all geographies at the same level. For example, if you selected a county, you will see all the counties in that state.
Geographies with numeric fact values are placed in ascending order and distributed into five groups containing the same number of geographies. The geography groups are then shaded from cyan (lowest values) to dark cyan (highest values). The value range for these groups will depend on the fact and geographies that fall within the group. Geographies with non-numeric fact values and footnotes are shaded with colors other than cyan and assigned to a specific footnote.
When viewing the entire US there are icons for Alaska, Hawaii and Puerto Rico in the corners that allow you to focus the map directly on those locations. When the map focuses on one of these locations their associated icon changes to the 48 contiguous states an allows you to reset the map to view the entire US.
In CHART view, how many geographies can I see? Can I see data?
When you select he CHART view icon, you are given a choice to ‘View Selected Locations' or choose one of the selected geographies. If you chose ‘View Selected Locations', you will see a chart for all selected geographies. If you only have one geography selected, the chart will open with this geography along with all sibling geographies. For example, if you have selected a state, you will see all the states, plus the District of Columbia and Puerto Rico. Hover over or click on each bar in the CHART to see the actual data value.
In DASHBOARD view, how many geographies can I see?
DASHBOARD view is a combination of all three views. When you select the DASHBOARD view icon, you are given a choice to create a dashboard for one of your selected geographies. DASHBOARD's TABLE shows fact data only for one selected geography. On DASHBOARD's TABLE you cannot add a geography. DASHBOARD's CHART shows data for the selected geography and all its siblings, same as the expanded CHART view. You can add and remove a selected geography from the dashboard chart. Selected Locations checkbox is not available on the DASHBOARD's CHART. The DASHBOARD's MAP shows data for the selected geography and places at the same level, just as in the expanded MAP view.
Where can I get data for other levels of geography, like metropolitan areas?
While not available in QuickFacts profiles, there are a number of sources on census.gov
for data about metropolitan areas.
How can I browse more datasets for my selected location?
Whenever you see an orange magnifying glass
, click it for all the detailed links to other datasets.
Can I share data from QuickFacts?
Yes. The MORE menu item opens a popup where you have options to PRINT, download a CSV, EMAIL, EMBED, and post on TWITTER and FACEBOOK.
What do these icons mean and what happens when I click them?
Click for additional information such as Sources, Definitions, and sometimes Margins of Error, or More Information.
Click for all the detailed links to other sets of data about the respective geography.
Click to set the application to its default state. This will remove all selected geographies and begin a new search. Your prior searches and results will not be saved.
Click to open the popup for all the download and share options.
Click this icon to delete a geography.
Click this icon to add a geography.
What are the footnotes at the bottom of all QuickFacts pages?
Value Notes
Estimates are not comparable to other geographic levels due to methodology differences that may exist between different data sources.
Some estimates presented here come from sample data, and thus have sampling errors that may render some apparent differences between geographies statistically indistinguishable. ]
Click the Quick Info
icon to the left of each row in TABLE view to learn about sampling error.
In Vintage 2022, as a result of the formal request from the state, Connecticut transitioned from eight counties to nine planning regions. For more details,
please see the Vintage 2022 release notes available here: Release Notes.
The vintage year (e.g., V2022) refers to the final year of the series (2020 thru 2022). Different vintage years of estimates are not comparable.
Users should exercise caution when comparing 2017-2021 ACS 5-year estimates to other ACS estimates.
For more information, please visit the 2021 5-year ACS Comparison Guidance
page. Fact Notes (a) Includes persons reporting only one race (c) Economic Census - Puerto Rico data are not comparable to U.S. Economic Census data (b) Hispanics may be of any race, so also are included in applicable race categories Value Flags - Either no or too few sample observations were available to compute an estimate, or a ratio of medians cannot be calculated because one or both of the median estimates falls in the lowest or upper interval of an open ended distribution. F Fewer than 25 firms D Suppressed to avoid disclosure of confidential information N Data for this geographic area cannot be displayed because the number of sample cases is too small. FN Footnote on this item in place of data X Not applicable S Suppressed; does not meet publication standards NA Not available Z Value greater than zero but less than half unit of measure shown
QuickFacts data are derived from: Population Estimates, American Community Survey, Census of Population and Housing, Current Population Survey, Small Area Health Insurance Estimates, Small Area Income and Poverty Estimates, State and County Housing Unit Estimates, County Business Patterns, Nonemployer Statistics, Economic Census, Survey of Business Owners, Building Permits. Close Close Please Note! Close
CONNECT WITH US
Information Quality Data Linkage Infrastructure
Data Protection and Privacy Policy Accessibility
FOIA Inspector General No FEAR Act
U.S. Department of Commerce USA.gov
Measuring America's People, Places, and Economy
Is this page helpful?
Yes No
Thank you for your feedback.
Comments or suggestions?
Comments or suggestions?
255 characters maximum
⚠ 255 characters maximum reached
NO THANKS SUBMIT | https://www.census.gov/quickfacts/fact/faq/US,NJ,hunterdoncountynewjersey,middlesexcountynewjersey,hudsoncountynewjersey,somersetcountynewjersey/PST045222 |
Molecules | Free Full-Text | Synthetic (E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1
Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a& ndash;d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51& ndash;7.70 & mu;M in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a& ndash;d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a& ndash;d is spontaneous and moderate (Ka ~ 104 M& minus;1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.
Background:
Synthetic ( E )-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1
by
Danilo Sousa-Pereira 1 ,
Thais Silva de Oliveira 2 ,
Rojane O. Paiva 2 ,
Otávio Augusto Chaves 1,3 ,
José C. Netto-Ferreira 1,4,* ,
Juliana Echevarria-Lima 2,* and
Aurea Echevarria 1,*
1
Instituto de Química, Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropédica, Rio de Janeiro 23.890-000, Brazil
2
Laboratório de Imunologia Básica e Aplicada, Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21.941-590, Brazil
3
Instituto SENAI de Inovação em Química Verde (ISI QV), Maracanã, Rio de Janeiro 20.271-030, Brazil
4
Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Divisão de Metrologia Química, Duque de Caxias, Rio de Janeiro 25.250-020, Brazil
*
Authors to whom correspondence should be addressed.
Received: 4 May 2020 / Revised: 20 May 2020 / Accepted: 26 May 2020 / Published: 29 May 2020
(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry )
Abstract
:
Synthesis of four compounds belonging to mesoionic class, (
E
)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (
5a
–
d
) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC
50
values of all compounds in the range of 1.51–7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that
5b
could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for
5b
could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (
5a
–
d
) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:
5a
–
d
is spontaneous and moderate (
K a
~ 10
4
M
−1
) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.
Keywords:
mesoionic compounds
;
HTLV-1
;
HSA interaction
;
multiple spectroscopic
;
molecular docking
Graphical Abstract
1. Introduction
In 2018, Global Cancer Statistics estimated that 18.1 million new cases of cancer and 9.6 million deaths (excluding nonmelanoma skin cancer) would occur around the world. Among these new cases, it was estimated that the incidence of leukemia and lymphoma (non-Hodgkin) would be approximately 1 million cases worldwide [ 1 ]. Leukemia was characterized by substantial impairment of bone marrow and the presence of circulating tumor cells in peripheral blood. Leukemia can be classified based on disease progression and related cell lines [ 2 ]. Human T-cell lymphotropic virus type 1 (HTLV-1) is an etiological agent of the adult T-cell leukemia/lymphoma (ATLL) malignancy [ 3 ] and the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an inflammatory disease [ 4 ]. The viral particles and reverse transcriptase enzyme were identified from a peripheral blood sample from a T-cell leukemia patient, leading HTLV-1 to be described as the first neoplastic-associated retrovirus in humans [ 5 ]. It is estimated that 10 to 20 million individuals worldwide are infected with HTLV-1. The HTLV-1 infection is higher prevalent in Japan, Africa, and Central and South America [ 6 ]. On the other hand, Japan has the highest prevalence of ATLL in the world and 1000 new cases are diagnosed annually [ 7 ].
The predominant target of HTLV-1 infection is the CD4 + T lymphocyte, which induces activation and leads to spontaneous proliferation of these cells [ 8 ]. Cell proliferation induces genomic instability, leading to chromosomal abnormalities, culminating in cell transformation [ 9 ]. Unfortunately, treatment with ATLL is restricted and patients with aggressive disease have poor prognosis due to the state of immunosuppression and resistance of the leukemic cells to multiple drugs. ATLL is classified into four subtypes, based on clinical differences and prognostic factors: acute, lymphoma, chronic, and smoldering [ 10 , 11 , 12 ]. Acute or lymphoma subtypes represent 60% of ATLL types, with a one-year prognosis of median survival, approximately [ 13 ]. The clinical features are heterogeneous lymphadenopathy, splenomegaly, hepatomegaly, hypercalcemia, skin and lung lesions, and lymphocyte infiltration [ 12 ].
The literature reports several treatment protocols for ATLL with variable results. The treatment strategy depends on ATLL subtype. Some protocols employ chemotherapy, with the use of ziduvidine (AZT)/interferon-α (IFN-α) and hematopoietic stem cell transplantation, which may occur in association or not depending on the aggressiveness of the disease [
14
]. The AZT/IFN-α association allowed good results, considering the acute, chronic, and indolent forms of ATLL, since the immunological effect of IFN-α is associated with the cytostatic effect of AZT on lymphoid cells [
15
]. The most-used treatment in the face of the lymphomatous and acute clinical forms of ATLL (more aggressive) is the use of the CHOP cocktail: (C) cyclophosphamide; (H) hydroxyldaunorubicin (doxorubicin); (O) oncovin (vincristine); and (P) prednisone. Cyclophosphamide is an alkylating agent that causes the formation of cross-links with deoxyribonucleic acid (DNA), hydroxyldaunorubicin damages DNA by inserting itself between the bases (intercalating agent), oncovin prevents cell duplication through binding to tubulin protein, and prednisone acts on cytokines (inflammatory process) [
13
].
Figure 1
shows the structures for CHOP and AZT chemotherapeutic drugs.
The AZT/IFN-α and CHOP combination showed more prolonged survival in patients when compared to chemotherapy alone. However, resistance to conventional chemotherapy, the increase in proteins responsible for resistance to multiple drugs (MDR—multiple drugs resistance), hepatic or renal dysfunction, and the state of immunodeficiency during chemotherapy are still factors associated with failure in the treatments used. In addition, the long latency of HTLV-1 infection may contribute to the failure of ATLL therapy [ 13 , 16 , 17 ]. Moreover, ATLL trial treatments using mogamulizumab (anti-CCR4 monoclonal antibody) or/and lenalidomide (( RS )-3-(4-amino-1-oxo-1,3-dihydro-2 H -isoindol-2-yl)piperidine-2,6-dione), a thalidomide derivate, were employed in Japan [ 18 ]. Mogamulizumab was also used in combination with multi-agent chemotherapy, improving the therapy response of 33% to 52% [ 19 ].
Heterocyclic compounds of the mesoionic class, especially those with 1,3,4-thiadiazole moiety, have been synthesized and their biological effects investigated, confirming their excellent potential biological activity. Different biological activities have been described for these compounds, such as anticancer [ 20 , 21 , 22 , 23 ], antiparasitic [ 24 , 25 , 26 ], anti-inflammatory, analgesic [ 27 , 28 ], and antimicrobial [ 29 , 30 ]. Mesoionic compounds have a betaine-like characteristic, with a positive charge on the heterocyclic ring and a negative charge on the exocyclic atom and, therefore, can be represented only by dipolar structures [ 31 ].
In our previous studies with 1,3,4-thiadiazolium salts (mesoionic compounds) containing a substituted styryl moiety, important results for in vitro cytotoxic activity in various types of tumor cells, including leukemias [ 23 , 32 , 33 , 34 ], and in vivo antitumor effects have been observed [ 35 , 36 ]. Besides, results on the antiviral activity of 1,3,4-thiadiazole derivatives against HIV-1 [ 37 , 38 , 39 , 40 ], which also belong to the same Retroviridae family, have also been reported in the literature. These results motivated us to synthesize new 1,3,4-thiadiazolium salts containing an unsubstituted styryl group, as well as a substituted phenyl ring linked to the exocyclic nitrogen ( Scheme 1 ).
Human serum albumin (HSA), one of major proteins in the human blood circulation system, takes part in many physiological functions. Its proportion in plasma proteins is about 55% [ 41 ]. HSA has a remarkable capacity for reversible binding with drugs, which helps in improving their solubility, protect their oxidation in plasma, and decrease toxicity. Because of these exceptional abilities, HSA is one of the key targets to predict the pharmacokinetic profile for development of a potential therapeutic agent [ 42 ]. From the structural point of view, HSA is a non-glycosylated heart-shaped single chain polypeptide with molecular weight of 66.5 kDa (80 × 80 × 30 Å in size), being divided into three analogous domains (I, II, and III) having amino acid residues of 1–195, 196–383, and 384–585, respectively [ 43 ]. Each domain comprises two subdomains (A and B) and all domains are balanced through a bridge of 17-disulfide bonding. HSA has two main hydrophobic cavities for ligand binding: subdomain IIA (site I) and subdomain IIIA (site II) [ 44 ]. The main fluorophore of HSA is the tryptophan (Trp-214) residue, which is located in a large hydrophobic cavity in subdomain IIA (site I) [ 45 ]. Therefore, the intrinsic fluorescence intensity of Trp-214 residue is a common phenomenon used to investigate the interaction of ligands with HSA [ 46 , 47 , 48 ].
Based on the importance of 1,3,4-thiadiazolium salts in the medicinal chemistry, the present study reports the synthesis and characterization of four heterocyclic compounds, namely (
E
)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives, where R = CH
3
(
5a
), OCH
3
(
5b
), Cl (
5c
), and Br (
5d
). Each compound was assayed against C91 and MT2 cell lines infected with HTLV-1 and a Jurkat cell line (lymphocytic leukemia). In addition, it was also investigated how the mesoionic compounds
5a
–
d
induce apoptotic cell death, as well as their preliminary pharmacokinetic profile via affinity for HSA by multiple spectroscopic techniques combined with molecular docking. It is important to highlight that the synthesis of the mesoionic compounds
5a
,
5b
, and
5d
have already been described [
29
] (
5c
is a new synthetic mesoionic), however, this work reports for the first time the evaluation of
5a
–
d
as promising chemotherapy agents.
2. Results and Discussion
2.1. Synthesis
The compounds ( E )-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives ( 5a–d ) were prepared following Scheme 1 as previously reported [ 23 ] using microwave irradiation as the power supply. Initially, the aryl-thioureas were prepared from substituted anilines and ammonium isothiocyanate in the presence of concentrated HCl and water as solvent. The aryl-thioureas obtained ( 2a–d ) were submitted under 8 h of reflux in chlorobenzene as solvent, and the aryl-isothiocyanates ( 3a–d ) were used immediately in the subsequent step as crude products [ 49 ] to obtain the N -aryl-2-phenyl-hydrazinecarbothioamides ( 4a–d ). The intermediates 4a–d were prepared in solvent free conditions using a grinding method with aryl-isothiocyanates and phenyl-hydrazine at room temperature for 2 min. These compounds were obtained in quantitative yields and high purity, and their structures were confirmed by FT-IR spectroscopy and NMR 1 H and 13 C spectrometry, in accordance with previous publications on mesoionic compounds [ 29 , 50 ].
The (
E
)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (
5a–d
) were prepared by reaction of cinnamaldehyde and the
N
-aryl-2-phenyl-hydrazinecarbothioamides (
4a–d
) in equimolar amounts, thionyl chloride (excess of three times), and enough drops of 1,4-dioxane to homogenize the reagents. The mixture was submitted to microwave irradiation for 5 min and then poured into 1,4-dioxane. After standing for 24 h, the products were isolated and washed thoroughly with ice water and obtained in good yields (96% to 98%). The compounds
5a–d
were characterized by FT-IR,
1
H, and
13
C-NMR spectroscopies (
Figures S1–S4 in the Supplementary Material
), and their purity was confirmed by elemental analysis. The infrared spectra showed the characteristic absorptions in the range of 3431–3433 cm
−1
assigned to C=N, 2717 cm
−1
and 2746 cm
−1
to
5b
and
5a
, respectively, and 2586 cm
−1
and 2663 cm
−1
to
5c
and
5d
, respectively, attributed to C=NH
+
(stretching), according to other compounds of this class [
23
]. In the
1
H-NMR spectra the chemical shift attributed to the exocyclic amino hydrogen was in the range of 12.58 to 12.86 ppm with a singlet feature. The signals of H-6 were assigned at 7.04–7.24 ppm, and of H-7 at 8.02–8.10 ppm, as doublets (
J
= 14 Hz). In the
13
C-NMR spectra the characteristic signals of heterocyclic carbons were attributed to C-2 at 128.5 ppm (
5a
), 156.0 ppm (
5b
), 158.8 ppm (
5c
), and 158.9 ppm (
5d
), and to C-5 159.8 ppm (
5a
), 161.3 ppm (
5b
), 163.2 ppm (
5c
), and 163.4 ppm (
5d
). The carbon atoms C-6 and C-7 showed signals coherent with the transmission of the electronic effect of substituents in the
N
-X-phenylamine group linked to the heterocyclic ring, that is, the C-6 had more shielding in 111.5 ppm to 115.5 ppm and C-7 had more deshielding in 142.8 ppm to 148.2 ppm. The other carbon atoms appeared with the chemical shifts as expected according to the literature [
15
].
2.2. Biological Activity
The anti-leukemia activity of mesoionic compounds has been investigated since the 1970s [ 51 ], with their anti-leukemia effects having been described both in vivo and in vitro [ 51 , 52 , 53 ]. However, the cytotoxicity effect of this class of compounds on cells infected with HTLV-1 has not yet been evaluated. In the present work, it was demonstrated for the first time that the cell lines (MT2 and C91/PL) infected with HTLV-1 and treated with mesoionic compounds 5a–d significantly reduced cell viability ( Figure 2 and Figure 3 ). In addition, 5a–d also exhibited a cytotoxicity effect against Jurkat cells, an uninfected cell line in adult T leukemia ( Figure 2 ). The results obtained demonstrated that treatment with these mesoionic compounds reduced cell viability in a dose-dependent manner ( Figure 2 , Figure 3 and Figure 4 ). From Figure 5 it can be seen that 5b was able to induce necrosis in Jurkat cells (75.37 ± 3.63%), MT2 (35.34 ± 7.80%), and C91/PL (33.75 ± 1.65%) after 24 h of cell treatment.
Each cell line showed different sensitivity to the 5a–d mesoionic compounds, as evidenced by the IC 50 values shown in Table 1 . Interestingly, our results indicated that the values obtained for IC 50 were less than 10 µM. Furthermore, these results clearly show that compound 5a has the highest cytotoxicity value against HTLV-1 infected cell lines, i.e., MT2 or C91/PL, with IC 50 values of 1.51 and 2.82 µM, respectively. On the other hand, compound 5b showed significant inhibitory activity in Jurkat cells with an IC 50 value of 1.74 µM. It is important to note that the mesoionic compounds with greater activity, 5a (R = CH 3 ) and 5b (R = OCH 3 ), have a substituent group displaying an electron donor property, which suggests that this characteristic may be related to the results of cytotoxicity. In addition, values of log Po/w of 3.74 and 3.35 for 5a (R = CH 3 ) and 5b (R = OCH 3 ), respectively, indicate that these compounds are less hydrophobic than compounds 5c (R = Cl) and 5d (R = Br), for which log Po/w are 3.97 and 4.10, respectively. In the literature, several authors have suggested that reduced hydrophobicity can be associated with the efficiency of cytotoxicity, as this property is directly related to the binding to cellular targets [ 54 , 55 ]. Besides, retrovirus infection alters lipid synthesis, leading to an alteration in the cell membrane [ 56 ]. The HTLV-1 genome has a pX region, which encodes viral accessory genes, such as tax. The transcription of the tax gene is a Tax protein responsible for modifying or decreasing the modulation of many cellular genes, interfering with cell proliferation, apoptosis, secretion, and others [ 57 ]. Thus, the difference observed between the effect of cytotoxicity in cells infected with HTLV-1 and Jurkat cells may be directly related to viral modulation in the synthesis of lipids and proteins.
It is known that mesoionic compounds can interact with the DNA molecule and their biological activity can be related with this interaction [
32
,
58
]. Based on this, the interaction of compounds
5a–d
with DNA was investigated using spectroscopic analysis. The fluorescence emission spectra of pure DNA and the corresponding DNA complex with the mesoionic compounds under study are shown in
Figure 6
for
5b,
whereas
Figure S5 in the Supplementary Material
shows the DNA assays for
5a
,
5c
, and
5d
. The experimental results suggested that only compound
5b
can interact with the DNA strands; however, the mechanism of this interaction remains unknown, and more tests are needed to indicate its nature.
Some anticancer drugs approved by the FDA (US Agency for Food and Drug Administration) can induce cytotoxicity effects through reactive oxygen species (ROS) modulation, including antileukemia drugs, such as L-asparaginase,
N
-benzyloxycarbonyl-IIe-Glu-(
O
-t-butyl)-Ala-leucinal, anthracyclines (doxorubicin and daunorubicin), arsenic trioxide, and 2-methoxyestradiol. These drugs diminished the reduced glutathione intracellular levels and induced mitochondrial dysfunction or ROS generation by other pathways [
59
]. Thus, the capacity of mesoionic compounds
5a–d
to produce ROS was evaluated. Using the fluorescent dye dihydrorhodamine 123 (DHR), it was observed that a short treatment (30 min) of the cells (MT2 and Jurkat) with these compounds induced an increase in ROS levels, indicating that the oxidative stress can be a mechanism of action of these substances (
Figure 7
). These mesoionic compounds can also induce nitric oxide production, which inhibits cellular proliferation and promotes cytostatic action [
53
,
60
]. Overall, our results suggest that the mesoionic compounds
5a–d
constitute a promising class of new anticancer drugs.
2.3. Interaction with HSA
2.3.1. Experimental Binding Ability
The steady-state fluorescence spectra for HSA (1.00 × 10
−5
M) in the absence and presence of successive additions of mesoionic compounds
5a–d
(concentration up to 1.32 × 10
−5
M) are shown in
Figure S6 in the Supplementary Material
. In the presence of these compounds, it is possible to observe the quenching of the fluorescence emission of the protein (λ
em
= 340 nm), which indicates the existence of a possible interaction between the Trp-214 residue, responsible for the emission of albumin, and
5a–d
[
50
,
61
]. The addition of any of these mesoionic compounds to the HSA solution did not result in a shift in the maximum fluorescence emission, indicating that the HSA:mesoionic compound interaction does not disturb the microenvironment surrounding the Trp-214 residue [
46
].
