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UNION SAFE DEPOSIT BANK v | 90 Cal.Rptr.2d 36 (1999) | ptr2d361112 | Leagle.com
HULL J. Defendant debtor appeals from a deficiency judgment entered on a claim for breach of an indebtedness secured by a helicopter...ptr2d361112
UNION SAFE DEPOSIT BANK v. FLOYD
No. C027158.
View Case
Cited Cases
Citing Case
90 Cal.Rptr.2d 36 (1999)
76 Cal.App.4th 25
UNION SAFE DEPOSIT BANK, Plaintiff and Respondent,
v.
Alvie R. FLOYD, Defendant and Appellant.
Court of Appeals of California, Third District. https://leagle.com/images/logo.png
October 27, 1999.
As Modified November 3, 1999.
Attorney(s) appearing for the Case
Lillick & Charles, James S. Monroe and Eric K. Larson, San Francisco, for Defendant and Appellant.
Steinheimer, Riggio, Haydel & Mordaunt, Kevin M. Seibert, Darin T. Judd, Stockton, Daniel C. Cederborg, Oakland, and Robert J. Stumpf, Jr., for Plaintiff and Respondent.
Court of Appeals of California, Third District.
HULL, J.
Defendant debtor appeals from a deficiency judgment entered on a claim for breach of an indebtedness secured by a helicopter. Defendant contends the judgment is not supported by the evidence because, among other things, he did not receive adequate notice prior to sale of the collateral. We agree and reverse.
FACTS AND PROCEDURAL HISTORY
On December 26, 1991, William C. Moore Helicopter Services (the partnership), a general partnership composed of William C. Moore (Moore), David Le Beouf (Le Beouf), Peter Marek (Marek), and defendant Alvie Floyd (Floyd), borrowed $241,110 from plaintiff Union Safe Deposit Bank (the Bank). In connection with the loan, the partnership issued an installment note signed by all four partners and the Bank took a security interest in a 1979 Bell 206BIII helicopter (the helicopter) owned by the partnership. On February 12, 1993, the debt was refinanced, with the partnership executing a new installment note signed by Floyd, Moore, and Lyle Coe (Coe), a new partner.
The loan went into default in November 1993 and the Bank repossessed the helicopter. On August 12, 1994, the Bank sent, by certified mail, to the partnership and each partner, including Floyd, a notice of intention to sell the helicopter (the notice). The notice, entitled "NOTICE OF INTENTION TO SELL AND RIGHT TO REDEEM REPOSSESSED MOTOR VEHICLE," read, in relevant part: "NOTICE IS HEREBY GIVEN of the undersigned's intent to sell the repossessed motor vehicle at the expiration of 5 days from the date this notice was mailed ... and `by private or public sale whichever deems
[sic
] necessary at redemption address at close of business day.'" The notice further described the debtor's right to redeem within this five-day period. Finally, the notice warned that the debtor is
[90 Cal.Rptr.2d 38]
"subject to suit and liability if the amount obtained upon sale of the vehicle is insufficient to pay the contract balance and any other amounts due."
On August 15, a postal employee attempted, unsuccessfully, to deliver the notice to Floyd. A note was left in Floyd's mailbox informing him of the availability of the notice at the post office. An additional note to this effect was left in Floyd's mailbox on August 27. Defendant never came to pick up the notice and it was returned to the Bank on September 4.
Meanwhile, on August 18, the notice was sent to Big Valley Aviation, a company claiming a mechanic's lien on the helicopter. At the time, Floyd was the president of Big Valley Aviation.
The Bank hired Kenneth Yunker to sell the helicopter. Yunker inspected the machine and its log book and informed the Bank that "[a]ll the airframe had been maxed out, all the engine time ha[d] been maxed out...." Yunker also noted a problem with the "chip light" on the helicopter, indicating the possibility of "[m]ajor engine problems." 1Yunker informed the Bank a complete inspection would cost between $7,000 and $10,000 and estimated the cost of repair to be $100,000.
The Bank hired Paul Wiemer to appraise the helicopter in preparation for sale. Wiemer found the helicopter to be in "poor" condition. Based on an "aircraft price bluebook" value for the helicopter if it had been in good condition and the projected cost of repairs, Wiemer arrived at a value of $79,000.
The Bank decided to sell the helicopter in its present, uncertain condition without incurring further expense for examination or repair. Yunker advertised the helicopter for sale and received approximately 20 inquiries as well as some telephone calls. Three bids were submitted and the helicopter was eventually sold for $80,500.
On March 14, 1995, the Bank sued Floyd and others for breach of the installment note. The matter was tried to a jury, which returned a special verdict finding, among other things, that the helicopter had been sold in good faith and in a commercially reasonable manner. Judgment was entered for the Bank in the amount of $239,122.59. Floyd appeals.
DISCUSSION
California Uniform Commercial Code section 9504, subdivision (3), states in relevant part: "Unless collateral is perishable or threatens to decline speedily in value or is of a type customarily sold on a recognized market, the secured party must give to the debtor ... a notice in writing of the time and place of any public sale or of the time on or after which any private sale or other intended disposition is to be made. Such notice must be delivered personally or be deposited in the United States mail postage prepaid addressed to the debtor at his or her address as set forth in the financing statement or as set forth in the security agreement or at such other address as may have been furnished to the secured party ... at least five days before the date fixed for any public sale or before the day on or after which any private sale or other disposition is to be made." (Further section references are to the California Uniform Commercial Code unless otherwise designated.)
"`The purpose of notice is to give the debtor an opportunity either to discharge the debt and redeem the collateral, to produce another purchaser, or to see that the sale is conducted in a commercially reasonable manner.' [Citations.]" (
Bank of America v. Lallana
(1998)
19 Cal.4th 203
, 214,
77 Cal.Rptr.2d 910
,
960 P.2d 1133
.) Failure to comply with this
[90 Cal.Rptr.2d 39]
notice requirement results in the loss of any right to a deficiency judgment. ( Canadian Commercial Bank v. Ascher Findley Co. (1991) 229 Cal.App.3d 1139 , 1149, 280 Cal.Rptr. 521 ; Rutan v. Summit Sports, Inc. (1985) 173 Cal.App.3d 965 , 971, 219 Cal.Rptr. 381 .)
Floyd contends the Bank failed to comply with its statutory notice requirement in several ways. First, he argues the Bank was required to notify each partner individually and to attempt a second notification when the first proved unsuccessful. Next, he argues the notice itself was deficient in failing to specify whether the sale would be public or private and, as to the eventual private sale, failing to state the helicopter would be sold on or aftera particular date. Finally, he argues the notice incorrectly described his redemption rights.
Without addressing the sufficiency of the Bank's efforts to serve Floyd with the notice of sale, we agree the content of the notice was deficient. The notice expressed the Bank's intent to sell the helicopter "at the expiration of 5 days from the date this notice was mailed" "`by private or public sale ... at redemption address at close of business day.'" As we shall explain, this notice was insufficient to satisfy 9-504, subdivision (3), and was defective in failing to specify the nature of the intended sale.
Although the issue has not arisen in this state, the courts in several other jurisdictions have held that a failure to indicate in the notice whether the sale will be public or private renders the notice defective. (See Davis v. Huntsville Production Credit Assn.(Ala.1985) (481 So.2d 1103, 1107; Benton-Lincoln Credit Service v. Giffin(1980)48 Or.App. 559,617 P.2d 662, 664; Liberty Nat. Bank of Fremont v. Greiner(1978)62 Ohio App.2d 125, 405 N.E.2d 317, 321; Aimonetto v. Keepes(Wy.1972)501 P.2d 1017, 1019; Citizens State Bank v. Sparks(1979)202 Neb. 661,276 N.W.2d 661, 663-664; Simmons Machinery Co., Inc. v. M & M Brokerage, Inc.(Ala. 1981)409 So.2d 743, 750; contra, Fidelity Consumer Discount Company v. Clark(1984)333 Pa.Super. 306,482 A.2d 580, 581-582.) Although the decisions from these sister states are not directly on point, inasmuch as the statutes at issue c
onform to the Uniform Commercial Code's requirement of reasonablenotice 2whereas section 9-504, subdivision (3), contains a specificnotice requirement (see In re Carter(9th Cir.1975)511 F.2d 1203, 1204), they are nevertheless instructive. If notice which fails to indicate whether the sale will be public or private is not reasonable notice, it can hardly be said to satisfy a specific notice requirement.
Other decisions have held that a failure to state whether the sale will be public or private is not fatal. However, in those cases the notice otherwise contained sufficient information from which this could be ascertained. (See, e.g., Lake Shore Nat. Bank v. McCann(1979)78 Ill.App.3d 580, 33 Ill.Dec. 577,396 N.E.2d 1301, 1305 [notice which said sale would be held "at 605 North Michigan Avenue, Chicago, Illinois on July 1, 1975 at 9 a.m." was deemed to be notice of a public sale]; All-States Leasing Co. v. Ochs(1979)42 Or.App. 319,600 P.2d 899, 906 [notice which indicated several offers had been received and creditor would sell at highest offer if no reply was received from debtor within 10 days was deemed to be notice of a private sale].)
The notice here does not contain sufficient information to ascertain with specificity the type of sale the Bank intended
[90 Cal.Rptr.2d 40]
to undertake. Section 9-504, subdivision (3), requires notice of "the time and place of any public sale" or "the time on or after which any private sale ... is to be made." The Bank's notice indicated the sale would be "at the expiration of 5 days from the date this notice was mailed ... at redemption address at close of business day." This arguably suggests either a public or a private sale. It specifies the time and place of a possible public sale, i.e., five days from the date of notice, at the close of the business day, at the redemption address. It also may be read to indicate the date after which a private sale will take place. Although the words "on or after" are not used, such meaning may be taken from the words "at the expiration of 5 days from the date this notice was mailed." It does not say the sale will take place on the fifth day but rather at the expiration of five days.
California law mandates strict compliance with the notice requirement of section 9-504, subdivision (3). (See Canadian Commercial Bank v. Ascher Findley Co., supra,229 Cal.App.3d at p. 1149,280 Cal.Rptr. 521; C.I.T. Corp. v. Anwright Corp.(1987)191 Cal.App.3d 1420, 1423-1424,237 Cal.Rptr. 108; Ford Motor Credit Co. v. Price(1985)163 Cal.App.3d 745, 748-751,210 Cal.Rptr. 17.) "Notice to the debtor is the mechanism that the Legislature and the drafters of the Uniform Commercial Code chose to ensure that sales of collateral are conducted in a commercially reasonable fashion. Notice serves this purpose by giving the debtor an opportunity to monitor the sale to ensure its commercial reasonableness. [Citations.] The right to a deficiency judgment is conditional and depends on strict compliance with the statutory requirements. As the court states in Atlas Thrift Co. v. Horan[1972]27 Cal.App.3d 999, 1009,104 Cal.Rptr. 315, `[t]he rule and requirement are simple. If the secured creditor wishes a deficiency judgment he must obey the law. If he does not obey the law, he may not have his deficiency judgment.'" ( Backes v. Village Corner, Inc.(1987)197 Cal.App.3d 209, 215-216,242 Cal.Rptr. 716.)
In enacting section 9-504, "[t]he Legislature rejected the Uniform Commercial Code's version ... which requires only `reasonable notification of the time and place of any public sale' — because the Uniform Commercial Code `does not specify either the manner in which notice must be given or the time within which it must be given.' (Sen. Fact Finding Com. on Judiciary, Sixth Progress Rep. to Leg., pt. 1 (1959-1961) Cal. U. Com.Code, p. 426.) The Senate Committee pointed out that the Uniform Commercial Code's general requirement `that every aspect of the sale be done in "a reasonably commercial" manner is too vague a requirement to be of any value and ... an invitation to litigation.' ( Ibid.) These concerns led our Legislature to conclude that `both the time and manner of giving notice should be specified, otherwise every sale is open to attack.' ( Ibid.) Accordingly, California Uniform Commercial Code section 9-504, subdivision (3) defines in detail the notice requirements for both public and private sales: A notice of publicsale informs the debtor of the time and place of sale. A notice of privatesale requires only that the debtor be told the collateral will be sold after the expiration of a certain period." ( Bank of America v. Lallana, supra,19 Cal.4th at p. 212,77 Cal.Rptr.2d 910,960 P.2d 1133.) If we were to apply a standard permitting substantial compliance, "we would be inviting exactly the kinds of complications which the Legislature intended to avoid." ( Ford Motor Credit Co. v. Price, supra,163 Cal.App.3d at pp. 750-751,210 Cal.Rptr. 17.)
California law requires strict compliance with the notice requirement. The purpose of this notice requirement is to alert the debtor of the need to take steps to protect his or her interests. In this regard, the California Uniform Commercial Code does not permit the creditor to leave the debtor guessing regarding the type of sale contemplated. If a public sale is intended,
[90 Cal.Rptr.2d 41]
notice of the time and place informs the debtor of the deadline for curing the default and, in the alternative, permits the debtor to arrange for someone to be present at the auction, either himself or another, to bid up the price. If a private sale is intended, notice of the date after which it will occur provides a minimum deadline for curing the default. The debtor may thereafter continue curative efforts until the collateral is sold and monitor the creditor's attempts to sell the collateral to assure commercial reasonableness.
We conclude the Bank's notice was defective in failing to state, expressly or impliedly whether the sale would be public or private and therefore the bank failed to comply with the specific notice requirements of section 9-504, subdivision (3). The Bank is precluded therefore from obtaining a deficiency judgment. 3
DISPOSITION
The judgment is reversed and the matter remanded to the trial court with directions to enter an order granting Floyd's motion for judgment notwithstanding the verdict and to enter judgment for Floyd on the Bank's complaint. Floyd shall receive his costs on appeal.
SIMS, Acting P.J., and CALLAHAN, J., concur.
FootNotes
1. According to the testimony at trial, a "chip light" or "chip plug" is used to detect whether a bearing is coming apart in the engine. Pieces of metal breaking off a bearing will collect on the plug, which is magnetized, and eventually create a metallic bridge. This completes a circuit, thereby illuminating the chip light. Once the light comes on, the aircraft should be brought down and inspected.
2. Section 9-504, subdivision (3), of the Uniform Commercial Code reads in relevant part: "Unless collateral is perishable or threatens to decline speedily in value or is of a type customarily sold on a recognized market,
reasonable notification
of the time and place of any public sale or
reasonable notification
of the time after which any private sale or other intended disposition is to be made shall be sent by the secured party to the debtor. (See 4 White & Summers, Uniform Commercial Code (4th ed.1995) § 34-10, p. 430, fn. 2, italics added.)
3. Having so concluded, we need not address the Bank's contention it was not required to give Floyd notice individually because it was enough that notice was given to the partnership or the other partners. If the content of the notice to Floyd was deficient, it was similarly deficient as to the other partners. We also need not address Floyd's contention the court erred in admitting evidence of his financial condition.
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c-Src Modulates Estrogen-Induced Stress and Apoptosis in Estrogen-Deprived Breast Cancer Cells | Cancer Research | American Association for Cancer Research
c-Src Modulates Estrogen-Induced Stress and Apoptosis in Estrogen-Deprived Breast Cancer Cells
Ping Fan
;
Ping Fan
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Obi L. Griffith
;
Obi L. Griffith
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Fadeke A. Agboke
;
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Pavana Anur
Pavana Anur
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Xiaojun Zou
Xiaojun Zou
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Russell E. McDaniel
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Karen Creswell
Karen Creswell
Sung Hoon Kim
Sung Hoon Kim
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
;
John A. Katzenellenbogen
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Joe W. Gray
;
Joe W. Gray
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
V. Craig Jordan
V. Craig Jordan
Authors' Affiliations: 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Lawrence Berkeley National Laboratory, Life Sciences Division, Cancer & DNA Damage Responses, Berkeley, California; 3 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois; and 4 Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon
Corresponding Author: V. Craig Jordan, Scientific Director of Lombardi Comprehensive Cancer Center, Georgetown University, E507A Research Bldg, 3970 Reservoir RD NW, Washington, DC 20057. Phone: 202-687-2897; Fax: 202-687-6402; E-mail: [email protected]
Current address for O.L. Griffith: Department of Medicine, Division of Oncology, The Genome Institute, Washington University, St. Louis, MO.
Corresponding Author: V. Craig Jordan, Scientific Director of Lombardi Comprehensive Cancer Center, Georgetown University, E507A Research Bldg, 3970 Reservoir RD NW, Washington, DC 20057. Phone: 202-687-2897; Fax: 202-687-6402; E-mail: [email protected]
Received: November 08 2012
Revision Received: March 22 2013
Accepted: April 22 2013
Online ISSN: 1538-7445
Print ISSN: 0008-5472
Cancer Res (2013) 73 (14): 4510–4520.
https://doi.org/10.1158/0008-5472.CAN-12-4152
Article history
Received:
November 08 2012
Revision Received:
March 22 2013
Accepted:
April 22 2013
Abstract
The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E 2) can induce apoptosis in breast cancer cells that have been selected for survival after E 2deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E 2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E 2in MCF-7:5C cells. E 2elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E 2activated c-Src through the ER. We found that E 2activated the sensors of the unfolded protein response (UPR), IRE1α ( ERN1) and PERK kinase ( EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E 2also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 ( HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK ( PRKAA2). Pharmacologic or RNA interference–mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E 2-induced ROS production, and inhibited E 2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E 2in long-term E 2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. Cancer Res; 73(14); 4510–20. ©2013 AACR.
Introduction
Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer (1, 2). Although aromatase inhibitors show considerable advantages over tamoxifen with respect to patient disease-free survival and tolerability, acquisition of resistance to all forms of endocrine treatments is inevitable (3, 4). Multiple mechanistic changes are involved in antihormone resistance, which provides the scientific rationale for the clinical development of additional targeted therapies (5, 6). It is well-known that the biologic actions of E 2are mediated through the ER, which functions in the nucleus as ligand-dependent transcription factors to promote gene transcription and stimulation of cell growth (7). Paradoxically, laboratory evidence shows that E 2can induce apoptosis in sensitive antihormone-resistant cells in vivo(8–10). This new targeted strategy provides novel therapeutic approaches to endocrine-resistant breast cancer. A recent phase II clinical trial reports that E 2provides a clinical benefit for patients with aromatase inhibitor–resistant advanced breast cancer (11). In addition, the laboratory results on E 2-induced apoptosis using antihormone-treated MCF-7 cells have been used to explain the reduction of breast cancer and the reduction in mortality observed in postmenopausal hysterectomized women in their 60s treated with conjugated equine estrogen (CEE) when compared with a placebo-treated control (12). The antitumor action of CEE is observed, not only during CEE treatment but also for 6 years after treatment. These data suggest a cidal effect for CEE and has been noted recently (13). These encouraging clinical results prompted us to investigate the mechanisms underlying E 2-induced apoptosis to increase the therapeutic benefits of E 2in aromatase inhibitor–resistant breast cancer.
Experimental evidence has established the oncogene, c-Src, as a critical component of multiple signaling pathways that regulate proliferation, survival, angiogenesis, and metastasis (14, 15). Increased c-Src activity is believed to play an important role in the development and progression of breast cancer (16), and c-Src has been considered as a survival signal for endocrine resistant breast cancer cells (17). Therefore, a c-Src inhibitor administered as a single-agent or in combination with other antihormone therapy has the potential to enhance the inhibitory effects of antihormones and delay antihormone resistance (18). These observations highlight c-Src as an important therapeutic target for the treatment of human breast cancer.
Mitochondria are important intracellular organelles involved in apoptosis via an intrinsic pathway (19). Although the molecular mechanisms of E 2-induced apoptosis are not fully understood, evidence indicates that mitochondria-related caspase pathways are involved (20, 21). Similarly, a variety of events in apoptosis focus on mitochondria, including the loss of mitochondrial transmembrane potential, release of cytochrome c, and participation of pro- and antiapoptotic Bcl-2 family proteins (22, 23). However, accumulating evidence suggests that the endoplasmic reticulum where members of the Bcl-2 family of proteins localize is also a major point of integration of pro-apoptotic signaling or damage sensing (24, 25). The endoplasmic reticulum senses local stress such as unfolded protein (UPR) through a set of pathways known as the UPR (26), which activates 3 transmembrane sensors PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring 1 alpha (IRE-1α), and activating transcription factor 6 (ATF-6) in endoplasmic reticulum (26). Depending on the duration and degree of stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic signals or death signals by inducing cell death programs (27, 28).
Materials
Estradiol was purchased from Sigma-Aldrich. c-Src inhibitor PP2 was purchased from CalBiochem. ERα antibody was from Santa Cruz Biotechnology. Total mitogen-activated protein kinase (MAPK), phosphorylated MAPK, phosphorylated c-Src, phosphorylated eIF2α, total eIF2α, and IRE1α antibodies were from Cell Signaling Technology. Total c-Src mouse antibody was from Millipore. Estrogen dendrimer conjugate (EDC) was a kind gift by Dr. J.A. Katzenellenbogen (University of Illinois at Urbana-Champaign, Urbana, IL).
Cell culture conditions and cell proliferation assays
Estrogen-deprived MCF-7:5C cells were maintained in estrogen-free RPMI-1640 medium supplemented with 10% dextran-coated charcoal-stripped FBS as previously described (20). The DNA fingerprinting pattern of cell line is consistent with the report by the American Type Culture Collection (29). The DNA content of the cells, a measure of proliferation, was determined by using a DNA fluorescence quantitation kit (29).
Cell-cycle analysis
Briefly, MCF-7:5C cells were treated with vehicle (0.1% EtOH) and E 2(10 −9mol/L), respectively. Cells were harvested and gradually fixed with 75% EtOH on ice. After staining with propidium iodide (PI), cells were analyzed using a FACSort flow cytometer (Becton Dickinson), and the data were analyzed with ModFit software.
Annexin V analysis of apoptosis
The FITC Annexin V Detection Kit I (BD Pharmingen) was used to quantify apoptosis by flow cytometry according to the manufacturer's instructions. In brief, MCF-7:5C cells were treated with different compounds, respectively. Cells were suspended in 1× binding buffer and 1 × 10 5cells were stained simultaneously with fluorescein isothiocyanate (FITC)-labeled Annexin V (FL1-H) and PI (FL2-H). Cells were analyzed using FACSort flow cytometer (Becton Dickinson).
Mitochondrial/TRANSMEMBRANE potential (Δψ m ) detection
Mitochondrial membrane potential was measured by flow cytometry using the cationic lipophilic green fluorochrome rhodamine-123 (Rh123; Molecular Probes) as previously described (20). Disruption of ΔΨ mis associated with a lack of Rh123 retention and a decrease in fluorescence.
Detection of oxidative stress
Intracellular reactive oxygen species (ROS) were detected by fluorescent dye 2′,7′-dichlorofluorescein diacetate (H 2DCFDA, Invitrogen; ref.30). Briefly, MCF-7:5C cells were treated with E 2for different time points using vehicle (0.1% EtOH) cells as control. Cells were loaded with 1 μmol/L CM-H 2DCFDA for 10 minutes and washed with PBS twice. Then, cells were monitored at fluorescence 530 nm and an excitation wavelength of 488 nm through flow cytometry.
Immunoblotting
Proteins were extracted in cell lysis buffer (Cell Signaling Technology) supplemented with Protease Inhibitor Cocktail (Roche) and Phosphatase Inhibitor Cocktail Set I and Set II (Calbiochem). The immunoblotting was conducted as previously described (29).
Transient transfection reporter gene assays
Transient transfection assay was conducted using a dual-luciferase system (Promega). To determine ER transcriptional activity, cells were transfected with an estrogen response element (ERE)-regulated (pERE (5×) TA-ffLuc plus pTA-srLuc) dual-luciferase reporter gene sets. The cells were treated with E 2for 24 hours following the transfection. Then, the cells were harvested and processed for dual-luciferase reporter activity, in which the firefly luciferase activity was normalized by Renillaluciferase activity.
Quantitative real-time reverse transcription PCR
Total RNA, isolated with an RNeasy Micro Kit (Qiagen), was converted to first-strand cDNA using a kit from Applied Biosystems. Quantitative real-time PCR assays were done with the SYBR Green PCR Master Mixes (Applied Biosystems) and a 7900HT Fast Real-time PCR System (Applied Biosystems). All primers were synthesized in Integrated DNA Technologies. The sequence of primers is shown in the Supplementary Table S1. All the data were normalized by 36B4.
RNA sequencing analysis
MCF-7:5C cells were treated with different compounds for 72 hours. Cells were harvested in TRIzol. Total RNA was isolated with an RNeasy Micro Kit. These long RNA samples were first converted into a library of cDNA fragments. Sequencing adaptors were subsequently added to each cDNA fragment and a 2 × 100 bp paired-end sequence was obtained from each cDNA using high-throughput sequencing technology (Illumina GAII). An average of 73.8 million such reads was produced for each sample. The resulting sequence reads were aligned to reference genome build hg19 using TopHat 1.3.0 (31), a splice junction aligner. Transcript abundance was estimated as Fragments Per Kilobase of exon per Million fragments mapped (FPKM), using Cufflinks 1.0.3 (32). Additional analysis was conducted with the alternative expression analysis by sequencing (Alexa-seq) software package as previously described (33). Gene expression measures were compared between Cufflinks and Alexa-seq for the set of 17,993 overlapping genes. Correlations were excellent with Spearman correlations of 0.955 to 0.971 for the 6 samples. Pathway analysis was conducted with DAVID (34) on lists of differentially expressed gene lists.
Statistical analysis
c-Src mediated estrogen-activated growth pathways in long-term estrogen-deprived breast cancer cells MCF-7:5C
It is well-documented that E 2stimulates growth and prevents apoptosis in wild-type breast cancer cells and estrogen-responsive osteoblast cells (35, 36). In contrast, physiologic concentrations of E 2induce apoptosis in long-term E 2-deprived breast cancer cells (20, 21). c-Src plays a critical role in relaying ER signaling pathways in breast cancer cells (37). To investigate the function of E 2and c-Src in long-term E 2-deprived breast cancer cells MCF-7:5C, a specific c-Src tyrosine kinase inhibitor, PP2, was used to block phosphorylation of c-Src (Fig. 1A). It also effectively abolished the growth pathways including the MAPK and phosphoinositide 3-kinase (PI3K)/AKT pathways in MCF-7:5C cells (Fig. 1A). E 2activated c-Src through ER as 4-hydroxytamoxifen (4-OHT) completely suppressed phosphorylation of c-Src (Fig. 1B). Although our previous finding showed that E 2initiates apoptosis in MCF-7:5C cells (20), E 2was able to activate nongenomic (Supplementary Fig. S1A) and genomic pathways in MCF-7:5C cells (Fig. 1C). These actions were blocked by the c-Src inhibitor, PP2 (Fig. 1Cand Supplementary Fig. S1A). Even though the characteristic E 2-induced apoptosis occurs after 72-hour treatment (20), cell numbers were initially increased by E 2with a high percentage in S-phase (Fig. 1D). All of these results suggested that E 2caused an imbalance between growth and apoptosis in MCF-7:5C cells.
Inhibition of c-Src suppressed estrogen-induced apoptosis in MCF-7:5C cells
We have shown that long-term E 2deprivation increases c-Src activity (29). Therefore, we addressed the question of whether the c-Src inhibitor, PP2, in combination with E 2would enhance apoptosis in MCF-7:5C cells. Unexpectedly, the c-Src inhibitor blocked apoptosis initiated by E 2(Fig. 2Aand Supplementary Fig. S1D). To confirm that inhibition of c-Src could block E 2-induced apoptosis, a specific siRNA was used to knock down c-Src in MCF-7:5C cells (Fig. 2B), which reduced the percentage of Annexin V binding induced by E 2(Fig. 2C). Further experiments showed that E 2disrupted mitochondrial membrane potential (ΔΨ m) after 48-hour treatment, which was measured by flow cytometry using Rh123 (Fig. 2D). The c-Src inhibitor PP2 and 4-OHT both prevented reduction of Rh123 retention induced by E 2(Fig. 2D). These data showed that E 2-triggered apoptosis use the c-Src tyrosine kinase pathway. To evaluate the role of the nongenomic pathway in E 2-induced apoptosis, studies were completed with a synthetic ligand, EDC, that only activates the nongenomic pathway at certain concentration (38). The results showed that EDC (10 −8mol/L) activated the nongenomic pathway incorporating c-Src (Supplementary Fig. S2). Importantly, EDC had no capacity to activate endogenous E 2target gene pS2 and did not induce apoptosis in MCF-7:5C cells (Supplementary Fig. S2). All of these findings suggested that the nongenomic pathway does not play a critical role in triggering E 2-induced apoptosis.