The steady-state fluorescence quenching of a protein can be classified as static and/or dynamic [ 62 ]. A Stern–Volmer analysis of the HSA quenching process for 5a–d ( Figure S7 in the Supplementary Material ) shows values for the bimolecular quenching rate constant of the order of k q ~ 10 13 M −1 s −1 ( Table 2 ). These values are about four orders of magnitude higher than for the water limiting diffusion rate constant ( k diff ~ 7.40 × 10 9 M −1 s −1 , at 298K [ 63 ]). This is an indication that the fluorescence quenching mechanism must be static, involving an association in the ground-state between albumin and mesoionic compounds 5a–d [ 50 ]. In addition, the values for the Stern–Volmer constant ( K SV ) at different temperatures are similar ( Table 2 ), suggesting that 5a–d show similar binding capacity towards HSA.
To further confirm which mechanism is operating in the fluorescence quenching of HSA by mesoionic compounds 5a–d , time-resolved fluorescence measurements were performed. The fluorescence decay for HSA is bi-exponential, with lifetimes of τ 1 = 1.73 ± 0.16 ns and τ 2 = 5.54 ± 0.12 ns ( Figure S8, Supplementary Material ), which is in accordance with literature data [ 64 , 65 ]. Both fluorescence lifetimes are independent of the addition of any of the mesoionic compounds 5a–d (1.35 × 10 −5 M concentration) ( Table 3 ), which is a clear indication of a static process as the main mechanism fluorescence quenching in the interaction between HSA and the mesoionic compounds under study [ 47 ]. Similar results have been reported previously for the interaction between HSA and piperonal mesoionic derivatives [ 66 ].
The modified Stern–Volmer binding constant ( K a ) is related to the protein–ligand interaction, and its magnitude is important for understanding the distribution of a drug in the human bloodstream [ 47 , 61 ]. Moderate values for K a , in the order of 10 4 M −1 , at 296, 303, and 310 K, were obtained for the interaction HSA: 5a – d ( Figure S9 in the Supplementary Material and Table 2 ), indicating the viability of the absorption and distribution of these mesoionic compounds to various tissues [ 46 , 48 , 61 ].
The thermodynamic parameters of enthalpy (
ΔH
°) and entropy (
ΔS
°) variation for the interaction between HSA and
5a
–
d
were calculated according to the van’t Hoff approximation (
Figure S10, Supplementary Material
, and
Table 3
). The positive values of
ΔS
° for all investigated compounds are related to hydrophobic forces, as a consequence of an interaction between the non-polar amino acid residues and the non-polar portions of the ligand structure. Furthermore, the same hydrophobic effect may also be related to the fact that both the water molecules responsible for the solvation of the ligand and those that occupied the protein cavity are expelled out of the cavity during the HSA:ligand interaction process. In this case, these water molecules present higher increased degrees of freedom and, therefore, an increase in the system disorder (
ΔS
° > 0) [
67
,
68
].
The ΔH ° < 0 values for HSA: 5a and HSA: 5b indicate a significant contribution of hydrogen bonding, whereas for HSA: 5c and HSA: 5d , ΔH ° > 0 and, in this case, the presence of electrostatic interaction forces can be suggested [ 67 , 69 ].
The negative sign for Gibb’s free energy values ( ΔG ° < 0, Table 2 ) for HSA:mesoionic compounds is a clear indication of the spontaneity of the binding process. A general analysis of the thermodynamic parameters leads us to conclude that the interaction between HSA: 5a and HSA: 5b is enthalpically and entropically driven, while for HSA: 5c and HSA: 5d it is only entropically driven [ 69 ].
2.3.2. Perturbation on the Surface and Secondary Structure of Albumin
Circular dichroism spectroscopy (CD) is a sensitive technique used to investigate the secondary structure of proteins after binding to a ligand [ 69 ]. The CD spectrum for HSA exhibits two negative peaks, at 208 nm and 220 nm, characteristic of the typical α-helix structure of proteins. These two peaks correspond to the π–π * and n–π * transitions, respectively [ 70 ]. After adding a solution of the mesoionic compounds 5a–d (1.32 × 10 −5 M) to the HSA solution (1.00 × 10 −5 M), a small decrease in intensity at 208 nm and 222 nm was clearly observed ( Figure S11, Supplementary Material ), indicating a slight change in the secondary structure of the HSA [ 50 ]. The variation in the secondary structure of albumin is about 5.0% in all cases, which is evidence that the 5a–d interaction can occur with a very slight disturbance in the secondary structure of albumin ( Table 4 ) [ 71 ]. The same trend has been reported previously for the interaction between HSA and piperonal mesoionic derivatives [ 66 ].
The zeta potential (ZP, ζ) is a useful and feasible parameter for characterizing the surface charge properties of proteins. Changes in the ZP for a protein may imply conformational changes in its structure, modifications on the surface, and/or unfolding or denaturation processes after its binding to the ligand [
72
].
Table 4
shows the ZP value for HSA without and in the presence of
5a–d
. The ZP values for HSA did not change significantly with the addition of these mesoionic compounds, with this change being within the standard error of the measurement. These results indicated that there is no significant structural change on the surface of the protein after its interaction with
5a–d
[
73
] and are fully in accordance with the results for circular dichroism described above.
2.4. Molecular Docking Evaluation
Molecular docking calculations have become an increasingly important tool for drug discovery, since they can offer a molecular level explanation on the binding ability of potential compounds towards biomacromolecules, as well as evaluate physical-chemical properties related to their biological activity [ 74 ]. In this sense, molecular docking calculations were carried out for both DNA and HSA binding ability to evaluate the main binding region and intermolecular forces related between the mesoionic compounds 5a–d and nucleobases/amino acid residues.
As previously described in
Section 2.2
, it is known that some mesoionic compounds are able to interact with DNA. However, the experimental data indicated that only
5b
could interact with DNA strands. Molecular docking runs for the interaction DNA:
5a–d
offered higher molecular docking score values for the minor groove than for the major groove of DNA strands, i.e., 84.8 and 10.6, respectively for DNA:
5b
, suggesting minor groove as the main possible region of DNA to interact with this mesoionic compound. Differently from the preliminary experimental data, molecular docking results suggested that the mesoionic compounds
5a–d
could interact with DNA, corroborating with the statement that more tests are needed to evaluate the biological mechanism.
Figure 8
shows the best docking pose for DNA:
5a–d
via top view representation of the minor groove, reinforcing that the mesoionic compounds can interact with DNA strands mainly via van der Waals interaction (interaction forces were not discussed in the present work).
The HSA structure is composed of three domains (I, II, and III), and each domain is divided into two subdomains (A and B). Pioneering studies by Sudlow using the fluorescent probes displacement method showed the presence of two main specific drug binding sites: Sudlow’s site I, also named the warfarin binding site (subdomain IIA—where Trp-214 residue can be found), and Sudlow’s site II, also named the ibuprofen binding site (subdomain IIIA) [ 75 , 76 ]. Compounds that strongly bind in the Sudlow’s site I are generally bulky heterocyclic molecules with a positive charge localized in its center. On the other hand, Sudlow’s site II is a largely non-polar cavity with a single dominant polar patch near the pocket entrance. This arrangement of polar and non-polar features is consistent with the typical structures of site II drugs, such as aromatic carboxylic acids with a negatively charged acid group at one end of the molecule, separated by a hydrophobic center [ 77 ]. Overall, Sudlow’s site II was proposed to be a smaller or narrower site than Sudlow’s site I, because large molecules rarely bind to site II [ 78 ]. Recently, subdomain IB, known as site III, was also characterized as a potential binding pocket for different ligands to the albumin structure [ 47 ].
Table 5
shows the docking score values for each of the mesoionic compounds
5a–d
to the three main binding sites of HSA. Since the highest docking score value was obtained for site I, molecular docking calculations suggested subdomain IIA, where Trp-214 can be found, as the main binding pocket for the compounds under study. From previous HSA fluorescence quenching studies and the chemical characteristics of each of the mesoionic compounds
5a–d,
it was expected that they should be located next to the amino acid Trp-214 residue in the subdomain IIA.
Figure 9
shows the best molecular docking pose for the interaction HSA:
5a–d
. From this Figure, it can be observed that the mesoionic compounds
5a
/
5b
and
5c
/
5d
present a similar docking pose, in accordance with the very close experimental binding parameters obtained from the fluorescence quenching experiments (see
Table 2
in
Section 2.3.1
). In addition, molecular docking results also suggested van der Waals and hydrogen bonding as the main intermolecular forces involved in the binding process, fully in accordance with the experimental data described using the van’t Hoff approximation.
3. Materials and Methods
3.1. General Information
Nuclear magnetic resonance (
1
H- and DEPTQ
13
C-NMR) spectra were recorded on a Bruker Avance III Ultrashield Plus spectrometer (
1
H, 500 MHz; DEPTQ, 125 MHz, Bruker, Rheinstetten, Germany) using DMSO-
d
6
as the solvent and tetramethylsilane (TMS) as the internal standard. Fourier-transformed infrared spectra (FT-IR) (ATR) were recorded on a Bruker Vertex 70 spectrophotometer. The elemental analyses were carried out with a Carlo Erba EA-1110 CHNS-O Elemental Analyzer (Elemental Microanalysis, New Jersey, NJ, USA). The melting points were determined on a Gehaka (PF1500 Farma, São Paulo, SP, Brazil) capillary melting point apparatus and uncorrected. The microwave-assisted organic reactions were performed in a CEM Discovery System reactor (CEM Corporation, North Carolina, NC, USA).
Human acute lymphocytic leukemia (Jurkat cells) were generously provided by Professor Ana Giannini from Universidade Federal do Rio de Janeiro (UFRJ, RJ, Brazil) and HTLV-1 transformed cell lines (MT-2 and C91/Pl) were a gift from the Fundação Oswaldo Cruz, RJ, Brazil. All cells were used and cultured in Roswell Park Memorial Institute (RPMI)-1640 medium supplemented with 10% fetal bovine solution (FBS) (Gibco/Thermo Fisher), 60 mg/mL penicillin and 100 mg/mL streptomycin (LGC, Brazil). They were incubated at 37 °C in a humidified atmosphere of air and 5% CO
2
. The cell line was passaged twice a week.
3.2. General Procedure for the Synthesis of Aryl-thioureas ( 2a – 2d )
The different aryl anilines (23.5 mmol) and ammonium isothiocyanate (23.5 mmol) were mixed in the presence of concentrated hydrochloric acid (23.5 mmol) and 3.17 mL of water as solvent. The reaction mixture was kept under reflux for 6 h. The solid product was obtained by filtration and washed with ice-cold water. All thioureas were identified by the comparison of analytical data (FT-IR, NMR data, and melting points) with literature reports [ 49 ].
3.3. General Procedure for the Synthesis of Aryl-isothiocyanates ( 3a – d )
The aryl-thioureas (7 mmol) was submitted under 8 h of reflux in chlorobenzene as solvent. The solution was then distilled under reduced pressure for chlorobenzene removal. The aryl-isothiocyanates ( 3a–d ) were used immediately in the subsequent step as crude products [ 49 ].
3.4. General Procedure for the Preparation of Hydrazinecarbothiamides ( 4a – d )
The phenylhydrazine (0.74 mmol) and aryl-isothiocyanate (0.74 mmol) were mixed at room temperature for 2 min in a porcelain mortar and pestle in the absence of any organic solvent. The formed solid was monitored by TLC and was obtained in high purity without recrystallization. All hydrazinecarbothiamides were identified by the comparison of analytical data (FT-IR, NMR data, and melting points) with literature reports [ 50 ].
3.5. General Procedure for the Preparation of Mesoionic Chlorides ( 5a – d )
The mixture containing the
N
-(4-R-phenyl)-2-phenylhydrazinecarbothioamide (0.38 mmol) and cinnamaldehyde (0.38 mmol) in the presence of SOCl
2
and a few drops of 1,4-dioxane was submitted to microwave irradiation for 5 min at 100 W. After this continuous time, the mixture was added to 1,4-dioxane and left to stand overnight at room temperature. The solid obtained was filtered and washed with ice-cold 1,4-dioxane and exhaustively with water. The solid formed was obtained in high purity without recrystallization. All mesoionic chlorides (
Figure 10
) were identified by melting point, FT-IR, NMR data, and elemental analyses [
29
].
( E )-3-Phenyl-5-(4′-methylphenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride ( 5a ).
Orange solid; yield 98%; mp 287–286 °C; FT-IR (ATR, υ cm
−1
): 3431 (N-H), 3039 (C-H), 2922 (C-H), 2746 (C=NH
+
), 1614 (C=C), 1564, 1452 (C=C), 1523 (C=N), 1340 (C-S), 1114 (C-H), 823, 763, 688 (C-H);
1
H-NMR (500 MHz, DMSO-
d
6
) δ 12.58 (s, 1H, N-H), 8.25 (d,
J
= 7.9 Hz, 2H, H-3′’, H-5′’), 8.10 (d,
J
= 15.9 Hz, 1H, H-7), 8.01 (d,
J
= 9.5 Hz, 2H, H-2′’, H-6′’), 7.83–7.75 (m, 6H, H-2′, H-3′, H-4′, H-5′, H-6′, H-4′’), 7.47 (d,
J
= 7.9 Hz, 2H, H-3′’’, H-5′’’), 7.25 (d,
J
= 15.9 Hz, 1H, H-6), 7.22 (d,
J
= 6.3 Hz, 2H, H-2′’’, H-6′’’), 2.27 (s, 3H, CH
3
);
13
C-NMR (125 MHz, DMSO-
d
6
) δ 159.8 (C-2), 148.5 (C-5), 144.5 (C-7), 139.9 (C-1′’’), 136.9 (C-1′), 133.6 (C-1′’), 131.8 (C-4′’), 130.2 (C-2′, C-6′), 130.1 (C-3′, C-5′), 129.9 (C-3′’, C-5′’), 126.1 (C-4′’’), 125.2 (C-2′’, C-6′’), 124.1 (C-3′’’, C-5′’’), 118.8 (C-2′’’, C-6′’’), 115.5 (C-6), 20.5 (CH
3
). Elemental analysis found: C, 67.98%; H, 4.92%; N, 10.41%. Calculated for C
23
H
20
ClN
3
S (MW 405.94): C, 68.05%; H, 4.97%; N, 10.35%.
( E )-3-Phenyl-5-(4′-methoxyphenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride ( 5b ).
Red solid; yield 96%; mp 292–291 °C; FT-IR (ATR, υ cm
−1
): 3431 (N-H), 3043 (C-H), 2929 (C-H), 2717 (C=NH
+
), 1622 (C=C), 1595, 1575, 1454 (C=C), 1512 (C=N), 1342 (C-S), 1244 (C-O), 1109 (OCH
3
), 954 (C-H), 829, 773, 694 (C-H);
1
H-NMR (500 MHz, DMSO-
d
6
) δ 12.73 (s, 1H, N-H), 8.24 (d,
J
= 9.7 Hz, 2H, H-3′’, H-5′’), 8.09 (d,
J
= 16.0 Hz, 1H, H-7), 8.00 (d,
J
= 9.7 Hz, 2H, H-2′’, H-6′’), 7.83-7.75 (m, 6H, H-2′, H-3′, H-4′, H-5′, H-6′, H-4′’), 7.52 (d,
J
= 9.7 Hz, 2H, H-2′’’, H-6′’’), 7.24 (d,
J
= 16.0 Hz, 1H, H-6), 6.99 (d,
J
= 9.7 Hz, 2H, H-3′’’, H-5′’’), 3.73 (s, 3H, OCH
3
);
13
C-NMR (125 MHz, DMSO-
d
6
) δ 161.3 (C-2), 156.0 (C-5), 148.5 (C-4′’’), 144.2 (C-7), 140.0 (C-1′), 137.0 (C-1′’), 131.8 (C-4′’), 131.7 (C-1′’’), 130.2 (C-2′, C-6′), 130.0 (C-3′’, C-5′’), 126.1 (C-2′’, C-6′’), 124.1 (C-2′’’, C-6′’’), 120.5 (C-4′), 115.5 (C-6), 114.6 (C-3′’’, C-5′’’), 55.3 (OCH
3
). Elemental analysis found: C, 65.05%; H, 4.58%; N, 10.04%. Calculated for C
23
H
20
ClN
3
OS (MW 421.94): C, 65.47%; H, 4.78%; N, 9.96%.
( E )-3-Phenyl-5-(4′-chlorophenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride ( 5c ).
Orange solid; yield 97%; mp 284–282 °C; FT-IR (ATR, υ cm
−1
): 3433 (N-H); 2922 (C-H); 2586 (C=NH
+
); 1620 (C=C); 1562, 1492 (C=C); 1537 (C=N); 1249 (C-S); 1097 (C-H); 1033 (C-Cl); 817 (C-H); 761e 686 (C-H).
1
H-NMR (500 MHz, DMSO-
d
6
) δ 12.82 (s, 1H, N-H), 8.02 (d,
J
= 19.7 Hz, 1H, H-7), 7.84 (dd,
J
= 3.9 Hz, 2H, H-3′’, H-5′’), 7.75 ( m, 5H, H-2′’, H-6′’, H-4′’, H-3′, H-5′), 7.61 (d,
J
= 10.5 Hz, 2H, H-2′, H-6′), 7.47 (m, 5H, H-2′’’, H-6′’’, H-3′’’, H-5′’’, H-4′), 7.04 (d,
J
= 19.7 Hz, 1H, H-6);
13
C-NMR (125 MHz, DMSO-
d
6
) δ 163.2 (C-2), 158.8 (C-5), 148.2 (C-7), 137.4 (C-1′’’), 136.9 (C-1′), 133.8 (C-1′’), 132.0 (C-4′’), 131.7 (C-4′), 130.2 (C-3′, C-5′), 129.4 (C-3′’’, C-5′’’), 129.1 (C-2′’’, C-6′’’), 129.2 (C-2′, C-6′), 127.7 (C-4′’’), 126.2 (C-2′’, C-6′’), 120.1 (C-3′’, C-5′’), 111.4 (C-6). Elemental analysis found: C, 61.84%; H, 3.97%; N, 9.98%. Calculated for C
22
H
17
Cl
2
N
3
S (MW 426.36): C, 61.98%; H, 4.02%; N, 9.86%.
( E )-3-Phenyl-5-(4′-bromophenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride ( 5d ).
Orange solid; yield 96%; mp 298–296 °C; FT-IR (ATR, υ cm
−1
): 3432 (N-H); 3037 (C-H); 2663 (C=NH
+
); 1604 (C=C); 1560, 1484 e 1442 (C=C); 1540 (C=N); 1309 (C-S); 1114 (C-H); 948, 669 (C-Br); 827 (C-H); 755, 690 (C-H).
1
H-NMR (500 MHz, DMSO-
d
6
) δ 12.62 (s, 1H, N-H), 8.03 (d,
J
= 19.7 Hz, 1H, H-7), 7.83 (dd,
J
= 4.5 Hz, 2H, H-3′’, H-5′’), 7.75 (m, 5H, H-2′’, H-6′’, H-4′’, H-3′, H-5′), 7.60 (d,
J
= 12.1 Hz, 2H, H-2′, H-6′), 7.54 (d,
J
= 12.1 Hz, 2H, H-3′’’, H-5′’’), 7.47 (m, 5H, H-2′’’, H-6′’’, H-4′), 7.04 (d,
J
= 19.7 Hz, 1H, H-6);
13
C-NMR (125 MHz, DMSO-
d
6
) δ 163.4 (C-2), 158.9 (C-5), 148.2 (C-7), 137.9 (C-1′’’), 136.9 (C-1′), 133.8 (C-1′’), 132.3 (C-3′’’, C-5′’’), 132.0 (C-4′’), 131.8 (C-4′), 130.2 (C-3′, C-5′), 129.2 (C-2′’’, C-6′’’), 129.2 (C-2′, C-6′), 126.2 (C-2′’, C-6′’), 120.5 (C-3′’, C-5′’), 115.8 (C-4′’’), 111.5 (C-6). Elemental analysis found: C, 56.08%; H, 3.57%; N, 9.02%. Calculated for C
22
H
17
BrClN
3
S (MW 470.81): C, 56.12%; H, 3.64%; N, 8.92%.
3.6. Biological Assays
3.6.1. Cell Viability Assays
The 1 × 10 5 cells/mL were incubated with or without compounds 5a , 5b , 5c, 5d or DMSO (Sigma-Aldrich/Merck, St. Louis, MO, USA) at 37 °C in humidified atmosphere with a 5% CO 2 . After 72 h, the cellular viability was assessed using 5 mg/mL of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma-Aldrich/Merck). Cells were incubated for 3 h, centrifuged, and formazan crystal was dissolved with DMSO. Plates were read on a Paradigma ® spectrofluorometer (Molecular Devices, San Jose, CA, USA) at a 490 nm wavelength. Cell death was also evaluated using Propidium Iodide (Biolegend) exclusion after a 24 h culture under the same conditions described above. The fluorescence was examined by FACSCalibus flow cytometry (BD) and 10,000 events were acquired for the experimental data. Analysis was accomplished using Summit V4.0 or FlowJo software (Becton, Dickingson and Company, Santa Barbara, CA, USA).
3.6.2. Reactive Oxygen Species (ROS) Detection
The 1 × 10 5 cells/mL were incubated with or without compounds 5a–d (12.5 µM) or DMSO for 30 min at 37 °C in a humidified atmosphere with a 5% CO 2 . Cells were washed with phosphate buffer (Sigma-Aldrich/Merck) and incubated with 50 µM of Dihydrorhodamine 123 (DHR; Sigma-Aldrich/Merck). After 15 min at 37 °C, cells were washed and the fluorescence was examined using FACSCalibus flow cytometry. A total of 10,000 events was acquired for the experimental data, and a gate based on forward and side scatter parameters was made to analyze only viable cells. Analysis was accomplished using Summit V4.0 or FlowJo software.
3.6.3. DNA Interaction Assay
Fluorescence emission spectroscopic titration experiments of DNA were conducted in the absence and presence of a constant concentration of the mesoionic compounds 5a–d . The assay was performed using 2 and 10 ng/mL of salmon DNA (Sigma-Aldrich/Merck) at 37 °C. After that, the fluorescence emission was recorded after 1 h of DNA incubation with or without compounds 5a–d (25 µM) or DMSO, over a wavelength range of 300 to 600 nm in a Tris-acetate-EDTA buffer (Promega) at room temperature. The slit widths for excitation and emission were set to 5.0 nm. The fluorescence was examined using a F4500 fluorometer (Hitachi, New Jersey, NJ, USA).
3.6.4. Statistical Analysis
Statistical analysis was performed by one-way analysis of variance (ANOVA) and means were compared using a Tukey post-test. The IC50 values were obtained using nonlinear regression. Data were analyzed using GraphPad Prism-5 software (GraphPad software, San Diego, CA, USA), and p ≤ 0.05 was considered statistically significant.