Suppression of E 2 -induced apoptosis by the c-Src inhibitor was independent of the classical ERE-regulated transcriptional genes in MCF-7:5C cells
The ER is the initial site for E 2to induce apoptosis as anti-estrogens ICI 182,780 and 4-OHT completely block apoptosis triggered by E 2(ref.20and Supplementary Fig. S3A). In addition to the mediation of ER growth pathways, c-Src is involved in the process of ligand-activated ER ubiquitylation (39). Therefore, blockade of c-Src tyrosine kinase with PP2 further increased ERα protein and mRNA expression levels in MCF-7:5C cells (Fig. 3A). E 2activated ERE activity, which could be blocked by 4-OHT but not by PP2 (Fig. 3B). It was interesting to find that the c-Src inhibitor alone could upregulate E 2-inducible gene pS2 and was additive with E 2to elevate pS2 mRNA level (Fig. 3C). Another important ER target gene progesterone receptor (PR) has been regarded as an indicator of a functional ER pathway, as expression of PR is regulated by E 2. Although the c-Src inhibitor alone did not elevate PR expression, it dramatically synergized with E 2to upregulate PR mRNA (Fig. 3D). All of these results showed that blockade of c-Src increased expression of classical ER target genes. It also implied that classical ER pathway might not directly involve in the E 2-induced apoptosis.
c-Src was involved in the process of triggering apoptosis-related genes by E 2 in MCF-7:5C cells
To further investigate the mechanisms of the suppression of E 2-induced apoptosis by PP2, RNA-seq analysis was conducted to examine the genes regulated by E 2to trigger apoptosis in MCF-7:5C cells. A wide range of apoptosis-related genes was activated by E 2(Fig. 4A), which were functionally classified into 3 groups: TP53-related genes (such as TP63, PMAIP1, and CYFIP2), stress-related genes (such as HMOX1, PPP1R15A, ZAK, NUAK2, etc.), and inflammatory response–related genes (such as LTB, FAS, TNFRSF21, CXCR4, etc.). Most were stress-related genes (Supplementary Fig. S3B). Consistent with the biologic experiments, 4-OHT and PP2 both blocked apoptosis-related genes induced by E 2but to a different extent in MCF-7:5C cells (Fig. 4A). The majority of these apoptosis-related genes were confirmed by real-time PCR with similar changes noted as in RNA-seq analysis (Fig. 4B–Dand Supplementary Fig. S4). E 2dramatically increased p63 mRNA levels (Fig. 4B) but did not arrest cells in the G 1phase. In fact, S-phase was markedly elevated in MCF-7:5C cells (Fig. 1D). Heme oxygenase 1 ( HMOX1), which is active at high concentrations of heme, catalyzes the degradation of heme and is thought to function as an oxidative stress indicator (40). In breast cancer cells, cytochrome cis a major source of heme protein found in the inner membrane of the mitochondrion. E 2markedly increased HMOX1in MCF-7:5C cells (Fig. 4C), thereby confirming that E 2may damage the mitochondria and caused cytochrome crelease. In contrast to MCF-7:5C cells, E 2decreased HMOX1levels in wild-type MCF-7 cells (Supplementary Fig. S5A) and clearly did not change HMOX1expression in another long-term E 2-deprived cell line MCF-7:2A (Supplementary Fig. S5B), both of MCF-7 and MCF-7:2A do not undergo apoptosis after exposure to E 2in the first 3 days. In addition, E 2upregulated TNF family members (such as TNFα, LTA, and LTB), which were abolished by 4-OHT and PP2 (Fig. 4Dand Supplementary Fig. S6A and S6B). Low dose of TNFα activated pro-apoptotic pathways in MCF-7:5C cells and inhibited cell growth (Supplementary Fig. S6C and S6D). All of these data suggested that E 2widely activated intrinsic and extrinsic apoptosis pathways and c-Src was directly involved in mediating apoptosis.
The c-Src inhibitor blocked estrogen-induced oxidative stress in MCF-7:5C cells
ROSs are the product of oxidative stress by mitochondria, whereas an increase in ROS contributes to degenerative changes in mitochondrial function (41). Under physiologic conditions, cellular ROS levels are tightly controlled by low-molecular-weight radical scavengers and by a complex intracellular network of enzymes such as catalases ( CAT) and superoxide dismutases ( SOD). Under conditions of lethal stress, ROSs are considered as key effectors of cell death (42). Intracellular ROSs were detected by CM-H 2DCFDA through flow cytometry (Fig. 5A). Detectable ROS appeared after 48 hours of treatment with E 2. The production of ROS reached a peak after 72-hour treatment (Fig. 5A and B). Blocking ER (by 4-OHT) and c-Src (by PP2) abolished ROS generation induced by E 2(Fig. 5C), indicating that both ER and c-Src were upstream signals of ROS. Free-radical scavengers Mn-TBAP, catalase, and sodium formate (SF) that respectively act on superoxide radical (O 2 −), H 2O 2, and hydroxyl radical (OH −) were used to suppress the production of ROS. Our results suggested that H 2O 2and OH −were the major sources of ROS induced by E 2. This conclusion was based on the observation that catalase and sodium formate inhibited E 2-induced apoptosis, whereas Mn-TBAP was less effective (Fig. 5D). The RNA-seq analysis showed that E 2did not significantly regulate antioxidant enzymes such as catalases ( CAT) and superoxide dismutases ( SOD) in MCF-7:5C cells (data not shown). Our results suggest that E 2has the potential to damage mitochondria to cause oxidative stress.
c-Src was involved in estrogen-induced endoplasmic reticulum stress in MCF-7:5C cells
Our previous global gene array data show that E 2activates genes related to endoplasmic reticulum stress in MCF-7:5C cells (25). To relieve stress, sensors of UPRs are activated as initial responses (43). In this study, a significant induction of UPR sensors, inositol-requiring protein 1 alpha (IRE1α) and PERK/eukaryotic translation initiation factor-2α (eIF2α), by E 2occurred after 24 hours of treatment and was further increased by prolonging treatment times in MCF-7:5C cells (Fig. 6A). The anti-estrogen 4-OHT completely abolished the response (Fig. 6A). The PERK inhibitor blocked phosphorylation of eIF2α and prevented E 2-induced apoptosis (Fig. 6B and C), confirming that endoplasmic reticulum stress was important in the apoptosis initiated by E 2. Phosphorylated eIF2α closely associates with an important cellular energy sensor, adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate protein translation and apoptosis (44). AMPK, which phosphorylates many metabolic enzymes to stimulate catabolic pathways and increases the capacity of cells to produce ATP (45), was significantly activated after 48-hour treatment with E 2(Fig. 6D). The c-Src inhibitor, PP2, blocked the phosphorylation of eIF2α but not IRE1α induced by E 2(Fig. 6E). PP2 also prevented the activation of AMPK after E 2treatment (Fig. 6F). All of these data indicate that c-Src acts as an important transducer in the protein kinase pathways (eIF2α and AMPK) of stress response (Fig. 6E and F) that result in apoptosis.
Discussion
We have previously investigated the inhibitory effects of E 2on long-term endocrine-resistant breast cancer tumor growth in vivo(8–10). And we have confirmed that this therapeutic effect is related with the apoptosis induced by E 2(20). This scientific discovery has been used in the clinical trials to treat aromatase inhibitor–resistant patients with breast cancer and 30% of patients receive benefit (11). The potential limitation on translational research in the treatment of hormone-responsive breast cancer is that only 4 ER-positive breast cancer cell lines are available to use routinely (46). Only MCF-7 of the 4 produces the phenotype of E 2-induced apoptosis observed clinically (20, 21). The purpose of establishing long-term E 2deprivation in vitromodels is to mimic administration of an aromatase inhibitor that reduces levels of circulating estrogen in clinical studies (47). After a period of proliferative quiescence lasting a few months, the return of proliferation is similar to the relapses observed 12 to 18 months after primary hormonal therapy in patients. Multiple pathways are involved in the adaptive response to the pressure of E 2deprivation (48). Although MCF-7 cells grown long-term have been shown to differ substantially in various properties depending upon the number of passages and geographic source of the cell lines, induction of apoptosis by physiologic concentrations of E 2is the common characteristic of these in vitromodel systems (20, 21). Nevertheless, how E 2induces apoptosis is at present unclear. Our new observation (29) that a c-Src inhibitor paradoxically can block E 2-induced apoptosis naturally demands further study. We examined this aspect of c-Src pharmacology to describe fully this phenomenon and gain an insight into the convergence of ER and c-Src pathways for the modulations of an apoptotic trigger in breast cancer. Here, for the first time, we document that c-Src participates in the mediation of stress responses induced by E 2to widely activate apoptosis-related genes involved in the intrinsic and the extrinsic apoptosis pathways.
The ER is the initial point for E 2to induce apoptosis, as anti-estrogens ICI 182,780 and 4-OHT completely block apoptosis triggered by E 2(ref.20and Supplementary Fig. S3A). Contradictory to the traditional apoptosis mechanism caused by cytotoxic chemotherapy with cell-cycle arrest, E 2-induced apoptotic cells simultaneously undergo proliferation with an increased S-phase of cell cycle resulting in increased cell number despite p53 family members being upregulated (Figs. 1Dand4B). E 2exerts a dual function on MCF-7:5C cells, with both initial proliferation and the apoptosis. In other words, the initial response of E 2to stimulate growth is the upregulating of classical transcriptional activity by ER (Fig. 3B) without any detected apoptotic changes in the first 24 hours. Activation of apoptotic genes appeared after 48-hour treatment with E 2(data not shown) and reached a peak by 72 hours (Fig. 4B–D). Consistently, characteristic apoptosis occurred at 72 hours (Fig. 2A). These data suggest that the higher rate of proliferation by E 2might activate other pathways to trigger apoptosis. Our data show that E 2caused endoplasmic reticulum stress, which activated the UPR within 24 hours (Fig. 6A). The initial aim of UPR is to restore normal function of the cell; however, if the damage is too severe to repair, the UPR ultimately initiates cell death through activation of the apoptotic pathway (49).
c-Src functioned as an important downstream signal of ER in MCF-7:5C cells, which was activated by E 2(Fig. 1B, Supplementary Fig. S1A–S1C) and showed multiple levels of association with ER (Figs. 1B and C,2A,3A, C, and D). An important finding in this study is that c-Src tyrosine kinase is critical for E 2-induced apoptosis (Fig. 2A, C, and D). This, therefore, raised the question of the actual role played by c-Src in the process of apoptosis induced by E 2. c-Src mediated PI3K/AKT and MAPK growth pathways by E 2(Fig. 1C). However, specific inhibitors of PI3K/Akt (LY294002) and MAPK (U0126) could inhibit cell growth but did not prevent E 2-induced apoptosis in MCF-7:5C cells (Supplementary Fig. S7), which imply that MAPK/Akt growth pathways are not directly involved in the apoptosis-induced by E 2. In MCF-7:5C cells, E 2activated the nongenomic pathway after 10-minute treatment and the c-Src inhibitor blocked the nongenomic pathway (Supplementary Fig. S1A and S1B). Detectable elevation of c-Src phosphorylation appeared after 30-minute treatment with E 2(Supplementary Fig. S1B). Consistent stimulation of c-Src appeared after 24-hour treatment and gradually increased when extending to 48 hours (Fig. 1Band Supplementary Fig. S1C). All of these data suggest that c-Src activation is a direct effect resulting from E 2. To further explore the function of the nongenomic pathway in the process of E 2-induced apoptosis, EDC was used to treat MCF-7:5C cell, which is very ineffective in stimulating transcription of endogenous E 2target genes (38). The EDC (10 −8mol/L) activated the nongenomic pathway but without capacity to activate genomic pathway and did not induce apoptosis in MCF-7:5C cells (Supplementary Fig. S2). All of these results suggest that the nongenomic pathway does not play a critical role in the E 2-induced apoptosis. Interestingly, the EDC could continuously activate c-Src and Akt but without any effect on MAPK after 24-hour treatment (Supplementary Fig. S2E), which may be resulted from enhanced association between ERα and membrane growth factor receptor (48).
In addition, E 2activated classical ERE activity but the c-Src inhibitor could not block the response (Fig. 3B). Furthermore, the c-Src inhibitor collaborated with E 2to upregulate endogenous ER target genes pS2 and PR (Fig. 3C and D). All of these results imply that classical ER transcriptional pathways are not directly involved in E 2-induced apoptosis. Similarly, Zhang and colleagues reported that the inhibitory effects of E 2on cell growth are independent of the classical ERE-regulated transcriptional genes (50). Our global gene array data suggest that E 2signaling can occur through a nonclassical transcriptional pathway involving the interaction of ER with other transcription factors such as activator protein-1 (AP-1) and Sp1, which may regulate stress responses (25). In the present study, E 2initiated UPR (Fig. 6A), increased ROS production (Fig. 5A), and widely activated apoptosis-related genes (Fig. 4A). The c-Src was involved in the stress responses and inhibition of c-Src decreased the expression of apoptosis-related genes induced by E 2, which are critical mechanisms for the blockade of c-Src to prevent E 2-induced apoptosis.
Overall, E 2induces endoplasmic reticulum and mitochondrial stresses in MCF-7:5C cells, which subsequently upregulates apoptosis-related genes to activate intrinsic and extrinsic apoptotic pathways. Unexpectedly, c-Src tyrosine kinase plays a critical role in the stress response induced by E 2. These data clearly raise a concern about the ubiquitous use of c-Src inhibitors to treat patients with advanced aromatase inhibitor–resistant breast cancer, thereby undermining the beneficial effects of E 2-induced apoptosis.
Conception and design:P. Fan, J. Katzenellenbogen, J.W. Gray, V.C. Jordan
Development of methodology:P. Fan, O.L. Griffith, F.A. Agboke, X. Zou, J. Katzenellenbogen, J.W. Gray
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.):P. Fan, F.A. Agboke, X. Zou, R.E. McDaniel, K. Creswell, J.W. Gray, V.C. Jordan
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):P. Fan, O.L. Griffith, P. Anur, K. Creswell, J. Katzenellenbogen, J.W. Gray, V.C. Jordan
Writing, review, and/or revision of the manuscript:P. Fan, O.L. Griffith, J. Katzenellenbogen, V.C. Jordan
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases):O.L. Griffith, R.E. McDaniel, V.C. Jordan
Study supervision:P. Fan, V.C. Jordan
Synthesis of EDC:S.H. Kim
Grant Support
V.C. Jordan is supported by the Department of Defense Breast Program under Award number W81XWH-06-1-0590 Center of Excellence; subcontract under the SU2C (AACR) Grant number SU2C-AACR-DT0409; the Susan G Komen For The Cure Foundation under Award number SAC100009; GHUCCTS CTSA (Grant # UL1RR031975); and the Lombardi Comprehensive Cancer Center Support Grant (CCSG) Core Grant NIH P30 CA051008. J.W. Gray is supported by a Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0409). J. Katzenellenbogen is supported by NIH grant (PHS 5R37DK015556). O.L. Griffith was supported by a fellowship from the Canadian Institutes of Health Research (CIHR).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisementin accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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7
Supplementary data
Supplementary Figure 1PDF file - 77K, 1A, The c-Src inhibitor blocked E2 activated non-genomic pathway. MCF-7:5C cells were treated with vehicle (0.1% DMSO), E2 (10-9 mol/L), PP2 (5x10-6 mol/L), E2 (10-9 mol/L) plus PP2 (5x10-6 mol/L) respectively for 10 minutes and the cell lysates were harvested. Phosphorylated MAPK and c-Src were examined by immunoblotting with primary antibodies. Immunoblotting for total MAPK and c-Src were used for loading controls. 1B, E2 rapidly activated MAPK and c-Src. MCF-7:5C cells were treated with vehicle (0.1% EtOH) and E2 (10-9 mol/L) for different time points as indicated and the cell lysates were harvested. Phosphorylated MAPK and c-Src were examined by immunoblotting with primary antibodies. Immunoblotting for total MAPK and c-Src were used for loading controls. 1C, E2 stimulated c-Src after 24 hours treatment. MCF-7:5C cells were treated with vehicle (0.1% EtOH) and E2 (10-9 mol/L) for different time points as indicated and the cell lysates were harvested. Phosphorylated c-Src was examined by immunoblotting with primary antibody. Immunoblotting for total c-Src was used for loading control. 1D, Quantification of Annexin V binding assay. MCF-7:5C cells were treated with vehicle (0.1% DMSO), E2 (10-9 mol/L), 4-OHT (10-6 mol/L), E2 (10-9 mol/L) plus 4-OHT (10-6 mol/L), PP2 (5x10-6 mol/L), E2 (10-9 mol/L) plus PP2 (5x10-6 mol/L) respectively for 72 hours and the cells were harvested for Annexin V binding assay through flow cytometry. The percentage of Annexin V binding was compared with control. P<0.05, * compared with control. All the data shown were representative of at least three separate experiments with similar results. - pdf file
Supplementary Figure 2PDF file - 104K, 2A, Activation of pS2 by different concentrations of estrogen dendrimer conjugate (EDC). MCF-7:5C cells were treated with vehicle (0.1% MeOH), different concentrations of EDC, E2, and empty dendrimer as indicated for 8 hours in triplicate. Cells were harvested in TRIzol for real-time PCR. 2B, Cell growth after EDC treatment. MCF-7:5C cells were treated with vehicle (0.1% MeOH), different concentrations of EDC, E2, and empty dendrimer as indicated for 7 days in triplicate. Cells were harvested and total DNA was determined using a DNA fluorescence quantitation kit. 2C, The c-Src inhibitor blocked EDC activated non-genomic pathway. MCF-7:5C cells were treated with vehicle (0.1% MeOH), EDC (10-8 mol/L), PP2 (5x10-6 mol/L), EDC (10-8 mol/L) plus PP2 (5x10-6 mol/L) respectively for 15 minutes and the cell lysates were harvested. Phosphorylated MAPK was examined by immunoblotting with primary antibody. Immunoblotting for total MAPK was used for loading control. 2D, EDC rapidly activated MAPK and c-Src in MCF-7:5C cells. MCF-7:5C cells were treated with vehicle (0.1% MeOH) and EDC (10-8 mol/L) for different time points as indicated and the cell lysates were harvested. Phosphorylated MAPK and c-Src were examined by immunoblotting with primary antibodies. Immunoblotting for total MAPK and c-Src were used for loading controls. 2E, EDC activated signaling pathways after 24 hours. MCF-7:5C cells were treated with vehicle (0.1% MeOH), EDC (10-8 mol/L), PP2 (5x10-6 mol/L), EDC (10-8 mol/L) plus PP2 (5x10-6 mol/L) respectively for 24 hours and 48 hours. Cell lysates were harvested. Phosphorylated MAPK, Akt, and c-Src were examined by immunoblotting with primary antibodies. Immunoblotting for total MAPK, Akt, and c-Src were used for loading controls. - pdf file
Supplementary Figure 3PDF file - 75K, 3A, The 4-OHT completely blocked E2-induced growth inhibition. MCF-7:5C cells were treated with vehicle (0.1% EtOH), E2 (10-9 mol/L), 4-OHT (10-6 mol/L), E2 (10-9 mol/L) plus 4-OHT(10-6 mol/L) respectively for 7 days. Cells were harvested and total DNA was determined using a DNA fluorescence quantitation kit. P<0.001, ** compared with control. All the data shown were representative of at least three separate experiments with similar results. 3B, Classification of E2-induced apoptosis-related genes selected by RNA-seq in MCF-7:5C cells. MCF-7:5C cells were treated with different compounds as above for 72 hours. Cells were harvested in TRIzol for RNA-seq analysis as in Material and Methods. - pdf file
Supplementary Figure 4PDF file - 76K, The c-Src inhibitor blocked apoptosis-related genes induced by E2. MCF-7:5C cells were treated with vehicle (0.1% DMSO), E2 (10-9 mol/L), 4-OHT (10-6 mol/L), E2 (10-9 mol/L) plus 4-OHT(10-6 mol/L), PP2 (5x10-6 mol/L), E2 (10-9 mol/L) plus PP2 (5x10-6 mol/L) respectively for 72 hours. Cells were harvested in TRIzol for real-time PCR. 4A, PPP1R15A (GADD34) gene. 4B, BCL2L11 (Bim) gene. 4C, NUAK2 gene. 4D, PMAIP1 (Noxa) gene. P<0.001, ** compared with control. All the data shown were representative of at least three separate experiments with similar results. - pdf file
Supplementary Figure 5PDF file - 47K, 5A, The oxidative stress indicator HMOX1 expressed in wild-type MCF-7 cells after E2 treatment. Wild-type MCF-7 cells were cultured in E2 free medium for three days. Then, cells were plated in six-well plates. After one day, cells were treated with vehicle (0.1% EtOH) and E2 (10-9 mol/L) for different time points as indicated and the cells were harvested in TRIzol for real-time PCR. P<0.001, ** compared with control. 5B, The oxidative stress indicator HMOX1 expressed in long-term E2 deprived MCF-7:2A cells after E2 treatment. MCF-7:2A cells were plated in six-well plates. After one day, cells were treated with vehicle (0.1% EtOH) and E2 (10-9 mol/L) for different time points as indicated and the cells were harvested in TRIzol for real-time PCR. P<0.05, * compared with control. 5C, The oxidative stress indicator HMOX1 expressed in long-term E2 deprived MCF-7:5C cells after E2 treatment. MCF-7:5C cells were plated in six-well plates. After one day, cells were treated with vehicle (0.1% EtOH) and E2 (10-9 mol/L) for different time points as indicated and the cells were harvested in TRIzol for real-time PCR. P<0.05, * compared with control. P<0.001, ** compared with control. - pdf file
Supplementary Figure 6PDF file - 82K, 6A, The c-Src inhibitor blocked tumor necrosis factor (TNF) super family genes induced by E2. MCF-7:5C cells were treated with vehicle (0.1% DMSO), E2 (10-9 mol/L), 4-OHT (10-6 mol/L), E2 (10-9 mol/L) plus 4-OHT (10-6 mol/L), PP2 (5x10-6 mol/L), E2 (10-9 mol/L) plus PP2 (5x10-6 mol/L) respectively for 72 hours. Cells were harvested in TRIzol. LTA (TNF super family member 1) gene was detected by real-time PCR. P<0.001, ** compared with control. 6B, LTB (TNF super family member 3) gene was detected by real-time PCR. P<0.001, ** compared with control. 6C, TNFα activated apoptotic pathways in MCF-7:5C cells. MCF-7:5C cells were treated with vehicle (H2O) and TNFα (5ng/mL) for 24 hours. Cell lysates were harvested. Pro-apoptotic pathways PARP and Caspase-9 were examined by immunoblotting with primary antibodies. Immunoblotting for beta-actin was detected for loading control. 6D, TNFα inhibited MCF-7:5C cell growth. MCF-7:5C cells were treated with vehicle (H2O) and TNFα (5ng/mL) for 7 days. Cells were harvested and total DNA was determined using a DNA fluorescence quantitation kit. P<0.001, ** compared with control. All the data shown were representative of at least three separate experiments with similar results. - pdf file
Supplementary Figure 7PDF file - 53K, 7A, Inhibitors of Akt could not block growth inhibition induced by E2 in MCF-7:5C cells. MCF-7:5C cells were treated with vehicle (0.1% EtOH), E2 (10-9 mol/L), LY294002 (10-6mol/L), and E2 (10-9 mol/L) plus LY294002 (10-6mol/L) respectively. Cells were harvested after 7 days treatment and total DNA was determined using a DNA fluorescence quantitation kit. 7B, Inhibitor of MAPK could not block growth inhibition induced by E2 in MCF-7:5C cells. MCF-7:5C cells were treated with vehicle (0.1% EtOH), E2 (10-9 mol/L), U0126 (5x10-6 mol/L), and E2 (10-9 mol/L) plus U0126 (5x10-6 mol/L) respectively. Cells were harvested after 7 days treatment and total DNA was determined using a DNA fluorescence quantitation kit. All data shown were representative of at least three separate experiments with similar results. - pdf file
Supplementary Table 1PDF file - 59K, Sequences of Primers. - pdf file
| https://aacrjournals.org/cancerres/article-split/73/14/4510/584796/c-Src-Modulates-Estrogen-Induced-Stress-and |
Interactive Quiz: Chronic Venous Ulcers | Consultant360
In this interactive quiz, we present a case of a 79-year-old man who has had a 5-month history of poorly healing venous ulcers on the anterior and medial aspect of the left calf, which had been recurring over 14 years. Can you take the correct diagnostic steps and treat this patient? Quizzes
Elderly Patients
Interactive Quiz: Chronic Venous Ulcers
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Welcome to Cardiology Consultant's latest interactive diagnostic quiz. Over the next few pages, we'll present a case and ask you to make the diagnostic steps and treat the patient. Along the way, we'll provide details about the case, and at the end, we'll share the patient's outcome.
Ready to get started? >>
First, let’s meet the patient…
A 79-year-old man with a history of type 2 diabetes mellitus and hypertension presented with a 5-month history of poorly healing venous ulcers on the anterior and medial aspect of the left calf, which had been recurring over 14 years.
The ulcers were limited to the patient’s left lower extremity and did not involve the contralateral limb, despite his having advanced venous stasis skin changes and swelling on both calves. He reported having leg heaviness and constant pain that is alleviated by elevation of his lower extremities. Additionally, he reported having debilitating venous claudication symptoms, which he described as left calf and thigh pain that radiates up to the flank and buttock upon walking 2 blocks.
The patient had previously been treated with compression stockings and Unna boots at a local wound-care center with minimal success; the ulcers had recurred, along with functionally debilitating symptoms consistent with venous hypertensive disease.
Physical examination revealed visually remarkable calf-size asymmetry, extensive hyperpigmentation, stasis dermatitis, indurated skin, and active open and healed ulcers on the left leg ( Figure 1). The left lower extremity demonstrated +3 (of 4) pretibial and ankle pitting edema extending to the mid-thigh, compared with +2 pitting edema limited to below the knee in the right lower extremity. There were palpable anterior tibial (AT), posterior tibial (PT), and dorsalis pedis (DP) pulses bilaterally.
Answer: All of the above
Lower-extremity arterial Doppler ultrasonography ruled out the presence of peripheral arterial disease. Venous Doppler ultrasonography findings showed no reflux in the superficial and deep vein systems. There was neither acute nor chronic deep vein thrombosis. Given the patient’s cardiovascular risk factors and bilateral leg swelling, transthoracic echocardiography was performed to rule out a cardiac etiology by confirming normal biventricular function.
Before this visit, the patient had had several consultations and vascular Doppler studies at various vein centers; however, he had not undergone intravascular ultrasonography (IVUS) guided endovascular therapy for possible proximal deep vein compression.
Answer: Yes
The decision was made to proceed with iliocaval venography and subsequent examination using IVUS. Under US guidance, the left great saphenous vein (GSV) was accessed using a micropuncture needle and a 4F sheath and subsequent upgrade to an 11F sheath using a Bentson guidewire. The wire was then advanced proximally into the left common iliac vein (CIV) up to the inferior vena cava (IVC); injection of contrast dye showed no apparent venous stenosis ( Figure 2).
However, on evaluation with IVUS, extrinsic compression of the CIV and external iliac vein (EIV), with approximately 70% reduction in diameter compared with the adjacent normal reference segment, was identified ( Figures 3 and 4).
Answer: Balloon dilation with stent deployment
Balloon dilation with stent deployment was performed successfully. Subsequent IVUS showed a complete resolution of diffuse iliac vein compression by right common iliac artery (CIA) after iliac vein stent implantation ( Figures 5 and 6).
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In addition, clear post-procedural improvement to 0% luminal narrowing and wall apposition were demonstrated. Despite this remarkable improvement in luminal patency recorded by IVUS, the post-stent venogram showed no significant difference from the one prior to intervention, demonstrating the important role of IVUS ( Figure 7) despite no identifiable change in luminogram by contrast fluoroscopy.
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Answer: At 1, 3, and 6 months and yearly thereafter
Stent patency was confirmed by duplex ultrasonography at 1, 3, and 6 months and yearly thereafter. Iliac vein stenting resulted in rapid healing of this patient's ulcer as well as in significant improvement in limb pain and swelling; those outcomes have continued without further reports of recurrent open ulcers. With relief of orthostatic leg pain and achiness, the patient returned to baseline normal daily activities. His venous stasis hyperpigmentation improved, and his leg swelling was significantly reduced.
Authors, citation >>
Authors:
Tae An Choi, ANP-BC; Esad Vucic, MD, CBNC; Back Kim, MD; and Nay Htyte, MD, MSc, DASNC
Heart Vein NYC, New York, New York
Citation:
Choi TA, Htyte N, Vucic E, Kim B. Chronic venous ulcer treated with iliac vein stenting for proximal deep vein compression [published online June 18, 2018]. Cardiology Consultant.https://www.consultant360.com/articles/chronic-venous-ulcer-treated-iliac-vein-stenting-proximal-deep-vein-compression.
Patients can be discouraged from continuing treatment if they experience flares at the initiation of urate-lowering therapy.
| https://www.consultant360.com/article/cardiology/interactive-quiz-chronic-venous-ulcers?page=1%3Fpage=6%3Fpage=6%3Fpage=1%3Fpage=1%3Fpage=5%3Fpage=3%3Fpage=4 |
Lateral Ventricle Volume is Poor Predictor of Post Unilateral DBS Motor Change for Parkinson's Disease | Request PDF
Request PDF | Lateral Ventricle Volume is Poor Predictor of Post Unilateral DBS Motor Change for Parkinson's Disease | Deep Brain Stimulation (DBS) surgery can effectively treat many debilitating motor symptoms of Parkinson's disease (PD), but axial symptom... | Find, read and cite all the research you need on ResearchGate
Lateral Ventricle Volume is Poor Predictor of Post Unilateral DBS Motor Change for Parkinson's Disease
February 2011
Parkinsonism & Related Disorders 17(5):343-7
DOI: 10.1016/j.parkreldis.2011.01.018
Abstract
Deep Brain Stimulation (DBS) surgery can effectively treat many debilitating motor symptoms of Parkinson's disease (PD), but axial symptom improvement is variable. Predictors for post-DBS axial symptom performance have yet to be identified. Pre-surgery ventricle volume may be one predictor, for increasing ventricular size has been associated with worsening gait disturbance. In PD, ventricle size may also increase with the advancement of motor symptoms.
To examine the hypotheses that 1) lateral ventricular volumes would predict motor and axial motor symptom change from pre to four months post unilateral DBS, and 2) PD patients have larger ventricle volumes contralateral to side of symptom onset.
Idiopathic PD patients (n = 37) completed pre-surgery volumetric brain scans and UPDRS motor testing (off-medication), unilateral DBS (Globus Pallidus interna, n = 11; subthalamic nucleus, n = 26), and 4-month follow-up motor assessments (on-stimulation). Ventricle volumes were normalized using total intracranial volume.
Total ventricular volume as well as measurements of contralateral/ipsilateral volumes to side of symptom onset or DBS lead placement did not predict outcome motor measures or correlate to axial motor change. Patients improving at least 2 standard errors of measurement (n = 6) did not have smaller ventricles relative to those without significant change. Post-operative hemorrhage (n = 1) had ventricle volumes similar to the group average. There was no asymmetry in ventricular volume by side of onset or side of lead placement.