3.7. Spectroscopic HSA Binding Studies
The steady-state fluorescence spectra were measured in the 290–450 nm range, at 296, 303, and 310 K, with the excitation wavelength at λ = 295 nm. To a 3.0 mL solution containing an appropriate concentration of HSA (1.00 × 10
−5
M), successive aliquots from a stock solution of each mesoionic under study (1.00 × 10
The binding properties of each ligand toward HSA—Stern–Volmer quenching constant (
K SV
), bimolecular quenching rate constant (
k q
), modified Stern–Volmer binding constant (
K a
), enthalpy change (
ΔH
°), entropy change (
ΔS
°), and Gibbs’ free energy change (
ΔG
°)—were calculated from the steady-state fluorescence quenching data according to Equations (2)–(5) [
47
,
48
]:
F
0
F
=
1
+
k
q
τ
0
[
Q
]
=
1
+
K
S
V
(2)
(3)
=
−
Δ
H
0
R
T
+
Δ
S
0
R
(4)
Δ
G
0
=
Δ
H
0
−
T
Δ
S
0
(5)
where
F 0
and
F
are the steady-state fluorescence intensities of HSA in the absence and presence of mesoionics, respectively. [
Q
] and
τ 0
are the ligand concentration and fluorescence lifetime, respectively, of the fluorophore in the absence of quencher (5.54 × 10
−9
s—experimental data, see
Section 2.3.1
). T,
ƒ
, and
R
are the temperature (296, 303, and 310 K), fraction of the initial fluorescence intensity that corresponds to fluorophore that is accessible to the quencher (
f
≈ 1.0), and gas constant (8.3145 J/mol.K), respectively.
The time-resolved fluorescence decay of a 3.0 mL solution of HSA (1.00 × 10 −5 M, in phosphate buffer solution-PBS) was measured in the absence and presence of the maximum concentration of each mesoionic used in the steady-state fluorescence studies (1.32 × 10 −5 M) at room temperature (ca 298 K).
The CD spectra were recorded in the 200–250 nm range at 310 K for free serum albumin (1.00 × 10
−6
M) and for HSA with the higher concentration of each mesoionic used in the steady-state fluorescence studies (1.32 × 10
−5
M). Each spectrum was taken on the average of three scans. The obtained data were further converted into mean residue ellipticity (MRE) according to Equation (6) [
50
]:
M
R
E
=
θ
(
10
.
n
.
l
.
C
p
)
(6)
where
θ
is the observed ellipticity (mdeg);
n
is the number of amino acid residues (585 to HSA) [
45
],
l
is the length of the optical cuvette (1.0 cm), and
C p
is the molar concentration of HSA (1.00 × 10
−6
M). The
5a–d
induced helical content perturbation at 208 and 222 nm were calculated using Equation (7) [
46
]:
(
A
)
α
−
h
(7)
where
MRE
208
and
MRE
222
are the significant molar residual ellipticities (deg.cm
2
/dmol) at 208 nm and 222 nm, respectively.
3.8. Zeta Potential Measurements for HSA Surface Perturbation
All zeta potential (ZP) measurements were performed with 10 runs at 298 K and results were reported in terms of ZP ± SD. The ZP was measured for the HSA solution (1.0 × 10 −5 M in PBS solution) without and in the presence of the mesoionic compounds at the maximum concentration used in the steady-state fluorescence experiments (1.32 × 10 −5 M) at room temperature (ca. 298 K).
3.9. Molecular Docking Procedure for DNA and HSA
The chemical structure for the mesoionic compounds ( 5a–d ) was built and energy-minimized with Density Functional Theory (DFT), with the Becke-3-Lee Yang Parr (B3LYP) method with the standard 6-31G* basis set, available in Spartan’18 software (Wavefunction, Inc., Irvine, CA, USA) [ 79 ]. The crystallographic structures for the DNA and HSA were obtained from the Protein Data Bank (PDB) with access codes 1BNA [ 80 ] and 1N5U [ 45 ], respectively. Molecular docking was performed with GOLD 5.7 software (CCDC) [ 81 ]. Hydrogen atoms were added to the macromolecules according to the data inferred by the GOLD 5.7 software (Cambridge Crystallographic Data Centre, Cambridge, CB2 1EZ, UK) on the ionization and tautomeric states. For DNA, a 10 Å radius spherical cavity around minor and major groove was defined as the binding site for the molecular docking calculations and for has, and a 10 Å radius spherical cavity around subdomains IIA, IIIA, and IB was defined. The scoring function used was “ ChemPLP ”, which is the standard function of GOLD 5.7 software. The figures of the docking poses for the largest docking score value were generated with the PyMOL Delano Scientific LLC program [ 82 ]. For more details, see previous publications [ 46 , 47 , 48 ].
4. Conclusions
The results obtained in this work show new promising chemotherapy agents against MT2 and C92 cell lines infected with HTLV-1, which causes adult T-cell leukemia/lymphoma (ATLL), and in uninfected Jurkat cells with IC 50 values lower the 10 μM. The compounds containing electron donor substituents (R=CH 3 or OCH 3 ) were more active and with lower hydrophobicity. Furthermore, the compounds showed cell death by necrosis and DNA interaction, especially those containing electron donor substituents.
The interaction between HSA and the mesoionic compounds is spontaneous and occurs via a ground-state association (static fluorescence quenching mechanism). The binding is moderate ( K a ~ 10 4 M −1 ), being enthalpically and entropically driven for HSA: 5a and HSA: 5b , while for the other mesoionic compounds, i.e., 5c and 5d , is only entropically driven. The binding does not significantly perturb both the secondary and surface structures of the albumin, and the main binding pocket is site I (subdomain IIA), where Trp-214 residue can be found. Overall, all the mesoionic compounds presented good binding parameters toward serum albumin, indicating feasible biodistribution in the human bloodstream.
Supplementary Materials
The following are available online at https://www.mdpi.com/1420-3049/25/11/2537/s1 , Figures S1–S4: FTIR, 1H-NMR and 13C-NMR spectra for 5a , 5b , 5c , and 5d , respectively. Figure S5: Fluorescence emission spectra for 5a , 5c , and 5d (25 μM) in the presence of 100 ng/mL of DNA. Figure S6: Steady-state fluorescence quenching for HSA without and in the presence of 5a , 5b , 5c , or 5d at 310 K. Figure S7: Stern–Volmer plots for the interaction between HSA and the mesoionic compounds at 296, 303, and 310 K. Figure S8: Time-resolved fluorescence decay for the interaction between HSA and the mesoionic compounds 5a–d in a PBS solution. [HSA] = 1.00 × 10 −5 M and [mesoionic] = 1.32 × 10 −5 M. IRF is the instrument response factor. Figure S9: Modified Stern–Volmer plots for the interaction between HSA and the mesoionic compounds at 296, 303, and 310 K. Figure S10: Van’t Hoff plot for the interaction between HSA and the mesoionic compounds. Figure S11: Circular dichroism spectra for HSA without and in the presence of 5a , 5b , 5c , or 5d at 310 K.
Author Contributions
Conceptualization, A.E., J.E.L., J.C.N-F. and O.A.C.; methodology, D.S.-P., T.S.d.O., R.O.P. and O.A.C.; software, O.A.C.; validation, A.E., J.E.-L. and J.C.N.-F.; formal analysis, A.E., J.E.-L., O.A.C., D.S-P. and J.C.N.-F.; investigation, D.S.-P., T.S.d.O., R.O.P. and O.A.C.; resources, A.E.; data curation, A.E., D.S.-P., J.E.-L., O.A.C. and J.C.N-F.; writing, A.E., D.S.-P., J.E.-L., O.A.C. and J.C.N-F.; funding acquisition, A.E. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the following Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq–Process: 310345/2015-4) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). J.C.N.-F. acknowledges Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO) for a Visiting Professor Fellowship.
Acknowledgments
C.M.R. Sant’Anna from Laboratório de Modelagem Molecular (Institute of Chemistry-UFRRJ) for the molecular docking facilities and N.C.L. Garden (Institute of Chemistry—UFRJ) for the time-resolved and synchronous fluorescence facilities.
Conflicts of Interest
The authors declare no conflict of interest.
References
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018 , 68 , 394–424. [ Google Scholar ] [ PubMed ][ Green Version ]
Pui, C.H.; Robison, L.L.; Look, A.T. Acute lymphoblastic leukaemia. Lancet 2008 , 371 , 1030–1043. [ Google Scholar ] [ PubMed ]
Uchiyama, T.; Yodai, J.; Sagawa, K.; Takatsuki, K.; Uchino, H. Adult T-cell leukemia: Clinical and hematologic features of 16 cases. Blood 1977 , 50 , 481–492. [ Google Scholar ] [ PubMed ]
Gessain, A.; Barin, F.; Vernant, J.C.; Gout, O.; Maurs, L.; Calender, A.; de Thé, G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 1985 , 326 , 407–510. [ Google Scholar ]
Poiesz, B.J.; Ruscetti, F.W.; Gazdar, A.F.; Bunn, P.A.; Mina, J.D.; Gallo, R.C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. USA 1980 , 77 , 7415–7419. [ Google Scholar ] [ CrossRef ][ Green Version ]
Gessain, A.; Cassar, O. Epidemiological aspects and world distribution of HTLV-1 infection. Front. Microbiol. 2012 , 3 , 388–411. [ Google Scholar ] [ CrossRef ][ Green Version ]
Iwanaga, M.; Watanabe, T.; Yamaguchi, K. Adult T-cell leukemia: A review of epidemiological evidence. Front. Microbiol. 2012 , 3 , 322–335. [ Google Scholar ]
Prince, H.E.; York, J.; Golding, J.; Owen, S.M.; Lal, R.B. Spontaneous lymphocyte proliferation in human T-cell lymphotropic virus type-I (HLTV-I) and HTLV-II infection: T-cell subset responses and their relationships to the presence of provirus and viral antigen production. Clin. Diagn. Lab. Immunol. 1994 , 1 , 237–282. [ Google Scholar ] [ CrossRef ]
Boxus, M.; Willems, L. Mechanisms of HTLV-I persistence and transformation. Br. J. Cancer 2009 , 101 , 1497–1501. [ Google Scholar ] [ CrossRef ][ Green Version ]
Shimoyama, M. Diagnostic criteria and classification and clinical subtypes of adult T-cell leukemia-lymphoma. A report from the Lymphoma Study Group. Br. J. Haematol. 1991 , 79 , 428–437. [ Google Scholar ] [ CrossRef ]
Matsuoka, M. Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene 2003 , 22 , 5131–5140. [ Google Scholar ]
Ishitsuka, K.; Tamura, K. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 2014 , 15 , 517–526. [ Google Scholar ]
Mehta-Shah, N.; Ratner, L.; Horwitz, S.M. Adult T-cell leukemia/lymphoma. J. Oncol. Pract. 2017 , 13 , 487–489. [ Google Scholar ] [ CrossRef ]
Tsukasaki, K.; Hermine, O.; Bazarbachi, A.; Ratner, L.; Ramos, J.C.; Harrington, W., Jr.; O’Mahony, D.; Janik, J.E.; Bittencourt, A.L.; Taylor, G.P.; et al. Definition, prognostic factors, treatment and response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus meeting. J. Clin. Oncol. 2009 , 27 , 453–459. [ Google Scholar ]
Yared, J.A.; Kimball, A.S. Optimizing management of patients with adult T cell leukemia-lymphoma. Cancers 2015 , 7 , 2318–2329. [ Google Scholar ] [ CrossRef ]
Marino-Merlo, F.; Mastino, A.; Grelli, S.; Hermine, O.; Bazarbachi, O.; Macchi, B. Future perspectives on drug targeting in adult T cell leukemia-lymphoma. Front. Microbiol. 2018 , 9 , 925–933. [ Google Scholar ] [ CrossRef ]
Hermine, O.; Ramos, J.C.; Tobinai, K. A review of new findings in adult T-cell leukemia-lymphoma: A focus on current and emerging treatment strategies. Adv. Ther. 2018 , 35 , 135–152. [ Google Scholar ] [ CrossRef ][ Green Version ]
Phillips, A.A.; Harewood, J.C.K. Adult T cell Leukemia-lymphoma (ATL): State of the art. Curr. Hematol. Malig. Rep. 2018 , 13 , 300–307. [ Google Scholar ] [ CrossRef ]
Ishida, T.; Takemoto, S.; Suzushima, H.; Uozumi, K.; Yamamoto, K.; Uike, N.; Saburi, Y.; Nosaka, K.; Utsunomiya, A.; Tobinai, K.; et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: A randomized phase II study. Br. J. Haematol. 2015 , 101 , 398–404. [ Google Scholar ] [ CrossRef ]
Cascioferro, S.; Petri, G.L.; Parrino, B.; El Hassouni, B.; Carbone, D.; Arizza, V.; Perricone, U.; Padova, A.; Funel, N.; Peters, G.J.; et al. 3-(6-phenylimidazo [2,1-b][1,3,4-thiadiazol-2-yl]-1H-indole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma. Molecules 2020 , 25 , 329. [ Google Scholar ] [ CrossRef ][ Green Version ]
Faraooqi, S.I.; Arshad, N.; Channar, P.A.; Perveen, F.; Saeed, A.; Larik, F.A.; Javeed, A. Synthesis, theoretical, spectroscopic and electrochemical DNA binding investigations of 1,3,4-thiadiazole derivatives of ibuprofen and ciprofloxacin: Cancer line studies. J. Photochem. Photobiol. B 2018 , 189 , 104–118. [ Google Scholar ] [ CrossRef ]
Brandt, A.P.; Gozzi, G.J.; Pires, A.R.A.; Martinez, G.R.; Canuto, A.V.S.; Echevarria, A.; Di Pietro, A.; Cadena, S.M.S.C. Impairment oxidative phosphorylation increase the toxicity of SYD-1 on hepatocarcinoma cells (HepG2). Chem. Biol. Interact. 2016 , 256 , 154–160. [ Google Scholar ] [ CrossRef ]
Dos Reis, C.M.; Echevarria-Lima, J.; Miranda, A.F.; Echevarria, A. Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity. J. Braz. Chem. Soc. 2011 , 22 , 1505–1510. [ Google Scholar ] [ CrossRef ][ Green Version ]
Soares-Bezerra, R.J.; Leon, L.L.; Echevarria, A.; Reis, C.M.; Gomes-Silva, L.; Agostinho, C.G.; Fernandes, R.A.; Canto-Cavalheiro, M.M.; Genestra, M. In vitro evaluation of 4-phenyl-5-(4′-X-phenyl)-1,3,4-thiadiazolium-2-phenylaminide chlorides and 3-[N-4′-X-phenyl-1,2,3-oxadiazolium-5-olate derivatives on nitric oxide synthase and arginase activity of Leishmania amazonensis. Exp. Parasitol. 2013 , 135 , 50–54. [ Google Scholar ] [ CrossRef ][ Green Version ]
Rodrigues, R.F.; Charret, K.S.; Campos, M.C.; Amaral, V.; Echevarria, A.; Reis, C.M.; Canto-Cavalheiro, M.M.; Leon, L.L. The in vivo activity of 1,3,4-thiadiazolim-2-aminide compounds in the treatment of cutaneous and visceral leishmaniasis. J. Antimicrob. Chemother. 2012 , 65 , 182–190. [ Google Scholar ] [ CrossRef ][ Green Version ]
Ferreira, W.S.; Freire-de-Lima, L.; Saraiva, F.; Alisson-Silva, V.B.; Mendonça-Previato, L.; Previato, J.O.; Echevarria, A.; Lima, M.E.F. Novel 1,3,4-thiadiazolium-2-phenylamine chlorides as trypanocidal agents: Chemical and biological studies. Bioorg. Med. Chem. 2008 , 16 , 2984–2991. [ Google Scholar ] [ CrossRef ]
Kalluraya, B.; Aamir, S.; Shabaraya, A.R. Regioselective reaction: Synthesis, characterization and pharmacological activity of some new Mannich and Schiff bases containing sydnone. Eur. J. Med. Chem. 2012 , 54 , 597–604. [ Google Scholar ] [ CrossRef ]
Ragab, F.A.; Heiba, H.I.; El-Gazzar, M.G.; Abou-Seri, S.M.; El-Sabaagh, W.A.; El-Hazek, R.M. Anti-inflammatory, analgesic and COX-2 inhibitory activity of novel thiadiazoles in irradiated rats. Photochem. Photobiol. 2017 , 166 , 285–300. [ Google Scholar ] [ CrossRef ]
Paiva, R.O.; Kneipp, L.F.; Reis, C.M.; Echevarria, A. Mesoionic compounds with antifungal activity against Fusarium verticillioides. BMC Microbiol. 2015 , 15 , 11–19. [ Google Scholar ] [ CrossRef ][ Green Version ]
Abo-Bakr, A.M.; Hashem, H.E. New 1,3,4-thiadiazole derivatives: Synthesis, characterization and antimicrobial activity. J. Heterocycl. Chem. 2019 , 56 , 1038–1047. [ Google Scholar ] [ CrossRef ]
Ollis, W.D.; Stanforth, S.P.; Ramsden, C.A. Heterocyclic mesomeric betaines. Tetrahedron 1985 , 41 , 2239–2329. [ Google Scholar ] [ CrossRef ]
Gozzi, G.J.; Pires, A.R.A.; Valdameri, G.; Rocha, M.E.M.; Martinez, G.R.; Noleto, G.R.; Acco, A.; Souza, C.E.A.; Echevarria, A.; Reis, C.M.; et al. Selective cytotoxicity of 1,3,4-thiadiazolium mesoionic derivatives on hepatocarcinoma cells (HepG2). PLoS ONE 2015 , 10 , e0130046–e0130053. [ Google Scholar ] [ CrossRef ]
Pires, A.R.A.; Noleto, G.R.; Echevarria, A.; Reis, C.M.; Rocha, M.E.M.; Carnieri, E.G.S.; Martinez, G.R.; Cadena, S.M.S.C. Interaction of 1,3,5-thiadiazolium mesoionic derivatives with mitochondrial membrane and scavenging activity: Involvement of their effects on mitochondrial energy-linked functions. Chem. Biol. Interact. 2011 , 189 , 17–25. [ Google Scholar ] [ CrossRef ]
Mendez-Sanchez, S.C.; Martinez, G.R.; Romão, S.; Echevarria, A.; Silva, E.F.; Rocha, M.E.M.; Noleto, G.R.; Cadena, S.M.S.C.; Oliveira, M.B.M. The inhibition of lipoperoxidation by mesoionic compound MI-D: A relationship with uncoupling effect and scavenging activity. Chem. Biol. Interact. 2009 , 179 , 125–130. [ Google Scholar ] [ CrossRef ]
Romão, S.; Cadena, S.M.S.C.; Amorim, J.C.; Mendez-Sanchez, S.C.; Silva, E.F.; Rocha, M.E.M.; Noleto, G.R.; Carnieri, E.G.S.; Martinez, G.R.; Oliveira, M.B.M. Metabolism of mesoionic compound (MI-D) by mouse liver microsome, detection of its metabolite, in vivo and acute toxicity in mice. J. Biochem. Mol. Toxicol. 2009 , 23 , 394–405. [ Google Scholar ] [ CrossRef ]
Senff-Ribeiro, A.; Echevarria, A.; Silva, E.F.; Veiga, S.S.; Oliveira, M.B.M. Effect of new 1,3,4-thiadiazolium mesoionic compound (MI-D) on B16-F10 murine melanoma. Melanoma Res. 2003 , 13 , 465–471. [ Google Scholar ] [ CrossRef ]
Senff-Ribeiro, A.; Echevarria, A.; Silva, E.F.; Veiga, S.S.; Oliveira, M.B.M. Antimelanoma activity of 1,3,4-thiadiazolium mesoionics: A structure-activity relationship study. Anti-Cancer Drugs 2004 , 15 , 269–275. [ Google Scholar ] [ CrossRef ]
Xiaohe, Z.; Yu, Q.; Hong, Y.; Xiuqing, S.; Rugang, Z. Synthesis, biological evaluation and molecular modeling studies of N-aryl-2-arylthioacetamides as non-nucleoside HIV-1 reverse transcriptase inhibitors. Chem. Biol. Drug Des. 2010 , 76 , 330–339. [ Google Scholar ] [ CrossRef ]
Shafique, M.; Hameed, S.; Naseer, M.M.; Al-Masoudi, N.A. Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity. Mol. Divers. 2018 , 22 , 957–968. [ Google Scholar ] [ CrossRef ]
Buemi, M.R.; Gitto, R.; Ielo, L.; Pannecouque, C.; De Luca, L. Inhibition of HIV-1 RT activity by a new series of 3-(1,3,4-thiadiazol-2-yl)-thiazolidine-4-one derivatives. Bioorg. Med. Chem. 2020 , 28 , 115431. [ Google Scholar ] [ CrossRef ]
Zhang, H.; Deng, H.; Wang, Y. Comprehensive investigations about the binding interaction of acesulfame with human serum albumin. Spectrochim. Acta A 2020 , 237 , 118410. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Singh, I.; Luxami, V.; Paul, K. Spectroscopy and molecular docking approach for investigation on the binding of nocodazole to human serum albumin. Spectrochim. Acta A 2020 , 235 , 118289. [ Google Scholar ]
Almutairi, F.M.; Ajmal, M.R.; Siddiqi, M.K.; Amir, M.; Khan, R.H. Multi-spectroscopic and molecular docking technique study of the azelastine interaction with human serum albumin. J. Mol. Struct. 2020 , 1201 , 127147. [ Google Scholar ] [ CrossRef ]
He, X.M.; Carter, D.C. Atomic structure and chemistry of human serum albumin. Nature 1992 , 358 , 209–215. [ Google Scholar ] [ CrossRef ][ Green Version ]
Wardell, M.; Wang, Z.; Ho, J.X.; Robert, J.; Rucker, F.; Ruble, J.; Carter, D.C. The atomic structure of human methemalbumin at 1.9Å. Biochem. Biophys. Res. Comm. 2002 , 291 , 813–819. [ Google Scholar ] [ CrossRef ]
Chaves, O.A.; Amorim, A.P.O.; Castro, L.H.E.; Sant’Anna, C.M.R.; Oliveira, M.C.C.; Cesarin-Sobrinho, D.; Netto-Ferreira, J.C.; Ferreira, A.B.B. Fluorescence and docking studies of the interaction between human serum albumin and pheophytin. Molecules 2015 , 20 , 19526–19539. [ Google Scholar ] [ CrossRef ][ Green Version ]
Chaves, O.A.; Santos, M.R.L.; Oliveira, M.C.C.; Sant’Anna, C.M.R.; Ferreira, R.C.; Echevarria, A.; Netto-Ferreira, J.C. Synthesis, tyrosinase inhibition and transportation behavior of novel β-enamino thiosemicarbazide derivatives by human serum albumin. J. Mol. Liq. 2018 , 254 , 280–290. [ Google Scholar ] [ CrossRef ]
Chaves, O.A.; Tavares, M.T.; Cunha, M.R.; Parise-Filho, R.; Sant’Anna, C.M.R.; Netto-Ferreira, J.C. Multi-spectroscopic and theoretical analysis on the interaction between human serum albumin and a capsaicin derivative—RPF101. Biomolecules 2018 , 8 , 78. [ Google Scholar ] [ CrossRef ][ Green Version ]
Britto, M.M.; Almeida, T.M.G.; Leitão, A.; Donnici, C.L.; Lopes, M.T.P.; Montanari, C.A. Synthesis of mesoionic 4-(para-substituted phenyl-5-2,4-dichlorophenyl)-1,3-4-thiadiazolium-2-aminides by direct cyclization via acylation of thiosemicarbazides. Synthetic Commun. 2006 , 36 , 3359–3369. [ Google Scholar ] [ CrossRef ]
Sousa-Pereira, D.; Chaves, O.A.; Reis, C.M.; Oliveira, M.C.C.; Sant’Anna, C.M.R.; Netto-Ferreira, J.C.; Echevarria, A. Synthesis and biological evaluation of N-aryl-2-phenyl-hydrazinecarbothioamides: Experimental and theoretical analysis on tyrosinase inhibition and interaction with HSA. Bioorg. Chem. 2018 , 81 , 79–87. [ Google Scholar ] [ CrossRef ]
Anderson, W.K.; Corey, P.F. Synthesis and antileukemic activity of 5-substituted 2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine diesters. J. Med. Chem. 1977 , 20 , 812–818. [ Google Scholar ]
Anderson, W.K.; Heider, A.R.; Raju, N.; Yucht, J.A. Synthesis and antileukemic activity of bis[[(carbamoyl)oxy]methyl]- substituted pyrrolo[2,1-a]isoquinolines, pyrrolo[1,2-a]quinolines, pyrrolo[2,1-a]isobenzazepines, and pyrrolo[1,2-a]benzazepines. J. Med. Chem. 1988 , 31 , 2097–2102. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Vilpo, J.A.; Vilpo, L.M.; Vuorinen, P.; Moilanen, E.; Metsä-Ketelä, T. Mode of cytostatic action of mesoionic oxatriazole nitric oxide donors in proliferating human hematopoietic cells. Anticancer Drug Des. 1997 , 12 , 75–89. [ Google Scholar ] [ PubMed ]
Hillard, E.A.; Pigeon, P.; Vessières, A.; Amatore, C.; Jaouen, G. The influence of phenolic hydroxy substitution on the electron transfer and anti-cancer properties of compounds based on the 2-ferrocenyl-1-phenyl-but-1-ene motif. Dalton Trans. 2007 , 43 , 5073–5081. [ Google Scholar ]
Gnanasekaran, K.K.; Pouland, T.; Bunce, R.A.; Darrell Berlin, K.; Abuskhuna, S.; Bhandari, D.; Mashayekhi, M.; Zhou, D.H.; Benbrook, D.M. Tetrahydroquinoline units in flexible heteroarotinoids (Flex-Hets) convey anti-cancer properties in A2780 ovarian cancer cells. Bioorg. Med. Chem. 2020 , 28 , 115244. [ Google Scholar ]
Lynn, W.S.; Tweedale, A.; Cloyd, M.W. Human Immunodeficiency Virus (HIV-1) cytotoxicity: Perturbation of the cell membrane and depression of phospholipid synthesis. Virology 1988 , 163 , 43–51. [ Google Scholar ] [ CrossRef ]
Olière, S.; Douville, R.; Sze, A.; Belgnaoui, S.M.; Hiscott, J. Modulation of innate immune responses during Human T-Cell Leukemia Virus (HTLV-1) pathogenesis. Cytokine Growth Factor Rev. 2011 , 22 , 197–210. [ Google Scholar ]
Glaser, R.; Wu, H.; Lewis, M. Cytosine catalysis of nitrosative guanine deamination and interstrand cross-link formation. J. Am. Chem. Soc. 2005 , 127 , 7346–7358. [ Google Scholar ] [ CrossRef ]
Gorrini, C.; Harris, I.S.; Mak, T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov 2013 , 12 , 931–947. [ Google Scholar ] [ CrossRef ]
Lähteenmäki, T.; Sievi, E.; Vapaatalo, H. Inhibitory effects of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives on vascular smooth muscle cell mitogenesis and proliferation in vitro. Br. J. Pharmacol. 1998 , 125 , 402–408. [ Google Scholar ]
Naveenraj, S.; Anandan, S. Binding of serum albumins with bioactive substances – Nanoparticles to drugs. J. Photochem. Photobiol. C 2013 , 14 , 53–71. [ Google Scholar ]
Koly, S.F.; Kundu, S.P.; Kabir, S.; Amran, M.S.; Sultan, M.Z. Analysis of aceclofenac and bovine serum albumin interaction using fluorescence quenching method for predictive, preventive, and personalized medicine. EPMA J. 2015 , 6 , 24–30. [ Google Scholar ] [ CrossRef ] [ PubMed ][ Green Version ]
Montalti, M.; Credi, A.; Prodi, L.; Gandolfi, M.T. Handbook of Photochemistry , 3rd ed.; CRC Press, Taylor & Francis: Boca Raton, FL, USA, 2006. [ Google Scholar ]
Millar, D.P. Time-resolved fluorescence spectroscopy. Curr. Opin. Struct. Biol. 1996 , 6 , 637–928. [ Google Scholar ] [ PubMed ]
Mondal, M.; Lakshmi, P.T.; Krishna, R.; Sakthivel, N. Molecular interaction between human serum albumin (HSA) and phloroglucinol derivative that shows selective anti-proliferative potential. J. Lumin. 2017 , 192 , 990–998. [ Google Scholar ] [ CrossRef ]
Lopes, N.D.; Chaves, O.A.; de Oliveira, M.C.C.; Sant’Anna, C.M.R.; Sousa-Pereira, D.; Netto-Ferreira, J.C.; Echevarria, A. Novel piperonal 1,3,4-thiadiazolium-2-phenylamines mesoionic derivatives: Synthesis, tyrosinase inhibition evaluation and HSA binding study. Int. J. Biol. Macromol. 2018 , 112 , 1062–1072. [ Google Scholar ] [ CrossRef ]
Ross, P.D.; Subramanian, S. Thermodynamics of protein association reactions: Forces contributing to stability. Biochemistry 1981 , 20 , 3096–3102. [ Google Scholar ] [ CrossRef ]
Chaves, O.A.; Jesus, C.S.H.; Henriques, E.S.; Brito, R.M.M.; Serpa, C. In-situ ultra-fast heat deposition does not perturb serum albumin structure. Photochem. Photobiol. Sci. 2016 , 15 , 1524–1535. [ Google Scholar ] [ CrossRef ]
Chaves, O.A.; Mathew, B.; Cesarin-Sobrinho, D.; Lakshminarayanan, B.; Joy, M.; Mathew, G.E.; Suresh, J.; Netto-Ferreira, J.C. Spectroscopic, zeta potential and molecular docking analysis on the interaction between human serum albumin and halogenated thienyl chalcones. J. Mol. Liq. 2017 , 242 , 1018–1026. [ Google Scholar ] [ CrossRef ]
Matei, I.; Hillebrand, M. Interaction of kaempferol with human serum albumin: A fluorescence and circular dichroism study. J. Pharm. Biomed. Anal. 2010 , 51 , 768–773. [ Google Scholar ] [ CrossRef ]
Qian, Y.; Zhou, X.; Chen, J.; Zhang, Y. Binding of bezafibrate to human serum albumin: Insight into the non-covalent interaction of an emerging contaminant with biomacromolecules. Molecules 2012 , 17 , 6821–6831. [ Google Scholar ]
Hosainzadeh, A.; Gharanfoli, M.; Saberi, M.R.; Chamani, J.K. Probing the interaction of human serum albumin with bilirubin in the presence of aspirin by multi-spectroscopic, molecular modeling and zeta potential techniques: Insight on binary and ternary systems. J. Biomol. Struct. Dyn. 2012 , 29 , 1013–1050. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Shen, G.-F.; Liu, T.-T.; Wang, Q.; Jiang, M.; Shi, J.-H. Spectroscopic and molecular docking studies of binding interaction of gefitinib, lapatinib and sunitinib with bovine serum albumin (BSA). J. Photochem. Photobiol. B 2015 , 153 , 380–390. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Meng, X.-Y.; Zhang, H.-X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Comput.-Aided Drug Des. 2011 , 7 , 146–157. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sudlow, G.; Birkett, D.J.; Wade, D.N. The characterization of two specific drug binding sites on human serum albumin. Mol. Pharmacol. 1975 , 11 , 824–832. [ Google Scholar ]
Sudlow, G.; Birkett, D.J.; Wade, D.N. Further characterization of specific drug binding sites on human serum albumin. Mol. Pharmacol. 1976 , 12 , 1052–1061. [ Google Scholar ]
Yamasaki, K.; Chuang, V.T.G.; Maruyama, T.; Otagiri, M. Albumin-drug interaction and its clinical implication. Biochim. Biophys. Acta 2013 , 1830 , 5435–5443. [ Google Scholar ] [ CrossRef ]
Chuang, V.T.; Otagiri, M. Flunitrazepam, a 7-nitro-1,4-benzodiazepine that is unable to bind to the indole-benzodiazepine site of human serum albumin. Biochim. Biophys. Acta 2001 , 1546 , 337–345. [ Google Scholar ] [ CrossRef ]
Hehre, W.J. A guide to molecular mechanics and quantum chemical calculations. In Wavefunction ; INC.: Irvine, CA, USA, 2003. [ Google Scholar ]
Drew, H.R.; Wing, R.M.; Takano, T.; Broka, C.; Tanaka, S.; Itakura, K.; Dickerson, R.E. Structure of a B-DNA dodecamer: Conformation and dynamics. Proc. Natl. Acad. Sci. USA 1981 , 78 , 2179–2183. [ Google Scholar ] [ CrossRef ][ Green Version ]
GOLD-Protein Ligand Docking Software. Available online: http://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/ (accessed on 30 April 2020).
DeLano, W.L. PyMOL User’s Guide ; DeLano Scientific LLC: San Carlos, CA, USA, 2002. [ Google Scholar ]
Sample Availability: Samples are available from the authors.
Figure 1. Chemical structures for the chemical compounds that make up the CHOP cocktail (cyclophosphamide, doxorubicin, prednisone, and vincristine) and AZT (ziduvidine) used in adult T-cell leukemia/lymphoma (ATLL) chemotherapy.
Scheme 1. Synthetic route for obtaining the target compounds 5a–d .
Scheme 1. Synthetic route for obtaining the target compounds 5a–d .
Figure 2. Effect of mesoionic compounds 5a–d on MT2 cells. The HTLV-1-infected cell line, i.e., MT2, was incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged, and DMSO was added to dissolve the crystals formed by reducing the MTT. The bars represent mean ± SEM values of % of viable cells from 4 to 5 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 2. Effect of mesoionic compounds 5a–d on MT2 cells. The HTLV-1-infected cell line, i.e., MT2, was incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged, and DMSO was added to dissolve the crystals formed by reducing the MTT. The bars represent mean ± SEM values of % of viable cells from 4 to 5 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 3. Effect of mesoionic compounds 5a–d on HTLV-1-infected cells. C91/PL cells were incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged, and DMSO was added to dissolve the crystals formed by reducing the MTT. The bars represent mean ± SEM values of % of viable cells from 4 to 7 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 3. Effect of mesoionic compounds 5a–d on HTLV-1-infected cells. C91/PL cells were incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged, and DMSO was added to dissolve the crystals formed by reducing the MTT. The bars represent mean ± SEM values of % of viable cells from 4 to 7 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 4. Effect of mesoionic compounds 5a–d on Jurkat cells. Cells were incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged and DMSO was added to dissolve the crystals formed by the MTT reduction. Bars represent mean ± SEM values of % of viable cells from 4 to 5 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 4. Effect of mesoionic compounds 5a–d on Jurkat cells. Cells were incubated in the presence or absence of 5a–d (0.78–25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 72 h, the cells were incubated with MTT for 3 h under the same conditions. Then, cells were centrifuged and DMSO was added to dissolve the crystals formed by the MTT reduction. Bars represent mean ± SEM values of % of viable cells from 4 to 5 independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 5. Effect of compound 5b on induction of necrosis in HTLV-1 infected MT2, C91/PL, and Jurkat cells. HTLV-1-infected cells and Jurkat cells were incubated with or without the compound 5b (25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 24 h, the cells were collected, and the cell viability was measured using PI (propidium iodide) labeling. Then, the fluorescence was examined using flow cytometry. A total of 10,000 events was acquired for the experimental data. Bars represent mean ± SEM values of % of necrotic cells from three independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 5. Effect of compound 5b on induction of necrosis in HTLV-1 infected MT2, C91/PL, and Jurkat cells. HTLV-1-infected cells and Jurkat cells were incubated with or without the compound 5b (25 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 24 h, the cells were collected, and the cell viability was measured using PI (propidium iodide) labeling. Then, the fluorescence was examined using flow cytometry. A total of 10,000 events was acquired for the experimental data. Bars represent mean ± SEM values of % of necrotic cells from three independent experiments. * p < 0.05 were considered statistically significant compared to control and DMSO.
Figure 6. Fluorescence emission spectra of 5b (25 μM) in the presence of increasing amounts of DNA (2, 10, and 100 ng/mL). A.U. = arbitrary unit.
Figure 6. Fluorescence emission spectra of 5b (25 μM) in the presence of increasing amounts of DNA (2, 10, and 100 ng/mL). A.U. = arbitrary unit.
Figure 7. Effect of mesoionic compounds 5a–d on reactive oxygen species (ROS) production. Jurkat ( A ) and MT2 ( B ) cells were incubated with or without 5a–d (12.5 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 30 min, the cells were washed and incubated with the ROS probe DHR (Dihydrorhodamine 123). Then, the fluorescence was examined using flow cytometry. A total of 10,000 events was acquired for the experimental data. Bars represent mean ± fold change of ROS production (DMSO was considered as a control) from two independent experiments.
Figure 7. Effect of mesoionic compounds 5a–d on reactive oxygen species (ROS) production. Jurkat ( A ) and MT2 ( B ) cells were incubated with or without 5a–d (12.5 µM) at 37 °C in a humid atmosphere containing 5% CO 2 . After 30 min, the cells were washed and incubated with the ROS probe DHR (Dihydrorhodamine 123). Then, the fluorescence was examined using flow cytometry. A total of 10,000 events was acquired for the experimental data. Bars represent mean ± fold change of ROS production (DMSO was considered as a control) from two independent experiments.
Figure 8. Top view representation for the best docking pose of the interaction ( A ) DNA: 5a , (B ) DNA: 5b , ( C ) DNA 5c , and ( D ) DNA: 5d in the minor groove. Mesoionic compounds 5a , 5b , 5c , and 5d are in stick representation in beige, pink, cyan, and brown, respectively. Elements’ colors: hydrogen: white; oxygen: red; nitrogen: dark blue; sulfur: yellow; bromine: wine; and chloro: green.
Figure 8. Top view representation for the best docking pose of the interaction ( A ) DNA: 5a , (B ) DNA: 5b , ( C ) DNA 5c , and ( D ) DNA: 5d in the minor groove. Mesoionic compounds 5a , 5b , 5c , and 5d are in stick representation in beige, pink, cyan, and brown, respectively. Elements’ colors: hydrogen: white; oxygen: red; nitrogen: dark blue; sulfur: yellow; bromine: wine; and chloro: green.
Figure 9. Superposition of the best docking pose for ( A ) HSA: 5a / 5b and ( B ) HSA: 5c / 5d in the subdomain IIA (site I). Representation of the main amino acid residues from the HSA structure, which can interact with ( C ) 5a , ( D ) 5b , ( E ) 5d , and ( F ) 5c . Selected amino acid residues and the mesoionic compounds 5a , 5b , 5c , and 5d are in stick representation in orange, beige, pink, cyan, and brown, respectively. Elements’ colors: hydrogen: white; oxygen: red; nitrogen: dark blue; sulfur: yellow; bromine: wine; and chlorine: green.
Figure 9. Superposition of the best docking pose for ( A ) HSA: 5a / 5b and ( B ) HSA: 5c / 5d in the subdomain IIA (site I). Representation of the main amino acid residues from the HSA structure, which can interact with ( C ) 5a , ( D ) 5b , ( E ) 5d , and ( F ) 5c . Selected amino acid residues and the mesoionic compounds 5a , 5b , 5c , and 5d are in stick representation in orange, beige, pink, cyan, and brown, respectively. Elements’ colors: hydrogen: white; oxygen: red; nitrogen: dark blue; sulfur: yellow; bromine: wine; and chlorine: green.
Figure 10. Mesoionic chlorides 5a–d numbered to the NMR attributions.
Figure 10. Mesoionic chlorides 5a–d numbered to the NMR attributions.
Table 1. In vitro anti-cancer activity results for the mesoionic compounds 5a–d.
Table 1. In vitro anti-cancer activity results for the mesoionic compounds 5a–d.
Cell Lines IC 50 Values for the Mesoionic Compounds 5a–d (μM) 5a 5b 5c 5d MT2 1.51 5.09 6.15 7.70 C91/PL 2.82 4.50 4.50 5.25 Jurkat 2.15 1.74 5.60 2.27
Table 2. Binding constant values for the interaction between human serum albumin (HSA) and the mesoionic compounds 5a–d.
Table 2. Binding constant values for the interaction between human serum albumin (HSA) and the mesoionic compounds 5a–d.
Sample T (K) K SV (× 10 5 ) (M −1 ) k q (× 10 13 ) (M −1 s −1 ) K a (× 10 4 ) (M −1 ) ΔH° (kJ.mol −1 ) ΔS° (× 10 −2 ) (kJ.mol −1 K −1 ) ΔG° (kJ.mol −1 ) 296 1.19 ± 0.03 2.15 7.68 ± 0.26 −27.7 HSA:5a 303 1.20 ± 0.03 2.16 7.51 ± 0.26 −2.64 ± 0.15 8.46 ± 0.05 −28.3 310 1.21 ± 0.03 2.18 7.32 ± 0.26 −28.9 296 1.10 ± 0.02 1.99 8.57 ± 0.26 −28.0 HSA:5b 303 1.14 ± 0.03 2.06 8.44 ± 0.26 −1.88 ± 0.17 8.81 ± 0.06 −28.6 310 1.15 ± 0.03 2.07 8.27 ± 0.26 −29.2 296 1.30 ± 0.03 2.35 8.53 ± 0.26 −28.1 HSA:5c 303 1.36 ± 0.04 2.45 9.06 ± 0.26 6.27 ± 0.10 11.6 ± 0.1 −28.9 310 1.40 ± 0.03 2.53 9.57 ± 0.26 −29.7 296 1.45 ± 0.02 2.61 8.71 ± 0.26 −27.9 HSA:5d 303 1.54 ± 0.03 2.79 9.02 ± 0.26 3.43 ± 0.16 10.6 ± 0.1 −28.7 310 1.60 ± 0.03 2.89 9.28 ± 0.26 −29.4
r 2 for K SV and k q : 0.9986–0.9999; r 2 for K a : 0.9961–0.9998; r 2 for ΔH°, ΔS° and ΔG° : 0.9920–0.9979.
Table 3. Time-resolved fluorescence parameters for the interaction between HSA and the mesoionic compounds 5a–d.
Table 3. Time-resolved fluorescence parameters for the interaction between HSA and the mesoionic compounds 5a–d.
Sample τ 1 (ns) Relative % τ 2 (ns) Relative % χ 2 HSA 1.73 ± 0.16 20.7 5.54 ± 0.12 79.3 1.095 HSA:5a 1.61 ± 0.13 26.4 5.38 ± 0.13 73.6 1.140 HSA:5b 1.66 ± 0.12 23.9 5.25 ± 0.11 76.1 1.106 HSA:5c 1.68 ± 0.11 33.0 5.66 ± 0.16 67.0 1.155 HSA:5d 1.65 ± 0.10 29.8 5.37 ± 0.13 70.2 1.038
Table 4. α-helix % values at 208 nm and 222 nm (Circular dichroism spectroscopy (CD) measurements) and ζ, conductance and current values (zeta potential (ZP) measurements) for HSA without and in the presence of mesoionic compounds 5a–d at 310 K.
Table 4. α-helix % values at 208 nm and 222 nm (Circular dichroism spectroscopy (CD) measurements) and ζ, conductance and current values (zeta potential (ZP) measurements) for HSA without and in the presence of mesoionic compounds 5a–d at 310 K.
CD Results ZP Results Sample 208 nm 222 nm ζ (mV) Conductance (µs) Current (mA) HSA 86.7% 80.1% −9.15 ± 1.79 29,645 150 HSA:5a 84.0% 78.5% −8.62 ± 1.40 29,615 150 HSA:5b 82.4% 77.3% −8.55 ± 1.46 29,642 150 HSA:5c 83.8% 78.8% −8.77 ± 1.52 29,622 150 HSA:5d 82.0% 77.7% −8.69 ± 1.50 29,638 150
Table 5. Molecular docking score values (dimensionless) for the interaction between DNA: 5a–d and HSA: 5a–d .
Table 5. Molecular docking score values (dimensionless) for the interaction between DNA: 5a–d and HSA: 5a–d .
DNA HSA Compound Minor Groove Major Groove Site I Site II Site III 5a 83.9 11.2 78.3 40.2 39.5 5b 84.8 10.6 80.1 40.0 38.1 5c 83.4 13.8 86.2 45.6 41.1 5d 87.4 13.6 85.0 42.9 40.8
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ).
MDPI and ACS Style
Sousa-Pereira, D.; Silva de Oliveira, T.; Paiva, R.O.; Chaves, O.A.; Netto-Ferreira, J.C.; Echevarria-Lima, J.; Echevarria, A. Synthetic ( E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1. Molecules 2020, 25, 2537.
https://doi.org/10.3390/molecules25112537
Sousa-Pereira D, Silva de Oliveira T, Paiva RO, Chaves OA, Netto-Ferreira JC, Echevarria-Lima J, Echevarria A. Synthetic ( E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1. Molecules. 2020; 25(11):2537.
https://doi.org/10.3390/molecules25112537
Sousa-Pereira, Danilo, Thais Silva de Oliveira, Rojane O. Paiva, Otávio Augusto Chaves, José C. Netto-Ferreira, Juliana Echevarria-Lima, and Aurea Echevarria. 2020. "Synthetic ( E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1" Molecules25, no. 11: 2537.
https://doi.org/10.3390/molecules25112537
| https://www.mdpi.com/1420-3049/25/11/2537/xml |
Proton radiography in background magnetic fields | Matter and Radiation at Extremes | AIP Publishing
Proton radiography has proved increasingly successful as a diagnostic for electric and magnetic fields in high-energy-density physics experiments. Most experime
0000-0002-8644-8118
;
C. Arran a)
Department of Physics, York Plasma Institute, University of York
, York YO10 5DD,
United Kingdom
a) Author to whom correspondence should be addressed: [email protected]
C. P. Ridgers
0000-0002-4078-0887
;
C. P. Ridgers
Department of Physics, York Plasma Institute, University of York
, York YO10 5DD,
United Kingdom
N. C. Woolsey
0000-0002-2444-9027
N. C. Woolsey
Department of Physics, York Plasma Institute, University of York
, York YO10 5DD,
United Kingdom
Author & Article Information
a) Author to whom correspondence should be addressed: [email protected]
Note: This paper is part of the Special Issue on Magnetized Plasmas in HED.