Ventricular volume was a poor predictor of acute motor change following DBS. Asymmetrical ventricles may not be a consistent imaging marker for PD motor dysfunction.
... Herein, 60 studies were included in the final review (the article selection process is presented in Fig. 1 83 observed in 30 studies. [23][24][25][26]28,30,[32][33][34][35][36][37][38][39]42,[44][45][46][47]
[48]
[50][51][52][53][54][55][56][57][58][59] The Movement Disorder Society-Sponsored Revision of the UPDRS (MDS-UPDRS III) 84 was used in eight studies. 27,29,31,40,41,43,60,61 The Gait and Falls Questionnaire (GFQ), Freezing of Gait Questionnaire (FoGQ) and a Stepping in place task (SIP), were used to assess axial symptoms in patients with Parkinson's disease. ...
... region prior to an automatic reconstruction. 26,
48,
70,71 A total of 17 studies utilised fully automated approaches to segment and process images for morphometric quantification. ...
... An important implication present in this review is the utility of markers that are inferred through means of association and correlation, versus prediction. Although many articles explicitly outlined the "predictive" ability of identified structural marker(s), analyses were restricted to correlations/associations. [24][25][26][27]30,33,37,38,43,44,46,
48,
57,59,62,[65][66][67]70,79,80 In such cases, derived markers cannot be strictly predictive as they reflect a potential disease/disorder correlate within the sample to which the model was fit. ...
A structural magnetic resonance imaging review of clinical motor outcomes from deep brain stimulation in movement disorders
Patients with movement disorders treated by deep brain stimulation do not always achieve successful therapeutic alleviation of motor symptoms, even in cases where surgery is without complications. Magnetic resonance imaging (MRI) offers methods to investigate structural brain-related factors that may be predictive for clinical motor outcomes. This review aimed to identify features which have been associated with variability in clinical post-operative motor outcomes in patients with Parkinson’s disease, dystonia, and essential tremor from structural MRI modalities. We performed a literature search for articles published between January 01, 2000, and April 01, 2022, and identified 5197 articles. Following screening through our inclusion criteria, we identified 60 total studies (39 = Parkinson’s disease, 11 = dystonia syndromes and 10 = essential tremor). The review captured a range of structural MRI methods and analysis techniques used to identify factors related to clinical post-operative motor outcomes from deep brain stimulation. Morphometric markers, including volume and cortical thickness were commonly identified in studies focused on patients with Parkinson’s disease and dystonia syndromes. Reduced metrics in basal ganglia, sensorimotor and frontal regions showed frequent associations with reduced motor outcomes. Increased structural connectivity to subcortical nuclei, sensorimotor and frontal regions were also associated with greater motor outcomes. In patients with tremor, increased structural connectivity to the cerebellum and cortical motor regions showed high prevalence across studies for greater clinical motor outcomes. In addition, we highlight conceptual issues for studies assessing clinical response with structural MRI and discuss future approaches towards optimising individualised therapeutic benefits. Although quantitative MRI markers are in their infancy for clinical purposes in movement disorder treatments, structural features obtained from MRI offer powerful potential to identify candidates who are more likely to benefit from deep brain stimulation and provide insight into the complexity of disorder pathophysiology.
... Analyses of the motor cortex showed promising results for the prediction of motor outcomes 10,11 , whereas some study negated the associations 12 . Volumes of brain ventricles were suggested in some studies to predict postsurgical outcomes [13][14][15][16] , while other studies did not corroborate these associations
17,
18 . Also, the value of these biomarkers in the prediction of DBS outcomes has not been fully investigated. ...
... After the removal of duplicates, 793 publications were scanned for title and abstract and a total of 25 studies were included in this review after full-text review ( Fig. 1): 13 studies analyzed the motor outcome of DBS including two studies focusing on the axial symptoms (Table 1, Supplementary Table 1); and 13 studies investigated non-motor outcomes, including cognitive impairment (eight studies) and psychiatric changes (six studies) (Fig. 2). UPDRSIII med off/ med off, stim on 13,
17
. Two studies used the ratio of UPDRSIII med off/ med off, stim on 11,14 . ...
... Brain volumetry: Ten studies investigating the relationship between volumetric changes and motor improvement were identified 13,14,
17,
[19][20][21][22][23][24][25] . One study utilized 2D measurements including the bicaudate ratio (ratio between the inter-caudate and skull distance) 26 , the Evans index (width of the anterior ventricular horn divided by biparietal cranium diameter) 27 , and the third ventricular width (largest width of the third ventricle at the level of the posterior commissure) 14 to assess subcortical changes 14 . ...
A systematic review of brain morphometry related to deep brain stimulation outcome in Parkinson's disease
While the efficacy of deep brain stimulation (DBS) is well-established in Parkinson's Disease (PD), the benefit of DBS varies across patients. Using imaging features for outcome prediction offers potential in improving effectiveness, whereas the value of presurgical brain morphometry, derived from the routinely used imaging modality in surgical planning, remains under-explored. This review provides a comprehensive investigation of links between DBS outcomes and brain morphometry features in PD. We systematically searched PubMed and Embase databases and retrieved 793 articles, of which 25 met inclusion criteria and were reviewed in detail. A majority of studies (24/25), including 1253 of 1316 patients, focused on the outcome of DBS targeting the subthalamic nucleus (STN), while five studies included 57 patients receiving globus pallidus internus (GPi) DBS. Accumulated evidence showed that the atrophy of motor cortex and thalamus were associated with poor motor improvement, other structures such as the lateral-occipital cortex and anterior cingulate were also reported to correlated with motor outcome. Regarding non-motor outcomes, decreased volume of the hippocampus was reported to correlate with poor cognitive outcomes. Structures such as the thalamus, nucleus accumbens, and nucleus of basalis of Meynert were also reported to correlate with cognitive functions. Caudal middle frontal cortex was reported to have an impact on postsurgical psychiatric changes. Collectively, the findings of this review emphasize the utility of brain morphometry in outcome prediction of DBS for PD. Future efforts are needed to validate the findings and demonstrate the feasibility of brain morphometry in larger cohorts.
... More recently, imaging studies demonstrated the predictive value of structural and functional connectivity for motor outcome of STN-DBS in PD patients based on diffusion tensor imaging (DTI) (Horn et al., 2017) and resting-state functional MRI (rs-fMRI) (Younce et al., 2020). Smaller ventricular volumes measured on T1 weighted images were associated with more favorable motor outcome in one report (Younce et al., 2019) but not in others
(Price et al., 2011)
. Nevertheless, predicting specific motor outcome based on individual level remains challenging. ...
... This study conducted RA-ML analysis of specific motor outcome which is not available in most previous studies
(Price et al., 2011;
Lönnfors-Weitzel et al., 2016;Horn et al., 2017;Younce et al., 2019Younce et al., , 2020. Cardinal motor symptoms in PD patients include rigidity, bradykinesia, and tremor. ...
Predicting Motor Outcome of Subthalamic Nucleus Deep Brain Stimulation for Parkinson’s Disease Using Quantitative Susceptibility Mapping and Radiomics: A Pilot Study
Article
Full-text available
Sep 2021
Yu Liu
Xiao bin
ChenCheng Zhang
Fuhua Yan
Background
Emerging evidence indicates that iron distribution is heterogeneous within the substantia nigra (SN) and it may reflect patient-specific trait of Parkinson’s Disease (PD). We assume it could account for variability in motor outcome of subthalamic nucleus deep brain stimulation (STN-DBS) in PD.
Objective
To investigate whether SN susceptibility features derived from radiomics with machine learning (RA-ML) can predict motor outcome of STN-DBS in PD.
Methods
Thirty-three PD patients underwent bilateral STN-DBS were recruited. The bilateral SN were segmented based on preoperative quantitative susceptibility mapping to extract susceptibility features using RA-ML. MDS-UPDRS III scores were recorded 1–3 days before and 6 months after STN-DBS surgery. Finally, we constructed three predictive models using logistic regression analyses: (1) the RA-ML model based on radiomics features, (2) the RA-ML+LCT (levodopa challenge test) response model which combined radiomics features with preoperative LCT response, (3) the LCT response model alone.
Results
For the predictive performances of global motor outcome, the RA-ML model had 82% accuracy (AUC = 0.85), while the RA-ML+LCT response model had 74% accuracy (AUC = 0.83), and the LCT response model alone had 58% accuracy (AUC = 0.55). For the predictive performance of rigidity outcome, the accuracy of the RA-ML model was 80% (AUC = 0.85), superior to those of the RA-ML+LCT response model (76% accuracy, AUC = 0.82), and the LCT response model alone (58% accuracy, AUC = 0.42).
Conclusion
Our findings demonstrated that SN susceptibility features from radiomics could predict global motor and rigidity outcomes of STN-DBS in PD. This RA-ML predictive model might provide a novel approach to counsel candidates for STN-DBS.
... His pre-surgical MRI indicated moderate cerebral atrophy with enlarged lateral and third ventricles 6 years prior. Ventricular dilation is hypothesized to impact the integrity of the basal ganglion [24] and facilitate the advancement of motor symptoms
[25]
, also it is a pre-operative anatomical feature that can predict DBS-related motor changes, especially postural instability [25]. Therefore, his pre-operative ventricular status likely played a major role in the loss of benefit from DBS, however, given the complexity of neural circuits, the underlying reasons should be further investigated. ...
... His pre-surgical MRI indicated moderate cerebral atrophy with enlarged lateral and third ventricles 6 years prior. Ventricular dilation is hypothesized to impact the integrity of the basal ganglion [24] and facilitate the advancement of motor symptoms [25], also it is a pre-operative anatomical feature that can predict DBS-related motor changes, especially postural instability
[25]
. Therefore, his pre-operative ventricular status likely played a major role in the loss of benefit from DBS, however, given the complexity of neural circuits, the underlying reasons should be further investigated. ...
Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia
Article
May 2017
Zhengdao Deng
DianYou Li
ChenCheng Zhang
Bo-Min Sun
Background
No effective treatment for tardive dystonia (TD) has been well established. Deep brain stimulation (DBS) can ameliorate motor manifestations in primary dystonia, and may also be an effective approach for TD.
Objectives
This study aimed to illuminate the long-term efficacy and safety of subthalamic nucleus (STN)-DBS in treating TD.
Methods
Ten patients with refractory TD underwent STN-DBS therapy and were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), Abnormal Involuntary Movement Scale (AIMS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and the Short Form (36) Health Survey (SF-36) at four time points: pre-operation, 1 week post-operation, 6 months post-operation, and at a final long-term postsurgical follow-up time point.
Results
The mean follow-up time was 65.6 ± 30.4 months (range, 12–105 months). At the first follow-up, BFMDRS motor and disability scores had improved by 55.9± 28.3% and 62.6± 32.0%, respectively, while AIMS scores improved by 53.3± 26.7%. At the second follow-up, BFMDRS motor and disability scores improved further, by 87.3± 17.0% and 84.3% ± 22.9%, respectively, while AIMS scores improved by 88.4 ± 16.1%. At the last follow-up, this benefit was sustained and had plateaued. Quality of life was improved significantly at the long-term follow-up, and the HAMA and HAMD scores displayed a significant reduction that persisted after the first follow-up.
Conclusion
STN-DBS may be an effective and acceptable procedure for TD, leading to persistent and significant improvement in both movement and psychiatric symptoms.
... Este procedimiento tiene una mayor probabilidad de romper el ventrículo lateral, con riesgos de hemorragia intraventricular y migración de líquido cefalorraquídeo hacia el parénquima cerebral alrededor de los electrodos, con el posterior desplazamiento del objetivo. Sin embargo, no hay ninguna contraindicación absoluta para esta cirugía en pacientes con ventriculomegalia y encontramos que el volumen del ventrículo no predice el cambio motor después la ECP
(18)
. La localización indirecta del núcleo de interés se basa en atlas estereotácticos estandarizados y en un método derivado de fórmulas basado en puntos de referencia la línea AC-PC (ver figura 1-C). ...
Indicación de estimulación cerebral profunda en casos complejos de enfermedad de Parkinson. Experiencia en el Hospital Clínico Universidad de Chile
Article
Feb 2020
Carlos Guevara O.
Eduardo Villa U.
Marcos Baabor A.
Introduction: Deep brain stimulation (DBS) is a standard surgical procedure for the treatment of advanced Parkinson Disease (PD) with motor complications that cannot be adequately managed by medical treatment. Currently available literature can guide physicians on basic aspects of patients’ selection and indications for DBS. However, there is a range of real-world clinical settings where the indications of DBS for Parkinson disease are debatable. Objective: to present the experience on PD patients with complex clinical manifestations treated with DBS in our hospital. Method: Report of four PD cases treated with DBS. Case 1: 63-year old woman with advanced PD and severe motor complications; Case 2: 60-year old man with 5 years of disease duration and mild motor complications; Case 3: 67-year old man with severe ventriculomegaly that may have precluded direct electrode passage to the surgical target; Case 4: 67- year-old woman with putative severe axial disability. Results: After one year of follow-up, all patients showed improvement on motor symptoms as well as quality of life. Discussion: We provide a brief rationale for the patient selection in each case to support the decision-making in the management of PD patients with complex clinical cases.
... Our exclusion criteria were as follows: no extracted data; no available data; inappropriate diagnosis, and comment/overview. Ultimately, this study included a total of 34 studies and 26 of which were included in quantitative studies (Gálvez-Jiménez et al., 1998;Kumar et al., 1999;Obeso et al., 2001;Ogura et al., 2004;Erola et al., 2005; -Oroz et al., 2005;Crenna et al., 2006;Piboolnurak et al., 2007;Tabbal et al., 2007;Temel et al., 2007;Tir et al., 2007;Chastan et al., 2008;Lefaucheur et al., 2008;Ballanger et al., 2009;Ferraye et al., 2009;Gervais-Bernard et al., 2009;Moro et al., 2009;Schneider et al., 2009;Fasano et al., 2010;Kelly et al., 2010;Caliandro et al., 2011;
Price et al., 2011;
Sidiropoulos et al., 2013;Katz et al., 2015;Vallabhajosula et al., 2015;Welter et al., 2015). ...
Comparison of the Efficacy of Deep Brain Stimulation in Different Targets in Improving Gait in Parkinson's Disease: A Systematic Review and Bayesian Network Meta-Analysis
Article
Full-text available
Oct 2021
FRONT HUM NEUROSCI
Tianyi Chen
Fabin Lin
Guoen Cai
Background: Although a variety of targets for deep brain stimulation (DBS) have been found to be effective in Parkinson's disease (PD), it remains unclear which target for DBS leads to the best improvement in gait disorders in patients with PD. The purpose of this network meta-analysis (NMA) is to compare the efficacy of subthalamic nucleus (STN)-DBS, internal globus pallidus (GPi)-DBS, and pedunculopontine nucleus (PPN)-DBS, in improving gait disorders in patients with PD.
Methods: We searched the PubMed database for articles published from January 1990 to December 2020. We used various languages to search for relevant documents to reduce language bias. A Bayesian NMA and systematic review of randomized and non-randomized controlled trials were conducted to explore the effects of different targets for DBS on gait damage.
Result: In the 34 included studies, 538 patients with PD met the inclusion criteria. The NMA results of the effect of the DBS “on and off” on the mean change of the gait of the patients in medication-off show that GPi-DBS, STN-DBS, and PPN-DBS are significantly better than the baseline [GPi-DBS: –0.79(–1.2, –0.41), STN-DBS: –0.97(–1.1, –0.81), and PPN-DBS: –0.56(–1.1, –0.021)]. According to the surface under the cumulative ranking (SUCRA) score, the STN-DBS (SUCRA = 74.15%) ranked first, followed by the GPi-DBS (SUCRA = 48.30%), and the PPN-DBS (SUCRA = 27.20%) ranked last. The NMA results of the effect of the DBS “on and off” on the mean change of the gait of the patients in medication-on show that, compared with baseline, GPi-DBS and STN-DBS proved to be significantly effective [GPi-DBS: –0.53 (–1.0, –0.088) and STN-DBS: –0.47(–0.66, –0.29)]. The GPi-DBS ranked first (SUCRA = 59.00%), followed by STN-DBS(SUCRA = 51.70%), and PPN-DBS(SUCRA = 35.93%) ranked last.
Conclusion: The meta-analysis results show that both the STN-DBS and GPi-DBS can affect certain aspects of PD gait disorder.
... Este procedimiento tiene una mayor probabilidad de romper el ventrículo lateral, con riesgos de hemorragia intraventricular y migración de líquido cefalorraquídeo hacia el parénquima cerebral alrededor de los electrodos, con el posterior desplazamiento del objetivo. Sin embargo, no hay ninguna contraindicación absoluta para esta cirugía en pacientes con ventriculomegalia y encontramos que el volumen del ventrículo no predice el cambio motor después la ECP
(18)
. La localización indirecta del núcleo de interés se basa en atlas estereotácticos estandarizados y en un método derivado de fórmulas basado en puntos de referencia la línea AC-PC (ver figura 1-C). ...
Indicación de estimulación cerebral profunda en casos complejos de enfermedad de Parkinson. Experiencia en el Hospital Clínico de la Universidad de Chile
Article
Full-text available
Dec 2020
Carlos Guevara
Eduardo Villa
Marcos Baabor
Introduction: Deep brain stimulation (DBS) is a standard surgical procedure for the treatment of advanced Parkinson Disease (PD) with motor complications that cannot be adequately managed by medical treatment. Currently available literature can guide physicians on basic aspects of patients' selection and indications for DBS. However, there is a range of real-world clinical settings where the indications of DBS for Parkinson disease are debatable. Objective: to present the experience on PD patients with complex clinical manifestations treated with DBS in our hospital. Method: Report of four PD cases treated with DBS. Case 1: 63-year old woman with advanced PD and severe motor complications; Case 2: 60-year old man with 5 years of disease duration and mild motor complications; Case 3: 67-year old man with severe ventriculomegaly that may have precluded direct electrode passage to the surgical target; Case 4: 67-year-old woman with putative severe axial disability. Results: After one year of follow-up, all patients showed improvement on motor symptoms as well as quality of life. Discussion: We provide a brief rationale for the patient selection in each case to support the decision-making in the management of PD patients with complex clinical cases.
... We decided to operate on this patient, as DBS was considered the only option to improve his quality of life, although ventriculomegaly that is sufficient to preclude direct electrode passage to the surgical target may be a contraindication to DBS. However, we did not find any absolute contraindication for this surgery, and we found that ventricle volume does not predict motor change following DBS
(6)
. Indirect targeting is based on standardized stereotactic atlas and on a formula-derived method based on AC-PC landmarks. ...
Deep Brain Stimulation Surgery for Parkinson Disease Coexisting With Communicating Hydrocephalus: A Case Report
Article
Full-text available
Nov 2018
Carlos Guevara
José de Grazia
Pedro Vazquez
Marcos Baabor
We report a successful bilateral globus pallidus internus-deep brain stimulation (GPi-DBS) for a Parkinson disease (PD) patient with idiopathic normal pressure hydrocephalus (INPH) and an unusually long anterior commissure-posterior commissure (AC-PC) line. A 54-year-old man presented with a history of 3 months of severe shuffling gait, rigidity, slow movements of the left side limbs, and difficulty managing finances. A brain MRI revealed marked ventriculomegaly (Evans index = 0.42). The patient was diagnosed with INPH and a ventriculoperitoneal shunt was placed. Cognitive impairment improved, but walking disturbances, slowness, and rigidity persisted. Then treatment with levodopa was added, and the patient experienced a sustained improvement. He was diagnosed with PD. After 7 years, the patient developed gait freezing and severe levodopa-induced dyskinesia. The patient underwent bilateral GPi-DBS. We used MRI/CT fusion techniques for anatomical indirect targeting. Indirect targeting is based on standardized stereotactic atlas and on a formula—derived method based on AC-PC landmarks. The AC-PC line was 40 mm (the usual length is between 19 and 32 mm). Intraoperative microelectrode recording was a non-expendable test, but multiple recordings were avoided to reduce the surgical risk of ventricular involvement. There was a 71% decrease in the UPDRS III score during the on-stimulation state (28 to 8). The patient's dyskinesias resolved dramatically with a UdysRS of 15 (88% improvement) during the on-stimulation condition. The observed motor benefits and the improvement of his daily activities have persisted 6 months after surgery. Deep brain stimulation surgery in PD with ventriculomegaly is a challenge. This procedure can result in a greater chance of breaching the ventricle, with risks of intraventricular hemorrhage and migration of cerebrospinal fluid into the brain parenchyma with target displacement. Furthermore, clinical judgment is paramount when recent onset of shuffling gait coexists with ventriculomegaly because the most common dilemma is differentiating between PD and INPH. For these reasons, neurologists and surgeons may refuse to operate on PD patients with ventriculomegaly. However, DBS should be considered for PD patients with motor complications when responsiveness to levodopa is demonstrated, even in the context of marked ventriculomegaly.
... There is evidence of greater contralateral neuronal loss in the substantia nigra in PD (22) but findings with other neuroanatomical structures are mixed. Lewis and colleagues (23) demonstrated lateral ventricular volume asymmetry (contralateral to symptom laterality) in PD but lateral ventricles are only indirect measures of atrophy and the results have not been replicated by others
(24)
. Basal ganglia neuronal loss also typically appears to be bilateral, regardless of side of onset (2). ...
Striatal and Hippocampal Atrophy in Idiopathic Parkinson’s Disease Patients without Dementia: A Morphometric Analysis
Article
Full-text available
Apr 2017
Jared J. Tanner
Nikolaus R. McFarland
Catherine Price
Background
Analyses of subcortical gray structure volumes in non-demented idiopathic Parkinson’s disease (PD) often, but not always, show volume loss of the putamen, caudate nucleus, nucleus accumbens, and hippocampus. There is building evidence that structure morphometry might be more sensitive to disease-related processes than volume.
Objective
To assess morphometric differences of subcortical structures (putamen, caudate nucleus, thalamus, globus pallidus, nucleus accumbens, and amygdala) as well as the hippocampus in non-demented individuals with PD relative to age and education matched non-PD peers.
Methods
Prospective recruitment of idiopathic no-dementia PD and non-PD peers as part of a federally funded investigation. T1-weighted isovoxel metrics acquired via 3-T Siemens Verio for all individuals [PD n = 72 (left side onset n = 27, right side onset n = 45); non-PD n = 48]. FIRST (FMRIB Software Library) applications provided volumetric and vertex analyses on group differences for structure size and morphometry.
Results
Group volume differences were observed only for putamen and hippocampi (PD < non-PD) with hippocampal volume significantly associating with disease duration. Group shape differences were observed for bilateral putamen, caudate nucleus, and hippocampus with greater striatal atrophy contralateral to side of motor symptom onset. Hippocampal shape differences disappeared when removing the effects of volume.
Conclusion
The putamen was the primary structure to show both volume and shape differences in PD, indicating that the putamen is the predominant site of basal ganglia atrophy in early- to mid-stage PD. Side of PD symptom onset associates with contralateral striatal atrophy. Left-onset PD might experience more extensive striatal atrophy than right-onset PD. Hippocampus morphometric results suggest possible primary atrophy of CA3/4 and dentate gyrus.
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Show abstract
... 14) Furthermore, an increase in lateral ventricle volume was reported as a predictive factor for poor improvement of motor function after STN-DBS.
15
) Some recent studies showed the association of specific genes as predictive factors for the beneficial outcome of STN-DBS. 16,17) As mentioned above, many studies of the predictive factors for the outcome of STN-DBS have already been reported. ...
Predictive Factors for Long-term Outcome of Subthalamic Nucleus Deep Brain Stimulation for Parkinson’s Disease
Despite the recognition of the usefulness of subthalamic nucleus deep brain stimulation (STN-DBS) for the treatment of Parkinson's disease (PD), preoperative predictive factors for the long-term outcome of STN-DBS are not sufficiently established. We performed this study to determine such predictive factors. The subjects were 66 patients who were classified into two groups on the basis of their activities of daily living (ADL) evaluated five years after the STN-DBS surgery: 33 patients were assigned to the independent ADL group (group I) and the remaining 33 patients to the dependent ADL group (group D). Group I patients showed a Schwab and England (S&E) scale score of more than 70 during the off-period, indicating that these patients can maintain their independent ADL all the time. Group D patients showed a score of 70 or lower during the off-period, indicating that these patients cannot maintain their independent ADL for an entire day. We studied the differences in the preoperative state between these two groups. Statistically significant differences were noted in PD onset age, age at surgery, preoperative unified Parkinson's disease rating scale (UPDRS) part I score, part II score, total subscore for axial symptoms in part III, mini-mental state examination (MMSE) score and S&E score. Multiple logistic regression analysis showed that the significant independent variables related to long-term independent ADL were the age at surgery, MMSE score and preoperative S&E scale score during the off-period. The PD onset age, age at surgery, preoperative high-level ADL, cognitive function, and axial symptoms are important predictive factors for the long-term outcome of STN-DBS.
... Motor laterality associates with contralateral neuronal loss in the substantia nigra in individuals with PD (Kempster, Gibb, Stern, & Lees, 1989). While one study showed larger contralateral ventricle volumes in individuals with PD (Lewis et al., 2009) another study did not
(Price et al., 2011)
. There is evidence that individuals with PD have bilateral basal ganglia volume loss regardless of side of onset (Geng, Li, & Zee, 2006) with the putamen the primarily affected structure (Garg, Appel-Cresswell, Popuri, McKeown, & Beg, 2015;Nemmi, Sabatini, Rascol, & Péran, 2015;Price et al., 2016). ...
Marked brain asymmetry with intact cognitive functioning in idiopathic Parkinson’s disease: A longitudinal analysis
Objective:
A 71-year-old (MN) with an 11-year history of left onset tremor diagnosed as Parkinson's disease (PD) completed longitudinal brain magnetic resonance imaging (MRI) and neuropsychological testing. MRI scans showed an asymmetric caudate nucleus (right < left volume). We describe this asymmetry at baseline and the progression over time relative to other subcortical gray, frontal white matter, and cortical gray matter regions of interest. Isolated structural changes are compared to MN's cognitive profiles.
Method:
MN completed yearly MRIs and neuropsychological assessments. For comparison, left onset PD (n = 15) and non-PD (n = 43) peers completed the same baseline protocol. All MRI scans were processed with FreeSurfer and the FMRIB Software Library to analyze gray matter structures and frontal fractional anisotropy (FA) metrics. Processing speed, working memory, language, verbal memory, abstract reasoning, visuospatial, and motor functions were examined using reliable change methods.
Results:
At baseline, MN had striatal volume and frontal lobe thickness asymmetry relative to peers with mild prefrontal white matter FA asymmetry. Over time only MN's right caudate nucleus showed accelerated atrophy. Cognitively, MN had slowed psychomotor speed and visuospatial-linked deficits with mild visuospatial working memory declines longitudinally.
Conclusions:
This is a unique report using normative neuroimaging and neuropsychology to describe an individual diagnosed with PD who had striking striatal asymmetry followed secondarily by cortical thickness asymmetry and possible frontal white matter asymmetry. His decline and variability in visual working memory could be linked to ongoing atrophy of his right caudate nucleus.
Subcortical Atrophy and Motor Outcomes in Pallidal Deep Brain Stimulation for Parkinson Disease
Background
Appropriate patient selection is critical for successful deep brain stimulation (DBS) for Parkinson’s disease (PD). Subcortical atrophy is a possible determinant of postoperative DBS outcomes in patients with idiopathic PD, but it has not been well evaluated for DBS of the globus pallidus interna (GPi). We investigated perioperative subcortical atrophy measures in PD patients and their relationship to postoperative motor response in bilateral GPi-targeted DBS.
Methods
A retrospective cohort study examined correlations among indices of subcortical volumetry, disease duration, and age with postoperative outcomes at 6 months (Unified Parkinson’s Disease Rating Scale-Part III motor score quotient [dUPDRS], levodopa equivalent daily dosing [LEDD], and Parkinson’s Disease Questionnaire 39 [PDQ-39] mobility subscore). Subcortical volumetry was assessed by bicaudate ratio, Evans index, and third ventricular width on perioperative imaging. Linear regression models established correlations between preoperative variables and postoperative outcomes.
Results
Data from 34 patients with PD who were treated with GPi-targeted DBS were evaluated. Age was found to exhibit statistically significant positive correlations with all three measures of subcortical atrophy (P ≤ 0.002). None of the measures correlated with disease duration. Only Evans index and third ventricular width correlated with preoperative medication response (P < 0.05). Age and all three measures of atrophy exhibited statistically significant correlations with dUPDRS (P ≤ 0.01), but not with LEDD or PDQ-39 motor subscores (P > 0.05).
Conclusion
Perioperative age and subcortical atrophy as measured in this study correlated with motor responsiveness at 6 months postoperatively among patients receiving bilateral GPi-targeted DBS stimulation for PD.
S1 PRISMA Checklist
PRISMA 2009 Checklist–Reports of 4 systematic reviews informing DBS CE model.
(PDF)
Pallidal vs Subthalamic Nucleus Deep Brain Stimulation in Parkinson Disease
Deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) has been reported to relieve motor symptoms and levodopa-induced dyskinesia in patients with advanced Parkinson disease (PD). Although it has been suggested that stimulation of the STN may be superior to stimulation of the GPi, comparative trials are limited.
To extend our randomized, blinded pilot comparison of the safety and efficacy of STN and GPi stimulation in patients with advanced PD.
This study represents the combined results from our previously published, randomized, blinded, parallel-group pilot study and additional patients enrolled in our single-center extension study.
Oregon Health and Science University in Portland.Patients Twenty-three patients with idiopathic PD, levodopa-induced dyskinesia, and response fluctuations were randomized to implantation of bilateral GPi or STN stimulators. Patients and evaluating clinicians were blinded to stimulation site. All patients were tested preoperatively while taking and not taking medications and after 3, 6, and 12 months of DBS.