Matter and Radiation at Extremes 6, 046904 (2021)
https://doi.org/10.1063/5.0054172
Article history
Received:
April 15 2021
Accepted:
June 18 2021
C. Arran, C. P. Ridgers, N. C. Woolsey; Proton radiography in background magnetic fields. Matter and Radiation at Extremes1 July 2021; 6 (4): 046904.https://doi.org/10.1063/5.0054172
Download citation file:
Ris (Zotero)
Reference Manager
EasyBib
Proton radiography has proved increasingly successful as a diagnostic for electric and magnetic fields in high-energy-density physics experiments. Most experiments use target-normal sheath acceleration sources with a wide energy range in the proton beam, since the velocity spread can help differentiate between electric and magnetic fields and provide time histories in a single shot. However, in magnetized plasma experiments with strong background fields, the broadband proton spectrum leads to velocity-spread-dependent displacement of the beam and significant blurring of the radiograph. We describe the origins of this blurring and show how it can be removed from experimental measurements, and we outline the conditions under which such deconvolutions are successful. As an example, we apply this method to a magnetized plasma experiment that used a background magnetic field of 3 T and in which the strong displacement and energy spread of the proton beam reduced the spatial resolution from tens of micrometers to a few millimeters. Application of the deconvolution procedure accurately recovers radiographs with resolutions better than 100 µm, enabling the recovery of more accurate estimates of the path-integrated magnetic field. This work extends accurate proton radiography to a class of experiments with significant background magnetic fields, particularly those experiments with an applied external magnetic field.
Topics
Magnetic fields
,
Bragg peak
,
Signal processing
,
High energy density physics
,
Magnetic reconnection
,
Plasmas
,
Radiography
Laser-driven proton radiography has proven to be an essential diagnostic for measuring magnetic field structures in plasmas. Typically, protons are produced using target-normal sheath acceleration (TNSA), 1pass through a magnetic field region of interest, and are measured by the proton dose absorbed by a stack of radiochromic film (RCF). By measuring the intensity pattern of the radiographs from different proton energies on different layers of film, the structure of the path-integrated magnetic field in both space and time can be accurately recovered, 2,3with high spatial resolution and laser synchronization providing excellent time resolution. This technique has been used to study a host of effects ranging from Nernst advection 4,5to magnetic reconnection 6,7and is of vital importance for studies of magnetized high-energy-density physics. As magnetic fields in plasmas are of great interest both in laboratory astrophysics experiments 8,9and for suppressing heat flow and instability growth and enhancing yield in inertial confinement fusion experiments 10,11and hybrid magnetized fusion schemes, 12,13it seems likely that proton radiography is only going to become more useful with time.
Several studies have sought to use an applied background magnetic field to explore conditions in a magnetized plasma, 14,15and platforms to apply strong pulsed-power magnetic fields to a plasma target and measure the associated effects are being developed at a number of laser facilities. 16–18Under these conditions, however, the performance of proton radiography can be severely affected by the deflection of the proton beam in the background field, which can overwhelm the signal from the magnetic field inside the plasma. Furthermore, the deflection of protons in the background field is energy-dependent, and this introduces problems for proton radiography with broadband sources.
In this paper, we seek to understand and remedy the effects of proton deflection in a strong background field. A recent experiment used laser-driven proton radiography to measure changes to an applied magnetic field. In the process, we observed both substantial deflection of the proton beam and also a blurring effect, where the spatial resolution of the radiographs was dramatically reduced in the direction of the deflection. First, we show that this issue originates from using a broadband energy spectrum TNSA proton source in combination with a stack of RCF that absorbs protons over a finite range of energies. Second, by understanding the source of the blurring, we show how this effect can be modeled by a linear convolution. Finally, we explore how a deconvolution process can recover a more accurate estimate for the magnetic field profile, and we demonstrate the conditions under which this deconvolution is successful, as well as its limitations.
II. BLURRING IN A BACKGROUND FIELD
We start by considering how protons of different energies passing through a significant background magnetic field are deflected by different angles depending on their energies, such as shown inFig. 1(a). This results in a succession of different radiographs from protons of different energies, imprinted one on the other, each shifted by a small distance, as shown inFig. 1(b). This plot shows proton radiographs calculated for the example magnetic field profile (with no electric fields) at three different distinct energies, from 10 to 14 MeV, with each monoenergetic radiograph slightly displaced because of the background magnetic field. Each layer of RCF absorbs protons over a finite range of energies, and so, when the proton beam has a broadband energy spectrum, the radiographs measured by each separate layer of film are all blurred in the direction of proton deflection.
FIG. 1.
(a) Example of the magnetic field structure, with a large background field surrounding a millimeter-scale signal region near the center (a close-up of which is shown in the inset on the top right). Overlaid are the paths of monoenergetic proton beams of energies 10 MeV (blue), 16 MeV (yellow), and 21 MeV (pink). (b) Example of three synthetic monoenergetic radiographs (dashed lines) at 10 MeV (blue), 12 MeV (green), and 14 MeV (red), compared with a composite combined radiograph (solid purple), modeled using a thermal proton distribution absorbed by a layer of RCF. (c) Magnetic field profile reconstructed from the combined blurred radiograph (bold purple line) compared with the true field profile (solid black) and the reconstruction from the monoenergetic radiograph at 14 MeV (dashed red).
FIG. 1.
(a) Example of the magnetic field structure, with a large background field surrounding a millimeter-scale signal region near the center (a close-up of which is shown in the inset on the top right). Overlaid are the paths of monoenergetic proton beams of energies 10 MeV (blue), 16 MeV (yellow), and 21 MeV (pink). (b) Example of three synthetic monoenergetic radiographs (dashed lines) at 10 MeV (blue), 12 MeV (green), and 14 MeV (red), compared with a composite combined radiograph (solid purple), modeled using a thermal proton distribution absorbed by a layer of RCF. (c) Magnetic field profile reconstructed from the combined blurred radiograph (bold purple line) compared with the true field profile (solid black) and the reconstruction from the monoenergetic radiograph at 14 MeV (dashed red).
In this example, the background field was chosen to resemble the conditions of a recent experiment. The peak field strength of 3 T along the xdirection extends over a diameter of around 40 mm, as shown inFig. 1(a), with the proton beam initially traveling along the zaxis and experiencing a total integrated field of ∫ B xd z≈ 90 T mm; the proton beam is therefore deflected in the ydirection. The synthetic radiograph intensities were calculated using the EPOCH particle-in-cell code 19and measured at an RCF position 100 mm from the origin. The radiographs were combined, weighted by a thermal proton spectrum at T= 5 MeV and by the calculated absorption of an RCF layer with an absorption peak at 10.6 MeV and a full width at half maximum of 0.4 MeV. Note that this blurring is asymmetric and changes both the shape and the symmetry properties of the final radiograph. Using this combined radiograph to reconstruct the magnetic field profile therefore gives a poor estimate, as shown inFig. 1(c). The amplitude of the signal reconstructed from the combined radiograph is much lower than the true value, as though the radiograph had been taken with very poor spatial resolution. The shape of the profile is also distinctly different owing to the asymmetric blurring. The reconstruction using a monoenergetic radiograph, on the other hand, is close to the true field, showing that the discrepancy arises from the blurring rather than from the reconstruction. To calculate the degree of blurring in these synthetic radiographs, we can consider each component in turn.
A. Proton deflection
First, we can calculate the deflection of protons in a known background magnetic field by tracking the path of the proton through the field, as shown in
Fig. 1(a)
. In experiments, however, if the background field is not well characterized, the deflection must normally be calibrated using a known fiducial. By placing a wire at the interaction point and taking measurements of the position of its shadow on different layers of RCF, we can estimate the vertical displacement of the beam on the stack
y ′ 0 ( E ) y ′ 0 ( E )
, as shown in
Fig. 2(a)
. Strictly speaking, this method assumes that the layers of RCF all lie in exactly the same place, since
y ′ 0 y ′ 0
also depends on the RCF position, but this assumption is accurate when the deflection angle
θ
y
is sufficiently small or the depth of the stack Δ
z
is sufficiently short that
θ y Δ z ≪ Δ y ′ 0 θ y Δ z ≪ Δ y ′ 0
. The measured points can then be fitted to a function of the form
y ′ 0 ( E ) ≈ a + b / √ E y ′ 0 ( E ) ≈ a + b / E − − √
, with fitting parameters
a
and
b
, to reflect the greater deflection of lower-energy protons. The steeper the change in
y ′ 0 ( E ) y ′ 0 ( E )
with changes in proton energy, the worse will be the effect of blurring.
FIG. 2.
(a) Deflection of the proton beam vs energy, measured by tracking the edge of the proton distribution in synthetic radiographs, and fitted to y ′ 0 ( E ) = a + b / √ E y ′ 0 ( E ) = a + b / E − − √ . (b) RCF absorption curves calculated by the finite element opacity model described in the text, with the first layer of RCF on the left. (c) Examples of proton energy distributions estimated from RCF doses measured on two different experimental laser shots, fitted to thermal distributions.
FIG. 2.
(a) Deflection of the proton beam vs energy, measured by tracking the edge of the proton distribution in synthetic radiographs, and fitted to y ′ 0 ( E ) = a + b / √ E . (b) RCF absorption curves calculated by the finite element opacity model described in the text, with the first layer of RCF on the left. (c) Examples of proton energy distributions estimated from RCF doses measured on two different experimental laser shots, fitted to thermal distributions.
B. Protons absorbed
Second, the energies deposited into the RCF stack by the proton beam can be calculated using a finite element opacity model, where for a number of protons N( E, z) of a given energy Eand depth in the stack z, the absorption in the stack is given by d N( E, z) = − σ( E, z) N( E, z)d zfor an opacity σ( E, z). σcan be tabulated against proton energy for different materials, with opacity higher for denser materials and for lower proton energies. The proton populations through the RCF stack can be calculated by integration as log[ N( E, z)/ N 0( E)] = −∫ σ( E, z)d z, for an initial proton energy spectrum N 0( E). The response function for a given slice of RCF labeled iwith thickness t iis then R i( E) = [ N( E, z i) − N( E, z i+ t i)]/ N 0( E). These response functions are plotted inFig. 2(b), showing the characteristic Bragg peaks. For each layer of RCF, this results in a negligible response at low energies (where almost all the protons have already been deposited earlier in the stack), followed by a sudden spike in absorption at a particular energy (where the integrated opacity is close to 1), followed by a decay in response at higher energies (where the integrated opacity remains much less than 1).
C. Proton spectrum
Finally, the response curves, which vary for each layer in the RCF stack, should then be weighted by the energy distribution of the proton beam, N 0( E), which is the same for all layers but varies from shot to shot. The spectrum is generally estimated using the dose measured on each piece of RCF, compared with the proton energy most strongly absorbed by each layer. Either fitting to an expected spectral shape [e.g., a thermal spectrum given by N 0( E) ∝ e − E / Tfor a temperature T] or interpolating between these measured points on the spectrum then gives an estimate of the proton energy distribution, with examples from two different laser shots shown inFig. 2(c)with estimated temperatures of 4.8 and 5.7 MeV. Strictly speaking, however, each layer of RCF absorbs protons from a range of energies, as we saw, and the proton spectrum should be found self-consistently, finding a spectrum N 0( E) such that the measured dose on each slice iis D i= ∫ R i( E) N 0( E)dE. This can be approached by inversion or iteratively, starting at the back of the RCF stack where the response is only due to high energies and R i( E) is mostly zero.
III. BLURRING AS A CONVOLUTION
Now we understand the causes of blurring in proton radiographs taken through a strong background magnetic field, we can work to remove the effect and recover an estimate of what the radiographs would look like without the background field. If the proton energy is conserved, then, in the absence of electric fields, the deflection of protons depends on the path-integrated magnetic field as ^ v f − ^ v 0 = ( q / γ m v ) ∫ ^ v × B d s . If the spatial scale of the background field is much larger than that of the field we wish to measure, then the path of the protons is dominated by the applied field, and we can safely calculate the degree of blurring from the background field alone.
On the other hand, the intensity of the proton radiograph is dependent on the gradient of the deflection. A one-dimensional radiograph has an intensity profile given by I/ I 0= | ∂y′/ ∂y| −1, where yis the position of protons as they pass through the object plane at z= 0, and y′ is the position of protons as they arrive at the RCF stack. This means that the relevant quantity for the intensity profile is ( q / γ m v ) ∂ ( ∫ ^ v × B d s ) / ∂ y . If the background field is only slowly varying in space, then the intensity profile of the radiograph is dominated by the lower-amplitude but more rapidly varying field that we wish to measure (the signal). The shape of an unblurred monoenergetic radiograph then depends only on the signal magnetic field.
Next, we assume that over the energy range of protons absorbed by a single layer of RCF, the radiograph is identical. Generally, lower-energy protons are deflected more by the magnetic fields, giving radiographs with higher variations in intensity and more caustic features. At low proton energies or strong fields, the assumption of identical radiographs over a small energy range is therefore not accurate. Where each RCF layer is only absorbing protons from a relatively narrow energy spread, however, we can write the intensity profile from protons of a given energy on a given shot as
I j ( y ′ ; E ) = I j 0 exp ( − E T j ) f ( y ′ − y ′ 0 ( E ) ; E 0 ) ,
(1)
where the proton spectrum on laser shot jis characterized by an intensity I j ,0and a temperature T jthat vary from shot to shot, the function f( y′; E 0) describes the shape of a monoenergetic radiograph at an energy E 0≈ E, which depends only on the signal magnetic field, and y ′ 0 ( E )describes the deflection, which depends only on the background magnetic field.
When these protons are absorbed by a given RCF layer i, they produce a measured dose shape of the form
D i j ( y ) = I j , 0 ∫ R i ( E ) exp ( − E T j ) f ( y ′ − y ′ 0 ( E ) ; E 0 ) d E = D j , 0 ∫ g i j ( y ′ 0 ) f ( y ′ − y ′ 0 ; E 0 ) d y ′ 0 ,
(2)
which is a linear spatial convolution of the monoenergetic radiograph with a kernel g( y′) given by
g i j ( y ′ ) = R i ( E ( y ′ ) ) exp [ − E ( y ′ ) T j ] d E d y ′ .
(3)
Furthermore, if the contrast of the radiograph is not so high as to form caustic features (i.e., I/ I 0− 1 ≪ 1), then we can generalize this convolution kernel to any RCF position or proton source location. If there is a direct mapping between points in the object plane described by the coordinate yand points on the RCF stack described by y ′ ≈ y ′ 0 ( E ) + M y(for a magnification M), then we can also describe the convolution kernel in terms of y. The width of the convolution kernel then describes the spatial resolution with which we can measure the magnetic field.
Some examples of convolution kernels are shown inFig. 3(a), calculated using the measured deflection and RCF response functions shown inFig. 2and the thermal proton energy spectra at T= 5 MeV and T= 10 MeV, and plotted vs position in the object plane. For the first RCF layer at the front of the stack, with proton energies around 5 MeV, the proton deflection is large, and the resulting blurring kernel has a broad tail to the left of the ideal monoenergetic peak. This would blur out any magnetic field features smaller than a few millimeters. By the fourth RCF layer in the stack, however, with proton energies around 15 MeV, the effect of blurring occurs over less than a millimeter.
FIG. 3.
View large Download slide
(a) Examples of convolution kernels calculated for different RCF layers for a T= 5 MeV thermal proton spectrum (solid lines) passing through a 3 T background field, compared with the kernels for a T= 10 MeV proton spectrum under the same conditions (dotted lines). (b) Standard deviation of the kernels plotted vs the mean proton energy absorbed by each RCF layer, comparing T= 5 MeV and T= 10 MeV proton beams passing through a 3 T background field with a T= 5 MeV proton beam passing through a 10 T background field.
FIG. 3.
(a) Examples of convolution kernels calculated for different RCF layers for a T= 5 MeV thermal proton spectrum (solid lines) passing through a 3 T background field, compared with the kernels for a T= 10 MeV proton spectrum under the same conditions (dotted lines). (b) Standard deviation of the kernels plotted vs the mean proton energy absorbed by each RCF layer, comparing T= 5 MeV and T= 10 MeV proton beams passing through a 3 T background field with a T= 5 MeV proton beam passing through a 10 T background field.
Comparing the results for a proton spectrum with T= 10 MeV, the broader energy range of protons incident on the RCF stack here results in broader blurring kernels. There is therefore a trade-off with proton energy: for higher-energy protons, deflection is small and blurring is negligible, but the dose absorbed in the RCF is lower, and the amplitude of the signal will also be smaller. Increasing the dose by obtaining higher-temperature proton spectra will also increase the effect of blurring.
We can compare the effective spatial resolutions by looking at the standard deviations of the convolution kernels, plotted inFig. 3(b)vs the mean proton energy absorbed by each layer of the RCF stack. This shows the reduction in the kernel width with proton energy, such that for a 3 T background field with a field integral of 90 T mm, the blurring width changes from around 2 mm in the object plane at 5 MeV to under 250 µm above 20 MeV. Increasing the temperature of the proton beam to 10 MeV could increase the proton dose at these higher energies, but would also lead to an increase in the blurring width by around 50%. If the field strength is increased to 10 T, on the other hand, the effect of blurring is very significant, even at these higher energies, with a blurring width of 1 mm in the object plane at 20 MeV. Whereas magnetized plasma experiments that employ proton radiography often attempt to increase the proton temperature or the magnetic field strength, both of these changes will lead to greater blurring, and great care must be taken if small features in the magnetic field are to be measured.
IV. DECONVOLUTION
Having expressed the blurring as a linear convolution, we can perform a deconvolution and recover the monoenergetic radiograph f( y′; E 0) from the measured dose profile. There are several possible deconvolution algorithms, of which we use the Richardson–Lucy technique 20,21for its stability.Figure 4(a)shows the same combined radiograph described earlier, calculated from a thermal proton spectrum with T= 5 MeV incident on a layer of RCF after passing through a background magnetic field with a strength of 90 T mm, as shown inFig. 1. This radiograph is compared with the 10 MeV monoenergetic radiograph predicted from particle-in-cell simulations and with the estimated radiograph recovered using deconvolution of the combined radiograph. This shows how the deconvolution increases the contrast of the radiograph, with the result closely approximating the profile of the monoenergetic radiograph. Under these conditions, this therefore makes the recovered magnetic field profile more accurate after deconvolution has been used, as shown inFig. 4(b). The deconvolved radiograph gives an estimate of the magnetic field that is almost an exact match to the true profile for | r| > 0.3 mm, with the same symmetry and amplitude. On-axis, however, the deconvolution leads to an exaggeration of the magnetic field strength and a significant error, demonstrating that this deconvolution is a useful tool, but not a perfect solution to the problem of blurring.
FIG. 4.
(a) Synthetic radiographs from a thermal proton beam passing through a background field with a strength of 90 T mm before being absorbed by a layer of RCF. The combined radiograph (purple line) and that after application of deconvolution (dash-dotted red line) are compared with a monoenergetic radiograph at a proton energy of 10 MeV (solid blue). (b) Reconstructed magnetic field profile recovered from the synthetic radiographs. Again, the result without deconvolution (purple line) and the result using deconvolution (dash-dotted red line) are compared with the true magnetic field profile (solid black line).
FIG. 4.
(a) Synthetic radiographs from a thermal proton beam passing through a background field with a strength of 90 T mm before being absorbed by a layer of RCF. The combined radiograph (purple line) and that after application of deconvolution (dash-dotted red line) are compared with a monoenergetic radiograph at a proton energy of 10 MeV (solid blue). (b) Reconstructed magnetic field profile recovered from the synthetic radiographs. Again, the result without deconvolution (purple line) and the result using deconvolution (dash-dotted red line) are compared with the true magnetic field profile (solid black line).
Deconvolution of a blurred radiograph clearly has limitations, and cannot perfectly recover a monoenergetic radiograph or the true magnetic field profile. First, applying any deconvolution algorithm to real data can amplify noise features, such as can be seen on the right ofFig. 4(a); instead of a flat I= I 0profile there is an artifact from the application of a deconvolution to noise. This can lead to inaccurate field reconstructions away from the main features, or where the amplitude of the noise is similar to that of the signal. Second, the shape of the radiograph is not identical for different proton energies, with the greater deflection of lower-energy protons leading to a higher-contrast radiograph. By assuming that the radiograph shape is constant, the deconvolved signal will tend to overestimate the amplitude of the magnetic field profile. Finally, the deconvolution process is only an estimate of the true deconvolution, and cannot perfectly recover the original signal. The broader the convolution kernel relative to the feature size of the signal, the more poorly will the deconvolution algorithm perform. All of these limitations mean that deconvolution is more helpful in estimating the true magnetic field profile under some conditions than others.
We can study the accuracy of the deconvolution under different conditions by simulating the blurring process and the deconvolution.Figure 5(a)shows an example of an arbitrary integrated magnetic field profile (solid black line), defined here as a sinusoid with a linearly increasing amplitude. The blurring is modeled by calculating a series of synthetic radiographs with different proton energies, before displacing the radiographs by the deflections shown inFig. 2(a). This assumes that the background field is constant over the signal region and does not change the shape of the radiograph. The proton source is point-like in these ideal synthetic radiographs, with the spatial resolution limited only by the grid size of 2 µm. The absorption of protons in the third layer of RCF is then modeled using a thermal proton spectrum with a temperature of 5 MeV and an RCF response curve as shown inFig. 2(b). This results in significant blurring of the recovered magnetic field profile (dashed blue line), with the amplitude of the sinusoid reduced by around a factor of three. Applying a deconvolution algorithm, however, with a convolution kernel such as shown inFig. 3(a), recovers a sharp radiograph. This gives an estimate of the magnetic field that closely matches the original profile.
FIG. 5.
(a) Arbitrary integrated magnetic field profile with a scale length of 0.5 mm (solid black line) compared with an example of a reconstructed field from a blurred radiograph (dashed blue line) and after deconvolution (dash-dotted red line). (b) Accuracy of the reconstruction before (dashed lines) and after (solid lines) deconvolution, plotted vs the mean proton energy absorbed in each layer of RCF, shown for thermal T= 5 MeV and T= 10 MeV protons passing through a background field of 90 or 300 T mm. (c) Estimate of the maximum feature size that can be resolved to better than 10% accuracy in the magnetic field profile with (solid lines, solid markers) and without the deconvolution (dashed lines, open markers), plotted vs the mean proton energy absorbed in each layer of RCF, shown for a thermal T= 5 MeV proton spectrum passing through background fields of different strengths.
FIG. 5.
(a) Arbitrary integrated magnetic field profile with a scale length of 0.5 mm (solid black line) compared with an example of a reconstructed field from a blurred radiograph (dashed blue line) and after deconvolution (dash-dotted red line). (b) Accuracy of the reconstruction before (dashed lines) and after (solid lines) deconvolution, plotted vs the mean proton energy absorbed in each layer of RCF, shown for thermal T= 5 MeV and T= 10 MeV protons passing through a background field of 90 or 300 T mm. (c) Estimate of the maximum feature size that can be resolved to better than 10% accuracy in the magnetic field profile with (solid lines, solid markers) and without the deconvolution (dashed lines, open markers), plotted vs the mean proton energy absorbed in each layer of RCF, shown for a thermal T= 5 MeV proton spectrum passing through background fields of different strengths.
Figure 5(b)shows how, under different conditions, the accuracy of the magnetic field reconstruction varies depending on the RCF layer, with layers that absorb higher-energy protons measuring less blurring and giving a lower error. The error is shown as the root-mean-square (rms) difference in integrated magnetic field, relative to the rms of the original integrated magnetic field profile. Whereas the blurred radiographs (dashed lines) give relative errors of around 50% or more, the error after applying the deconvolution (shown by the solid lines) falls to under 10%. The deconvolution is not perfect, however, and for the first layer in the RCF stack, absorbing proton energies around 5 MeV, the relative error after deconvolution is still around 50%. At these low proton energies, the large widths of the kernels make the deconvolution inaccurate, while the shape of the radiograph also changes rapidly with proton energy and the blurring is not described well by a convolution. We can therefore establish first that applying a deconvolution with the relevant kernel substantially improves the accuracy of reconstructing the magnetic field, and second that this deconvolution performs better at higher proton energies, above 10 MeV.
By changing the modeled deflection and proton spectrum, we can also explore how the strength of the background field and the temperature of the proton beam affect the accuracy of the reconstruction. As expected, and in agreement withFig. 3(b), both a higher background field and a higher-temperature proton beam cause greater blurring and a reduction in accuracy of the reconstruction, both before and after the application of deconvolution. Whereas increasing the proton beam temperature from 5 MeV (shown by the blue lines) to 10 MeV (red lines) makes the relative error without any deconvolution around 10% worse, the main effect on the deconvolution process is to increase the proton energy required for an accurate reconstruction. A higher proton temperature not only increases the width of the smearing kernel, but also weakens the assumptions of a linear convolution. The shape of the radiograph can vary considerably over the larger energy range, making the deconvolution inaccurate below 15 MeV. Above this point, however, the assumptions hold and the kernel is narrower, making the deconvolution accurate to better than 10%.
Similarly, increasing the background field strength from 90 to 300 T mm (shown by the purple lines) makes the convolution kernels much broader, and increases the relative error of the blurred reconstruction by around 20%. The kernels for RCF layers at the front of the stack have widths greater than 2 mm in the object plane, as shown inFig. 3(b), and it is therefore unsurprising that the deconvolution cannot accurately recover the features of the true magnetic field profile. By RCF layers deeper in the stack absorbing higher proton energies, on the other hand, the deconvolution accurately reproduces the true magnetic field profile, with a relative error of less than 10% for proton energies greater than 20 MeV. In this way, accurately probing magnetic fields in the presence of a strong background field requires high doses of high-energy protons, but unfortunately using high-temperature proton beams to achieve this can be counterproductive. Deconvolution is very successful at recovering the signal magnetic field profile even when blurring is severe, but spatial features that are too small are lost—a feature that we explore in detail next.
We can estimate the spatial resolution of the deconvolved radiographs by calculating the radiograph and the reconstructed magnetic field profile as before, now using a series of magnetic field profiles with the same form as shown inFig. 5(a)but with wavelengths from 16 mm down to 12.5 µm. For each layer of RCF, the smallest wavelength is found that still gives less than 10% rms error. The accuracy of the blurred radiographs, on the other hand, is estimated using the convolution kernel by finding the wavenumber where the Fourier transform of the relevant kernel falls to 90% of the maximum amplitude, thereby introducing a 10% error in the corresponding wavelength.
The resulting estimates of the spatial resolution in the object plane are shown inFig. 5(c), with the maximum spatial resolution that can be recovered with an accuracy of better than 10% plotted vs proton energy for synthetic radiographs, both before and after the application of deconvolution, and for different background magnetic field strengths. This shows how the blurring strongly limits the spatial resolution, with this effect being worse at lower proton energies, but still problematic for proton energies above 20 MeV. At 20 MeV, the spatial resolution is limited to around a millimeter for a background field strength of 30 T mm, but around 10 mm for a background field strength of 300 T mm.
Applying the deconvolution improves the spatial resolution above 10 MeV by around an order of magnitude. For a 30 T mm background field, spatial resolutions of tens of micrometers in the object plane are achievable for proton energies higher than 20 MeV. The deconvolution is not perfect and cannot recover all of the lost resolution, with the front layers of the RCF stack experiencing little benefit when absorbing protons around 10 MeV and below. Higher proton energies, which experience less deflection, again correspond to better spatial resolution. For the strongest 300 T mm background field, the spatial resolution even after using deconvolution is around a millimeter at 15 MeV, or 300 µm at 25 MeV. When using a proton source with a broad energy spread to conduct radiography in applied magnetic fields, increasing the magnetic field strength will reduce the spatial resolution achievable, even after using deconvolution.
V. CONCLUSIONS
We have extended proton probing to a new class of experiments that use applied magnetic fields surrounding the region of interest. These experiments encounter significant difficulties, because not only is the proton beam deflected by the background field, but this deflection is energy-dependent. When combined with a broadband proton energy spectrum and absorption in layers of RCF, this deflection results in significant blurring of the proton radiograph. This blurring is most severe for layers of RCF at the front of the stack, which absorb lower-energy protons, but is also a significant problem for protons of higher energies, above 20 MeV for the conditions considered here. Furthermore, increasing the temperature of the proton beam to access higher proton energies will itself worsen the effect of blurring.
However, we have also shown that under certain conditions, the blurring can be modeled as a linear convolution and removed using a deconvolution algorithm. When the background field is large and slowly varying in space compared with the signal, and the relative energy spread of protons absorbed by the RCF is sufficiently small, we can therefore recover a good estimate for a monoenergetic radiograph and accurately reconstruct the magnetic field that we wish to measure, despite the presence of a strong background field. By looking at how the convolution kernel changes with the background field strength, the proton temperature, and the RCF absorption, we can estimate the loss of spatial resolution caused by the blurring and calculate the deconvolution required.
We have shown how deconvolution substantially increases the accuracy of the reconstructed magnetic field profile, with the error in the reconstruction falling from over 50% to under 10%, and the spatial resolution of the radiographs is improved by an order of magnitude. While no estimate of the true magnetic field profile will be perfect, calculating the kernel and applying deconvolution allows us to recover much greater spatial resolution than is possible from the blurred radiographs, down to around 100 µm for a 90 T mm background field. We have in this way extended the power of proton radiography to experiments with applied magnetic fields, allowing researchers to study changes to electric and magnetic fields even under these challenging experimental conditions.
SUPPLEMENTARY MATERIAL
See thesupplementary materialfor the RCF stack design used throughout and the reconstruction process for recovering magnetic fields from the one-dimensional proton intensity profile.
1.
M. Borghesi
,
J. Fuchs
,
S. V. Bulanov
,
A. J. MacKinnon
,
P. K. Patel
, and
M. Roth
, “
Fast ion generation by high-intensity laser irradiation of solid targets and applications
,”
Fusion Sci. Technol.
49
,
412
–
439
).
https://doi.org/10.13182/fst06-a1159
2.
N. L. Kugland
,
D. D. Ryutov
,
C. Plechaty
,
J. S. Ross
, and
H.-S. Park
, “
Invited article: Relation between electric and magnetic field structures and their proton-beam images
,”
Rev. Sci. Instrum.
2012
3.
M. F. Kasim
,
A. F. A. Bott
P. Tzeferacos
,
D. Q. Lamb
G. Gregori
S. M. Vinko
, “
Retrieving fields from proton radiography without source profiles
L. Willingale
A. G. R. Thomas
P. M. Nilson
M. C. Kaluza
S. Bandyopadhyay
,
R. G. Evans
,
P. Fernandes
,
M. G. Haines
,
C. Kamperidis
,
R. J. Kingham
,
S. Minardi
,
M. Notley
,
C. P. Ridgers
,
W. Rozmus
,
M. Sherlock
,
M. S. Wei
,
Z. Najmudin
, and
K. Krushelnick
, “
Fast advection of magnetic fields by hot electrons
,”
Phys. Rev. Lett.
F. H. Séguin
,
J. A. Frenje
N. Sinenian
M. J. Rosenberg
M. J.-E. Manuel
H. G. Rinderknecht
A. B. Zylstra
R. D. Petrasso
P. A. Amendt
O. L. Landen
A. J. Mackinnon
,
S. C. Wilks
,
R. Betti
,
D. D. Meyerhofer
,
J. M. Soures
,
J. Hund
,
J. D. Kilkenny
, and
A. Nikroo
, “
Proton imaging of hohlraum plasma stagnation in inertial-confinement-fusion experiments
,”
Nucl. Fusion
53
,
073022
2013
).
https://doi.org/10.1088/0029-5515/53/7/073022
6.
C. A. J. Palmer
,
P. T. Campbell
,
Y. Ma
,
L. Antonelli
,
A. F. A. Bott
,
G. Gregori
,
J. Halliday
,
Y. Katzir
,
P. Kordell
,
K. Krushelnick
,
S. V. Lebedev
,
E. Montgomery
,
M. Notley
,
D. C. Carroll
,
C. P. Ridgers
,
A. A. Schekochihin
,
M. J. V. Streeter
,
A. G. R. Thomas
,
E. R. Tubman
,
N. Woolsey
L. Willingale
, “
Field reconstruction from proton radiography of intense laser driven magnetic reconnection
,”
Phys. Plasmas
26
,
083109
(
2019
).
https://doi.org/10.1063/1.5092733
7.
E. R. Tubman
,
A. S. Joglekar
,
A. F. A. Bott
,
M. Borghesi
,”
Nat. Phys.
10
,
520
–
524
(
2014
).
https://doi.org/10.1038/nphys2978
10.
L. J. Perkins
,
D. D.-M. Ho
,
B. G. Logan
,
G. B. Zimmerman
,
M. A. Rhodes
,
D. J. Strozzi
,
D. T. Blackfield
, and
S. A. Hawkins
, “
The potential of imposed magnetic fields for enhancing ignition probability and fusion energy yield in indirect-drive inertial confinement fusion
,”
Phys. Plasmas
24
,
062708
(
2017
).
https://doi.org/10.1063/1.4985150
11.
C. A. Walsh
,
K. McGlinchey
,
J. K. Tong
,
B. D. Appelbe
,
A. Crilly
,
M. F. Zhang
, and
J. P. Chittenden
, “
Perturbation modifications by pre-magnetisation of inertial confinement fusion implosions
,”
Phys. Plasmas
26
,
022701
(
2019
).
https://doi.org/10.1063/1.5085498
12.
S. A. Slutz
and
R. A. Vesey
, “
High-gain magnetized inertial fusion
,”
Phys. Rev. Lett.
108
,
025003
(
2012
).
https://doi.org/10.1103/PhysRevLett.108.025003
PubMed
13.
A. B. Sefkow
,
S. A. Slutz
,
J. M. Koning
,
M. M. Marinak
,
K. J. Peterson
,
D. B. Sinars
, and
R. A. Vesey
, “
Design of magnetized liner inertial fusion experiments using the Z facility
,”
Phys. Plasmas
21
,
072711
(
https://doi.org/10.1063/1.4890298
14.
P. Y. Chang
,
G. Fiksel
,
M. Hohenberger
,
J. P. Knauer
,
R. Betti
,
F. J. Marshall
,
D. D. Meyerhofer
,
F. H. Séguin
, and
R. D. Petrasso
Fusion yield enhancement in magnetized laser-driven implosions
,”
Phys. Rev. Lett.
107
,
035006
(
2011
).
https://doi.org/10.1103/PhysRevLett.107.035006
15.
M. Hohenberger
,
P.-Y. Chang
,
G. Fiksel
,
R. Betti
,
F. J. Marshall
,
D. D. Meyerhofer
,
F. H. Séguin
, and
R. D. Petrasso
, “
Inertial confinement fusion implosions with imposed magnetic field compression using the OMEGA laser
,”
Phys. Plasmas
19
,
056306
(
2012
).
16.
M. J.-E. Manuel
,
C. C. Kuranz
,
A. M. Rasmus
,
S. R. Klein
,
M. J. MacDonald
,
M. R. Trantham
,
J. R. Fein
,
P. X. Belancourt
,
R. P. Young
,
P. A. Keiter
,
R. P. Drake
B. B. Pollock
,
J. Park
,
A. U. Hazi
,
G. J. Williams
, and
H. Chen
, “
Experimental results from magnetized-jet experiments executed at the Jupiter Laser Facility
,”
High Energy Density Phys.
17
,
52
–
62
(
2015
).
https://doi.org/10.1016/j.hedp.2014.07.003
17.
B. Albertazzi
,
E. Falize
,
A. Pelka
,
F. Brack
,
F. Kroll
,
R. Yurchak
,
E. Brambrink
,
P. Mabey
,
N. Ozaki
,
S. Pikuz
L. Van Box Som
,
J. M. Bonnet-Bidaud
,
J. E. Cross
,
E. Filippov
,
G. Gregori
,
R. Kodama
,
M. Mouchet
,
T. Morita
,
Y. Sakawa
,
R. P. Drake
,
C. C. Kuranz
,
M. J.-E. Manuel
,
C. Li
,
P. Tzeferacos
,
D. Lamb
,
U. Schramm
, and
M. Koenig
, “
Experimental platform for the investigation of magnetized-reverse-shock dynamics in the context of POLAR
,”
High Power Laser Sci. Eng.
6
,
e43
(
2018
).
https://doi.org/10.1017/hpl.2018.37
Google Scholar
Crossref
18.
P. Bradford
,
M. P. Read
,
M. Ehret
,
L. Antonelli
,
M. Khan
,
N. Booth
,
K. Glize
,
D. Carroll
,
R. J. Clarke
,
R. Heathcote
,
S. Ryazantsev
,
S. Pikuz
,
C. Spindloe
,
J. D. Moody
,
B. B. Pollock
,
V. T. Tikhonchuk
,
C. P. Ridgers
,
J. J. Santos
, and
N. C. Woolsey
, “
Proton deflectometry of a capacitor coil target along two axes
,”
High Power Laser Sci. Eng.
8
,
e11
(
2020
).
https://doi.org/10.1017/hpl.2020.9
Google Scholar
Crossref
19.
T. D. Arber
,
K. Bennett
,
C. S. Brady
,
A. Lawrence-Douglas
,
M. G. Ramsay
,
N. J. Sircombe
,
P. Gillies
,
R. G. Evans
,
H. Schmitz
,
A. R. Bell
, and
C. P. Ridgers
, “
Contemporary particle-in-cell approach to laser-plasma modelling
,”
Plasma Phys. Controlled Fusion
57
,
113001
(
2015
).
https://doi.org/10.1088/0741-3335/57/11/113001
20.
Bayesian-based iterative method of image restoration
,”
J. Opt. Soc. Am.
62
,
55
–
59
(
1972
).
https://doi.org/10.1364/josa.62.000055
21.
L. B. Lucy
, “
An iterative technique for the rectification of observed distributions
,”
Astron. J.
745
(
1974
).
https://doi.org/10.1086/111605
Supplementary Material - zip file
| https://pubs.aip.org/aip/mre/article/6/4/046904/253070/Proton-radiography-in-background-magnetic-fields |
Untreated Rupture of the Tunica Albuginea - Mayo Clinic Proceedings
Rapid Communication
|
Volume 61, ISSUE 12
,
P975-977,
December 1986
Untreated Rupture of the Tunica Albuginea
THOMAS J. STILLWELL, M.D.
THOMAS J. STILLWELL
Affiliations
Resident in Urology *
CARL C. READING, M.D.
CARL C. READING
Affiliations
FRANK J. LEARY, M.D.
FRANK J. LEARY
Correspondence
Address reprint requests to Dr. F. J. Leary, Department of Urology, Mayo Clinic, Rochester, MN 55905
Affiliations
Department of Urology
Show footnotes Hide footnotes
Author Footnotes
* Mayo Graduate School of Medicine, Rochester, Minnesota.
DOI: https://doi.org/10.1016/S0025-6196(12)62640-8
REFERENCES
Article info
Figures
A patient with untreated rupture of the tunica albuginea underwent surgical exploration 6 weeks after acute scrotal trauma. A layer of epithelium had grown across the bulging seminiferous tubules, and no further surgical repair was necessary. This spontaneous repair phenomenon has not previously been reported pictorially in the human testis. The recommended treatment of testicular rupture is surgical exploration and repair.
REPORT OF CASE
A 29-year-old man sustained nonpenetrating left scrotal trauma. His left hemiscrotum gradually enlarged, reaching “grapefruit” size at 6 weeks after the injury. He ultimately consulted his physician, who advised an operation. He requested a second opinion at our institution. Examination revealed a 12-cm, smooth, firm, nontransilluminating left scrotal mass. No definite intrascrotal structures were palpable, and tenderness was minimal. Ultrasonographic examination revealed a collection of fluid with fine internal echoes that surrounded a normal left testis (
Fig. 1
). At operation, a thickened tunica vaginalis was incised, and 200 ml of fluid was drained from a hematocele. The testis had a 4-cm tear in the tunica albuginea through which seminiferous tubules bulged (
Fig. 2
). The tubules were completely covered by a translucent layer of tissue. The hematocele sac was excised. The patient recovered uneventfully.
Fig. 1 Transverse sonogram of left hemiscrotum of 29-year-old man 6 weeks after sustaining nonpenetrating left scrotal trauma. Portion of normal left testicle ( T ) is surrounded by fluid ( F ) that contains diffuse fine internal echoes, consistent with hematocele.
Fig. 2 Intraoperative photograph taken after excision and drainage of hematocele sac. Edges of thickened tunica vaginalis are retracted; note exposed left testis ( T ), head of epididymis ( E ), and seminiferous tubules ( ST ) that were covered with reepithelialized layer of tissue.
A follow-up ultrasound study 1 month later showed no residual hematocele and a normal left testis (
Fig. 3
). At 9 months, the patient had minimal swelling and tenderness and a normal-sized testis. His wife was 6 months' pregnant.
Fig. 3 Follow-up longitudinal sonogram of left hemiscrotum ( S ) 1 month after surgical exploration, demonstrating normal left testicle ( T ) and no evidence of residual hematocele.
DISCUSSION
Blunt trauma to the scrotum causes testicular rupture in approximately 45% of cases.
1
Cass AS
Testicular trauma.
J Urol. 1983; 129 : 299-300
,
2
Živković SM
Janjic G
Traumatic rupture of the testis and epididymis.
J Pediatr Surg. 1980; 15 : 287-288
Abstract
Scopus (6)
Google Scholar
,
3
McCrea LE
Rupture of the testicle.
J Urol. 1951; 66 : 270-273
Abstract
,
4
Wesson MB
Traumatism of the testicle: report of a case of traumatic rupture of a solitary testicle.
Urol Cutan Rev. 1946; 50 : 16-19
A tear in the tunica albuginea allows herniation of seminiferous tubules into the potential space within the tunica vaginalis. A reactive hydrocele often develops, and with concomitant bleeding, a hematocele may eventually form.
Nausea, vomiting, pain, and an enlarging scrotal mass usually prompt the patient to seek medical attention early.
5
Wasko R
Goldstein AG
Traumatic rupture of the testicle.
J Urol. 1966; 95 : 721-723
PubMed
,
6
Pohl DR
Johnson DE
Robison JR
Bilateral testicular rupture: report of a case.
J Urol. 1968; 99 : 772-773
Physical examination discloses a variable-sized nontransilluminating scrotal mass.
The differential diagnosis includes epididymitis, orchitis, torsion of the testis or testicular appendages, reactive hydrocele, hematocele, ruptured varicocele, and testicular tumor.
2
Živković SM
Janjic G
Traumatic rupture of the testis and epididymis.
J Pediatr Surg. 1980; 15 : 287-288
Abstract
Scopus (6)
Google Scholar
,
5
Wasko R
Goldstein AG
Traumatic rupture of the testicle.
J Urol. 1966; 95 : 721-723
The correct diagnosis is difficult to make on the basis of the history and physical examination alone.
Recently, the availability of ultrasonography of the scrotum has decreased some of the confusion associated with a nontransilluminating scrotal mass. This procedure enables the distinction of fluid and solid masses, identifies hydroceles and hematoceles, and produces an architectural image of the impalpable testicle within a fluid-filled sac (
Fig. 1
,
Fig. 3
).
7
Friedman SG
Rose JG
Winston MA
Ultrasound and nuclear medicine evaluation in acute testicular trauma.
J Urol. 1981; 125 : 748-749
,
8
Albert NE
Testicular ultrasound for trauma.
J Urol. 1980; 124 : 558-559
,
9
Anderson KA
McAninch JW
Jeffrey RB
Laing FC
Ultrasonography for the diagnosis and staging of blunt scrotal trauma.
J Urol. 1983; 130 : 933-935
In a case of rupture of the testis, the exact location of the injury may not be visualized with ultrasonography, but a focal area of altered echo pattern as a result of hemorrhagic or infarcted parenchyma is typically discernible.
10
McAninch JW
Kahn RI
Jeffrey RB
Laing FC
Krieger MJ
Major traumatic and septic genital injuries.
J Trauma. 1984; 24 : 291-297
Crossref
The recommended treatment of a ruptured testicle is surgical exploration and repair.
1
Cass AS
Testicular trauma.
J Urol. 1983; 129 : 299-300
Closure of the tunica albuginea should be undertaken with or without partial trimming of extruded or necrotic seminiferous tubules.
11
Campbell MF
Pediatric Urology. Vol 2. Macmillan Publishing Company , New York 1937 : 188
Early intervention increases the possibility of testicular salvage.
12
McConnell JD
Peters PC
Lewis SE
Testicular rupture in blunt scrotal trauma: review of 15 cases with recent application of testicular scanning.
J Urol. 1982; 128 : 309-311
,
13
Rao KG
Traumatic rupture of testis.