Postoperatively, response of symptoms to DBS, medication, and combined medication and DBS was evaluated. Twenty patients (10 in the GPi group and 10 in the STN group) completed 12-month follow-up.
Off-medication Unified Parkinson's Disease Rating Scale motor scores were improved after 12 months of both GPi and STN stimulation (39% vs 48%). Bradykinesia tended to improve more with STN than GPi stimulation. No improvement in on-medication function was observed in either group. Levodopa dose was reduced by 38% in STN stimulation patients compared with 3% in GPi stimulation patients (P = .08). Dyskinesia was reduced by stimulation at both GPi and STN (89% vs 62%). Cognitive and behavioral complications were observed only in combination with STN stimulation.
Stimulation of either the GPi or STN improves many features of advanced PD. It is premature to exclude GPi as an appropriate target for DBS in patients with advanced disease.
In Parkinson's disease, unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN), unlike bilateral stimulation, excludes ipsilateral confounding effects so that the contralateral effects of DBS on motor performance can be investigated alone. Because no kinematic study has yet investigated how unilateral STN-DBS affects the performance of a contralateral fast sequential motor act, ... [Show full abstract] we performed a kinematic analysis of the movement duration, switching time and spatial accuracy of a motor arm sequence in 10 parkinsonian patients. Patients were studied without dopaminergic therapy and when they were OFF and ON unilateral STN-DBS. We found that unilateral STN-DBS significantly improved movement time of a motor sequence and the switching time from one sequential step to the next, whereas accuracy deteriorated. We conclude that unilateral STN-DBS improves the performance of contralateral sequential arm movements in patients with Parkinson's disease.
| https://www.researchgate.net/publication/49966429_Lateral_Ventricle_Volume_is_Poor_Predictor_of_Post_Unilateral_DBS_Motor_Change_for_Parkinson%27s_Disease |
Nonallergic rhinitis: What clinicians should know - Pulmonology Advisor
Nonallergic rhinitis: What clinicians should know
Take-home message
NAR is a common and often overlooked disorder because of its many nonspecific symptoms, lack of diagnostic testing, and frequent coexistence with AR. Proper diagnosis of NAR requires a high level of suspicion. A careful review of the patient’s history is essential, and allergen testing should be conducted to rule out AR; however, positivity for AR does not exclude the presence of NAR. Once diagnosed, use of topical intranasal glucocorticoids and topical antihistamines has been shown to provide the greatest relief of symptoms across the NAR spectrum, but treatment should always be tailored to the patient’s specific symptoms. In many cases, multifaceted interventions that use pharmacologic and adjunct strategies, such as trigger avoidance, are necessary for optimal relief.
Are there different types of NAR?
NAR has several subtypes. The most common is vasomotor rhinitis, which was the first form identified and has been reported to comprise >70% of NAR cases. 5Vasomotor rhinitis is thought to occur secondary to disturbed regulation of the parasympathetic and sympathetic systems, resulting in vasodilation and edema of the nasal vasculature (Table 1). 6-8Less common forms of NAR include infectious rhinitis, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, and NAR with eosinophilia syndrome.
Are there different types of NAR?
NAR has several subtypes. The most common is vasomotor rhinitis, which was the first form identified and has been reported to comprise >70% of NAR cases. 5Vasomotor rhinitis is thought to occur secondary to disturbed regulation of the parasympathetic and sympathetic systems, resulting in vasodilation and edema of the nasal vasculature (Table 1). 6-8Less common forms of NAR include infectious rhinitis, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, and NAR with eosinophilia syndrome.
What are the symptoms of NAR?
NAR causes symptoms similar to AR, regardless of NAR subtype, most commonly including postnasal drip, nasal congestion, runny nose, and sneezing. 6,9Patients with infectious NAR might also experience persistent facial pain or pressure, dysosmia, and cough. Patients with NAR typically do not have itchiness of the nose, eyes, or throat, which are hallmarks of AR. 6,9NAR symptoms can be intermittent, but they are usually chronic and present year-round. Symptoms are often initiated or exacerbated by a variety of triggers.
What triggers have been associated with NAR?
Many nonallergic triggers have been associated with NAR. These include weather changes (temperature and humidity); consumption of alcohol or hot or spicy foods; exposure to environmental or occupational irritants, such as tobacco smoke, strong odors (eg, perfumes), potent fumes (eg, car exhaust), and dust or smog; use of certain medications (Table 2); and hormonal changes. 10,11Patients with NAR are not bothered by allergic triggers, such as pollen or animal dander, unless they have mixed AR. 11However, regardless of the trigger, all patients with NAR experience swollen nasal membranes.
What risk factors have been associated with NAR?
Several risk factors have been associated with NAR. The most significant risk factor is age, with approximately 70% of cases developing after age 20 years. 6In contrast, AR often manifests in childhood. 10Being female is another major risk factor, particularly during times of hormonal imbalance. Demographic data regarding vasomotor rhinitis have indicated a 2:1 female-to-male ratio, with a mean age of onset of 40 years. 5Exposure to environmental and occupational irritants is another major risk factor, but there are no epidemiologic data to categorize NAR based on trigger type. 5Physical and emotional stress and the presence of certain health conditions, particularly hypothyroidism and chronic fatigue syndrome, have also been noted to increase the risk of NAR. 10
What complications are associated with NAR?
Prolonged inflammation from NAR can cause a variety of other conditions, most notably nasal polyps, sinusitis, and middle ear infections, which are associated with their own complications and challenges. 10Large or multiple nasal polyps can impede breathing and impair sense of smell, whereas sinusitis can increase the risk of secondary bacterial infections, requiring use of antibiotics. Middle ear infections can impair hearing and balance and even result in rare but life-threatening complications, such as cerebrospinal fluid leak. 6A small observational study found NAR to be associated with an increased risk of obstructive sleep apnea syndrome (OSAS), which has previously been associated with AR. 12The study suggests that NAR poses a greater risk of OSAS than AR. This finding was based on polysomnography results and Epworth Sleepiness Scale scores. In general, study patients with NAR were found to have significantly shorter sleep durations and worse sleep efficiency than their AR counterparts.
How is NAR diagnosed?
NAR is considered a diagnosis of exclusion. Careful review of a patient’s medical and social history can help point to the diagnosis by enabling irritant triggers and risk factors to be identified. Diagnostic tests, including a skin test and a blood test, should be used to rule out allergic causes. 13The skin test assesses for a reaction to common airborne allergens, such as pollen, mold, and dander, whereas the blood test measures the immune system’s response to such allergens by assessing IgE levels. If these tests are negative, a diagnosis of NAR is made. However, a positive finding on these tests does not necessarily rule out NAR, as it can coexist with AR. 13If treatments in patients with AR are unsuccessful or suboptimal, coexisting NAR should be considered.
What pharmacologic agents are available to treat NAR?
Treatment of NAR requires an individual management approach that depends on the type identified and a patient’s symptoms. 13The most common pharmacologic treatments include nasal glucocorticoids, nasal antihistamines, anticholinergics, and decongestants, depending on a patient’s presentation. Of these, topical intranasal glucocorticoids and topical antihistamines have been reported to be the most useful in managing all symptoms associated with chronic NAR, regardless of NAR etiology, and appear to be most effective when used in combination in patients with moderate to severe NAR. 3,11,13If these treatments do not sufficiently address nasal congestion, a decongestant can be added to the regimen, and if postnasal drip remains bothersome, a first-generation H1 antihistamine can be added. 3,11In patients with the primary symptom of rhinorrhea, such as those with gustatory NAR, ipratropium bromide may be sufficient. 3,11
Can anything else be done to manage NAR?
Other important management strategies include avoiding triggers whenever possible, such as exposure to tobacco smoke and occupational and environmental irritants. 7Some patients may benefit from avoiding strong perfumes and other strongly scented products. Using a high-efficiency particulate air (HEPA) filter and a humidifier might be beneficial in some cases. 7Most patients require multifaceted interventions to optimize results. 7Some patients have been reported to benefit from nasal rinsing and irrigation with saline, particularly in the setting of postnasal drip. 3,11Nasal rinsing is recommended before use of any nasal medications so that the nasal lining is cleansed and topical medications are not rinsed away prematurely. 3,11If patients are found to have drug-induced NAR, they might require adjustments to their medication regimen. If relief of symptoms is not obtained after repeated interventions, surgical consultation might be warranted in some patients. 3,11
Take-home message
NAR is a common and often overlooked disorder because of its many nonspecific symptoms, lack of diagnostic testing, and frequent coexistence with AR. Proper diagnosis of NAR requires a high level of suspicion. A careful review of the patient’s history is essential, and allergen testing should be conducted to rule out AR; however, positivity for AR does not exclude the presence of NAR. Once diagnosed, use of topical intranasal glucocorticoids and topical antihistamines has been shown to provide the greatest relief of symptoms across the NAR spectrum, but treatment should always be tailored to the patient’s specific symptoms. In many cases, multifaceted interventions that use pharmacologic and adjunct strategies, such as trigger avoidance, are necessary for optimal relief.
Are there different types of NAR?
NAR has several subtypes. The most common is vasomotor rhinitis, which was the first form identified and has been reported to comprise >70% of NAR cases. 5Vasomotor rhinitis is thought to occur secondary to disturbed regulation of the parasympathetic and sympathetic systems, resulting in vasodilation and edema of the nasal vasculature (Table 1). 6-8Less common forms of NAR include infectious rhinitis, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, and NAR with eosinophilia syndrome.
Are there different types of NAR?
NAR has several subtypes. The most common is vasomotor rhinitis, which was the first form identified and has been reported to comprise >70% of NAR cases. 5Vasomotor rhinitis is thought to occur secondary to disturbed regulation of the parasympathetic and sympathetic systems, resulting in vasodilation and edema of the nasal vasculature (Table 1). 6-8Less common forms of NAR include infectious rhinitis, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, and NAR with eosinophilia syndrome.
What are the symptoms of NAR?
NAR causes symptoms similar to AR, regardless of NAR subtype, most commonly including postnasal drip, nasal congestion, runny nose, and sneezing. 6,9Patients with infectious NAR might also experience persistent facial pain or pressure, dysosmia, and cough. Patients with NAR typically do not have itchiness of the nose, eyes, or throat, which are hallmarks of AR. 6,9NAR symptoms can be intermittent, but they are usually chronic and present year-round. Symptoms are often initiated or exacerbated by a variety of triggers.
What triggers have been associated with NAR?
Many nonallergic triggers have been associated with NAR. These include weather changes (temperature and humidity); consumption of alcohol or hot or spicy foods; exposure to environmental or occupational irritants, such as tobacco smoke, strong odors (eg, perfumes), potent fumes (eg, car exhaust), and dust or smog; use of certain medications (Table 2); and hormonal changes. 10,11Patients with NAR are not bothered by allergic triggers, such as pollen or animal dander, unless they have mixed AR. 11However, regardless of the trigger, all patients with NAR experience swollen nasal membranes.
What risk factors have been associated with NAR?
Several risk factors have been associated with NAR. The most significant risk factor is age, with approximately 70% of cases developing after age 20 years. 6In contrast, AR often manifests in childhood. 10Being female is another major risk factor, particularly during times of hormonal imbalance. Demographic data regarding vasomotor rhinitis have indicated a 2:1 female-to-male ratio, with a mean age of onset of 40 years. 5Exposure to environmental and occupational irritants is another major risk factor, but there are no epidemiologic data to categorize NAR based on trigger type. 5Physical and emotional stress and the presence of certain health conditions, particularly hypothyroidism and chronic fatigue syndrome, have also been noted to increase the risk of NAR. 10
What complications are associated with NAR?
Prolonged inflammation from NAR can cause a variety of other conditions, most notably nasal polyps, sinusitis, and middle ear infections, which are associated with their own complications and challenges. 10Large or multiple nasal polyps can impede breathing and impair sense of smell, whereas sinusitis can increase the risk of secondary bacterial infections, requiring use of antibiotics. Middle ear infections can impair hearing and balance and even result in rare but life-threatening complications, such as cerebrospinal fluid leak. 6A small observational study found NAR to be associated with an increased risk of obstructive sleep apnea syndrome (OSAS), which has previously been associated with AR. 12The study suggests that NAR poses a greater risk of OSAS than AR. This finding was based on polysomnography results and Epworth Sleepiness Scale scores. In general, study patients with NAR were found to have significantly shorter sleep durations and worse sleep efficiency than their AR counterparts.
How is NAR diagnosed?
NAR is considered a diagnosis of exclusion. Careful review of a patient’s medical and social history can help point to the diagnosis by enabling irritant triggers and risk factors to be identified. Diagnostic tests, including a skin test and a blood test, should be used to rule out allergic causes. 13The skin test assesses for a reaction to common airborne allergens, such as pollen, mold, and dander, whereas the blood test measures the immune system’s response to such allergens by assessing IgE levels. If these tests are negative, a diagnosis of NAR is made. However, a positive finding on these tests does not necessarily rule out NAR, as it can coexist with AR. 13If treatments in patients with AR are unsuccessful or suboptimal, coexisting NAR should be considered.
What pharmacologic agents are available to treat NAR?
Treatment of NAR requires an individual management approach that depends on the type identified and a patient’s symptoms. 13The most common pharmacologic treatments include nasal glucocorticoids, nasal antihistamines, anticholinergics, and decongestants, depending on a patient’s presentation. Of these, topical intranasal glucocorticoids and topical antihistamines have been reported to be the most useful in managing all symptoms associated with chronic NAR, regardless of NAR etiology, and appear to be most effective when used in combination in patients with moderate to severe NAR. 3,11,13If these treatments do not sufficiently address nasal congestion, a decongestant can be added to the regimen, and if postnasal drip remains bothersome, a first-generation H1 antihistamine can be added. 3,11In patients with the primary symptom of rhinorrhea, such as those with gustatory NAR, ipratropium bromide may be sufficient. 3,11
Can anything else be done to manage NAR?
Other important management strategies include avoiding triggers whenever possible, such as exposure to tobacco smoke and occupational and environmental irritants. 7Some patients may benefit from avoiding strong perfumes and other strongly scented products. Using a high-efficiency particulate air (HEPA) filter and a humidifier might be beneficial in some cases. 7Most patients require multifaceted interventions to optimize results. 7Some patients have been reported to benefit from nasal rinsing and irrigation with saline, particularly in the setting of postnasal drip. 3,11Nasal rinsing is recommended before use of any nasal medications so that the nasal lining is cleansed and topical medications are not rinsed away prematurely. 3,11If patients are found to have drug-induced NAR, they might require adjustments to their medication regimen. If relief of symptoms is not obtained after repeated interventions, surgical consultation might be warranted in some patients. 3,11
Take-home message
NAR is a common and often overlooked disorder because of its many nonspecific symptoms, lack of diagnostic testing, and frequent coexistence with AR. Proper diagnosis of NAR requires a high level of suspicion. A careful review of the patient’s history is essential, and allergen testing should be conducted to rule out AR; however, positivity for AR does not exclude the presence of NAR. Once diagnosed, use of topical intranasal glucocorticoids and topical antihistamines has been shown to provide the greatest relief of symptoms across the NAR spectrum, but treatment should always be tailored to the patient’s specific symptoms. In many cases, multifaceted interventions that use pharmacologic and adjunct strategies, such as trigger avoidance, are necessary for optimal relief.
Rhinitis is an irritation or inflammation of the nasal mucous membranes. It can be caused by infectious pathogens, irritants, or allergens. Allergic rhinitis (AR), which is triggered by allergens such as dust, mold, and pollen, is the most common form, affecting 10% to 30% of persons worldwide. 1In the United States, this translates to approximately 84 million people. 2Nonallergic rhinitis (NAR) is a form of rhinitis that does not involve the immune system and often has an unknown etiology, though many triggers have been identified. The prevalence of NAR remains unclear, but it appears to be common, with some estimates suggesting 19 million persons in the United States are affected. 2However, this number likely underestimates its prevalence because NAR is difficult to diagnose in the setting of allergen-specific immunoglobulin E (IgE) positivity and the condition has been found to coexist with AR in a substantial number of patients. 2,3Based on such findings, it has been suggested that 50% to 80% of patients with rhinitis may have NAR, whether alone or, more commonly, as a mixed disease with some form of AR. 2,4To ensure a proper diagnosis, which is essential for optimal relief of symptoms and avoidance of unnecessary medications and treatments, clinicians must maintain a high degree of suspicion for NAR and should not rule out its presence based on an AR diagnosis alone.
References
American Academy of Allergy Asthma & Immunology. Allergy statistic. www.aaaai.org/about-aaaai/newsroom/allergy-statistics . Accessed February 14, 2017.
Settipane RA, Charnock DR. Epidemiology of rhinitis: allergic and nonallergic. Clin Allergy Immunol . 2007;19:23-34. europepmc.org/abstract/med/17153005 . Accessed February 15, 2017.
Lieberman PL. Chronic nonallergic rhinitis. UptoDate. cursoenarm.net/UPTODATE/contents/mobipreview.htm?2/9/2193?source=see_link . Accessed February 15, 2017.
Groves M. Non-allergic perennial rhinitis: a family of disorders. www.bcm.edu/departments/otolaryngology/education/grand-rounds/non-allergic-perennial-rhinitis-disorders-fam . Accessed February 14, 2017.
Settipane RA. Epidemiology of vasomotor rhinitis. W orld Allergy Organ J . 2009;2:115-118.
Nozad CH, Michael LM, Betty Lew D, Michael CF. Non-allergic rhinitis: a case report and review. Clin Mol Allergy . 2010;8:1.
Tran NP, Vickery J, Blaiss MS. Management of rhinitis: allergic and non-allergic. Allergy Asthma Immunol Res . 2011;3:148-156.
Ramakrishnan VR, Cooper S. Pharmacotherapy for nonallergic rhinitis. emedicine.medscape.com/article/874171-overview . Accessed February 14, 2017.
American Academy of Allergy Asthma & Immunology. Nonallergic rhinitis (vasomotor rhinitis). www.aaaai.org/conditions-and-treatments/conditions-dictionary/nonallergic-rhinitis-vasomotor . Accessed February 14, 2017.
Mayo Clinic. Nonallergic rhinitis. www.mayoclinic.org/diseases-conditions/nonallergic-rhinitis/home/ovc-20179167 . Accessed February 15, 2017.
Lieberman PL. Patient education: Nonallergic rhinitis (runny or stuffy nose) (Beyond the Basics). www.uptodate.com/contents/nonallergic-rhinitis-runny-or-stuffy-nose-beyond-the-basics . Accessed February 15, 2017.
Kalpaklioğlu AF, Kavut AB, Ekici M. Allergic and nonallergic rhinitis: the threat for obstructive sleep apnea. Ann Allergy Asthma Immunol . 2009;103:20-25.
Scarupa MD, Kaliner MA. Nonallergic rhinitis, with a focus on vasomotor rhinitis: clinical importance, differential diagnosis, and effective treatment recommendations. World Allergy Organ J . 2009;2:20-25.
| https://www.pulmonologyadvisor.com/slideshow/slides/nonallergic-rhinitis-what-clinicians-should-know/ |
On-site HIV rapid test and brief, prevention counseling og On- site HIV rapid test & amp; information og Referral for off-site HIV testing i Stof-relaterede lidelser - Kliniske forsøgsregister - ICH GCP
This is a randomized controlled clinical trial in which adults receiving drug abuse treatment will be recruited to participate in a multi-center HIV testing and.... Kliniske forsøgsregister. ICH GCP.
Rapid HIV Testing and Counseling in Drug Abuse Treatment
HIV Rapid Testing and Counseling in Drug Abuse Treatment Programs in the U.S.
This is a randomized controlled clinical trial in which adults receiving drug abuse treatment will be recruited to participate in a multi-center HIV testing and counseling study.
The purpose of this study is to assess the relative effectiveness of three HIV testing strategies on increasing receipt of test results: (1) on-site HIV rapid testing with brief, participant-tailored prevention counseling, (2) on-site HIV rapid testing with information only, and (3) referral for off-site HIV testing.
The study will also assess the effectiveness of the three testing strategies in reducing HIV risk behaviors.
Studieoversigt
Status
Afsluttet
Betingelser
Stof-relaterede lidelser
Intervention / Behandling
Adfærdsmæssigt: On-site HIV rapid test and brief, prevention counseling
Adfærdsmæssigt: On- site HIV rapid test & information
Adfærdsmæssigt: Referral for off-site HIV testing
Detaljeret beskrivelse
This is a randomized controlled clinical trial in which individuals receiving drug abuse treatment will be recruited to participate in a multi-center HIV testing and counseling study.
The purpose of this study is to assess the relative effectiveness of three HIV testing strategies on increasing receipt of HIV test results: (1) on-site HIV rapid testing with brief, participant-tailored prevention counseling, (2) on-site HIV rapid testing with information only, and (3) referral for off-site HIV testing.
The study will also assess the effectiveness of the three testing strategies in reducing HIV sexual risk behaviors.
Injection drug risk behavior will be a secondary outcome.
Participants will complete a baseline assessment to report their demographics, HIV testing history and sexual and drug-using risk behaviors, and will be randomized to one of three groups.
At one month post-randomization, participants will complete a follow-up assessment to determine whether or not they received their HIV test results.
At six months post-randomization, participants will complete a follow-up assessment to assess any changes in their HIV sexual risk behaviors.
Undersøgelsestype
Interventionel
Tilmelding (Faktiske)
1281
Fase
Fase 3
Kontakter og lokationer
Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.
Studiesteder
Forenede Stater
Arizona
Connecticut
Maryland
Missouri
New Mexico
North Carolina
Oregon
Pennsylvania
Pittsburgh, Pennsylvania, Forenede Stater, 15213
South Carolina
Columbia, South Carolina, Forenede Stater, 29203
Columbia, South Carolina, Forenede Stater, 29250
Virginia
Chesterfield, Virginia, Forenede Stater, 23832
Deltagelseskriterier
Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.
Berettigelseskriterier
Aldre berettiget til at studere
18 år og ældre (Voksen, Ældre voksen)
Tager imod sunde frivillige
Ingen
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria:
At least 18 years of age
HIV-negative or HIV status unknown
No receipt of results from HIV test initiated within last 12 months
Be able to communicate in English
Studieplan
Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
Primært formål : Forebyggelse
Tildeling : Randomiseret
Interventionel model : Parallel tildeling
Maskning : Ingen (Åben etiket)
3
Våben og indgreb
Deltagergruppe / Arm Intervention / Behandling Eksperimentel: HIV rapid test & counseling Participants will be offered an oral fluid HIV rapid test (via oral swab) and brief prevention counseling that addresses both risk reduction and motivation to be HIV tested based on an evidence-based counseling approach (Project RESPECT-2 counseling).
Prior to receiving testing, study participants must first provide consent for HIV testing.
Consent for testing will be obtained through a second consent form required of all participants who wish to proceed with the HIV test. Adfærdsmæssigt: On-site HIV rapid test and brief, prevention counseling Participants will be offered an on-site oral fluid HIV rapid test with brief prevention counseling that addresses both risk reduction and motivation to be HIV tested based on an evidence-based counseling approach. Eksperimentel: HIV rapid test and info Participants will be offered an oral fluid HIV rapid test (via oral swab).
Prior to receiving testing, study participants must first provide consent for HIV testing.
Again, consent for testing will be obtained through a second consent form required of all participants who wish to proceed with the HIV test.
Participants will receive rapid HIV testing and test results after signing the consent to be tested.
In both Groups 1 and 2, participants who test reactive (preliminary positive) will be counseled on the sexual risk behaviors associated with transmission of HIV and the acquisition of STDs, as is current clinical practice with those testing HIV positive.
Confirmed positives will be linked to HIV primary care. Adfærdsmæssigt: On- site HIV rapid test & information Participants will be offered an on-site oral fluid HIV rapid test with basic info. Aktiv komparator: HIV testing referral Participants randomized to group 3 will receive a referral list for HIV community-testing agencies.
Each CTP site will have previously prepared an extensive referral list of testing sites in the surrounding geographic area.
By virtue of their status as patients in the CTPs, they will receive whatever HIV testing and HIV education referrals the CTPs normally provide to their patients.
This is the standard of care at CTPs that do not provide on-site testing. Adfærdsmæssigt: Referral for off-site HIV testing Participants will be offered a referral list of HIV testing agencies in the community.
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål Foranstaltningsbeskrivelse Tidsramme Self-Report Receipt of HIV Test Results Tidsramme: One month post-randomization The HIV testing primary outcome is self-reported receipt of HIV test results.
This will be measured at one month post-randomization for all participants.
We recognize that there are three potential HIV testing behaviors that could be evaluated in this study: acceptance of HIV testing, completion of HIV testing, and receipt of HIV testing results.
Acceptance of testing refers to whether or not a participant would accept the offer of an HIV test.
Completion of testing refers to whether or not a participant completes the HIV test.
Receipt of HIV test results refers to whether or not a participant self-reports having received the results of the HIV test. One month post-randomization Number of Risky Sexual Behaviors Tidsramme: Six months post-randomization The sexual risk behavior primary outcome is self-reported sexual risk behavior, which will be measured at baseline and six months post-randomization as the self-reported number of unprotected sex acts (vaginal or anal sex without a condom). Six months post-randomization
Sekundære resultatmål
Resultatmål Foranstaltningsbeskrivelse Tidsramme Sharing of Needles Used in Drug Use Tidsramme: Six months Change in sharing of needles.
The number of individuals reporting needle sharing at baseline and 6-month follow-up were measured and the change in sharing of needles assessed. Six months Self-Report of Ever Having Been Tested Tidsramme: 1 month post-randomization The HIV testing secondary outcomes are all binary (Yes/No).
The below data represents self-reported completion of HIV test by 1 month. 1 month post-randomization
Samarbejdspartnere og efterforskere
Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.
Sponsor
University of Miami
Samarbejdspartnere
National Institute on Drug Abuse (NIDA)
University of California, San Francisco
Efterforskere
Ledende efterforsker: Lisa Metsch, Ph.D., Columbia University
Ledende efterforsker: Grant Colfax, M.D., PATH
Publikationer og nyttige links
Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.
Generelle publikationer
Metsch LR, Feaster DJ, Gooden L, Matheson T, Mandler RN, Haynes L, Tross S, Kyle T, Gallup D, Kosinski AS, Douaihy A, Schackman BR, Das M, Lindblad R, Erickson S, Korthuis PT, Martino S, Sorensen JL, Szapocznik J, Walensky R, Branson B, Colfax GN. Implementing rapid HIV testing with or without risk-reduction counseling in drug treatment centers: results of a randomized trial. Am J Public Health. 2012 Jun;102(6):1160-7. doi: 10.2105/AJPH.2011.300460. Epub 2012 Apr 19.
Schackman BR, Metsch LR, Colfax GN, Leff JA, Wong A, Scott CA, Feaster DJ, Gooden L, Matheson T, Haynes LF, Paltiel AD, Walensky RP. The cost-effectiveness of rapid HIV testing in substance abuse treatment: results of a randomized trial. Drug Alcohol Depend. 2013 Feb 1;128(1-2):90-7. doi: 10.1016/j.drugalcdep.2012.08.009. Epub 2012 Sep 9.
Schackman BR, Leff JA, Barter DM, DiLorenzo MA, Feaster DJ, Metsch LR, Freedberg KA, Linas BP. Cost-effectiveness of rapid hepatitis C virus (HCV) testing and simultaneous rapid HCV and HIV testing in substance abuse treatment programs. Addiction. 2015 Jan;110(1):129-43. doi: 10.1111/add.12754.
Datoer for undersøgelser
Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.
Studer store datoer
Studiestart
1. januar 2009
Primær færdiggørelse (Faktiske)
1. december 2009
Studieafslutning (Faktiske)
1. februar 2010
Datoer for studieregistrering
Først indsendt
16. december 2008
Først indsendt, der opfyldte QC-kriterier
16. december 2008
Først opslået (Skøn)
17. december 2008
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Skøn)
14. oktober 2015
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
13. oktober 2015
Sidst verificeret
1. september 2014
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
Psykiske lidelser
Kemisk inducerede lidelser
Stof-relaterede lidelser
Andre undersøgelses-id-numre
20080379
U10DA013720 (U.S. NIH-bevilling/kontrakt)
Disse oplysninger blev hentet direkte fra webstedetclinicaltrials.govuden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du [email protected]. Så snart en ændring er implementeret påclinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .
| https://ichgcp.net/da/clinical-trials-registry/NCT00809445 |
Optical Coherence Tomography Angiography. - Free Online Library
Free Online Library: Optical Coherence Tomography Angiography.(Editorial) by " Case Reports in Ophthalmological Medicine" ; Health, general Bevacizumab
Optical Coherence Tomography Angiography.
Page/Link:
Page URL:
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Citations:
MLA style: "Optical Coherence Tomography Angiography.." The Free Library . 2018 Hindawi Limited 02 Jun. 2023 https://www.thefreelibrary.com/Optical+Coherence+Tomography+Angiography.-a0587875741
Chicago style: The Free Library . S.v. Optical Coherence Tomography Angiography.." Retrieved Jun 02 2023 from https://www.thefreelibrary.com/Optical+Coherence+Tomography+Angiography.-a0587875741
APA style: Optical Coherence Tomography Angiography.. (n.d.) >The Free Library. (2014). Retrieved Jun 02 2023 from https://www.thefreelibrary.com/Optical+Coherence+Tomography+Angiography.-a0587875741
Optical coherence tomography angiography (OCT-A) is a relatively
new, noninvasive outpatient imaging test that provides both structural
and functional information about the macula and midperipheral retina.
OCT-A is complementary to traditional imaging modalities, such as fundus
photography, fluorescein angiography (FA), and spectral domain optical
coherence tomography (SD-OCT).