Urology. 1982; 20 : 624-625
Conservative therapy without operation is discouraged and has resulted in an orchiectomy rate as high as 45%.
1
Cass AS
Testicular trauma.
J Urol. 1983; 129 : 299-300
In one study, two thirds of the patients with a ruptured testicle who underwent exploration after a delay of 3 or more days eventually had to undergo orchiectomy.
14
Del Villar RG
Ireland GW
Cass AS
Early exploration following trauma to the testicle.
J Trauma. 1973; 13 : 600-601
Crossref
Scopus (25)
Infection can cause necrosis of the testis, or testicular atrophy may result from the presence of a tense hematocele or from massive herniation of the seminiferous tubules through an extensive tear.
The case presented herein illustrates for the first time in humans the healing reaction in which reepithelialization occurred between the split edges of the tunica albuginea, covering the herniated seminiferous tubules. Mesothelial healing has recently been demonstrated experimentally in the tunica albuginea of the rat. Cellular ingrowth from the wound edges proceeded to cover and seal the exposed parenchyma within 4 to 5 days. Adhesions to the tunica vaginalis did not occur, and tissue integrity remained intact.
15
Whitaker D
Papadimitriou J
Mesothelial healing: morphological and kinetic investigations.
J Pathol. 1985; 145 : 159-175
Crossref
Although we report the healing process that occurred in an untreated case of rupture of the tunica albuginea, we do not advocate delayed or conservative treatment of severe testicular trauma.
REFERENCES
Cass AS
Testicular trauma.
J Urol. 1983; 129
:
299-300
Živković SM
Janjic G
Traumatic rupture of the testis and epididymis.
J Pediatr Surg. 1980; 15
:
287-288
McCrea LE
Rupture of the testicle.
J Urol. 1951; 66
:
270-273
Wesson MB
Traumatism of the testicle: report of a case of traumatic rupture of a solitary testicle.
Urol Cutan Rev. 1946; 50
:
16-19
Wasko R
Goldstein AG
Traumatic rupture of the testicle.
J Urol. 1966; 95
:
721-723
Pohl DR
Johnson DE
Robison JR
Bilateral testicular rupture: report of a case.
J Urol. 1968; 99
:
772-773
Friedman SG
Rose JG
Winston MA
Ultrasound and nuclear medicine evaluation in acute testicular trauma.
J Urol. 1981; 125
:
748-749
Albert NE
Testicular ultrasound for trauma.
J Urol. 1980; 124
:
558-559
Anderson KA
McAninch JW
Jeffrey RB
Laing FC
Ultrasonography for the diagnosis and staging of blunt scrotal trauma.
J Urol. 1983; 130
:
933-935
McAninch JW
Kahn RI
Jeffrey RB
Laing FC
Krieger MJ
Major traumatic and septic genital injuries.
J Trauma. 1984; 24
:
291-297
Campbell MF
Pediatric Urology.
Vol 2.
Macmillan Publishing Company
,
New York
1937
:
188
McConnell JD
Peters PC
Lewis SE
Testicular rupture in blunt scrotal trauma: review of 15 cases with recent application of testicular scanning.
J Urol. 1982; 128
:
309-311
Rao KG
Traumatic rupture of testis.
Urology. 1982; 20
:
624-625
Del Villar RG
Ireland GW
Cass AS
Early exploration following trauma to the testicle.
J Trauma. 1973; 13
:
600-601
View
in Article
Whitaker D
Papadimitriou J
Mesothelial healing: morphological and kinetic investigations.
J Pathol. 1985; 145
:
159-175
Article info
Identification
DOI:https://doi.org/10.1016/S0025-6196(12)62640-8
Copyright
© 1986 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Fig. 1
Fig. 2
Fig. 3
Figures
Fig. 1 Transverse sonogram of left hemiscrotum of 29-year-old man 6 weeks after sustaining nonpenetrating left scrotal trauma. Portion of normal left testicle ( T ) is surrounded by fluid ( F ) that contains diffuse fine internal echoes, consistent with hematocele.
Fig. 2 Intraoperative photograph taken after excision and drainage of hematocele sac. Edges of thickened tunica vaginalis are retracted; note exposed left testis ( T ), head of epididymis ( E ), and seminiferous tubules ( ST ) that were covered with reepithelialized layer of tissue.
Fig. 3 Follow-up longitudinal sonogram of left hemiscrotum ( S ) 1 month after surgical exploration, demonstrating normal left testicle ( T ) and no evidence of residual hematocele.
| https://www.mayoclinicproceedings.org/article/S0025-6196(12)62640-8/fulltext |
Death and the Found Object: Virginia Woolf, Lucy Skaer, and Becky Beasley | Article index | Articles | British Art Studies
An online, open-access and peer-reviewed academic journal for research on all aspects of British art, architecture and visual culture.
ArticlebyMargaret Iversen
Lucy Skaer, (Death), 2006, permanent marker pen and pencil on paper.
Digital image courtesy of Lucy Skaer (all rights reserved).
Abstract
Virginia Woolf's short story “Solid Objects” (1920) offers a thought-provoking starting point for reflection on the continuing preoccupation of many artists with the found object. The story implies that the disconcerting and fascinating effect of certain found objects is bound up with their relation to death. With reference to Woolf and to the philosopher Maurice Blanchot, this article argues that the work produced by two contemporary British artists, Becky Beasley and Lucy Skaer, occupies a liminal space on the threshold between life and death, like the objects in Woolf’s story.
Introduction
2
I would add to this list a further and crucially important type of liminality: the objects in the story occupy a space on the threshold between life and death. Of course, Woolf’s prose style more generally can also be considered liminal since it resists determinate, solid signification.
image
(and sometimes an aesthetic object like those ‘outmoded objects, fragmented, unusable, almost incomprehensible, perverse,’ which Breton loved.) In this case the tool, no longer disappearing into its use,
appears
”. That which
appears
in this strange way is “the object’s double”.
3
This fascinating phantom-double, which no longer refers to anything beyond itself, grips the imagination. Similarly, the stuff of art and poetry can only appear when released from its communicative or referential functions. In short, according to Blanchot, a thing only appears when it is dead, obsolescent, or useless.
4
5
Yet “Solid Objects” does more than provide a critical framework; it is, in my view, exemplary of an artistic engagement with the found object that ties it closely to death. Accordingly, it sits alongside and has the same status as the works of visual art.
6
Given that Beasley and Skaer draw inspiration from fiction, it seems especially important to make use of the resources that literature and literary criticism offer the art historian. A brief introduction to the two artists, highlighting some of their shared concerns, is followed by sections devoted to “Solid Objects”, Skaer, and Beasley.
7
Liminality
Lucy Skaer’s imagination is fed by her reading of Woolf and Blanchot, and also touched by Surrealism. This latter aspect of her work was evident in her fugitive public intervention of placing a scorpion and diamond side by side on an Amsterdam sidewalk. The work, which exists now as a photograph,
Scorpion/Diamond
Further Consumption
/
Blue Window
(2017), for instance, consists of an old sash window and frame removed from her childhood bedroom and displayed either propped against the gallery wall or lying flat on the floor (
fig. 1
8
The piece occupies a shallow liminal space between inner and outer worlds, between representation and refusal.
DOI Figure 1.Lucy Skaer, Consumption/Blue Window, 2017, window frame with lapis lazuli.Digital image courtesy of Lucy Skaer / Photograph Ausgustin Garza (all rights reserved).
DOI
Although Becky Beasley’s practice draws upon works of fiction from Herman Melville to Franz Kafka to Thomas Bernhard, she does not make direct reference to Woolf. However, since both she and Skaer find inspiration in Blanchot’s writing, many of their concerns overlap. For instance, the motif of the blocked window occurs in both artists’ work, although in Beasley’s case the medium is photographic.
Curtains (I), (II), (III)
(2009) consists of three silver gelatin prints of curtains glazed with green acrylic (
fig. 2
).
9
10
Or, as she put it elsewhere, “I’m interested in retaining an essential opacity”.
11
Silence, opacity, and ambiguity are, for her, means that art has for avoiding cliché and resisting power. The extended subtitles of
Curtains
only obliquely refer to the motif. They consist of excerpts from an interview with pianist Glenn Gould about his habit of spending three hours in the recording studio in a state of uncertainty, experimenting with a composition until he finds a rendition suitable for recording.
12
Gould was famous for being a brilliant recording artist who adamantly refused to perform live concerts—a fact that must be relevant to Beasley’s sense of photography as a medium. Although it is not “live”, photography bears a strange relationship to the real, and so, as she said, it “pulsates with the potential to destroy order, habit and jargon”.
13
The photograph, as she so pithily put it, is “dead, yet vital”.
14
In
Curtains
, this ambiguity is manifested by the contrast between the blocked view and reticent treatment of the curtain motif, on the one hand, and the luminous blue-green glazing, on the other. In these artworks by Skaer and Beasley, the function of the windows is negated, forcing an encounter with the mute object itself. They embody the essential ambiguity and liminality of art.
15
DOI Figure 2.Becky Beasley, Curtains (I), (II), (III), 2009, three photographs, gelatin silver prints on paper, archival tape, green acrylic glazing, each 181 × 70.5 cm. Collection of Tate (P82486).Digital image courtesy of Becky Beasley / Photograph Galeria Plan B (all rights reserved).
Solid Objects
16
One man, Charles, starts skimming flat stones over the water, while the other, John, digs his hand “down, down” into the wet sand, where he discovers a lump of green-tinted glass “so thick as to be almost opaque; the smoothing of the sea had completely worn off any edge or shape”. He pockets the piece of glass and later places it on his mantelpiece.
17
18
19
—
the tropes of dreamwork
—
"transform such everyday objects into veritable philosopher’s stones; they become infinitely displaceable, perpetually unstable”.
20
Freud himself noted psychoanalysts’ tendency “to divine secret and concealed things from unconsidered and unnoticed details, from the rubbish heap, as it were, of our observations”.
21
Surrealist artists and writers were attracted to this same rubbish heap. Because the surrealist found object is marked by love, loss, and anxiety (Eros and the death drive), it should be clearly differentiated from Marcel Duchamp’s readymade, which is mass-produced and governed by an aesthetic of indifference.
22
23
Objects placed on a mantelpiece are normally thought to consolidate the collector’s identity. In her 1927 essay “Street Haunting”, Woolf acknowledged this function of objects displayed in the home: “for there we sit surrounded by objects which perpetually express the oddity of our own temperaments and enforce the memories of our own experience”.
24
Although John’s collection certainly does express the oddity of his temperament, it does nothing to enforce his memory of the past or affirm his sense of personal identity. On the contrary, as Douglas Mao pointed out, John does not possess his objects; rather, we should speak of his “profound possession
by
things”.
25
26
None of the commentaries I have seen remark on the mention in the opening paragraph of a single and prominent object on the beach where the two men pause to rest. Yet it seems to me probable that the “ribs and spine of the stranded pilchard boat” is to be understood as a whale-sized, skeletal
memento mori
27
Rose argued that Woolf’s proximity to death was the very source of her artistic vision. She refers to Michael Levenson’s
The Genealogy of Modernism
, which includes a discussion of the well-known opening stanza of T.S. Eliot’s
The Waste Land
(1922), the first section of which is entitled “The Burial of the Dead” and begins:
April is the cruellest month, breeding
Lilacs out of the dead land, mixing
Memory and desire, stirring
Dull roots with spring rain.
Winter kept us warm, covering
Earth in forgetful snow, feeding
A little life with dried tubers.
DOI
Levenson observes that these lines issue from a point of view underground, more specifically from the point of view of a corpse—but a corpse that breeds and sprouts. Rose concludes that the catastrophes experienced by both Eliot and Woolf drove their imaginations underground.
28
The same relation to death orients John’s imagination. His objects, retrieved from the ground or underground, exert a force akin to gravity pulling him away from the high ground of received social convention, careerism, and timekeeping. As Hermione Lee pointed out, in Woolf’s fiction, “silence, darkness, death pull against social convention”.
29
30
Lucy Skaer
DOI
Skaer’s work is both full of meaningful resonances and resistant to them, so it is not surprising to learn that she is attracted to Woolf’s more experimental fiction. In 2016, she produced an installation,
One Remove
(
fig. 3
), that was inspired by Woolf’s novel
The Waves
(1931).
31
Asked about this work, Skaer responded: “
The Waves
is a big influence, particularly the first chapter, where the world seems to start before language and then the utterances are spoken as if for the first time. There is an ambivalence towards language in my work, I think, which links perhaps to prehistory, time without narrative”.
32
Also important for her are the italicised impersonal interludes in
The Waves
The Waves
is composed of intertwined interior monologues of six friends as their lives merge and separate over the course of decades, from childhood to middle age. As one character observes, “meeting and parting, we assemble different forms, make different patterns”.
33
One Remove
they are rendered unfamiliar through rhythmical repetition and the apparent liquefaction of solid things. In the second interlude of
The Waves
, Woolf describes how the sun’s morning rays transform the interior of the house: “
Everything became softly amorphous, as if the china of the plate flowed and the steel of the knife were liquid
”.
34
One Remove
is an installation that aims to embody in the form of modified found objects something of the liquid, liminal world created by Woolf.
DOI Figure 3.Lucy Skaer, One Remove, 2017, installation view.Digital image courtesy of Lucy Skaer / Photograph Ausgustin Garza (all rights reserved).
DOI
Skaer’s lapis-encrusted window,
Further Consumption
/
Blue Window
, is part of a series of enigmatic pieces made from reconfigured and embellished wooden floorboards and doors taken from her childhood home. This group of works was first exhibited in a one-person show called
Una
Casa Más Pequena (A Smaller House)
, at the Museo Tamayo in Mexico City in 2017. In the catalogue, Skaer described it as “an exhibition made from my childhood home, devouring parts of the building”.
35
This kind of cannibalisation is at work in
Eccentric Boxes
(2016–2019). It consists of a series of wooden crates made with old floorboards lifted from the house and encrusted with strips of lapis, slices of ceramic bowls, casts of an unusual stick collection, and a deconstructed small mahogany chest of the sort that might hold a collection of small treasures (
fig. 4
36
Mourning the imminent loss of her family home, she preserved a smaller version of it as an installation.
Eccentric Boxes
DOI Figure 4.Lucy Skaer, Eccentric Boxes, 2016–2019, wooden box.Digital image courtesy of Lucy Skaer / Photograph Ausgustin Garza (all rights reserved).
DOI
Dance of Death
frescos in Basel, she said: “That’s why death plays a part in the piece, as it has done in others I’ve made, because death crosses between these two realms. It’s the symbolism of death which interests me, rather than the actual event”.
37
DOI
The symbolism of death dominated Skaer’s Turner Prize exhibition at Tate Britain in 2009, for which she exhibited two whale skeletons—large-scale
memento mori
.
Leviathan Edge
(2009), consisted of the mysterious skeleton of a sperm whale, borrowed from a natural history museum. The skeleton was obscured by a specially constructed partition with slits that allow only partial views. Seen as a series of optical fragments, it had to be synthesised by the viewer. The other whale exhibited was a 1:1 scaled drawing of the skeleton of a pygmy right whale. This drawing, called
(Death)
(2006), forms part of a series of so-called “Black Drawings” (
fig. 5
38
The critic Isla Leaver-Yap stressed the effect of the black drawings’ “moment of encounter”. When one is looking at
(Death)
, the dark solidity of the surface pattern “occasionally gives way to an image seemingly embedded within the surface of the drawing”, but only briefly, as “the whale manages to evade definitive presence”.
39
The experience of Skaer’s drawing recalls Blanchot’s account of the disturbing but fascinating elusiveness of the image. As philosopher Simon Critchley put it, image fascination “describes the experience when we are caught by something that we can neither grasp fully nor relinquish”, such as the vanishing face of Eurydice.
40
Skaer memorably remarked that she aimed at “a re-creation of the feeling of the whale moving beneath you”.
41
DOI Figure 5.Lucy Skaer, (Death), 2006, permanent marker pen and pencil on paper.Digital image courtesy of Lucy Skaer (all rights reserved).
DOI
42
This is an allusion to the middle non-narrative section of Woolf’s
To the Lighthouse
, “Time Passes”, in which the deaths of three characters are briefly noted in brackets in the course of an extended description of the corrosive effects of time, wind, and rain on a seaside house abandoned during the Great War. Skaer’s allusion to “Time Passes” might explain the parentheses around the title of her drawing,
(Death)
.
DOI
Becky Beasley
DOI
43
Gloss II
(2007), is a large matt silver gelatin print of a bookshelf-like structure that the artist had constructed and painted in matt and gloss black paint (
fig. 6
). The structure is a two-thirds scale model based on the proportions of an upright piano, but one emptied of its guts.
Gloss
was inspired by the artist’s reading of Thomas Bernhard’s novel
The Loser
(1983), which is the tragic story of two talented pianists whose careers are ruined by the presence of a third student, the exceptionally gifted Glenn Gould. The narrator-pianist gives away his piano, while the loser, destroyed by Gould’s perfect rendition of Bach’s
Goldberg Variations
, commits suicide.
44
DOI Figure 6.Becky Beasley, Gloss ll, 2017, black and white matt fibre-based photography, archival linen tape, eyelets, 172 × 210 cm.Digital image courtesy of Becky Beasley / Photograph Galeria Plan B (all rights reserved).
DOI
As the example of
Gloss
indicates, Beasley finds in fiction a source of inspiration. Her hybrid photograph/sculpture
Literary Green
(2009) was inspired by Herman Melville’s novella
Bartleby, The Scrivener: A Story of Wall Street
, published in 1853 (
fig. 7
45
Beasley’s interest in Bartleby was no doubt partly inspired by Blanchot’s commentary on the ambiguous stance of Melville’s strange character. In his book
The Writing of the Disaster
46
Similarly, Beasley is an artist who attempts to find a third position between explicit political opposition and submission.
Bartleby
47
Literature, for Blanchot, is a special use of language that seeks the silence of things before the imposition of naming: “The language of literature is the search for this moment that precedes literature”.
48
DOI Figure 7.Becky Beasley, Literary Green, 2009, black and white matt gelatin silver print, green acrylic glass, steel, 218 × 154 × 45 cm.Digital image courtesy of Becky Beasley / Photograph Galeria Plan B (all rights reserved).
DOI
Literary Green
Literary Green
is hinged somewhere between an architectural fitting, an object, and an image. This arrangement invites the viewer to imagine standing in Bartleby’s position at a high clerk’s desk behind the screen, effectively transforming his and our space into an enclosure, a box or corner, for solitary, immobile reverie.
49
A way of inhabiting space and resisting authority is elided in the work. Beasley cites Blanchot’s writing on cadavers (objects) and corners (spaces) and notes that these are forms with which she has long been “compelled and obsessed” and, further, that they “would be the way I would, with hindsight, orient my journey most specifically”.
50
Literary Green
51
DOI
Spring Rain
52
One reviewer of the
Spring Rain
exhibition noted this change, commenting that “her early sculptures and photographs were brooding, mute and darkly glowering, communicating the inability or refusal to speak”. More recently, however, the work has softened or lightened.
53
DOI
54
Later, he takes an evening walk in a light spring rainfall which seems to excite and soften him. The darkness and cold mist allow him, briefly, to feel his own emotions, to talk, and to cry. It is very likely that the title and theme of Malamud’s story allude to Eliot’s description of how spring rain breeds lilacs, mixes memory and desire, and stirs dull roots. The exhibition included
Family
Cucurbitaceae I–IV
(2013), a series of four hand-tinted silver prints of a family of oddly shaped, home-grown gherkins posed against a stark white ground. There were also strings of small brass-cast gherkins arranged as a motorised mobile suspended from the ceiling,
Spring Rain (Family)
(2013). Although the size and shape of the gherkins invite a tactile grip, they are prickly—perhaps suggesting the inevitable ambivalence of family relations.
55
Beasley wrote: “For this reader, it is a story about love and how hard love is to communicate, and how the effort to do so can be extremely tender”.
56
Another exhibit in
Spring Rain
,
Eclipse (I) (Pearwoods Nos. I & III)
(2013), is a small abstracted wooden couple painted black and standing on a table. Each personage rotates on its own axis, making their gendered peg and hole intermittently align—perhaps hinting at the possibility of connection. Beasley also displayed a series of photographs of this odd couple (
fig. 8
). These and other works in the show hint at the poignancy and difficulty of love and family relations. Because they are both abstract and intimate, our reception of them is likewise twofold.
57
They recall Blanchot’s idea of that fascination as involving both separation and contact: “although at a distance it seems to touch you with a gripping contact”.
58
DOI Figure 8.Becky Beasley, Extensions (Elaboration No.1), 2012, gelatin silver print, 164.5 × 123 cm.Digital image courtesy of Becky Beasley / Photograph Galeria Plan B (all rights reserved).
DOI
The Waves
in which he stated that her work “seems like one of the rare creations of our time”.
59
In a later review article, on the French translation of Woolf’s diaries, he insisted upon the necessity of her moments of despair: “She must encounter the void … in order, starting from this void, to begin to see, even if it be the humblest things, and to grasp what she calls
reality
”.
60
This
reality
, in italics, emerges from an encounter with the “void”, and this, wrote Blanchot, was the risk Woolf took at every step of her writing practice. “Down there, in
The Waves
, roars the risk of a work in which one has to disappear”.
61
Her work eludes our grasp, linked as it is “to dispersion, to intermittency, to the fragmented brilliance of images, to the shimmering fascination of the instant”.
62
Acknowledgements
DOI
This article began life as notes for a symposium presentation in conjunction with the exhibition
Transparent Things
. The show, which included work by fourteen artists, was installed at Goldsmiths Centre for Contemporary Art, London. It opened in late February 2020 and closed prematurely owing to the COVID-19 lockdown, and the symposium was cancelled. Curated by Natasha Hoare, the exhibition proposed that Nabokov’s fictional evocation of the perception of objects in
Transparent Things
About the author
Margaret Iversen is professor emerita at the University of Essex, England. Her books include Photography, Trace and Trauma(2017); Beyond Pleasure: Freud, Lacan, Barthes(2007); and Alois Riegl: Art History and Theory(1993). She is co-editor with Diarmuid Costello of special issues for Art History, “Photography after Conceptual Art”, (2010) and for Critical Inquiry, “Agency and Automatism: Photography and Art since the Sixties” (2012) .She is co-author with Stephen Melville of Writing Art History(2010). She also edited the Documents of Contemporary Artvolume on Chance(2010). Her current work continues to explore the overlapping fields of contemporary art, photography, psychoanalysis, and literature.
Footnotes
Virginia Woolf, “Phases of Fiction”, Part 1, The Bookman(April 1929): 124, 125. Reprinted in Woolf, Granite and Rainbow: Essays by Virginia Woolf, ed. Leonard Woolf (London: Harcourt Brace Jovanovich, 1958), 95.
1
Peter Schwenger, The Tears of Things: Melancholy and Physical Objects(Minneapolis: University of Minnesota Press, 2006), 82–83.