Advantages of OCT-A include visualization of vascular flow signal,
en face imaging, no need for dye injection, and segmentation of the
posterior segment structures from the vitreomacular interface, through
the retinal layers, and to the choroid. Disadvantages of OCT-A include
increased costs and longer acquisition times than SD-OCT. Because of the
longer acquisition times, it may be difficult to obtain high-quality
OCT-A images in eyes with poor visual acuity that cannot fixate well.
The use of OCT-A is currently best established in the care of
patients with retinal vascular diseases, choroidal vascular diseases,
and ophthalmic oncology. Its role appears to be emerging in patients
with other macular and retinal diseases (including uveitis) as well as
optic nerve diseases and glaucoma.
This special issue, which had opened for 6 months in the second
half of 2017, focuses on various clinical applications of OCT-A.
V. M. Villegas et al. present two patients with choroidal nevi,
including one halo nevus, and report decreased vascular flow signal in
most or all layers on OCT-A. This decreased vascular flow signal is
proposed to be due to blockage from the choroidal nevus, true diminished
blood flow (ischemia), or unknown causes. Because choroidal melanoma
frequently demonstrates increased vascularity on FA, the authors propose
that OCT-A might represent a noninvasive test to screen suspicious nevi
for evidence of early malignant transformation.
V. Shah et al. report one patient with a unilateral congenital
retinal macrovessel in the macula. OCT-A demonstrates replacement of the
normal foveal avascular zone (FAZ) by abnormal vascular bifurcations,
yet this disturbance of the FAZ is associated with relatively normal
foveal anatomy, as imaged by swept-source OCT, and a best-corrected
visual acuity of 20/20.
B. M. Hampton et al. present one patient with bilateral choroidal
neovascularization (CNV) due to punctate inner choroidopathy (PIC). In
this patient, OCT-A demonstrates bilateral submacular abnormal vessels
consistent with CNV, and FA demonstrates late vascular leakage,
confirming the diagnosis.
V. M. Villegas and J. L. Kovach report one patient with bilateral
macular telangiectasia type 2 (MacTel2) and unilateral subretinal
neovascularization (SNV). In the eye with SNV, OCT-A demonstrates
abnormal submacular vessels consistent with SNV. In the fellow eye,
OCT-A demonstrates abnormal vessels temporal to the center of the macula
consistent with nonproliferative MacTel2.
P. Shah et al. present two patients with acute central retinal
artery occlusion (CRAO), including one with cilioretinal artery sparing,
imaged with both FA and OCT-A. In both patients, the images obtained by
FA and OCT-A are very similar. Because of this similarity, the authors
propose that patients with acute CRAO in whom OCT-A can be obtained
might not require additional imaging with FA.
M. Kaya et al. report one patient with chronic combined
cilioretinal artery occlusion and central retinal vein occlusion (CRVO).
In this patient, FA performed 10 months after the combined occlusion is
relatively normal but OCT-A demonstrates a wedge-shaped area of
decreased vascular flow signal consistent with the cilioretinal artery
occlusion. The authors propose that different imaging studies may be
relatively more useful in the acute and chronic phases of this disease.
S. Wu et al. present a somewhat similar patient with combined CRAO
and CRVO. In this patient, symptoms began immediately following cataract
surgery with retrobulbar anesthesia. OCT-A demonstrates profound
decreased vascular flow signal in the superficial and deep retinal
plexuses but relatively normal vascular flow signal in the
choriocapillaris and choroid.
T. Y. A. Liu et al. report one patient with CNV due to presumed
ocular histoplasmosis syndrome (POHS). Three monthly injections of
intravitreal bevacizumab were given. On follow-up examinations up to 6
months, CNV activity is not detectable by FA or SD-OCT but is detectable
by oCtA. The authors propose that OCT-A might be more sensitive than FA
for this indication.
H. Hamoudi et al. present one patient with unilateral Purtscher
retinopathy following thoracic trauma sustained in a motor vehicle
accident. OCT-A demonstrates decreased vascular flow signal in the
superficial and deep retinal capillary plexuses of the affected eye and
is normal in the fellow eye.
V. S. Chang et al. report one patient with unilateral retinal
arterial macroaneurysm (RAM) treated with two injections of intravitreal
bevacizumab. At presentation, OCTA demonstrated increased vascular flow
signal in the walls of the RAM. After treatment with bevacizumab was
initiated, follow-up OCT-A studies demonstrate progressive reduction in
the vascular flow signal within the walls of the RAM, suggesting
progressive sclerosis of the lesion.
A. Fukutomi et al. present one patient with nonischemic CRVO that
progressed to ischemic CRVO. At presentation, OCT-A demonstrated some
reduction in vascular flow signal in the small capillaries but
relatively preserved vascular flow signal surrounding the FAZ.
Subsequent OCT-A studies demonstrate progressive expansion of the area
of decreased vascular signal flow, consistent with progressive expansion
of capillary nonperfusion.
In summary, this special issue contains many interesting case
reports, which collectively illustrate many uses of OCTA in patients
with retinal vascular disease, choroidal vascular disease, and ocular
oncology.
https://doi.org/10.1155/2018/7140164
Acknowledgments
The Guest Editors express great appreciation to all authors for
their excellent contributions and to all peer reviewers for their
critical assistance. In addition, the Guest Editors thank the Editorial
Board of this journal for their approval of this important topic and
their continuous support in successful publication of this special
issue. Finally, the Lead Guest Editor wishes to thank his four
colleagues for their valuable expertise and dedication. We are very
confident that this special issue increases our understanding of OCT-A
as an emerging technology that can help clinicians better manage their
patients.
Stephen G. Schwartz [ID], (1) Harry W. Flynn Jr., (1) Andrzej
Grzybowski [ID], (2,3) Avinash Pathengay, (4) and Ingrid U. Scott (5,6)
(1) Department of Ophthalmology, Bascom Palmer Eye Institute,
University of Miami Miller School of Medicine, Miami, FL, USA
(2) Institute for Research in Ophthalmology, Poznan, Poland
(3) Department of Ophthalmology, University of Warmia and Mazury,
Olsztyn, Poland
(4) Retina and Uveitis Department, LVPrasad Eye Institute, GMR
Varalakshmi Campus, Visakhapatnam, Andhra Pradesh, India
(5) Department of Ophthalmology, Penn State College of Medicine,
Hershey, PA, USA
(6) Department of Public Health Sciences, Penn State College of
Medicine, Hershey, PA, USA
Correspondence should be addressed to Stephen G. Schwartz;
[email protected]
Received 25 March 2018; Accepted 26 March 2018; Published 6 June
2018
Article Details
Title Annotation:
Editorial
Author:
Schwartz, Stephen G.; Flynn, Harry W., Jr.; Grzybowski, Andrzej; Pathengay, Avinash; Scott, Ingrid U
Publication:
Case Reports in Ophthalmological Medicine
Date:
Jan 1, 2018
Words:
1092
| https://www.thefreelibrary.com/Optical+Coherence+Tomography+Angiography-a0587875741 |
Oil Spills and Polycyclic Aromatic Hydrocarbons
Download Citation | Oil Spills and Polycyclic Aromatic Hydrocarbons | Crude oil contains many kinds of polycyclic aromatic hydrocarbons, and its release into the marine environment causes serious damage. It is... | Find, read and cite all the research you need on ResearchGate
Chapter
Oil Spills and Polycyclic Aromatic Hydrocarbons
February 2018
DOI: 10.1007/978-981-10-6775-4_16
In book: Polycyclic Aromatic Hydrocarbons (pp.213-223)
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Kazuichi Hayakawa
Kazuichi Hayakawa
Abstract
Crude oil contains many kinds of polycyclic aromatic hydrocarbons, and its release into the marine environment causes serious damage. It is important to understand the behavior and biological effects of PAHs as components of oil. Over the last five decades, many large-scale oil spills, including the Gulf War oil spill in 1991 and the Gulf of Mexico oil spill in 2010, have occurred in the world. This chapter describes the long-term impact on marine and coastal environments by C-heavy (the last distilled fraction of heavy oil) oil spilled from the Nakhodka in the Japan Sea in 1997, where polycyclic aromatic hydrocarbons were monitored as pollution markers.
<here is a image 175d1bd4b7439d95-754927124da715c1>
... Les produits chimiques à base d'hydrocarbures sont des composants majeurs du pétrole brut et sont classés comme HAPs, hydrocarbures aliphatiques saturés, hydrocarbures aliphatiques insaturés et hydrocarbures saturés alicycliques
(Hayakawa et al., 2018)
. L'impact de ces quatre catégories sur l'écosystème est particulièrement préoccupant en raison de leur toxicité spécifique. ...
... Concernant la pollution des milieux aquatiques par les HAPs, les accidents de marée noire sont parmi les plus conséquents de ponit de vus degrés d'exposition (Uno et al., 2017 ;
Hayakawa et al., 2018)
. Au cours des dernières décennies, plusieurs déversements d'hydrocarbures se sont produits partout dans le monde et d'énormes quantités de pétrole brut ont été rejetées dans le milieu aquatique. ...
Toxicité des pesticides et des hydrocarbures sur les bivalves marins : impact de l'exposition aux nanoparticules métalliques
Thesis
May 2022
<here is a image 552ea37642d5444d-28bc3e0785539b96> Imen Bouzidi
L’objectif de cette thèse est d’étudier les effets de l’exposition individuelle ou en combinaison de certaines nanoparticules (NPs), de certains hydrocarbures polycycliques et pesticide sur les bivalves par le biais d’une approche multi-marqueurs (chimique, physiologique et biochimique). Pour atteindre cet objectif, le modèle biologique choisis est la moule Mytilus galloprovincialis. La réponse physiologique corresponde à l’évaluation de la capacité de filtration et de respiration de la moule et la réponse biochimique est étudiée à travers quelques biomarqueurs tels que la superoxyde dismutase (SOD), la catalase (CAT), le malondialdéhyde (MDA) et l'acétylcholinestérase (AChE). Les principaux résultats des analyses chimiques en utilisant la microscopie électronique à transmission (MET), la diffraction des rayons X, la diffusion dynamique de la lumière et le potentiel zêta confirment la taille nanométrique des NPs considérées et révèlent leurs stabilités aux changements des paramètres environnementaux (pH et salinité). L’estimation de la toxicité des NPs, des HAPs et des pesticides au moyen des paramètres physiologiques ont montré que l’effet dépend du produit chimique considéré et de la concentration. De plus, les paramètres de stress oxydants et de neurotoxicité ont montré que l’impact dépend du contaminant, de la concentration et de l’organe mis en jeu. Au vu d’ensemble, l’utilisation d’une approche intégrative associant des analyses chimiques et écotoxicologiques représente un bon moyen pour comprendre le profil relationnel entre les contaminants et les organismes aquatiques qui s’écoule dans le cadre de programmes de biosurveillance des écosystèmes côtiers.
... Regarding PAH pollution in aquatic environments, oil spill accidents are among the most concerning exposure events
[14]
[15][16][17][18][19]. Hydrocarbon chemicals are major components of crude oil and are classified as PAHs, aliphatic saturated hydrocarbons, aliphatic unsaturated hydrocarbons, and alicyclic saturated hydrocarbons [14]. ...
... Regarding PAH pollution in aquatic environments, oil spill accidents are among the most concerning exposure events [14][15][16][17][18][19]. Hydrocarbon chemicals are major components of crude oil and are classified as PAHs, aliphatic saturated hydrocarbons, aliphatic unsaturated hydrocarbons, and alicyclic saturated hydrocarbons
[14]
. The impact of these four categories on the ecosystem from PAHs is especially concerning because of their specific toxicity. ...
Toxicities of Polycyclic Aromatic Hydrocarbons for Aquatic Animals
Article
Full-text available
<here is a image ae0c103d71b74f84-5d9e76765d91fd8c> Masato Honda
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nobuo Suzuki
Polycyclic aromatic hydrocarbons (PAHs) are organic compounds that are widely distributed in the air, water, and soil. Recently, the amount of PAHs derived from fuels and from incomplete combustion processes is increasing. In the aquatic environment, oil spills directly cause PAH pollution and affect marine organisms. Oil spills correlate very well with the major shipping routes. Furthermore, accidental oil spills can seriously impact the marine environment toxicologically. Here, we describe PAH toxicities and related bioaccumulation properties in aquatic animals, including invertebrates. Recent studies have revealed the toxicity of PAHs, including endocrine disruption and tissue-specific toxicity, although researchers have mainly focused on the carcinogenic toxicity of PAHs. We summarize the toxicity of PAHs regarding these aspects. Additionally, the bioaccumulation properties of PAHs for organisms, including invertebrates, are important factors when considering PAH toxicity. In this review, we describe the bioaccumulation properties of PAHs in aquatic animals. Recently, microplastics have been the most concerning environmental problem in the aquatic ecosystem, and the vector effect of microplastics for lipophilic compounds is an emerging environmental issue. Here, we describe the correlation between PAHs and microplastics. Thus, we concluded that PAHs have a toxicity for aquatic animals, indicating that we should emphasize the prevention of aquatic PAH pollution.
... The International Agency for Cancer Research, for example, has noted an increased risk of cancer following exposure to at least 60 different PAHs and materials containing these compounds (IARC, 2010) and the United States Environmental Protection Agency (EPA) lists several of these compounds as national priority pollutants, which must be frequently monitored in industrial effluents (EPA, 2008). Additionally, evaluating PAHs exposure and marine environment and biota effects is also of particular interest due to their association with oil spill events, since they constitute considerable portions of crude oil
(Hayakawa et al., 2018)
. ...
Explaining the Environmental Fate of PAHs in Indoor and Outdoor Environments by the Use of Artificial Intelligence
Chapter
May 2022
<here is a image 171017e2f2c6c052-b7d4bbda842cff1a> Svetlana M. Stanišić
<here is a image 9e8c8e7c69ce18b7-751658025e489a7a> Gordana Vuković
<here is a image a3c0f5fd7dead9f0-30b387b30b777236> Mirjana Perisic
<here is a image 398670a51f2bbb5b-a363faaa7d1e70ba> Andreja Stojić
... They are ubiquitous, especially in aquatic ecosystems (rev. in Honda and Suzuki, 2020). There are four principal classes of PAHs based on the origin: biogenic (from natural metabolic pathways), petrogenic (e.g. from crude oil and fuels), diagenetic (from an in-sediment transformation of buried organic matter) and pyrogenic (from incomplete combustion of fossil fuels and organic matter) (rev. in
Hayakawa, 2018;
Balmer et al., 2019). Importantly, PAHs usually exist in the form of complex mixtures of different classes and in combination with other contaminants such as heavy metals, organochlorines, pesticides, etc., that get into marine environments with urban/industrial/agricultural sewage (Incardona et al., 2005(Incardona et al., , 2006Huang et al., 2020). ...
Effects of natural and anthropogenic stressors on fecundity, developmental abnormalities, and population recruitment in intertidal gastropod Littorina saxatilis
Article
Apr 2022
ESTUAR COAST SHELF S
<here is a image eefdf0983465a830-eb201b799676a16a> Arina Maltseva
<here is a image bb59a780b9f75d61-5e65d314c0583fa2> Marina Varfolomeeva
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Anna Vadimovna Kursheva
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Andrei I Granovitch
Coastal marine ecosystems in the Arctic are extremely vulnerable to human activities associated with oil and gas exploration, transportation and processing and with industrial and urban development. The effects of complex pollutant mixtures interact with environmental factors. Here we assessed the effects of two anthropogenic and one natural factor on the reproduction, development and adult shell shape of the intertidal ovoviviparous gastropod Littorina saxatilis at 12 sites in the Barents and the Norwegian Sea. The stressors studied were toxicity equivalency (TEQ) of the polycyclic aromatic hydrocarbons (PAH), the proximity of the site to urban/industrial locations as a proxy for urban pollution, and salinity. Total fecundity of the snails decreased at sites with low salinity but was not affected by PAH pollution. Allometric relationships of L. saxatilis shell shape varied between sites depending on the proximity of urban/industrial locations; the intrapopulation morphological disparity increased near urban sites. The frequency of abnormal embryos per brood and the incidence of females with abnormal embryos in the brood pouch increased at urban sites, especially under conditions of low salinity, but was unrelated to PAH pollution. Monte Carlo simulation showed that the registered embryotoxic effect of the proximity to urban/industrial locations was unlikely to result in a significant reduction of the population recruitment of L. saxatilis due to the high fecundity of these snails. Elucidation of the mechanisms of low sensitivity of L. saxatilis to PAHs in concentrations registered in our study and identification of the cause of embryotoxic effects associated with the proximity of urban/industrial locations are promising directions of further studies. Our results highlight the importance of considering multiple stressors when assessing anthropogenic impacts on coastal systems. We show that L. saxatilis can be an informative indicator of coastal urban pollution across its wide distribution range.
... The International Agency for Cancer Research, for example, has noted an increased risk of cancer following exposure to at least 60 different PAHs and materials containing these compounds (IARC, 2010) and the United States Environmental Protection Agency (EPA) lists several of these compounds as national priority pollutants, which must be frequently monitored in industrial effluents (EPA, 2008). Additionally, evaluating PAHs exposure and marine environment and biota effects is also of particular interest due to their association with oil spill events, since they constitute considerable portions of crude oil
(Hayakawa et al., 2018)
. ...
Polycyclic Aromatic Hydrocarbon Contamination in Sharks and Batoids (Chondrichthyes: Elasmobranchii) and Ensuing Ecological Concerns
Chapter
Polycyclic Aromatic Hydrocarbons (PAHs) are ubiquitous organic compounds in the marine environment, originating mainly from anthropogenic sources. Due to their physico-chemical properties and ability to bioaccumulate in living organisms, PAHs are of great ecotoxicological concern, and their carcinogenic, and genotoxic properties make these compounds particularly harmful to exposed organisms. In this context, marine fauna assessments are paramount to estimate PAH environmental bioavailability, biochemical effects, as well et al. 38 as potential ecological effects. Evaluations in marine organisms, such as bony fish, are readily available. Studies concerning sharks and batoids (elasmobranchs), however, are still scarce, which is interesting as this group is an important part of marine trophic network interactions and highly threatened by anthropogenic activities, including chemical contamination. In this context, this chapter will discuss PAH exposure and their associated effects in elasmobranchs. Furthermore, ensuing ecological concerns and public health implications due to contaminated elasmobranch meat consumption shall also be reflected upon.
... The research into the consequences of oil pollution has been long and extensive. The effects to wildlife are broad, ranging from exposure of birds (Jenssen, 1994;Stephenson, 1997;Fox et al., 2016) and mammals (Engelhardt, 1987;Bodkin et al., 2002;Ridoux et al., 2004) to oil to toxic, mutagenic and/or carcinogenic effects of polycyclic aromatic hydrocarbons (PAHs) present in crude oil and products based on fossil oil (Hylland, 2006;Abdel-Shafy and Mansour, 2016;
Hayakawa, 2018;
Honda and Suzuki, 2020). Besides harming the natural environment, oil spills can impair the economy in the affected region (Cohen, 1993;Taleghani and Tyagi, 2017;Ribeiro et al., 2021) and have adverse effects on human health and psychology (D'Andrea and Reddy, 2014;Shultz et al., 2015;Sandifer et al., 2021). ...
Oil Spill Detection Using Fluorometric Sensors: Laboratory Validation and Implementation to a FerryBox and a Moored SmartBuoy
A large part of oil spills happen near busy marine fairways. Presently, oil spill detection and monitoring are mostly done with satellite remote sensing algorithms, or with remote sensors or visual surveillance from aerial vehicles or ships. These techniques have their drawbacks and limitations. We evaluated the feasibility of using fluorometric sensors in flow-through systems for real-time detection of oil spills. The sensors were capable of detecting diesel oil for at least 20 days in laboratory conditions, but the presence of CDOM, turbidity and algae-derived substances substantially affected the detection capabilities. Algae extract was observed to have the strongest effect on the fluorescence signal, enhancing the signal in all combinations of sensors and solutions. The sensors were then integrated to a FerryBox system and a moored SmartBuoy. The field tests support the results of the laboratory experiments, namely that the primary source of the measured variation was the presence of interference compounds. The 2 month experiments data did not reveal peaks indicative of oil spills. Both autonomous systems worked well, providing real-time data. The main uncertainty is how the sensors' calibration and specificity to oil, and the measurement depth, affects oil detection. We recommend exploring mathematical approaches and more advanced sensors to correct for natural interferences.
... PAHs originate mainly from the incomplete combustion and/or pyro-synthesis of organic materials through fossil-fuel usage, biomass burning, industrial processes, waste incineration, and vehicle exhaust emissions [6][7][8]. PAHs can be transported into aquatic ecosystems through various processes, including atmospheric deposition [9], wastewater discharge from urban sewage treatment plants, as well as industrial sites
[10]
, or surface runoff from urban or industrial areas [11]. The PAHs discharged into the aquatic environment are prone to combining with fine particles, being ultimately deposited into sediments due to their hydrophobic nature and resulting low solubility [12,13]. ...
A 110 Year Sediment Record of Polycyclic Aromatic Hydrocarbons Related to Economic Development and Energy Consumption in Dongping Lake, North China
A sedimentary record of the 16 polycyclic aromatic hydrocarbon (PAH) pollutants from Dongping Lake, north China, is presented in this study. The influence of regional energy structure changes for 2–6-ring PAHs was investigated, in order to assess their sources and the impact of socioeconomic developments on the observed changes in concentration over time. The concentration of the ΣPAH16 ranged from 77.6 to 628.0 ng/g. Prior to the 1970s, the relatively low concentration of ΣPAH16 and the average presence of 44.4% 2,3-ring PAHs indicated that pyrogenic combustion from grass, wood, and coal was the main source of PAHs. The rapid increase in the concentration of 2,3-ring PAHs between the 1970s and 2006 was attributed to the growth of the urban population and the coal consumption, following the implementation of the Reform and Open Policy in 1978. The source apportionment, which was assessed using a positive matrix factorization model, revealed that coal combustion was the most important regional source of PAHs pollution (>51.0%). The PAHs were mainly transported to the site from the surrounding regions by atmospheric deposition rather than direct discharge.
... Since the last few decades, marine oil spills have become a recurring disaster. Amoco Cadiz (1978), Ixtoc I (1979), Atlantic Empress (1979), Exxon Valdez (1989), Kuwaiti Oil Lakes (1991), Kuwaiti Oil Fires (1991), Gulf War (1991, and Deepwater Horizon (2010) oil spills released massive amounts of crude and refined fuel rich in PAHs in aquatic environment
(Hayakawa 2018)
. ...
Anaerobic microbial degradation of polycyclic aromatic hydrocarbons: A comprehensive review
Polycyclic aromatic hydrocarbons (PAHs) are a class of hazardous organic contaminants that are widely distributed in nature, and many of them are potentially toxic to humans and other living organisms. Biodegradation is the major route of detoxification and removal of PAHs from the environment. Aerobic biodegradation of PAHs has been the subject of extensive research; however, reports on anaerobic biodegradation of PAHs are so far limited. Microbial degradation of PAHs under anaerobic conditions is difficult because of the slow growth rate of anaerobes and low energy yield in the metabolic processes. Despite the limitations, some anaerobic bacteria degrade PAHs under nitrate-reducing, sulfate-reducing, iron-reducing, and methanogenic conditions. Anaerobic biodegradation, though relatively slow, is a significant process of natural attenuation of PAHs from the impacted anoxic environments such as sediments, subsurface soils, and aquifers. This review is intended to provide comprehensive details on microbial degradation of PAHs under various reducing conditions, to describe the degradation mechanisms, and to identify the areas that should receive due attention in further investigations.
Unravelling the molecular mechanism of mutagenic factors impacting human health
Environmental mutagens are chemical and physical substances in the environment that has a potential to induce a wide range of mutations and generate multiple physiological, biochemical, and genetic modifications in humans. Most mutagens are having genotoxic effects on the following generation through germ cells. The influence of germinal mutations on health will be determined by their frequency, nature, and the mechanisms that keep a specific mutation in the population. Early prenatal lethal mutations have less public health consequences than genetic illnesses linked with long-term medical and social difficulties. Physical and chemical mutagens are common mutagens found in the environment. These two environmental mutagens have been associated with multiple neurological disorders and carcinogenesis in humans. Thus in this study, we aim to unravel the molecular mechanism of physical mutagens (UV rays, X-rays, gamma rays), chemical mutagens (dimethyl sulfate (DMS), bisphenol A (BPA), polycyclic aromatic hydrocarbons (PAHs), 5-chlorocytosine (5ClC)), and several heavy metals (Ar, Pb, Al, Hg, Cd, Cr) implicated in DNA damage, carcinogenesis, chromosomal abnormalities, and oxidative stress which leads to multiple disorders and impacting human health. Biological tests for mutagen detection are crucial; therefore, we also discuss several approaches (Ames test and Mutatox test) to estimate mutagenic factors in the environment. The potential risks of environmental mutagens impacting humans require a deeper basic knowledge of human genetics as well as ongoing research on humans, animals, and their tissues and fluids.
Metabolism of Naphthalene in Bacterial Strains Isolated from Oil Well Soils
Two bacterial strains, N-21 and N-22, which were isolated from natural oil-producing wells at Kurokawa, Niigata Prefecture, Japan, were identified as Pseudomonas cepacia by using the phylogenetic analysis based on the 16SrDNA sequences. Both strains were gram negative rods capable of decomposing naphthalene. The degradation rates were 2.24 × 10-5 M/h in both strains. The main metabolite was cis-1,2-dihydro-1,2-naphthalenediol. Salicylaldehyde, salicylic acid, gentistic acid and catechol were also identified. These metabolites were less mutagenic than naphthalene itself in the Ames test using the S. typhimurium TA100 strain. The mutagenicity of naphthalene also decreased by the two bacterial strains.
Estimation of polycyclic aromatic hydrocarbon concentrations in the water column based on tissue residues in mussels and salmon: An equilibrium partitioning approach
ENVIRON TOXICOL CHEM
Equilibrium partitioning was used to estimate concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs) in the water column from PAH residues in tissues of mussels and juvenile pink salmon collected from coastal marine waters affected by the Exxon Valdez oil spill. Estimated concentrations were within factors of 2 to 5 for fish and 5 to 10 for mussels of average total dissolved and particulate PAHs measured in concurrent water samples. Temporal trends of estimated and measured water‒column PAH concentrations were comparable. Water‒column PAH concentrations estimated from residues in tissues of mussels (Mytilus trossulus) were higher than estimates based on residues in tissues of juvenile pink salmon (Oncorhynchus gorbuscha). Possible reasons for this difference include seasonal variations in mussel lipid content, differences in PAH uptake and depuration rates between fish and mussels, differences in how fish and mussels interact with particulate oil, and possible short exposure times for juvenile pink salmon. All of these factors may play a role. In any event, estimates of dissolved PAHs in the water column, based on PAH residues in either fish or mussel tissue, confirm that PAH concentrations generally did not exceed water quality standards for protection of marine life.
Long-term Monitoring of Polycyclic Aromatic Hydrocarbons in Mussels (Mytilus edulis) Following the Braer Oil Spill†
ANALYST
| https://www.researchgate.net/publication/322935452_Oil_Spills_and_Polycyclic_Aromatic_Hydrocarbons |
(PDF) Performance Overhead from the Usage of Software Abstraction on Complex Embedded Systems
PDF | Abstract -- Nowadays major embedded systems functionalities are developed in software. Moreover, to attend the market exigencies the software... | Find, read and cite all the research you need on ResearchGate
Performance Overhead from the Usage of Software Abstraction on Complex Embedded Systems
November 2011
DOI: 10.1109/SBESC.2011.39
Conference: Computing System Engineering (SBESC), 2011 Brazilian Symposium on
Authors:
<here is a image babf6bb407710c6c-b3a299a7f761cbb4>
Ulisses Brisolara Corrêa
Universidade Federal de Pelotas
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Luigi Carro
Universidade Federal do Rio Grande do Sul
Abstract
Abstract -- Nowadays major embedded systems functionalities are developed in software. Moreover, to attend the market exigencies the software productivity has to be improves. This work analyzes the overhead caused by the application of abstraction levels in embedded systems software development. This analysis was done based in Google Android. The obtained results showed that even about 80% of the executed instructions where in the lower levels from the layer architecture in applications that reuse framework components.
Content uploaded by Ulisses Brisolara Corrêa
<here is a image e991fff7f331e484-213b4789a1a0e76b>
Remote video monitoring system based on ARM and Linux
Conference Paper
Jul 2012
Xiaodong Zhang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Xiujuan Li
Ke Lu
The capability of remote video surveillance is an important application for embedded system. However, the main challenge of such applications is the limitations on flexibility and reliability, especially for high requirements of image quality. In this paper, a kind of new surveillance technology for real-time remote video monitoring is presented. To verify the performance of the proposed technique, a new remote video monitoring system based on S3C2410X microprocessor and Linux OS has been implemented successfully. Hardware architecture and video capture program of the remote video monitoring system are proposed in detail. The experimental results demonstrate that the new monitoring system has a satisfactory performance in comparison with the traditional surveillance methods. It is applicable to replace the traditional remote video surveillance systems completely.
Vertical profiling: Understanding the behavior of object-oriented applications
Conference Paper
Full-text available
Oct 2004
ACM SIGPLAN NOTICES
<here is a image f86751be20b00e31-55d79171fd6c4a82> Matthias Hauswirth
<here is a image 767f8a230f321905-4bb0dac942d51e1f> Peter F. Sweeney
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Amer Diwan
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Michael Hind
Object-oriented programming languages provide a rich set of features that provide significant software engineering benefits. The increased productivity provided by these features comes at a justifiable cost in a more sophisticated runtime system whose responsibility is to implement these features efficiently. However, the virtualization introduced by this sophistication provides a significant challenge to understanding complete system performance, not found in traditionally compiled languages, such as C or C++. Thus, understanding system performance of such a system requires profiling that spans all levels of the execution stack, such as the hardware, operating system, virtual machine, and application. In this work, we suggest an approach, called vertical profiling , that enables this level of understanding. We illustrate the efficacy of this approach by providing deep understandings of performance problems of Java applications run on a VM with vertical profiling support. By incorporating vertical profiling into a programming environment, the programmer will be able to understand how their program interacts with the underlying abstraction levels, such as application server, VM, operating system, and hardware.
Developing and Benchmarking Native Linux Applications on Android
Conference Paper
Full-text available
Apr 2009
<here is a image 150eee83d18ced72-55edb84fcfe71506> Leonid Batyuk
Aubrey-Derrick Schmidt
Hans-Gunther Schmidt
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Sahin Albayrak
Smartphones get increasingly popular where more and more smartphone platforms emerge. Special attention was gained by the open source platform Android which was presented by the Open Handset Alliance (OHA) hosting members like Google, Motorola, and HTC. Android uses a Linux kernel and a stripped-down userland with a custom Java VM set on top. The resulting system joins the advantages of both environments, while third-parties are intended to develop only Java applications at the moment.
In this work, we present the benefit of using native applications in Android. Android includes a fully functional Linux, and using it for heavy computational tasks when developing applications can bring in substantional performance increase. We present how to develop native applications and software components, as well as how to let Linux applications and components communicate with Java programs. Additionally, we present performance measurements of native and Java applications executing identical tasks.
The results show that native C applications can be up to 30 times as fast as an identical algorithm running in Dalvik VM. Java applications can become a speed-up of up to 10 times if utilizing JNI.
2001 Technology Roadmap for Semiconductors
Article
Full-text available
Feb 2002
COMPUTER
Alan Allan
Don Edenfeld
Joyner
<here is a image d40897fd47dcade2-de35e472d8a144d5> Y. Zorian
The International Technology Roadmap for Semiconductors (ITRS) is a collaborative effort within the semiconductor industry to confront the challenges implicit in Moore's law. The roadmap's goal is to present an industry-wide consensus on the "best current estimate" of its R&D needs out to a 15-year horizon. As such, the ITRS provides a guide to the efforts of companies, research organizations, and governments to improve the quality of R&D investment decisions made at all levels. The 2001 Roadmap is notable because it was developed with truly international representation. In this article, representatives of the International Technology Working Groups for Design and Test showcase some of the contributions from 839 international experts seeking to address the difficult and exciting challenges facing the design and test communities and the semiconductor industry as a whole
Vertical profiling
Conference Paper
Oct 2004
ACM SIGPLAN NOTICES
Performance pathologies can be found in almost any software, from user to kernel, applications, drivers, etc. At Sun we’ve spent the last several years applying state-of-the-art tools to a Unix kernel, system libraries, and user applications, and have found that many apparently disparate performance problems in fact have the same underlying causes. Since software patterns are considered abstractions of positive experience, we can talk about the various approaches that led to these performance problems as anti-patterns—something to be avoided rather than emulated.
| https://www.researchgate.net/publication/229519214_Performance_Overhead_from_the_Usage_of_Software_Abstraction_on_Complex_Embedded_Systems |
Ceremony marks Organ Donation Day 2019 and 50th anniversary of first kidney transplant in Hong Kong (with photos)
Ceremony marks Organ Donation Day 2019 and 50th anniversary of first kidney transplant in Hong Kong (with photos)
The Food and Health Bureau, the Department of Health (DH) and Radio Television Hong Kong (RTHK) held a ceremony today (November 9) to celebrate Organ Donation Day 2019 and the 50th anniversary of the first kidney transplant in Hong Kong.
Speaking at the ceremony, the Secretary for Food and Health, Professor Sophia Chan, said that the Government has been making continuous efforts to promote organ donation. Following the establishment in 2016 of the Committee on Promotion of Organ Donation, which aims to co-ordinate and integrate the relevant work by various departments and organisations, the number of registrations recorded in the Centralised Organ Donation Register (CODR) (
www.codr.gov.hk
) has increased from less than 200 000 to more than 310 000 in three years.
"Organ transplants may offer the only hope for some patients suffering from organ failure. Due to the limited supply of transplantable organs from donation, more than 2 000 patients are waiting for organ transplants in Hong Kong every day. Many of them may pass away before the right organ match comes," Professor Chan said.
She encouraged members of the public to put words into actions by signing up in the CODR and telling family members about their wishes for organ donation, so as to enable more patients to live on through organ transplants.
Also attending the ceremony, the Director of Health, Dr Constance Chan, said that more than 580 companies, organisations and schools have pledged to promote the culture of organ donation internally and in the community by signing the Organ Donation Promotion Charter since its launch in 2016. She expressed her gratitude to the institutions and organisations for their support in promoting organ donation over the years, and called on different sectors in society to continue to collaborate with the DH in promoting and fostering a positive culture of organ donation in Hong Kong.
Dr Chan added that, since early this year, the DH has set up booths at the Hong Kong Island and West Kowloon Smart Identity Card Replacement Centres of the Immigration Department, and sent colleagues to other Smart Identity Card Replacement Centres, to call for support from the general public and assist them to register in the CODR on-site.
In commemoration of the 50th anniversary of the first kidney transplant in Hong Kong, the chief surgeon of the operation conducted in 1969, Dr Leong Che-hung, was invited to attend the ceremony. Dr Leong recalled that, 50 years ago, the general public had limited knowledge on organ transplants. Many of them had a strong traditional mindset of keeping the body intact after death.
"Owing to medical advancements in the past 50 years, many challenges in the past can now be overcome. Despite this, in order for patients in need of organ transplants to live on, we need each and every one of us to support organ donation and register our wish to donate organs," Dr Leong said.
At the ceremony, Organ Donation Promotion Ambassador and athlete Stephanie Au and Organ Donation Day 2019 Ambassador and artiste Alfred Hui shared their views with the audience and pledged to assist in spreading the message of supporting organ donation to every corner of society. Other guests, including organ recipients, a patient waiting for an organ transplant and an Organ Donation Coordinator, also spoke on their experiences with the audience, so as to convey to the public the message that organ donation not only helps patients in need but also their families.
The Government has designated the second Saturday of November every year as Organ Donation Day. To tie in with the celebration, the DH's organ donation promotion vehicle will visit different locations across the territory this month and in December to raise the public's awareness on organ donation with fun educational games, as well as call for registration in the CODR. In addition, interviews and programmes with messages on organ donation will be aired on Radio 1, Radio 5 and the Putonghua Channel of RTHK from this month onwards.
For more information on organ donation, members of the public may visit the DH's thematic website (
www.organdonation.gov.hk
). They are also invited to "like" and follow the DH's Organ Donation@HK Facebook page (
www.fb.com/organdonationhkeng
| http://www.info.gov.hk/gia/general/201911/09/P2019110800693p.htm |
(PDF) Giant thermal magnetoresistance driven by graphene magnetoplasmon
PDF | In this work, we have predicted a giant thermal magnetoresistance for the thermal photon transport based on the tunable magnetoplasmon of... | Find, read and cite all the research you need on ResearchGate
Giant thermal magnetoresistance driven by graphene magnetoplasmon
Applied Physics Letters 117(12)
DOI: 10.1063/5.0022261
Abstract and Figures
In this work, we have predicted a giant thermal magnetoresistance for the thermal photon transport based on the tunable magnetoplasmon of graphene. By applying an external magnetic field, we find that the heat flux can be modulated by approximately three orders of magnitude. Accordingly, negative and giant relative thermal magnetoresistance ratios are both achieved for magnetic fields with a maximum strength of 4 Tesla. This effect is mainly caused by the suppression and enhancement of scattering interactions mediated by graphene magnetoplasmon. Specifically, it has never been achieved before for nanoparticles, which have no response to magnetic fields. The effect is remarkable at these reasonable strengths of fields, and thus has considerable significance for the real-life applications. It is also expected to enable technological advances for the thermal measurement-based magnetic sensor and magnetically thermal management.
1
Giant Thermal Magnetoresistance Driven by Graphene Magnetoplasmon
Ming-Jian He 1,2 , Hong Qi 1,2,* , Yan-Xiong Su 1,2 , Ya -Tao Ren 1,2 , Yi -Jun Zhao 1 , and Mauro Antezza 3,4
1 School of Energy Science and Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China
2 Key Laboratory of Aerospace Thermophysics, Ministry of Industry and Information Technology, Harbin 150001, P. R. China
3 Laboratoire Charles Coulomb (L2C), UMR 5221 CNRS-Université de Montpellier , F-34095 Montpellier, France
4 Institut Universitaire de France, 1 rue Descartes , F-75231 Paris, France
*Corresponding authors: Email: [email protected] (H. Qi)
Abstract: In this work, we have predicted a giant thermal magnetoresistance for the thermal photon transport
based on the tunable magnetoplasmon of graphene . By applying an external magnetic field, we find that the heat
flux can be modulated by approximately three orders of magnitude . Accordingly, negative and giant relative
thermal magnetoresistance ratios are both achieved for magnetic field s with a maximum strength of 4 Tesla . This
effect is mainly caused by the suppression and enhancement of scattering interactions mediated by g raphene
magnetoplasmon. Specifically, it has never been achieved before for nanoparticles, which have no response to
magnetic fields. The effect is remarkab le at these reasonable strengths of fields, and thus has considerable
significance for the real-life applications. It is also expected to enable technological advances for the thermal
measurement-based magnetic sens or and magnetically thermal management.
2
The giant magnetoresistance effect discovered by Grünberg and Fert in 1988 [1] is considered as one of the
most fascinating advances in solid state physics. Since then, extensive applications of magnetoresistance have
been developed in electronics , such as magnetic sensors and hard-disk read-heads [2] . Inspired by the unique
effect , a thermal analog named giant thermal magnetoresistance (GTM) effect is predicted in magneto-optical
plasmonic structures in the context of radiative heat transfer [3]. Nowadays, the radiative heat transfer at the
nanoscale is of great cu rrent interest [4-8] and has highlighted the possibility of modulating heat flux [9- 13 ]. With
the application of an external magnetic field, some unique phenomena can be observed in magnetophotonic
crystals [ 14 ] and magnetoplasmonics [ 15 , 16 ]. Among them, the near- complete violation of Kirchhoff’s law is
control [ 17 , 18 ]. The magne to -optical material InSb has show ed remarkable perf ormance in modulating t he
radiative heat tran sfer due to the magnetically tunable properties [5 , 19 - 23 ]. More recently, by investigating the
near-field radiative heat transfer between two InSb particles , a huge anisotropic thermal magnetoresistance with
values of up to 800% is achieved with a magnetic field of 5 T [ 24 ] . The GTM effect has great application
significance for the thermal measurement-based magnetic sensing and magnetically thermal management.
However, the GTM in plasmonic structures ha s so far strictly relied on the magneto-optical nanoparticles made of
semiconductors, like InSb. The realization of GTM is still demanding for nanoparticle structures made of
conventional materials, which has no response to magnetic field.
By locating a substrate near two nanoparticles, Dong et al. [ 25 ] ha ve introduced a channel of propagating
surface waves to assist the heat transfer. They have delay ed the deterioration of thermal photon transport ,
especially in long distance . Then the performance of the long -distance energy-exchange was improved by exciting
the surface plasmon polaritons of graphene [8 , 26 ]. Specifically, in the presence of an external mag netic field,
hybridization occurs between cyclotron excitations and plasmons in graphene, originating magnetoplasmon
polaritons (MPP) [ 27 ]. The MPP effect has been utilized to realize magnetically tunable near-field radiative heat
transfer between suspended graphene sheets [28 , 29 ] and gratings [ 30 ]. In the present work, based on the graphene
MPP, we have proposed a scheme to induce a GTM effect between two nanoparticles, made of common materials
silicon dioxide (SiO 2 ). It should be mentioned that the giant thermal magnetoresistance effect obtained in the
present work is indeed remarkable and much stronger than those in the previous study [3].
Here we consider two SiO 2 [ 31 ] nanoparticles located above a graphene sheet with a distance z n , and they are
3
separat ed with a distance d as illustrated in F ig . 1. The radii of the two nanoparticles are identical and selected as
5 nm, which has been widely used in the previous studies [ 20 , 26 , 32 ] . We limit the calculations with the
particle-surface distance z n = 50 nm and particle-particle distance d ≥ 100 nm to guarantee the validity of the
dipolar approximation [ 20 , 26 ]. The two nanoparticles are kept at temperature T 1 and T 2 . A static magnetic field
with intensity B is applied perpendicularly to the graphene sheet. It should be mentioned that, the substrate effect
is ignored in the present work to avoid the MPP hybridization with other modes. Thus the pure effect of MPP on
the heat transfer mechanism can be distinguished clearly. Moreover, suspended graphene sheets are always
considered as ideal physical models for the studies of near-field radiative heat transfer [ 11 , 28 , 29 , 33 ] . As
illustrated in Fig . 1, the thermal photons transfer through two channels, (1) the direct particle-particle channel via
vacuum interaction and (2) the particle-graphene-particle channel via scattering interaction.
With the application of an external magnetic field, a characteristic op tical quantum Hall effect occur s to
graphene electrons [ 34 ]. The conductivity of graphene becomes a tensor with nonzero elements in off-diagonal
parts
xx xy LH
HL
yx yy
=
−
(1)
where
L and
H denote the longitudinal and Hall conductivities, respectively. T he magneto-optical conductivit ies
are taken from Refs. [ 34 , 35 ] and
the chemical potential of graphene is selected as
= 0.08 eV throughout the
letter. The intensity of magnetic field is limited to B = 0~ 4 T, which has significance for the real -life applications .
Under this circumstance, the effect of magnetic fields on modifying the optical properties of SiO 2 can be ignored
[ 36 ]. T he violation of Kirchhoff’s law in non-reciprocal systems, as demonstrated in Refs . [ 17 , 18 ], is not
considered in the present work, for the reason that the off-di agonal conductivities of magneto-optical graphene
result in insignificant nonreciprocity.
Based on the dipole approximation, the electric polarizabilities of the nanoparticles are given as [ 26 ]
( )
( ) ( )
( )
0 3 1
4 2
R
−
= +
(2)
where R and
(
) are the radius and dielectric function of the nanoparticles, respectively. The polarizability needs
to be modified by fluctuation-dissipation theorem
( ) ( ) ( )
3 2
0
Im 6
k
=−
(3)
4
where
( )
( )
( )
( )
( )
( )
00
33
/ 1 / 6 ic
=−
is the dressed polarizability with the radiation correction and
k 0 =
/ c .
Then we introduce the radiative heat transfer in the proposed system. The whole system including the
graphene sheet is assumed to be thermalized at T = T 1 = T 2 =300 K at the initial state, then na noparticle 1 is heated up
to
1
T T T = +
. This causes a heat flux
between the two nanoparticles . It should be menti oned that the
graphene sheet also emits thermal radiation, whereas the effect is considered in the scattering interaction. The
main point of the present work is to investigate the energy exchange between the two nanoparticles, and thus the
heat transfer between the graphene and the nanoparticles are not investigated here. A radiative heat transfer
conductance is defined to quantitatively evaluate the heat flux
( )
( )
4 2 *
0
0 0
,
lim 4 Tr
2 GG
T
nT
d
h k
TT
+
→
==
(4)
where
( )
1
B
, exp( ) 1 nT kT
−
=−
is the Bose-Einstein distribution and * denotes conjugate transpose . G is the
dyadic Green tensor composed of two parts, i.e., G = G (0) +G (sc) . G (0) and G (sc) represent the contributions of
vacuum and scattering interaction, accounting for direct particle -particle and particle-interface-particle channels,
respectively. The two parts read as
( )
0
0
23
0
00
00
4 00
G ik d a
e b
kd b
=
(5 - a)
( )
( )
sc
0
2
2
0 2 2
G S P
z
ik z
sp
z
dk ike rr
kk
+
=+
(5 - b)
where
0
22 a ik d =−
,
0
22 0 1 b k d ik d = + −
. k and
22
0 z
k k k =−
are the parall el and perpendicular wave-vectors.
More details including the matrices S and P can be found in Refs. [ 26 ] . We note that due to the Hall conductivities ,
the cross-polarization reflection coefficients r sp and r ps are involved in the reflection characteristics of
magneto-optical graphene [ 28 - 30 ] . They do not appear in Eq. (5 -b), whereas it does not mean that the Hall
conductivities play no role in the scattering interaction. In particular, the r s and r p in Eq. (5 -b) is modified to take
in consideration of the effects of both
L and
H [ 37 ]
5
( )
( ) ( )
2 2 2
0
22
0
2
22
h
L L H
s he
L L H
Z
r ZZ
++
= − + + −
(6 - a)
( )
( ) ( )
2 2 2
0
22
0
2
22
e
L L H
p he
L L H
Z
r ZZ
++
= + + +
(6 - b)
where Z h = i
0 / k , Z e = ik /
0 , and
0 denotes the free-space impedance .
A recent experimental study ha s shown that the radiative heat transfer between two coplanar membranes can
be modulated by bringing a third planar object into close proximity [9]. The configuration is similar to the present
work. However, wit h the determined geometric parameters in the system, the heat flux is fixed. This work
presents a scheme for the configuration to dynamically modulate thermal transport with the magnetic method . In
Fig. 2(a) , for different separation distance d between the two particles, the modulation pe rformance of magnetic
field is demonstrated by the modulation factors
= h ( B )/ h (0) as the f unction of B . We show that by tuning the
intensit ies of the magnetic fields, the heat transfer can be either enhanced or suppressed compared to that of zero
field . The factor
can be tuned nearly over three orders of magnitude with the reasonable strength of fields, B =
0-4 T. In addition, we ob serve a slight oscillation of
emerging at weak fields B = 0-0.6 T. To reveal the GTM in
the proposed system, a relative thermal magnetoresistance ratio is defined as
R TMR =[ R ( B )- R (0) ]/ R (0) =[ h (0)/ h ( B )- 1] ×100%, where the thermal magnetoresistance is given by R =1/ h . As given
by the definition, the positive and negative values of R TMR represent the decayed and enhanced heat transport
compared to the zero field . It is shown in Fig. 2(a) that at d = 1556 nm, R TMR reaches values of up to 635% and
low to -83.7% at the field B = 4 T and 1.17 T, respectively. For d = 673 nm, the maximum and minimum of R TMR
are achieved at B = 4 T and 1.09 T for 7734% and -58.5%, respectively. It should be mentioned that the giant
R TMR = 7734% is much larger than those of previous studies [3 , 19 , 24 ]. Additionally, the negative R TMR = -83.7%
reveals relatively strong enhancement of heat transfer with reasonable strengths of the fields, which are m uch
weaker than those of the existing studies on magnetically tunable radiative heat transfer [ 22 , 28 ]. To make out the
heat transfer mechanism accounting for the above GTM, we plot in Fig. 2(b) the scattering ratios defined as
S =
h / h (0,0) , wher e h (0,0) denotes the contribution of vacuum interactions in the heat transfer conductance. A horizontal
dashed line corresponding to
S = 1 is added in Fig. 2(b), which denotes the circumstance when scattering
interactions vanish. The results demonstrate that scattering ratios
S in Fig. 2(b) and the modulation factors
in
6
Fig. 2(a) exhibit similar variety trends with B . As discussed above, the higher
S stands for more participation of
scattering interaction, which is dominated by the graphene MPP . Despite of the slight oscillation at weak fields,
the primary trend of
S is decaying with B. This phenomenon implies that a transition from scattering
enhancement to scattering suppression occurs with the enlarging magnetic fields.
To explore the physical mechanism of the GTM, the radiative heat transfer conductance h ( B ,
) is
demonstrated in Fig. 3(a) for d =1556 nm. As investigated in previous studies, the phonon polaritons of SiO 2 are
excited in the frequency ranges 8.67× 10 13 ~9.47× 10 13 rad/s and 2.03× 10 14 ~2.35× 10 14 rad/s [8 , 38 ] . The two
branches at the specific frequencies are also ob served in Fig. 3(a), whereas they differ from each other sharply in
magnetic-dependent spectrum. The low-frequency branch converts to broadband at weak fields due to the
interactions with graphene MPP. Then, as B enhances, this branch is divided into two parts. They correspond to
the intraband (low-frequency) and the first interband transitions (high-frequency) of graphene MPP [ 30 , 34 ],
respectively. The maximum of h ( B ,
) occurs at B = 1.17 T and
= 0.92× 10 14 rad/s, where the first interband
MPP interacts with low-frequency phonon polaritons of SiO 2 and forms a strong coupling. To take a deep insight
into the effect of the strengths of magnetic fields, we plot h (
) in Fig. 3(b) corresponding to different cases: (1)
the vacuum conductance without graphene, and (2) different strengths of fields, which are sliced with dashed lines
in Fig. 3(a). The peak value of h (
) fo r B = 1.17 T is larger than those of B = 0, 2 T and B = 3, 4 T by
approximately one and two orders of magnitude. We can infer that this enhancement of h (
) leads to the R TMR =
-83.7% in Fig. 2(a). In addition, we find that as B enhances and exceeds 3 T, the intraband MPP almost fade out
and the interband MPP decouple with phonon polaritons of SiO 2 . This results in the decaying trend of h (
) with B ,
and h (
) nearly reduces to that of vacuum interaction with B > 3 T. The above results imply that the evolution of
the MPP modes with magnetic fields plays a crucial role in GTM. Therefore in Fig. 3(c), we demonstrate the
propagating properties of the MPP modes. They are given by the reciprocal of localization length in x direction ,
defined as l x = q '/ q " [ 27 ] . q ' and q " represent the real and imaginary parts of complex longitudinal wave vector ,
respectively. A red dashed line is added in Fig. 3(c), indicating the same frequency with that in Fig. 3(b). The
different peak values of h (
) can be well explained by the magnitudes of l x . We can confirm that the MPP
modulates the scatt ering interactions based on the strong dependence of propagating length on the intensities of
magnetic fields.
To have an intuitive understanding of the scattering characteristics , in Fig. 4(a), the electric field energy
7
density u e [ 25 ] is illustrated in x - y plane ( z = z n /2) for
= 0.92× 10 14 rad/s, corresponding to the peak in Fig. 3(b).
u e of B = 4 T are considerably weakened compared to those of zero field and B = 1.17 T. In addition, compared to
zero field, u e has enhanced when a magnetic field B = 1.17 T is applied. In Figs. 4(b) and 4(c), the ratios of u e in B
= 1.17 T and B = 4 T to that in zero field are demonstrated in the x - z plane. The two nanoparticles are indicated by
red spots near x = ± 0.8
m. The positive and negative ratios represent the enhancement and suppression of u e . A
scattering enhancement occurs in Fig. 4(b) between the two nanoparticles, and it is concentrated above the
graphene with a distance z ≈ 1.5
m . Interestingly, the strongest enhancement locates away from the graphene
surface, and even higher than the nanoparticles. It should be pointed out that, the electric field energy density
remains confined near the graphene surface at different magnetic fields. The enhancement is demonstrated by the
ratio of u e distribution at different fields compared to zero field. As is known, the surface plasmon polaritons of
graphene are always excited and confined near the interface [ 27 ], and it is the same with the scattering
enhancement by graphene [8]. The unique scattering enhancement at this position has never been observed in
graphene plasmons before. The enhancement, which is far away from the interface, is mainly caused by the
considerable difference between the surface plasmon modes in the absence and presence of magnetic fields. The
MPP modes at B = 1.17 T have a greater ability to assist the heat t ransfer than the surface plasmon polaritons at
zero modes, especially at this location. Specifically, a remarkable scattering suppression is observed in Fig. 4(c)
near the graphene sheet. The B = 4 T field shuts off the energy-exchange channel dominated by graphene, and
thus an attenuation works on the heat flux between the particles. Then, we can conclude from the above results
that, the negative and giant thermal magnetoresistance effects are attributed to the MPP scattering enhancement
and MPP scattering suppression, respectively.
In summary, we have predicted a negative and a giant thermal magnetoresistance effect between two SiO 2
nanoparticles based on the graphene MPP. T he relative thermal magnetoresistance rati o can reach values of up to
7734 % and low to -83.7% for a magnetic field of 4 T and 1.17 T, respectively. These values are indeed
remarkable at these strengths of fields and have never been achieved in nanoparticle structures made of
conventional materials, which has no response to magnetic field. We show that this behavior is mainly resulted
from the suppression and enhancement of scattering interaction mediated by graphene MPP. The effect in the
present work is promising for the thermal measurement-based magnetic sensing and magnetically thermal
management. The physics in this work are limited to the fixed chemical potentials of graphene and geomet ry size s
8
( R , z n ). However, it does not mean the GTM obtained in this wor k is a special c ase. By applying different
properties of graphene and nanoparticles, different magnitudes and even much greater GTM effects can be
predicted. The prediction in this work is universal and we believe that the optimized parameters can result in more
considerable GTM effect . Moreover, we expect in the future work, magneto-optical materials like InSb can act as
the substrate and assist the GTM.
ACKNOWLEDGEMENTS
The supports of this work by the National Natural Science Foundation of China (No. 51976044, 51806047) are
gratefully acknowledged. Heilongjiang Touyan Innovation Team Program is gratefully acknowledged. M. A.
acknowledges support from the Institute Universitaire de France, Paris, France (UE).
DATA AVAILABILITY
The data that support the findings of this study are available from the corresponding author upon reasonable
request.
9
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11
FIG. 1 Schematic of radiative heat transfer between two nanoparticles (separated with a distance d ) located
above a graphene sheet with a distance z n . A static magnetic field with intensity B is applied perpendicularly to the
graphene sheet. There are two channels for energy-exchange, (1) the direct particle-particle channel via vacuum
interaction, and (2) the particle-graphene-particle channel via scattering interaction.
FIG. 2 (a) Modulation factors
=
h ( B )/ h (0) together with the relative thermal magnetoresistance ratio R TMR =
[ R ( B )- R (0) ]/ R (0) =[ h (0)/ h ( B )- 1] ×100%. (b) Scattering ratios defined as
S = h / h (0,0) , where h (0,0) denotes the
contribution of vacuum interactions in the heat transfer conductance.
FIG. 3 (a) Radiative heat transfer conductance h ( B ,
) for d =1556 nm. (b) Spectral heat transfer conductance
h (
) for vacuum interaction and different fields with scattering. (c) Propagating properties of the MPP modes as
the reciprocal of localization length in x direction.
FIG. 4 (a) Electric field energy density u e in x - y plane ( z = z n /2) for
= 0.92× 10 14 rad/s. Ratio of u e in (b) B =
1.17 T and (c) B = 4 T to that in zero field in the x - z plane. The two nanoparticles are indicated by red spots near x
= ± 0.8
m.
... This observation is attributed to the pronounced spectral dependence of localized multiple MPP on the magnetic field magnitude. Furthermore, when compared to existing literature on thermal magnetoresistance [36,37], the results obtained in this study using multiple MPP in graphene demonstrate exceptional performance despite the relatively simple structure employed
[65]
. The key structural parameters in the current configuration are the separation distances between the two bodies and the adjacent graphene sheets, labeled as d and din, respectively. ...
Multiple magnetoplasmon polaritons of magneto-optical graphene in near-field radiative heat transfer
Graphene, as a two-dimensional magneto-optical material, supports magnetoplasmon polaritons (MPP) when exposed to an applied magnetic field. Recently, MPP of a single-layer graphene has shown an excellent capability in the modulation of near-field radiative heat transfer (NFRHT). In this study, we present a comprehensive theoretical analysis of NFRHT between two multilayered graphene structures, with a particular focus on the multiple MPP effect. We reveal the physical mechanism and evolution law of the multiple MPP, and we demonstrate that the multiple MPP allow one to mediate, enhance, and tune the NFRHT by appropriately engineering the properties of graphene, the number of graphene sheets, the intensity of magnetic fields, as well as the geometric structure of systems. We show that the multiple MPP have a quite significant distinction relative to the single MPP or multiple surface plasmon polaritons (SPPs) in terms of modulating and manipulating NFRHT.
View
... This study sheds light on the effect of substrate on HPs and provides theoretical guidance for designing near-field thermal radiation devices. polaritons can further enhance the NFRHT [44][45][46][47][48][49][50]
[51]
[52][53][54] . In addition, metamaterials are gradually being explored with the advancement of micro/nano processing, providing new opportunities for NFRHT [55][56][57][58][59] . ...
Effect of substrate on the near-field radiative heat transfer between α-MoO3 films
Near-field radiative heat transfer (NFRHT) has promising prospects in modern nanotechnology, such as near-field thermal microscopy, nanoscale non-contact thermal management, and information processing. Experimentally, supported substrates are crucial in ensuring structural stability, especially in ultrathin structures. However, the effect of the substrate on the NFRHT has seldom been explored. Here, the NFRHT between α-MoO 3 films with different permittivities of substrate is studied. For lossless substrates, the NFRHT is suppressed as the permittivity of the substrate increases when the heat transfer is along the [010] and [100] crystal directions of α-MoO 3. When the NFRHT is along the [001] crystal direction of α-MoO 3 , high-permittivity substrates suppress the NFRHT when the film is thin (< 10 nm), while enhancing the NFRHT in thicker films (> 10 nm). Moreover, we find that the effect of the substrate on the NFRHT highly relies on film thickness. The effect of lossy substrate on NFRHT is also discussed. We find that the loss of the substrate is more significant for the enhancement of heat flux at a small gap distance (20 nm). However, when the gap distance is large (100 nm), the excessive loss suppresses the NFRHT. Hyperbolic polaritons (HPs) can effectively explain the above phenomenon, as confirmed by energy transmission coefficients distribution and dispersion relation in wavevector space. In particular, the volume-confined hyperbolic polaritons play a dominant role in the flux variation between the thin films (1 nm and 10 nm). For the 100-nm film, surface-confined hyperbolic polaritons are more important. This study sheds light on the effect of substrate on HPs and provides theoretical guidance for designing near-field thermal radiation devices.
... 6 In contrast, hyperbolic materials (HMs), whose dispersion curve is an open hyperbola, may further enhance the NFRHT.