2
Maurice Blanchot, “The Two Versions of the Imaginary”, in The Space of Literature, trans. Ann Smock (Lincoln, NE: University of Nebraska Press, 1982), 258. The Breton quotation is from Nadja(1928), trans. Richard Howard (London: Penguin Books 1999), 52.
3
John Stezaker, “An Interview with John Stezaker and Andrew Warstat”, Parallax16, no. 2 (April 2010): 75. Stezaker taught Beasley when she was a student at art school.
4
I wrote an article that made similar critical use of Woolf and the literary critic Ann Banfield: “The World without a Self: Edward Hopper and Chantal Akerman”, Art History41, no. 4 (September 2018): 742–60. One art historian who makes good use of the resources of literature for art criticism is Briony Fer. See, for example, her use of Proust to frame a discussion of installation: “The Somnambulist’s Story: Installation and Tableau”, Oxford Art Journal24, no. 2 (January 2001): 75–92.
5
In her introductory chapter to the special issue of Art History“Creative Writing and Art History”, Catherine Grant explains that the volume addresses the relationship between creative writing and art-historical writing. This article, in contrast, is mainly concerned with artists’ creative engagement with literary texts. See Catherine Grant and Patricia Rubin, eds., Creative Writing and Art History (Art History Special Issues): 8(Oxford: Wiley-Blackwell, 2012).
6
Other artists one could productively discuss in these terms include Felix Gonzalez-Torres, David Hammons, and Zoe Leonard. Beasley’s practice includes writing, as does the practice of an increasing number of artists. I am thinking particularly of Moyra Davey and Susan Morris, about whom I have written: Margaret Iversen, “The Diaristic Mode in Contemporary Art after Barthes”, Art History44, no. 4 (September 2021), 798–822.
7
Isla Leaver-Yap, “Lucy Skaer’s ‘Black Drawings’: Encounter and Aftermath”, in Fiona Bradley, ed., Lucy Skaer(Edinburgh: Fruitmarket Gallery, 2008), exhibition catalogue, 94.
8
Beasley’s triptych is in the Tate collection. The tinted glazing would seem to allude to the practice common in silent movies of tinting monochrome film various colours to evoke different moods or times of day.
9
Beasley, “Based on Paper: A Conversation (with John Slyce)”, American Letter(London: Laura Bartlett Gallery, 2007), 43. Published to accompany the exhibition Becky Beasley: Three Notable American Novellas, Laura Bartlett Gallery, London.
10
Beasley, Becky Beasley in Conversation with Claire Scanlon, ed. Adam Gibbons and Eva Wilson (Hastings: Nero Books, 2019), 41.
11
The long subtitles are as follows: Curtains (I)(There have been many occasions when I have recorded something and I have come into the studio at 10 o’clock on a Monday morning and really been in sixteen, not just two different minds, but sixteen different minds as to how it should go...); Curtains (II)(... and this sense of option is really quite a marvellous luxury. It’s a luxury that you cannot permit yourself in the concert hall, you simply cannot, you would be dead if you walked on stage not being quite certain.); Curtains (III)(... But in fact what happens is that by one o’clock in the afternoon having given it three hours of work I may not have come to any definitive conclusions, but I will finally have selected one of these options and made it my priority, and out of this created a viable performance.) (Glenn Gould), 2009.
12
Beasley, “The Man without References”, in American Letter, 33.
13
Beasley, “Based on Paper: A Conversation”, 43.
14
Another contemporary artist who has made the blocked window a repeated motif is Anna Barriball.
15
Virginia Woolf, “Solid Objects”, in Selected Short Stories(London: Penguin Books, 2000), 61–67. Since the story is so short, detailed page references are unnecessary.
16
In her diary for 1919, Woolf reported that her chemist gave her a long-coveted green glass jar. She remarked that “glass is the best of all decorations, holding the light and changing it”. Woolf, The Diary of Virginia Woolf, vol. 1, ed. Anne Olivier Bell (Harmondsworth: Penguin, 1981), 170.
17
Sigmund Freud, “The Theme of the Three Caskets” (1913), in The Standard Edition of the Complete Psychological Works of Sigmund Freud, vol. 12, ed. James Strachey (London: Hogarth Press, 1958), 289–302.
18
Woolf, The Diary of Virginia Woolf,vol. 2, ed. Anne Olivier Bell (Harmondsworth: Penguin, 1981), 305.
19
John Forrester, “Collector, Naturalist, Surrealist”, in Dispatches from the Freud Wars: Psychoanalysis and Its Passions(Cambridge, MA: Harvard University Press, 1997), 125.
20
Sigmund Freud, “The Moses of Michelangelo” (1914), in Standard Edition, vol. 13, 265.
21
See Margaret Iversen, “Readymade, Found Object, Photograph”, Art Journal63, no. 2 (Summer 2004): 44–57. See also Iversen, Photography, Trace, and Trauma(Chicago: University of Chicago Press, 2017).
22
D.W. Winnicott, “Primitive Emotional Development”, in The Collected Papers of D.W. Winnicott, vol. 2, 1939–1945, ed. Lesley Caldwell and Helen Taylor Robinson (Oxford: Oxford University Press, 2017), 362. See also Winnicott, “Transitional Objects and Transitional Phenomena” (1951), Playing and Reality(London: Routledge, 1990), 1–34.
23
Woolf, “Street Haunting: A London Adventure”, in Street Haunting and Other Essays, ed. Stuart N. Clarke (London: Vintage Books, 2014), 226.
24
Douglas Mao, Solid Objects, Modernism and the Test of Production(Princeton: Princeton University Press, 1998), 27.
25
For an alternative reading, see Bill Brown, “The Secret Life of Things (Virginia Woolf and the Matter of Modernism)”, Modernism and Modernity6, no. 2 (April 1999): 4–5, 12. Brown’s article is primarily concerned with post-war scarcity and the role that particular materials, including glass, china, and iron, played in the political economy of the period and in Woolf’s imagination. See also Brown, “Things”, Critical Inquiry28, no.1 (Autumn, 2001): 1–22.
26
See David Bradshaw, “Mrs. Dalloway and the First World War”, British Library, 25 May 2016, https://www.bl.uk/20th-century-literature/articles/mrs-dalloway-and-the-first-world-war.
27
Jacqueline Rose, “Virginia Woolf and the Death of Modernism”, in On Not Being Able to Sleep: Psychoanalysis and the Modern World(London: Vintage, 2004), 85. Rose examines Woolf’s early novel, The Voyage Out(1915). See also Michael H. Levenson, A Genealogy of Modernism: A Study of English Literary Doctrine, 1908– 1922(Cambridge: Cambridge University Press, 1984).
28
Hermione Lee, Virginia Woolf(London: Vintage, 1997), 375.
29
See Blanchot, “The Gaze of Orpheus”, in The Gaze of Orpheus and Other Literary Essays, trans. Lydia Davis (Barrytown, NY: Station Hill Press, 1981), 99–104.
30
One Remove
, curated by Natasha Hoare, was held at the Witte de With Centre for Contemporary Art, Rotterdam, 2016. It was one of a series of shows called
Para/Fictions
that involved five artists making new work that responded to a work of fiction. See
https://lucyskaer.com/exhibitions/one-remove
.
31
Skaer, email correspondence with the author, June 2020.
32
Woolf, The Waves(London: Leonard and Virginia Woolf at the Hogarth Press, 1933), 184.
33
Woolf, The Waves(London: Leonard and Virginia Woolf at the Hogarth Press, 1933), 29–30.
34
The catalogue is available online:https://lucyskaer.com/exhibitions/una-casa-m-s-pequena. See also Gallery guide for Lucy Skaer, Sentiment, at Peter Freeman, Inc., New York, 2018,https://www.galleriesnow.net/shows/lucy-skaer-sentiment/.
35
Skaer, “Leaving the House”, conversation with Anna Reid, British Art Talks, podcast audio, 28 October 2022. Paul Mellon Centre for Studies in British Art, London,https://audioboom.com/posts/7715859-lucy-skaer-leaving-the-house. Curiously, Beasley also made a piece out of twigs collected by her father. She made brass casts of twigs and fixed them together to form a long arm suspended from a device on the ceiling that made it revolve at one rpm. The piece is called Bearings, but the revolving pointer, like the spinning needle of a compass, suggests a loss of bearings.
36
Cited in David Pollock, “Renaissance Woman: Lucy Skaer”,
The List
, no. 603 (22 May 2008),
https://list.co.uk/news/35043/lucy-skaer
.
37
Chris Sharp, “Lucy Skaer at Kunsthalle Basel”, Art in America97, no. 8 (September 2009): 159. The drawing was first exhibited as part of the show Leonora, at the Elisabeth Kaufmann Gallery, Zurich, 2006.
38
Leaver-Yap, “Lucy Skaer’s ‘Black Drawings’”, in Lucy Skaer, ed. Fiona Bradley (Edinburgh: Fruitmarket Gallery, 2008, 94, exhibition catalogue.
39
Simon Critchley, Very Little … Almost Nothing: Death, Philosophy and Literature(London: Routledge, 2004), 44.
40
Skaer, cited in Melissa Gronlund, “Mining for Gold”, Frieze111 (November–December 2007): 128,https://www.frieze.com/article/mining-gold-0
41
Jac Mantle, “Lucy Skaer: A Brief History of Time”, The Skinny(September 2013),https://www.theskinny.co.uk/art/interviews/lucy-skaer-a-brief-history-of-time.
42
Beasley, “Being Silence, in Conversation with Becky Beasley”, IIIIXIII( Four by Three Magazine), Silence Issue (July 2016): n.p., https://christine-jakobson.squarespace.com/issue/silence/becky-beasley-interview .
43
Thomas Bernhard, The Loser, trans. Jack Dawson (London: Faber and Faber, 2019).
44
Beasley, “The Man without References”, 31, 33.
45
Blanchot, The Writing of the Disaster, trans. Ann Smock (Lincoln, NE: University of Nebraska Press, 1986), 17, 101.
46
Beasley, Becky Beasley in Conversation with Claire Scanlon.
47
Blanchot, “Literature and the Right to Death”, in The Gaze of Orpheus and Other Literary Essays, trans. Lydia Davis (Barrytown, NY: Station Hill Press, 1981), 46.
48
See also Gaston Bachelard, “Corners”, in The Poetics of Space, trans. Maria Jolas (Boston, MA: Beacon Press, 1969), 136–47.
49
Beasley, “Being Silence”. The discussion of the cadaver and mention of the corner can be found in Blanchot, “The Two Versions of the Imaginary”, 254–63.
50
Beasley, “Based on Paper: A Conversation”, 46.
51
Beasley, “Being Silence”. In this text, Beasley alludes to the personal significance of this change in her view of photography as a medium: “As a depressive, this turn has also had a profound effect on my life and how I make choices”. Beasley has described depression as a component of her practice. In the last couple of years, however, she discovered that peri-menopausal hormonal imbalances and undiagnosed autism have been important factors in her condition.
52
Laura McLean-Ferris, “Becky Beasley: Spring Rain”, Art Monthly364 (March 2013): 30–31.
53
Bernard Malamud, “Spring Rain” (1942), in Becky Beasley, Spring Rain(Bristol: Spike Island, 2012), 7, exhibition catalogue.
54
The cast gherkins also have a comic-erotic charge. They relate to Duchamp’s moulds of female genitalia and to the missing lead weights in a sash window that resulted in young Tristram Shandy being accidentally circumcised.
55
Beasley, “Three-Part Invention”, in Beasley, Spring Rain, 3. The exhibition had two other sources of inspiration: Duchamp’s Étant donnésand Laurence Sterne’s Tristram Shandy.
56
The overt references in Spring Rainto Duchamp’s Étant donnésprompt speculation that Beasley is positioning herself as working in his wake and yet, as a feminist woman with strong familial ties, also separating herself from him. The plan of the footprint of Duchamp’s peep show, rendered in black lino in the opening room, suggests a template for modification. As Parveen Adams observed, instead of presenting a female nude with legs spread, Beasley has hung a homespun checked tablecloth with a hole in the centre to accommodate a parasol. See Parveen Adams, “what would happen … if one were to stop copying?” in Beasley, Spring Rain, 19–25.
57
Blanchot, “The Essential Solitude”, in The Space of Literature,32.
58
For this review, written in 1937, see “Time and the Novel”, in Blanchot, Faux Pas, trans. Charlotte Mandell (Stanford, CA: Stanford University Press, 2001), 248. See also Mary Ann Caws and Nicola Luckhurst, eds., The Reception of Virginia Woolf in Europe(London: Continuum, 2002).
59
Blanchot, “The Failure of the Demon: The Vocation”, in The Book to Come[1959], trans. Charlotte Mandell (Stanford, CA: Stanford University Press, 2003), 113.
60
Blanchot, “Diary and Story”, in The Book to Come, 185.
61
Blanchot, “The Failure of the Demon”, in The Book to Come, 101.
62
Bibliography
Adams, Parveen. “what would happen … if one were to stop copying?”. In Becky Beasley, Spring Rain, 19–25. Bristol: Spike Island, 2012. Exhibition Catalogue. Spike Island, Bristol.
Bachelard, Gaston. “Corners”. In The Poetics of Space, translated by Maria Jolas, 136–47. Boston, MA: Beacon Press, 1969.
Beasley, Becky. “Based on Paper: A Conversation (with John Slyce)”. In American Letter, 41–47. London: Laura Bartlett Gallery, 2007. Published to accompany the exhibition Becky Beasley: Three Notable American Novellas: Laura Bartlett Gallery, London.
Beasley, Becky. Becky Beasley in Conversation with Claire Scanlon, edited by Adam Gibbons and Eva Wilson. Hastings: Nero Books, 2019.
Beasley, Becky. “Being Silence: In Conversation with Becky Beasley”. IIIIXIII( Four by Three Magazine), Silence Issue (July 2016): n.p.https://christine-jakobson.squarespace.com/issue/silence/becky-beasley-interview
Beasley, Becky. “The Man without References”. In American Letter, 30–35. London: Laura Bartlett Gallery, 2007. Published to accompany the exhibition Becky Beasley: Three Notable American Novellas: Laura Bartlett Gallery, London.
Beasley, Becky. “Three Part Invention”. In Spring Rain, 7–9. Bristol: Spike Island, 2012. Exhibition Catalogue: Spike Island, Bristol.
Bernhard, Thomas. The Loser, translated by Jack Dawson. London: Faber and Faber, 2019.
Blanchot, Maurice. “Diary and Story”. In The Book to Come[1959], translated by Charlotte Mandell, 183–188. Stanford, CA: Stanford University Press, 2003.
Blanchot, Maurice. “The Essential Solitude”. In The Space of Literature, translated by Ann Smock, 19–34. Lincoln, NE: University of Nebraska Press, 1982.
Blanchot, Maurice. “The Failure of the Demon: The Vocation”. In The Book to Come[1959], translated by Charlotte Mandell, 97–106. Stanford, CA: Stanford University Press, 2003.
Blanchot, Maurice. “The Gaze of Orpheus.” In The Gaze of Orpheus and Other Literary Essays, translated by Lydia Davis, 99–104. Barrytown, NY: Station Hill Press, 1981.
Blanchot, Maurice. “Literature and the Right to Death”. In The Gaze of Orpheus and Other Literary Essays, translated by Lydia Davis, 31–62. Barrytown, NY: Station Hill Press, 1981.
Blanchot, Maurice. “Time and the Novel”. In Faux Pas, translated by Charlotte Mandell, 248–51. Stanford, CA: Stanford University Press, 2001.
Blanchot, Maurice. “The Two Versions of the Imaginary”. In The Space of Literature, translated by Ann Smock, 254–63. Lincoln, NE: University of Nebraska Press, 1982.
Blanchot, Maurice. The Writing of the Disaster, translated by Ann Smock. Lincoln, NE: University of Nebraska Press, 1986.
Bradshaw, David. “ Mrs. Dallowayand the First World War”. British Library (25 May 2016).https://www.bl.uk/20th-century-literature/articles/mrs-dalloway-and-the-first-world-war.
Breton, André. Nadja[1928], translated by Richard Howard. London: Penguin Books, 1999.
Brown, Bill. “The Secret Life of Things (Virginia Woolf and the Matter of Modernism)”. Modernism and Modernity6, no. 2 (April 1999): 1–28.https://doi.org/10.1353/mod.1999.0013
Brown, Bill. “Things”. Critical Inquiry28, no.1 (Autumn 2001): 1–22.https://doi.org/10.1086/449030
Caws, Mary Ann and Nicola Luckhurst, eds. The Reception of Virginia Woolf in Europe.London: Continuum, 2002.
Critchley, Simon. Very Little … Almost Nothing: Death, Philosophy and Literature. London: Routledge, 2004.https://doi.org/10.4324/9780203462935
Fer, Briony. “The Somnambulist’s Story: Installation and Tableau”. Oxford Art Journal24, no. 2 (January 2001): 75–92.https://doi.org/10.1093/oxartj/24.2.75
Forrester, John. “Collector, Naturalist, Surrealist”. In Dispatches from the Freud Wars: Psychoanalysis and Its Passions. 107–37. Cambridge, MA: Harvard University Press, 1997.
Freud, Sigmund. “The Moses of Michelangelo” (1914). In The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol. 13, edited by James Strachey, 209–38. London: Hogarth Press, 1953.
Freud, Sigmund. “The Theme of the Three Caskets” (1913). In The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol. 12, edited by James Strachey, 289–302. London: Hogarth Press, 1958.
Grant, Catherine and Patricia Rubin, eds. Creative Writing and Art History(Art History Special Issues): 8 .Oxford: Wiley-Blackwell, 2012.
Gronlund, Melissa. “Mining for Gold”. Frieze111 (November–December 2007): 107–37.https://doi.org/10.5040/9781474293761.0098
Iversen, Margaret. “The Diaristic Mode in Contemporary Art after Barthes”. Art History44, no. 4 (September 2021): 798–822.https://doi.org/10.1111/1467-8365.12587
Iversen, Margaret. Photography, Trace, and Trauma. Chicago: University of Chicago Press, 2017.https://doi.org/10.7208/chicago/9780226370330.001.0001
Iversen, Margaret. “Readymade, Found Object, Photograph”. Art Journal63, no. 2 (Summer 2004): 44–57.https://doi.org/10.1080/00043249.2004.10791125
Iversen, Margaret. “The World without a Self: Edward Hopper and Chantal Akerman”. Art History41, no. 4 (September 2018): 742–60.https://doi.org/10.1111/1467-8365.12398
Leaver-Yap, Isla, “Lucy Skaer’s ‘Black Drawings’”. In Lucy Skaer, edited by Fiona Bradley, 92–99. Edinburgh: Fruitmarket Gallery, 2008. Exhibition Catalogue: Fruitmarket Gallery, Edinburgh.
Lee, Hermione. Virginia Woolf. London: Vintage, 1997.
Levenson, Michael H. A Genealogy of Modernism: A Study of English Literary Doctrine, 1908– 1922.Cambridge: Cambridge University Press, 1984.
Malamud, Bernard. Spring Rain(1942). In Becky Beasley, Spring Rain, 7–9. Bristol: Spike Island, 2012. Exhibition Catalogue: Spike Island, Bristol.
Mantle, Jac. “Lucy Skaer: A Brief History of Time”. The Skinny, September 2013.https://www.theskinny.co.uk/art/interviews/lucy-skaer-a-brief-history-of-time.
Mao, Douglas. Solid Objects, Modernism and the Test of Production. Princeton: Princeton University Press, 1998.https://doi.org/10.1515/9781400822706
McLean-Ferris, Laura. “Becky Beasley: Spring Rain”. Art Monthly364 (March 2013): 30–31.
Pollock, David. “Renaissance Woman: Lucy Skaer”. The List, no. 603 (May 2008).https://list.co.uk/news/35043/lucy-skaer.
Rose, Jacqueline. “Virginia Woolf and the Death of Modernism”. In On Not Being Able to Sleep: Psychoanalysis and the Modern World, 72–88. London: Vintage, 2004.
Schwenger, Peter. The Tears of Things: Melancholy and Physical Objects. Minneapolis: University of Minnesota Press, 2006.
Sharp, Chris. “Lucy Skaer at Kunsthalle Basel”. Art in America97, no. 8 (September 2009): 159.
Skaer, Lucy. “Leaving the House”. Conversation with Anna Reid. British Art Talks(podcast audio). Paul Mellon Centre for Studies in British Art, London. Premiered on 28 October 2020.https://audioboom.com/posts/7715859-lucy-skaer-leaving-the-house.
John Stezaker. “An Interview with John Stezaker and Andrew Warstat”. In Parallax16, no. 2 (April 2010): 67–68.https://doi.org/10.1080/13534641003634697
Winnicott, D.W. “Primitive Emotional Development” (1945). In The Collected Works of D.W. Winnicott. Vol. 2, 1939–1945, edited by Lesley Caldwell and Helen Taylor Robinson. Oxford: Oxford University Press, 2017.https://www.oxfordclinicalpsych.com/view/10.1093/med:psych/9780190271343.001.0001/med-9780190271343-chapter-58
Winnicott, D.W. “Transitional Objects and Transitional Phenomena” [1951]. In Playing and Reality, 1–34 .London: Routledge, 1990.
Woolf, Virginia. The Diary of Virginia Woolf. Vols. 1 and 2, edited by Anne Olivier Bell. Harmondsworth: Penguin, 1981.
Woolf, Virginia. “Phases of Fiction”, Part 1. The Bookman. April 1929. Reprinted in Woolf, Granite and Rainbow: Essays by Virginia Woolf, edited by Leonard Woolf, 93–148. London: Harcourt Brace Jovanovich, 1958.
Woolf, Virginia. “Solid Objects”. In Selected Short Stories, edited by Sandra Kemp, 61–67. London: Penguin Books, 2000.
Woolf, Virginia. “Street Haunting: A London Adventure”. In Street Haunting and Other Essays, edited by Stuart N. Clarke, 225–40. London: Vintage Books, 2014.
Woolf, Virginia. The Waves. London: Leonard and Virginia Woolf at the Hogarth Press, 1933.
Imprint
Author
Margaret Iversen ORCID
Date
27 July 2022
Category
Article
Review status
Peer Reviewed (Double Blind)
Licence
CC BY-NC International 4.0
Downloads
PDF format
Article DOI
https://doi.org/10.17658/issn.2058-5462/issue-23/miversen
Cite as
Margaret Iversen, "Death and the Found Object: Virginia Woolf, Lucy Skaer, and Becky Beasley", British Art Studies, Issue 23, https://doi.org/10.17658/issn.2058-5462/issue-23/miversen
NextThe Black Prince, the Trinity, and the Art of Commemoration
| https://www.britishartstudies.ac.uk/index/article-index/death-and-the-found-object/search/dx.doi.org/article-category/look-first/year/wormworm.org |
Subsets and Splits