[49]
[50][51][52][53] The underlying physical mechanism can be explained by the excitation of hyperbolic phonon polaritons (HPPs). [54][55][56] Compared to the manufacturing challenges of forming hyperbolic metamaterials, [57][58][59][60][61] natural HMs are more convenient to implement in experiments. ...
Substrate effects on the near-field radiative heat transfer between two hBN films
Apr 2023
Jihong Zhang
Near-field radiative heat transfer (NFRHT) could surpass the blackbody limit defined by Stefan-Bolzmann’s law by several orders of magnitude, which has potential applications in thermal switching, thermal management, and photovoltaics. To further develop the NFRHT from theory to application, the substrate, which could enhance the stability of the structure, is a critical factor not to be ignored. However, the substrate effect on the NFRHT is still rarely discussed. In this work, we investigate the NFRHT between hexagonal boron nitride (hBN) films with different permittivities of the substrate. Results demonstrate that when the thickness of the film is 1 nm, increasing the permittivity of the substrate will suppress the NFRHT. In contrast, when the thickness of the film is larger (>2 nm), the high-permittivity substrate could enhance the NFRHT. The spectral heat flux (SHF) corresponding to substrates with different permittivities was investigated. The SHF in Type I hyperbolic band of hBN increases with the increase in the permittivity of the substrate, while that in Type II hyperbolic band is completely opposite. This competitive relationship leads to the above-mentioned phenomenon of NFRHT. The underlying physics mechanism can also be explained by the hyperbolic phonon polaritons (HPPs), which are analyzed by the energy transmission coefficients and dispersion relations. The findings in this work will deepen the understanding of the substrate on HPPs and pave a novel way for near-field radiation devices based on hyperbolic materials.
... Various nonreciprocal materials, including magneto-optic materials and magnetic Weyl semimetals, are designed to break the reciprocity between absorption and emission [10][11][12][13][14][15]17,26,27,[31][32][33][34][35][36]
[37]
[38]. Weyl semimetals have moderate nonreciprocity in the mid-infrared without an external magnetic field [12-14, [38-41]. ...
High quality factor nonreciprocal thermal radiation in a weyl semimetal film via the strong coupling between tamm plasmon and defect mode
In this work, we propose a composite multilayer structure consisting of a Weyl semimetal (WS) film and photonic crystal (PC) with a defect layer to achieve nonreciprocal thermal radiation with high quality factor. This high quality factor results from the strong coupling between Tamm plasmon (TP) and defect mode (DM). The quality factor of nonreciprocal thermal radiation can be as high as 221.27 at a wavelength of 9.736 μm. The magnetic field distribution inside the structure and the reflection spectrum of the photonic crystal are also shown, which is beneficial to reveal its physical mechanism. Based on the variation of absorption and emission spectrum with different defect layer thicknesses, the splitting appears in the figure, which proves the strong coupling between Tamm plasmon and defect mode. We believe that these results will provide a new way to realize nonreciprocal thermal radiation applications.
... Wu et al. showed a predictable change of heat flux by changing the orientation of hBN optical axis [31] , and the ratio of maximum value to minimum value in modulation, i.e., modulation contrast is 12.45 with a hBN-α-MoO 3 configuration [48] . Recently, NFRHT between nanoparticles (NPs) in the presence of a substrate of magneto-optical materials [ 49 , 50 ] and two-dimensional materials
[51]
Modulation of near-field radiative heat transfer (NFRHT) with rotated anisotropic hBN and α-MoO3 nanoparticles (NPs) are investigated. The spectral heat power, total heat power and electric field energy density are calculated at different particle orientations. Numerical results show that the modulation factor of the α-MoO3 NPs could be up to ∼12,000 with particle radius of 40 nm at a gap distance of 200 nm, which is ∼ 10-fold larger than the state of the art. Excitation of localized hyperbolic phonon polaritons (LHPPs) in different particle orientations allow for the excellent modulation. The modulation factor of the hBN NPs is 5.9 due to the insensitivity of the LHPPs in the type II hyperbolic band to the particle orientations. This work might be helpful in designing a high performance near-field radiative modulator in particle systems.
... Recently, various nonreciprocal materials, including Weyl semimetals and magneto-optical materials, were utilized to break the traditional Kirchhoff's law and construct nonreciprocal thermal emitters [14][15][16][17][18][19][20][21][22][23][24]
[25]
. For instance, the nonreciprocal radiation around the wavelength of 16 μm is realized with magneto-optical material InAs under a magnetic field of B = 3 T [14]. ...
Dual-band nonreciprocal thermal radiation by coupling optical Tamm states in magnetophotonic multilayers
This article reviews the physical mechanism of spin-dependent magnetoresistance and its early application in sensors. The magnetic field performance generated by the current to be measured is explained. According to the realization of the magnetoresistance measurement of this characteristic, seven main indicators of the current sensor are summarized. Starting with the structure of magnetoresistance devices and magnetoresistance units of current sensors based on spin-dependent magnetoresistance effect, several design methods of sensors and their advantages and disadvantages are analyzed. Starting from the role of AMR, GMR and TMR in magnetoresistance cells, the structure of series and parallel arrays, permanent magnet bias, coil bias, coil reset, flux aggregator and superconducting ring are analyzed, and several design methods of sensors are summarized as well as their advantages and disadvantages. Finally, the possible development direction of the current sensor is forecasted based on the recently discovered spin correlation effect.
Real-time estimation of thermal boundary conditions and internal temperature fields for thermal protection system of aerospace vehicle via temperature sequence
We theoretically investigate the active control of the near-field radiative heat transfer (NFRHT) between two multilayered metamaterials consisting of alternating two kinds of magneto-optical materials, i.e., graphene and InSb. The active control of NFRHT can be realized by applying an external perpendicular magnetic field. We found that, when the chemical potential of graphene μ is 0.05 eV or 0.1 eV, the surface magneto-plasmon polaritons (MPPs) gradually split, and one part moves toward higher frequencies with the increase of the magnetic field. When H = 7 T, the relative thermal magnetoresistance ratio is as high as 82.2% compared with the zero field for μ = 0.05 eV. And most importantly, due to the strong coupling between the MPPs of graphene and the surface modes of InSb, when μ = 0.7 eV, the heat flux reaches 286% compared with the zero field by changing the magnetic field to 1 T. In addition, the effect of the thicknesses of InSb, period number and vacuum gap on heat transfer are also investigated. Through the combined effect of the external magnetic field, the chemical potential of graphene and other factors on the local surface electromagnetic modes, the active control of the NFRHT between two multilayered metamaterials can be realized.
| https://www.researchgate.net/publication/344159335_Giant_thermal_magnetoresistance_driven_by_graphene_magnetoplasmon |
Materials | Free Full-Text | Hybrid Polymer Composites Used in the Arms Industry: A Review
Polymer fiber composites are increasingly being used in many industries, including the defense industry. However, for protective applications, in addition to high specific strength and stiffness, polymer composites are also required to have a high energy absorption capacity. To improve the performance of fiber-reinforced composites, many researchers have modified them using multiple methods, such as the introduction of nanofillers into the polymer matrix, the modification of fibers with nanofillers, the impregnation of fabrics using a shear thickening fluid (STF) or a shear thickening gel (STG), or a combination of these techniques. In addition, the physical structures of composites have been modified through reinforcement hybridization; the appropriate design of roving, weave, and cross-orientation of fabric layers; and the development of 3D structures. This review focuses on the effects of modifying composites on their impact energy absorption capacity and other mechanical properties. It highlights the technologies used and their effectiveness for the three main fiber types: glass, carbon, and aramid. In addition, basic design considerations related to fabric selection and orientation are indicated. Evaluation of the literature data showed that the highest energy absorption capacities are obtained by using an STF or STG and an appropriate fiber reinforcement structure, while modifications using nanomaterials allow other strength parameters to be improved, such as flexural strength, tensile strength, or shear strength.
Hybrid Polymer Composites Used in the Arms Industry: A Review
Katarzyna Bulanda 2 ,
Mariusz Oleksy 2 ,
Grzegorz Budzik 3 and
Aleksander Mazurkow 3
1
Doctoral School of Engineering and Technical Sciences at the Rzeszow University of Technology, 35-959 Rzeszow, Poland
2
Department of Polymer Composites, Faculty of Chemistry, Rzeszow University of Technology, 35-959 Rzeszow, Poland
3
Department of Machine Construction, Faculty of Mechanical Engineering and Aeronautics, Rzeszow University of Technology, 35-959 Rzeszow, Poland
*
Author to whom correspondence should be addressed.
Materials 2021 , 14 (11), 3047; https://doi.org/10.3390/ma14113047
Received: 29 April 2021 / Revised: 28 May 2021 / Accepted: 1 June 2021 / Published: 3 June 2021
(This article belongs to the Special Issue Structure–Physical Properties Relationship of Polymer and its Composites )
Abstract
Polymer fiber composites are increasingly being used in many industries, including the defense industry. However, for protective applications, in addition to high specific strength and stiffness, polymer composites are also required to have a high energy absorption capacity. To improve the performance of fiber-reinforced composites, many researchers have modified them using multiple methods, such as the introduction of nanofillers into the polymer matrix, the modification of fibers with nanofillers, the impregnation of fabrics using a shear thickening fluid (STF) or a shear thickening gel (STG), or a combination of these techniques. In addition, the physical structures of composites have been modified through reinforcement hybridization; the appropriate design of roving, weave, and cross-orientation of fabric layers; and the development of 3D structures. This review focuses on the effects of modifying composites on their impact energy absorption capacity and other mechanical properties. It highlights the technologies used and their effectiveness for the three main fiber types: glass, carbon, and aramid. In addition, basic design considerations related to fabric selection and orientation are indicated. Evaluation of the literature data showed that the highest energy absorption capacities are obtained by using an STF or STG and an appropriate fiber reinforcement structure, while modifications using nanomaterials allow other strength parameters to be improved, such as flexural strength, tensile strength, or shear strength.
Keywords:
polymer composites
;
shear thickening fluid
;
nanofillers
;
fiber
;
ballistic properties
1. Introduction
Over the years, composite materials, especially polymeric fiber composites, have gained popularity in every industry sector. The high mechanical and thermal strength, low specific gravity, and weather resistance make these composites a competitive construction material compared to traditional materials, such as wood, steel, and concrete. Composites are used extensively in the construction, aerospace, automotive, and sports equipment sectors. The physical and mechanical properties of polymer composites are closely related to the type and modification of the polymer matrix, the structure and composition of the reinforcement, and the constituent elements. A classical composite material is composed of a matrix-coated reinforcement. The polymer matrix can be a thermoplastic polymer (polycarbonate, polyamide) or a duroplastic resin (epoxy, polyester). The composite reinforcement can be in the form of fabrics, mats (glass, carbon, aramid, basalt, or hybrid fiber), or powder fillers dispersed in the matrix. The main function of the composite reinforcement is to carry external loads. The properties of the fibers forming the composite reinforcement play a key role here. They should have high tensile strength and Young’s modulus, low elongation at break, and low density. Such fibers are referred to as high-performance fibers, which include ( Table 1 ) glass fibers of E and S type, carbon fibers, and ceramic and polymer fibers (p-aramids, high-molecular-weight UHMWPE-polyethylene, and aromatic polyesters). A common characteristic of these fibers is that their tensile strength and Young’s modulus increase with decreasing diameter, at the expense of decreasing elongation at break. Due to their properties, these fibers can find potential applications in the arms industry. However, the most popular and widely used fibers are glass, carbon, and aramid reinforcements [ 1 , 2 , 3 , 4 ].
Table 1. Summary of the mechanical properties of selected high-strength fibers [ 4 , 5 , 6 , 7 , 8 ].
High-strength fibers are also preferred by the arms industry and have replaced steel structures, with composites reinforced mainly with aramid fabrics. Modern military conflicts are characterized by increasing asymmetry, i.e., a significant disproportion of equipment, weaponry, technology, and resources between the fighting sides. The weaker side usually adopts a strategy of offensive, partisan warfare. The attack-and-escape tactic is characterized by close-range combat, continuous movement of forces, surprise attacks, traps, and improvised explosive devices [ 9 ]. The experience of Russian troops in the fighting in Afghanistan and Chechnya shows the effectiveness of partisan tactics. During ambushes, heavily armored tanks and combat vehicles, due to their heavy weight, had difficulty performing maneuvers. They became easy targets for anti-tank weapons. At close range, the classical armor was no obstacle for an anti-tank missile. Asymmetric warfare forced the vehicle armor and the materials from which it was made to be modified. Until now, vehicles were reinforced with steel armor. To increase protection, the armor was thickened, significantly increasing its weight. However, this reduced mobility, increased fuel consumption, and made air transport impossible. The ideal solution was the use of polymer composites. Currently, polymer fiber composites are used by the arms industry to produce not only helmets and inserts for bulletproof vests but also ballistic shields for light armored vehicles, patrol boats, and helicopters. The biggest advantage of composites is their low weight in comparison to steel. This translates into a reduction in vehicle weight, while maintaining full mobility and the same level of crew protection [ 10 ]. Resins, including epoxy, are mainly used as the matrix due to their good mechanical and thermal properties. They are resistant to moisture and most chemicals (including oils and greases) and are characterized by low shrinkage after hardening and ease of processing. We can divide the composite armor into inner cladding and outer ballistic panels. The former is designed to catch metal pieces of the inner side of the vehicle hull that have broken off after missile impact [ 9 ]. A ballistic shield consists of an outer ceramic layer and a multilayer laminate underneath. The function of ceramic panels is to absorb the impact energy, reduce the velocity of and crush the projectile blade, and change the direction of penetration. The composite performs the role of the ceramic. An additional function is to completely break and catch the projectile or its fragments [ 11 ]. Penetration of the laminate by a projectile is a complex process involving two stages of destruction ( Figure 1 ). First, the impact energy causes shearing of the facing matrix layers and reinforcement, leading to fiber breakage. Shear destruction absorbs most of the projectile’s energy, which is lost with the successive layers. Second, the matrix is destroyed and the fibers are stretched at the point of impact energy concentration, which leads to interfacial delamination [ 12 , 13 ].
Figure 1. Two-stage laminate destruction process based on [ 13 ]. (From open access publication).
In practice, layouts of fabric-reinforced epoxy laminates alone do not create an effective or efficient shield. Adding more layers of fabric increases the thickness and weight of the armor, which is not a good approach. Therefore, the first and most important stage of designing composite materials for the arms industry is appropriate selection of the matrix and the reinforcement; the fundamental requirement is that they must be as light as possible, be mechanically strong, and also be able to absorb large amounts of energy. Therefore, the arms industry is looking for new material and construction solutions, which is also a challenge for scientists [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Considering the design assumptions, the roles and tasks of composite materials in ballistic shields, and the required mechanism of action of structural materials used in the arms industry, the current work focuses on the development of hybrid composites (materials consisting of two or more types of matrixes or/and reinforcements) [ 21 ]. Hybrid fiber composites are obtained by modifying the matrix and reinforcing it by introducing nanofillers into it, grafting nanofillers on the surface of the fibers, impregnating fabrics using a shear thickening fluid (STF) or a shear thickening gel (STG), or using a combination of these techniques. In addition, the physical structures of the composites are modified by the hybridization of fibers; the appropriate design of roving, weaving, and mutual orientation of fabric layers; and the development of 3D structures.
The constant development of weapons and warfare agents and the numerous methods of modifying polymer composites in order to improve their performance in protective applications confirm that the topic of hybrid fiber composites dedicated to the arms industry is interesting for scientists and important in terms of application. However, there are no review articles focusing on the achievements in this field to date. Therefore, this article discusses the modifications used to improve the ability of composites to absorb energy and other mechanical properties. The composites are categorized based on three basic fabrics: glass, carbon, and aramid. The focus is on the technologies of the applied solutions, in particular matrix modification and reinforcement with nanofillers and STFs. Their effects on the properties of composites are analyzed, and basic knowledge of the design assumptions related to the selection of fabrics and their orientation is assessed.
Based on the review, the best possibilities for energy absorption are revealed by using an STF or STG and an appropriate structure of the fibrous reinforcement. Modification with nanomaterials allows for the improvement of other strength parameters. Unfortunately, a significant part of the literature does not contain information about the mass of the developed hybrid composites, which is important as it largely determines the application possibilities of the discussed modification methods.
2. Hybrid Composites
In recent years, many scientific publications, including those on composites used in the arms industry, have been devoted to hybrid polymer composites. The main reason for developing hybrid polymer composites is the continuous search for new materials that, in addition to a favorable weight, are characterized by improved functional properties, including impact strength and durability. A well-designed hybrid composite uses the advantages of its individual components to minimize the disadvantages resulting from individual use of those components [ 22 , 23 ].
The continuous development of hybrid composite materials is associated with the search for new modifiers and nanofillers with unique functional properties, whose small contribution to the composite significantly improves its properties. Moreover, in polymeric fiber composites, nanofillers play an important role: when added separately or in several combinations, they improve the morphology of the composites, which, in turn, translates into improvement in their functional properties. The structure of the reinforcement is also important in terms of the weave and fiber structure, the arrangement of reinforcement layers in relation to each other at different angles, the use of different fibers, and the use of appropriate surface preparation of the reinforcing material [
3
,
4
,
23
].
2.1. Composites with the Addition of Nanofillers
There are many publications on the preparation of polymer nanocomposites in which nanofiller particles are uniformly distributed and one of the dimensions of these particles does not exceed the nano size. In addition to fibrous materials, nanoparticles in the form of plates, spheres, tubes, or rods can also be used as reinforcement in these composites. These include inorganic nanofillers, such as bentonite, silica, and metals (copper, zinc, silver, etc.) and their oxides, as well as organic ones, such as carbon black, graphene, graphite, carbon nanotubes (CNTs), and polymethyl methacrylate (PMMA) (
Figure 2
) [
24
].
Figure 2. Summary effect of individual matrix modifications and fibrous reinforcement on the performance of epoxy composites.
Compared to fiber composites, composites reinforced with hybrid nanoparticles and fibers show improved mechanical and fatigue properties, a higher Young’s modulus, and better abrasion resistance. They show increased impact energy absorption. This allows for a reduction in the number of fiber reinforcement layers, resulting in less thickness and weight. Introduction of conductive nanoparticles, such as carbon black, CNTs, graphite, graphene, or metals, gives composites the ability to conduct electricity. Due to these advantages, composites are used mainly in the arms industry, in the production of smart vests, helmets, and armor [ 23 , 25 , 26 , 27 , 28 ].
A composite is reinforced with nanoparticles by dispersion of the nanofiller in the matrix [ 23 ] or impregnation of the fibers or both techniques [ 26 ]. An interesting phenomenon of nanofiller growth on glass fibers was described by Nasser et al. They placed the fabric in zinc salt solution and coated the fabric fibers with a ZnO layer, which increased the stiffness and tensile strength and improved the adhesion of the fibers and the matrix as well as the energy absorption mechanism [ 29 ]. The following sections of this paper present the effects of the abovementioned methods on the mechanical strength of composites reinforced with glass, carbon, and aramid fibers. For composites dedicated to arms applications, fabrics impregnated with liquids (STF) and gels (STG) thicken in shear [ 27 ] or by the growth of nanofillers on them [ 30 ]. An STF is a non-Newtonian liquid consisting of two dispersion phases. The first phase is usually ethylene glycol (average molecular weight of 200, 400, or 600 g/mol) or propylene glycol (average molecular weight of 400 g/mol), in which silica with a particle size between 100 and 750 nm, calcium carbonate, or PMMA (the second phase) is usually dispersed ( Figure 3 ) [ 3 , 31 , 32 , 33 ].
Figure 3. STF fabrication scheme based on the procedure in [ 34 ].
The use of an STF increases the friction between the fabric of the fibers and energy absorption. This allows for a reduction in reinforcement layers, and thus, the thickness and weight of the composite, while maintaining the same strength. The use of larger SiO
2
nanoparticles (about 500 nm) decreases the critical shear rate, improving the mechanism of action and efficiency of the STF. The critical shear rate is defined as the value of the shear rate at which a sharp increase in viscosity is observed (
Figure 4
). The STF changes from a liquid state to a nearly solid state [
3
,
35
]. The STG is a polymer that changes from a liquid state to a rubbery state when subjected to shear [
36
]. Similar to an STF, the use of an STG reduces the impact force by several tens of percentage points.
Figure 4. Overview graph showing the change in STF viscosity as a function of shear rate. [ 37 ]. (Adapted with permission from [ 37 ]. Copyright 2019 John Wiley and Sons).
Additionally, an STF is more stable and insensitive to moisture. The hygroscopic nature of glycol in an STF makes it prone to absorbing moisture, which weakens the shear mechanism [ 27 , 36 , 38 ].
2.1.1. Glass-Fiber-Reinforced Polymer Composites
Glass-fiber-reinforced polymer composites make up about 90% of all polymer fiber composites used in industry. Glass fibers in the form of roving, mats, fabrics, and chopped fibers are mainly used in the manufacture of boat hulls, yachts, tanks, bathtubs, roof gutters, pipes, and machine housings [ 5 , 39 ]. To improve the mechanical properties of epoxy-glass composites, Tate et al. separately introduced 6, 7, and 8 wt% of nanosilica, 20 nm in size, into the matrix. Improvements in mechanical properties were observed in all samples containing the filler ( Table 2 ). The composite containing 6 wt% of nanosilica showed the highest increase in tensile strength (22%) and elongation and interlaminar shear strength (ILSS) (26%). The composite containing 7 wt% of nanosilica had the highest elastic modulus and flexural strength [ 40 ]. Ravi et al. investigated the effect of reinforcing the composite with PMMA and silicon carbide (SiC) beads. The addition of only PMMA (10 vol%) to the matrix increased the flexural strength and flexural modulus at the expense of elasticity compared to the composite reinforced only with glass fabric. The introduction of both PMMA beads (10 vol%) and SiC particles (1 vol%) increased the tensile and flexural strengths by 8% and 37%, respectively, compared to the fiber composite and 32% and 23%, respectively, compared to the sample containing PMMA [ 41 ]. Rahmat et al. prepared glass-fiber-reinforced composites with boron nitride nanotubes (BNNT). The addition of 1% BNNT improved the impact strength, flexural strength, and shear strength, on average, by 22%, 15%, and 8%, respectively [ 42 ]. Zeng et al. improved the mechanical properties of composites by grafting the glass fabric with multiwalled carbon nanotubes (MWCNTs). The fabrics were impregnated in a suspension of nanofillers in ammonium persulfate (APS) and ethanol solution. An increase of approximately 33% in flexural and tensile strengths was observed for the epoxy–glass composite containing carbon nanotubes compared to the reference sample. The Young’s modulus and flexural modulus increased by 41% and 36.7%, respectively, and the ILSS increased by 40.5%. The researchers also found that fabric impregnation eliminates the disadvantages that occur with dispersion in the matrix, i.e., the tendency to form agglomerates and the uneven dispersion of the nanofiller between layers and along fabrics in the infusion method. In addition, APS facilitated and affected the uniform saturation of the glass fabric and improved interfacial adhesion [ 43 ]. Vigneshwaran et al. investigated the mechanical properties of epoxy–glass composites upon the addition of 0.2, 0.6, and 1 wt% graphene nanoplatelets (GnP). One-half of the nanofiller was dispersed in the matrix, while the other half was used to coat the glass mat. Compared with the reference sample, the laminate containing 1 wt% GnP had twice the tensile strength and a 70% higher Young’s modulus. In addition, there was a 45% increase in impact strength and a 38% increase in energy absorption. The composite also exhibited 87% less surface damage area. Impregnation of the mat with GnP improved the adhesion of the fibers to the matrix [ 44 ].
Table 2. Summary of publications in which the epoxy matrix was modified with nanofillers.
Nasser et al. investigated the interfacial shear strength (IFSS) of epoxy composites reinforced with glass fibers coated with ZnO nanoparticles (NPs) and nanowires (NWs). The fibers were functionalized with an oxidizing mixture (sulfuric acid and perhydrol) to increase adhesion and enhance coverage. The wall strength at a quasi-static strain rate increased for ZnO NWs and NPs by 96% and 44%, respectively. At medium and high strain rates, IFSS saps of 29% and 68% were observed for ZnO NWs, respectively, and 27% and 22% for ZnO NPs, respectively. This result indicates the viscoelastic nature of the material, which can compensate for impact energy. This effect also reduces the probability of delamination or cracking of the reinforcement [
29
].
2.1.2. Carbon-Fiber-Reinforced Polymer Composites
Carbon-fiber-reinforced polymer composites are extremely strong, lightweight, rigid structural materials resistant to high temperatures, friction, and corrosion. Because of these unique properties, they are used at a large scale in aviation, the automotive industry (machine skeletons and shells), armaments (ballistic shielding), and electronics (shielding enclosures) [ 25 , 50 , 51 , 52 , 53 , 54 , 55 ]. Tareq et al. investigated the effect of adding nanoclay and graphene to the carbon-fabric-reinforced composite matrix. Laminates containing 2 wt% nanoclay had the highest stiffness and the highest increase (28%) in the flexural modulus. Samples with graphite had the highest strength. The addition of 0.1 wt% of this filler resulted in a 21% increase in flexural strength. Compared with these samples, the composite containing both nanoadditives showed lower modulus and flexural strength. This was due to the dispersion time being too short [ 45 ]. Moghimi et al. also investigated the synergistic effect of reinforcing epoxy–carbon composites with two types of nanofillers. They used multiwalled carbon nanotubes (MWCNTs) and nanosilica in three ratios: 0.2%/0.7%, 0.7%/0.2%, and 0.45%/0.45% by weight. The sample containing equal amounts of both nanoadditives had the best mechanical and tribological properties. The tensile strength and Young’s modulus increased by 25.2% and 31%, respectively; the coefficient of friction decreased by 88%; and the wear resistance increased by 98%. SEM analysis showed good dispersion of nanofillers in the matrix, which improved interfacial adhesion [ 46 ]. Khan et al. carried out the functionalization of graphite nanoparticles in two ways: attachment of (3-glycidyloxypropyl) trimethoxysilane (GPTMS) and attachment of epichlorohydrin (EP). In addition to a reference sample, they fabricated graphite-reinforced epoxy–carbon composites: unmodified (N-CFRP), GPTMS-modified (G-CFRP), and EP (E-CFRP). The best mechanical properties were found for G-CFRP. The modulus and flexural strength increased by 34% and 36% for G-CFRP, by 16% and 16% for E-CFRP, and by 10% and 3% for N-CFRP, respectively. The tensile strength and Young’s modulus increased by 36% and 29% for G-CFRP and by 14% and 7% for N-CFRP, respectively. For E-CFRP, the tensile strength increased by 20% and Young’s modulus decreased by less than 10% [ 47 ]. Wang and Cai performed carbon fabric impregnation using a spray method ( Table 3 ). The spray solution was a suspension of graphene nanoplatelets in an epoxy–acetone mixture. They prepared four laminates containing 0%, 0.1%, 0.3%, and 0.5% by weight of graphene. The uniform coating of the fabrics with the nanofiller increased the interfacial bonding and fracture toughness. The flexural modulus increased with the amount of filler. The sample containing 0.3% GnP showed the highest increase in flexural strength (27.2%) and the ILSS (24.5%) [ 56 ]. Badakhsh et al. performed a two-step carbon nanotube (CNT) impregnation of carbon fabrics. First, the cleaned fabrics were coated with nickel using electroplating. Then, CNTs were applied to the fabrics by gas phase chemical deposition. Nickel catalyzed the deposition and growth of CNTs. The highest efficiency was achieved at 15 wt% of nickel. In addition, the researchers developed a composite consisting of a carbon fabric coated with only a nickel layer and an epoxy resin in which CNTs were dispersed. For the composite reinforced with the Ni-CNT-modified carbon fabric, the flexural strength increased by 52.9% compared to the reference sample. The ductility index was 40% lower than that of the composite with dispersed CNTs [ 57 ]. Nasser et al. also deposited ZnO nanoparticles and wires on carbon fibers that were pre-functionalized with 70% nitric acid. The composites containing ZnO NWs showed a decrease of 62% and 73% in the IFSS, respectively, at medium and high strain rates; for ZnO NPs, the decrease was 40% and 58%, respectively. The results show an increase in the ballistic performance of composites reinforced with impregnated fibers [ 58 ]. Selver investigated the strength of epoxy–carbon and epoxy–glass composites reinforced with a shear thickening fluid. The STF was prepared by dispersing (10%, 15%, and 20% by weight) nanosilica in PEG. Glass- and carbon-fabric-reinforced composites containing 15 wt% of silica showed a 12% and 10% increase in tensile strength, respectively, and a 24% increase in Young’s modulus. Energy absorption also increased (up to 27%). However, the flexural strength of these composites deteriorated compared to the reference sample [ 59 ].
Table 3. Summary of publications in which the reinforcement was modified with nanofillers.
2.1.3. p-Aramid-Fiber-Reinforced Composites
In the arms industry, p-aramid fibers, known commercially as Kevlar (DuPont) or Twaron (Teijin), are the main reinforcement of polymer composites used for helmets, bulletproof vests, body armor, and ballistic shields [ 4 , 19 , 62 , 63 ]. Suresha et al. reinforced epoxy–aramid composites by dispersing them in a matrix of 0.15, 0.3, and 0.5 wt% MWCNTs. The addition of the filler improved the interfacial adhesion. The sample containing 0.3 wt% MWCNTs had the best mechanical properties. The tensile strength and Young’s modulus increased by 46% and 22.1%, while the flexural strength and modulus increased by 74% and 54%, respectively. Additionally, impact strength improved (31.2%) [ 48 ]. Dharmavarapu and Reddy investigated the effect of adding (0.5%, 1%, and 2% by volume) modified nanosilica on the mechanical properties of epoxy–aramid composites. The silica was surface-treated with 3-aminopropyltrimethoxysilane (APTMS) by acid hydrolysis. The composite containing 1 vol% of nanofiller had the highest mechanical strength. The tensile strength, flexural strength, impact strength, and hardness increased by 27.5%, 17%, 67%, and 14%, respectively, compared to the reference sample. The addition of 1 vol% of modified nanosilica improved the energy absorption from 6.5 to 8.2 J [ 49 ]. APTMS can also be used to modify fibers. Jia et al. performed multistep grafting of 3-aminopropyltrimethoxysilane onto an aramid surface using γ-radiation, 1, 4-dichlorobutane, and sodium hydroxide. The modified fiber surface exhibited increased roughness. APTMS formed chemical bonds with the epoxy resin, resulting in improved interfacial properties. The IFSS of the laminate containing the modified aramid reinforcement increased by 51.03% compared to the reference sample [ 60 ]. Malakooti et al. subjected composites reinforced with aramid fabric impregnated with ZnO nanowires to ballistic and strength tests. The tensile strength and Young’s modulus of the composites increased by 13.2% and 8.8%, respectively, and the impact resistance increased by 66%. The presence of ZnO nanowires on the fiber surface increased the friction between the yarns and reduced their mobility in the fabric [ 30 ]. Aramid fibers show sensitivity to UV radiation. Zhang and Teng showed that after 168 h of UV exposure, epoxy composites reinforced with modified and impregnated aramid fibers showed 97.2% of the original tensile strength value. The fibers were functionalized with poly-L-3, 4-dihydroxyphenylalanine (PDOPA) and coated with ZnO. PDOPA facilitated the grafting and growth of ZnO nanowires and, as a whole, increased the surface roughness and improved the matrix–reinforcement adhesion [ 61 ]. Liu and Ávila studied the effect of the presence of an STF on composites reinforced with aramid fabrics. STF-reinforced composites based on silica and CaCO 3 (75% and 25%, respectively, by weight) prepared by Ávila showed the best results in ballistic tests. The work required to stop bullets was 40% less compared to the reference sample. The researchers showed that the presence of an STF increased the friction between the yarns and led to deformation of the bullets. Additionally, the STF allowed the reduction of reinforcement layers from 32 to 19, while maintaining the same ballistic properties of the composite [ 64 ] ( Table 4 ). The laminates made by Liu additionally reinforced with an STF based on silica and CNTs had more than 50% higher puncture resistance, absorbed 65% more energy, and thus, could withstand more impact force [ 65 ]. Dixit showed that STF impregnation increases energy absorption of the reinforced fabric by 10% more compared to pure Kevlar fabric. Additional coating of ZnO fibers increased the absorption by 36% compared to the control sample [ 66 ]. Zhao et al. focused on the impregnation of aramid reinforcement using an STG. They made 5-, 10-, 15-, and 20-layer laminates reinforced with an STG, and corresponding reference samples. In the ballistic tests, the impact force recorded by the detector decreased (from 805 to 223 N) as the layers of the STG-reinforced composite increased (from 5 to 20). For the reference samples, the impact force decreased from 1125 to 460 N. Additionally, composites containing an STG with carbon black absorbed 21.6% more impact energy. The addition of STG allowed for increased friction between the fibers, enabled the composites to absorb more energy, and improved their ballistic properties [ 28 , 38 ]. He et al. demonstrated synergies between STF and STG used to impregnate Kevlar fabric. Compared to composites impregnated with an STF alone, composites impregnated with a hybrid showed increased mechanical strength, elastic modulus, and impact resistance. Reducing fabric layers improved the energy dissipation mechanism and reduced weight and thickness. The addition of STG stabilized the protective coating of the STF, which increased the friction between fibers and their strength [ 37 ].
Table 4. Summary of publications that used reinforcement impregnated with an STF/STG.
2.2. Hybridization of Fiber Reinforcement of Polymer Composites
Due to (fibrous) reinforcement, two types of hybrid composites are distinguished, layered (interply) and interwoven (intraply), which are shown in Figure 5 .The first type, interply, consists of stacked layers of individual reinforcements in the form of fabrics or mats ( Figure 5 A).
Figure 5. Hybrid fiber reinforcement systems of ( a ) interply and ( b ) intraply type.
In intraply, each reinforcement, in the form of a fabric or a mat, consists of several types of fibers, e.g., carbon and glass ( Figure 5 B) [ 67 , 68 , 69 ]. To obtain hybrid composites with the best possible mechanical strength, it is necessary to select appropriate fiber types. It is assumed that one is an expensive fiber with high Young’s modulus, and the other is a cheaper fiber with low Young’s modulus. The next step is to determine the order/sequence of their arrangement. The first layers are of a hard shear-resistant material that absorbs the impact energy. The middle and back layers should consist of tensile-resistant fibers. They accept and distribute the remaining energy. Usually, the top layers consist of fiberglass or p-aramid materials [ 70 ]. Randjbaran et al. showed that using glass fabric instead of Kevlar fabric in the first layer enables higher energy absorption [ 71 ]. The middle part is mostly carbon fiber reinforcement [ 72 , 73 , 74 ]. As the volume percentage of carbon reinforcement increases, the flexural and tensile strengths of the composite increase [ 75 ]. Carbon material is not recommended for use as the top layers. As mentioned earlier, glass reinforcement is preferred at the front, while Kevlar is used for the back layers [ 71 , 74 , 76 ].
2.2.1. Influence of Ply Orientation on the Performance Properties of Hybrid Polymer Composites
The arrangement of reinforcement (fabrics) layers at different angles plays an important role in absorbing impact energy. In the case of unidirectional fabrics, during impact, the energy is distributed between the fibers along the 0° axis. When we apply another layer perpendicular to the first layer, the energy is distributed along the 0° and 90° axes. The trace after the impact resembles a quadrilateral pyramid. By adding more layers at different angles, the whole gain becomes increasingly isotropic.
The energy is distributed over increasing axes, and the post-impact shape is similar to a cone [ 3 , 77 , 78 ]. Figure 6 illustrates the four ways of orienting reinforcement layers. An increase is observed in the isotropy of the gain with the addition of another layer and changes in the orientation angle. The impact energy spreads in 10 directions for the [0/22.5/45/67.5/90] system and only in 4 directions for the [0/0/0/0] system. As previously mentioned, this translates into the composite’s ability to absorb energy. Researchers have shown that layer orientation allows the absorption of approximately 11% to 20% more impact energy. When orienting layers, it is recommended to keep the angles between the axes equal and as large as possible. For composites consisting of two, three, or four layers of woven cloth, the angles (0°, 45°), (0°, 30°, 60°), and (0°, 22.5°, 45°, 67.5°) are used sequentially. In subsequent layers, the analogy is followed or the given sequence is repeated several times [ 4 , 78 , 79 , 80 , 81 ].
Figure 6. Angular orientations for the four reinforcement layers. (Adapted with permission from [ 78 ]. Copyright 2019 Elsevier).
2.2.2. Effect of 2D and 3D Structure on Mechanical Properties of Hybrid Polymer Composites
Two-dimensional fabrics are commonly used as reinforcement for composites. Their properties depend not only on the fiber from which they are made but also on the weave. There are three basic weaves: linen, twill, and satin. Linen is characterized by symmetry, durability, and a tendency to fold. Threads of weft and warp pass alternately above and below each other. Twill is strong, smooth, and well-shaped. Each weft thread passes under and over the warp thread(s), creating a characteristic twill pattern. In satin weave, the warp threads are raised above the weft threads, providing the fabric with a smooth surface and easy draping ability 0 [ 4 , 58 , 82 ]. Among the aforementioned types, twill exhibits higher flexural, tensile, and shear strengths [ 80 , 83 , 84 ]. Cavallaro showed that the use and proper arrangement of fabrics with different weaves (linen and twill as the outer layer and satin as the inner layer) can increase their resistance and energy absorption capacity compared to laminates containing fabrics of one type [ 85 ].
In contrast to 2D fabrics, three-dimensional (3D) fabrics have an additional thread (binding) in the z direction, which is the thickness. They are characterized by stiffness and strength in x, y, and z directions; better structural integrity; and stress transfer between layers. Compared to 2D-reinforced composites, 3D-reinforced composites exhibit higher impact strength, flexural strength, compressive strength, and interlaminar fracture. Upon impact, they absorb and dissipate twice as much energy. Unlike 2D fabrics, the damage area is small and delamination is practically absent [ 3 , 83 , 86 , 87 ]. Among 3D fabrics, several types of structures are distinguished, of which orthogonal ones are the most popular and most commonly used as reinforcement in composites with increased mechanical strength. Due to their simple microstructure, high stiffness, strength in all directions, low cost, and efficient production, 3D fabrics are readily used in the aviation, automotive, and, especially, arms industries, where 2D/3D fabric hybrids are used as reinforcement for bulletproof vests or body armor [ 58 , 82 , 88 ].
3. Conclusions
Fiber-reinforced polymer composites are being increasingly used in the defense industry. However, for protective applications, in addition to high specific strength and stiffness, polymer composites are also required to have a high energy absorption capacity. Furthermore, the properties of polymeric composite materials are still clearly different from those of metallic and ceramic materials used in industry. Therefore, the first and most important stage of designing composite materials for the arms industry is appropriate selection of the matrix and reinforcement to obtain the required mechanism of action. The literature review presented in this article on improvements in the properties of polymeric composites provides information about their application in the arms industry. The selection of specific fillers and other modifiers and their introduction into polymer composites make it possible to change their properties with respect to the predicted working conditions. In addition to nanofillers, various types of fibers (glass, carbon, and aramid) and the fabrics obtained from them, with different weaves, orientations, and impregnation (STF and STG), are used in polymer composites. Their use mainly improves the composites’ strength against mechanical damage by enhancing energy absorption, thus reducing the area of damage. The multiple ways to improve the mechanical strength of composites and the possibility of their simultaneous use give scientists a wide spectrum of research, as well as an opportunity to develop new types of hybrid composites with unique properties. However, the replacement of metal alloys and ceramics by polymeric composite materials, to ensure economy of production, usually requires a complete change in the concept of product design. Therefore, a very significant challenge associated with hybrid composites is their technological and application capabilities. In addition, weight and thickness should be considered when hybrid fiber composites are designed. Evaluation of the literature data showed that research on impact-resistant polymer composites should be focused on the development of hybrid systems, i.e., combining matrix modifications (via STF) and an appropriate fiber reinforcement structure. Among others, this ability to modify makes them unique materials for the 21st century.
Author Contributions
Conceptualization, K.C., R.O., and M.O.; methodology, K.C., R.O., K.B., G.B., and A.M.; validation, M.O., G.B., and A.M.; formal analysis, K.C., D.K., and K.B.; investigation, K.C., D.K., and K.B.; data curation, K.C., R.O., D.K., and K.B.; writing—original draft preparation, K.C., R.O., and D.K.; writing—review and editing, R.O., K.B., M.O., G.B., and A.M.; visualization, K.C. and R.O.; supervision, R.O., M.O., G.B., and A.M.; funding acquisition, M.O., G.B., and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Two-stage laminate destruction process based on [ 13 ]. (From open access publication).
Figure 2. Summary effect of individual matrix modifications and fibrous reinforcement on the performance of epoxy composites.
Figure 3. STF fabrication scheme based on the procedure in [ 34 ].
Figure 4. Overview graph showing the change in STF viscosity as a function of shear rate. [ 37 ]. (Adapted with permission from [ 37 ]. Copyright 2019 John Wiley and Sons).
Figure 5. Hybrid fiber reinforcement systems of ( a ) interply and ( b ) intraply type.
Figure 6. Angular orientations for the four reinforcement layers. (Adapted with permission from [ 78 ]. Copyright 2019 Elsevier).
Table 1. Summary of the mechanical properties of selected high-strength fibers [ 4 , 5 , 6 , 7 , 8 ].
Fiber Density (g/cm 3 ) Tensile Strength (GPa) Young’s Modulus (GPa) Elongation at Break (%) E glass fiber 2.63 3.5 68.5 4.0 S glass fiber 2.48 4.4 90.0 5.7 Carbon fiber(Celton) 1.80 4.0 230.0 1.8 p-Aramid (Kevlar 149) 1.47 3.5 179.0 1.6 m-Aramid (Nomex) 1.40 0.7 17.0 22.0 UHMWPE (Dyneema SK76) 0.97 3.6 116.0 3.8 Zylon AS 1.54 5.8 180.0 3.5 Zylon HM 1.56 5.8 270.0 2.5 Vectran 1.47 3.2 91.0 3.0 M5 1.70 5.8 310.0 1.4 Boron fiber 2.64 3.5–4.2 420.0–450.0 3.7 Silicon carbide 2.80 4.0 420.0 0.6 Alumina III (Nextel) 2.50 1.7 152.0 2.0
Table 2. Summary of publications in which the epoxy matrix was modified with nanofillers.
Ref. Reinforcement Fiber Type Filler Content Effect [ 40 ] Tate et al. Glass fiber SiO 2 6, 7, and 8 wt% Increase in tensile, flexural, and interlaminar shear strengths Increase in modulus and elongation [ 41 ] Ravi et al. PMMA 10 vol% Increase in tensile strength, flexural strength, and modulus Improved thermal stability and abrasion resistance SiC 1 vol% [ 42 ] Rahmat et al. BNNT 1 wt% Increase in flexural, shear, and impact strengths [ 44 ] Vigneshwaran et al. GnP 0.2, 0.6, and 1 wt% (of which 50% was used to impregnate the fiber) Increase in impact energy absorption, tensile strength, and modulus Reduction in surface damage area Improved adhesion between components [ 45 ] Tareq et al. Carbon fiber Nanoclay 2 wt% Increase in flexural strength and modulus when added separately Higher stiffness and GnP with the best thermomechanical stability in samples with nanoclay GnP 0.1 wt% [ 46 ] Moghimi et al. MWCNTSiO 2 0.2 and.7 wt% Increase in tensile strength and Young’s modulus Reduction in the abrasion coefficient Improved interfacial adhesion 0.7 and 0.2 wt% 0.45 and 0.45 wt% [ 47 ] Khan et al. N-CFRP Improvement of tensile and flexural strength and modulus by modified graphite G-CFRP E-CFRP [ 48 ] Suresha et al. Aramid fiber MWCNT 0.15, 0.3, and 0.5 wt% Increase in tensile strength, flexural strength, modulus, hardness, and impact strength [ 49 ] Dharmavarapu and Reddy SiO 2 modified with APTMS 0.5, 1, and 2 vol% Improved tensile strength, flexural strength, impact strength, and hardness Increase in impact energy absorption
Ref. Reinforcement Fiber Type Filler/Impregnator Effect [ 43 ] Zeng et al. Glass fiber MWCNTs modified with APS Increase in tensile strength, flexural strength, and modulus Improved ILSS and interfacial adhesion [ 29 ] Nasser et al. ZnO nanoparticles functionalized by piranha solution Decrease in IFSS at medium and high and increase at low strain rates Improved interfacial adhesion ZnO nanowires functionalized by piranha solution [ 56 ] Wang and Cai Carbon fiber GnP Increase in flexural strength, interlaminar shear, flexural modulus, and thermal conductivity [ 57 ] Badakhsh et al. Nickel (galvanization): phase I CNT (gas-phase deposition): phase II Improved flexural strength Decrease in electrical resistance and ductility index [ 58 ] Nasser et al. ZnO nanoparticles functionalized by 70% nitric acid Decrease in IFSS at medium and high strain rates ZnO nanowires functionalized by 70% nitric acid [ 60 ] Jia et al. Aramid fiber Grafting of APS by γ-ray and chemical treatment Increase in fiber surface roughness and IFSS [ 30 ] Malakooti et al. ZnO nanowires Increase in Young’s modulus, tensile strength, and impact strength [ 61 ] Zhang and Teng PDOPA functionalization and ZnO nanowire coating Increase in UV resistance fiber surface roughness Improved IFSS and interfacial adhesion
Table 4. Summary of publications that used reinforcement impregnated with an STF/STG.
Ref. Reinforcement Fiber Type Impregnation Type Filler in STF/STG Filler Content Effect [ 59 ] Selver Glass fiber STF SiO 2 10, 15, and 20 wt% Improvement in tensile strength, Young’s modulus, and energy absorption for 10 and 15 wt% Decrease in flexural strength and modulus for all samples Carbon fiber [ 64 ] Ávila et al. Aramid fiber SiO 2 0, 25, 50, 75, and 100 wt% of the filler mixture Increase in the impact energy absorption and friction between fibers CaCO 3 0, 25, 50, 75, and 100 wt% of the filler mixture [ 65 ] Liu et al. CNT Increase in resistance to fiber pull-out strength and puncture Increase in energy absorption SiO 2 71 wt% [ 66 ] Dixit et al. SiO 2 65 wt% Increase in fiber pull-out strength and impact energy absorption Impregnation of ZnO nanowires [ 38 ] Zhao et al. STG Increase in impact energy absorption and friction between fibers [ 28 ] Zhao et al. Carbon black Increase in impact energy absorption Mechanical–electrical coupling in the form of a change in resistivity as a function of impact energy, due to addition of carbon black [ 36 ] He et al. STF + STG SiO 2 (STF) Increase in impact strength and modulus Improved energy dissipation mechanism Reduction in composite weight and thickness STF stabilization and increase in traction between fibers, due to addition of STG
| https://www.mdpi.com/1996-1944/14/11/3047/html |
Symmetry | Free Full-Text | Quantifying Shape Variation in an Antisymmetrical Trait in the Tropical Fish Xenophallus umbratilis
Antisymmetry is a striking, yet puzzling form of biological asymmetry. The livebearing fish Xenophallus umbratilis exhibits antisymmetry in the male intromittent organ and provides a system that is well-suited for studying the nature of variation in antisymmetrical traits. Using geometric morphometrics, we test the hypothesis that because the gonopodium is critical to fitness there will not be significant differences in gonopodium shape between the two gonopodial morphs in this species. Our results are consistent with this prediction, though we found that gonopodium shape differed with gonopodium size.
Quantifying Shape Variation in an Antisymmetrical Trait in the Tropical Fish Xenophallus umbratilis
by Mary-Elise Nielsen 1,* and Jerald B. Johnson 1,2
1
Evolutionary Ecology Laboratories, Department of Biology, Brigham Young University, Provo, UT 84602, USA
2
Bean Life Science Museum, Brigham Young University, Provo, UT 84602, USA
*
Author to whom correspondence should be addressed.
Symmetry 2023 , 15 (2), 489; https://doi.org/10.3390/sym15020489
Received: 14 December 2022 / Revised: 9 January 2023 / Accepted: 2 February 2023 / Published: 13 February 2023
(This article belongs to the Section Biology and Symmetry/Asymmetry )
:
Antisymmetry is a striking, yet puzzling form of biological asymmetry. The livebearing fish Xenophallus umbratilis exhibits antisymmetry in the male intromittent organ and provides a system that is well-suited for studying the nature of variation in antisymmetrical traits. Using geometric morphometrics, we test the hypothesis that because the gonopodium is critical to fitness there will not be significant differences in gonopodium shape between the two gonopodial morphs in this species. Our results are consistent with this prediction, though we found that gonopodium shape differed with gonopodium size.
Keywords:
gonopodium
;
asymmetry
;
Poeciliidae
;
geometric morphometrics
1. Introduction
Understanding and explaining morphological variations has long been a topic of interest in evolutionary biology. Some of the most widespread and easily discernable forms of variation are breaks in symmetry, also known as asymmetry. Several types of asymmetries exist. Fluctuating asymmetries are subtle, random deviations from symmetry that are classically associated with parasites, environmental stress, and homozygosity [ 1 , 2 , 3 , 4 , 5 ]. This type of asymmetry typically results from aberrations in development and has been shown to reliably signal genome quality as well [ 6 , 7 , 8 ]. Directional asymmetries are those where all individuals share the same direction of asymmetry and the direction of asymmetry usually has a genetic basis [ 9 , 10 ]. Finally, antisymmetry is a type of asymmetry wherein “left-handed” and “right-handed” forms are both present within a population [ 11 ]. Antisymmetry is sometimes referred to as random asymmetry because the direction of asymmetry in such traits appears to be random and is sometimes not heritable [ 12 ].
Some have suggested that traits that are non-heritable, e.g., many asymmetrical and antisymmetrical traits, are evolutionarily unimportant [ 13 , 14 ]. However, such conclusions are not universally accepted [ 13 , 15 ]. One of the challenges in understanding the evolutionary impact of antisymmetrical traits is that researchers often focus on traits that may not be readily linked to fitness. What is needed is a study that examines antisymmetry in a trait that is clearly and directly linked to fitness, such as those used for reproduction or rearing offspring.
We have identified a species of livebearing freshwater fish, Xenophallus umbratilis [ 16 ], that fits these criteria. This species exhibits antisymmetry in the male intromittent organ called the gonopodium, a modified anal fin that is used to inseminate females [ 17 , 18 ]. Gonopodia in livebearing fish are often elaborated, featuring barbs, claws, and serrae that presumably help males anchor more securely to the female urogenital pore during copulation [ 17 , 19 ]. The gonopodium in X. umbratilis terminates with a hook-like structure that curves to the left (sinistral) or to the right (dextral) ( Figure 1 ).
Here, we evaluate the extent of shape variation in the degree of curvature in the gonopodium between sinistral and dextral males in
X. umbratilis
using geometric morphometrics. Because the degree of curvature in the gonopodium likely impacts a male’s ability to successfully transfer sperm (too curved or not curved enough may both inhibit copulation), we predict that curvature will be maintained by common selective pressures regardless of chirality and will therefore be identical between the two morphs.
2. Materials and Methods
2.1. Study System and Sampling
Xenophallus umbratilis
is a livebearing freshwater fish native to northern Costa Rica. The species is typically found in small streams and is most abundant at the headwaters of river drainages at high elevations [
20
X. umbratilis
employs internal fertilization and gives birth to live young. The gonopodium in
X. umbratilis
is antisymmetrical, exhibiting a sinistral (left-handed) or dextral (right-handed) hook at the terminus. Populations of
X. umbratilis
are usually composed of a mixture of sinistral and dextral individuals, though several populations that are fixed for either morph have been observed in the wild [
21
].
We studied X. umbratilis from ten different localities that contained both gonopodium morphs collected from tributaries and streams in Costa Rica between 2005 and 2007 ( Figure 2 , Table 1 ). These specimens came from the Brigham Young University Bean Life Science Museum collections. Fish were collected and humanely euthanized in the field with an overdose of the anesthesia tricane methanesulfonate (MS-222) at a concentration of 250 mg/L [ 22 , 23 ]. Fish were preserved in the field in ethyl alcohol and each specimen was assigned a museum ID number.
Populations that were fixed for either the sinistral or dextral morph were excluded from this study. We sorted each of the ten populations to remove females and juveniles, and then sorted the remaining mature males by gonopodium morph. Using an Olympus DP74 camera mounted on an Olympus MVX10 microscope (Tokyo, Japan), we took photographs of males with their ventral side facing up to the camera lens. We placed males in a black, plastic trough for photographing to make their positioning under the lens easier to control and more consistent across images. Following photographing, we returned males to their original museum collection jars.
2.2. Geometric Morphometric Analysis
We employed landmark-based geometric morphometrics to quantify gonopodium shape in
X. umbratilis
[
24
]. Prior to landmarking, we used Olympus cellSens software [
25
] to screen images and ensure that specimens were in focus and that the gonopodium was level in the dorso-ventral and anteroposterior axes. We re-photographed specimens to correct any rotation or focus errors and excluded males with damaged or underdeveloped gonopodia from our analysis (
n
= 3). Additionally, for our analysis, we rotated or flipped images so that all gonopodia were oriented such that they appeared to be dextral. This reduced observer bias by making it impossible to visually distinguish sinistral and dextral gonopodia. In total, 246 males (135 sinistral, 111 dextral) were included in this study.
We used the program tpsDig [ 26 ] to digitize landmarks on each specimen and to measure variation in sinistral and dextral gonopodia. We used seven landmarks to outline the shape of the gonopodium ( Figure 3 ). Landmarks were placed by a single researcher on each specimen and specimens were processes in random order.
We generated shape variables from our landmark data in tpsRelw [ 26 ]. After producing shape variables using a general Procrustes analysis [ 27 ], tpsRelw runs a principal components analysis and calculates relative warps and centroid size. For this analysis, tpsRelw calculated ten relative warps. We used the first six of these relative warps, which accounted for 99.89% of total shape variation, for additional analysis, and excluded four relative warps that accounted for less than 0.5% of variation. Excluding these relative warps allowed us to avoid inflating the degrees of freedom in our shape analysis [ 28 , 29 ].
2.3. Statistical Analysis
We used a multivariate linear mixed model to evaluate the effects of morph (sinistral or dextral), centroid size (a measure of size commonly used in geometric morphometrics) [
30
], and locality on shape variation [
28
,
29
]. In each analysis, we used relative warps (shape variables) as our response variable. Because relative warps come from a matrix of shape variables, we had to convert the shape variable matrix into columns of vectors to be used in our multivariate linear mixed model. This conversion subsequently required the creation of an index variable that retained individual information for each of the relative warps in our analyses. We included the index variable in our analysis as a predictor variable and it is necessary to meaningfully measure the differences in shape variation between groups. Hence, it is the two-way interactions between morph and the index variable, centroid size and the index variable, locality and the index variable, and the three-way interactions between morph, centroid size and the index variable, and locality, centroid size and the index variable, that allowed us to comprehensively determine what factors significantly influence gonopodium shape variation [
31
].
To test our hypothesis, we ran three models. We first needed to determine if centroid size and locality were significant predictors of shape variation to inform how we constructed subsequent models that tested for the effect of gonopodial morph on shape. Our first model tested for the impact of centroid size on shape. The second model included centroid size and locality. Our third model tested for the effects of morph and centroid size and included locality as a random effect. Across all three models, relative warps (shape variables) were used as the response variable (see
Table 2
for details on each model’s components). We used the Akaike Information Criterion (AIC) to determine which of the three models provided the best fit [
32
].
We estimated the degrees of freedom in our analyses using the Kenward-Roger method [ 33 ] and ran our multivariate linear mixed models in SAS software, using the Proc MIXED protocol (SAS version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
Neither morph nor locality were significant predictors of gonopodium shape. That is, we could not reject the hypothesis that the shape of dextral and sinistral gonopodial morphs are the same ( Table 3 ). Gonopodium shape in X. umbratilis did differ significantly by centroid size in both models 1 and 3 (see the two-way interaction between centroid size and the index variable from models 1 and 3 in Table 2 ). Of the three models, model 2 had the lowest AIC score (−10,768.2) and best fit the data. The terminus of the gonopodium becomes slightly more open moving from the smallest centroid size to the largest ( Figure 4 ). Although a significant predictor, the extent of shape variation that centroid size explains appears to be relatively limited compared to the overall variation in shape captured across Relative Warps 1 and 2 ( Figure 5 ). In other words, the primary difference in gonopodium as a function of centroid size was a slight change at the tip of the gonopodium ( Figure 4 ).
4. Discussion
This study provides insight on variation in antisymmetrical traits. We predicted that the shape of gonopodial curvature would not differ between sinistral and dextral individuals in
X. umbratilis
and our results support this prediction. We also found that centroid size is a significant predictor of gonopodium shape. Males of many poeciliid species exhibit determinate growth, so this finding suggests that the size at which males mature may affect gonopodium shape [
34
,
35
]. However, it seems unlikely that centroid size impacts gonopodium shape in a biologically meaningful way, as the variation due to centroid size is minimal when considered with the overall shape variation in the gonopodium we observed.
Asymmetry is typically considered in a morphological context, though asymmetry can also be demonstrated behaviorally [
36
]. Previous research in
X. umbratilis
from Johnson et al. [
21
] found that gonopodial morphology reliably predicted detour behaviors and eye-bias for potential mates and predators. In that study, dextral (right morph) males detoured to the right to view potential mate and predator stimuli. Sinistral (left morph) males’ behaviors were completely opposite, with males detouring to the left for the same set of stimuli. Our work aligns with these observed patterns. We found that sinistral and dextral gonopodial morphs were essentially mirror images of each other, which is consistent with a specific morph type predicting detour behavior in this species. Another study found that individuals from a fixed sinistral population of
X. umbratilis
preferentially positioned themselves wherein males were primarily on the left side of a female during mating interactions [
37
]. However, individuals from fixed dextral populations did not display side-biased positioning behavior. Our results provide some context for the strong side-bias in the sinistral population and the lack of side-bias in the dextral population by ruling out the possibility that unequal degrees of curvature in the gonopodium influenced mating positioning behaviors.
A critical component of studying morphology and its evolutionary implications is tying morphology to function and fitness. Though the gonopodium certainly is important to fitness in
X. umbratilis
, very little is understood about the actual mechanisms that facilitate insemination in this species and livebearing fish in general. Given that dextral and sinistral gonopodia are essentially mirror images of each other, we might expect that functional behavior associated with fertilization in this species will also reflect antisymmetry in the gonopodium. Future work should focus on understanding the mechanisms involved in copulation and how this compares between gonopodial morphs.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/sym15020489/s1 .
Author Contributions
Conceptualization, M.-E.N., J.B.J.; investigation, M.-E.N.; data curation, M.-E.N.; formal analysis, M.-E.N.; visualization, M.-E.N.; writing—original draft preparation, M.-E.N.; writing—review and editing, M.-E.N. and J.B.J. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Data Availability Statement
The data presented in this study are available in a supplementary material file .
Acknowledgments
We thank Riley Nelson and Tanner Van Orden for providing microscope and imaging software, and for assistance photographing specimens, respectively. We also thank Mark Belk for his help with image screening and data analysis.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Photographs of ventral view male specimens with sinistral ( A ) and dextral ( B ) gonopodia.
Figure 2. Map of the ten localities sampled in Costa Rica. Rivers and tributaries are shown in gray and localities are denoted by black dots. Localities were sampled between 2005 and 2007. Image generated with ArcGIS.
Figure 2. Map of the ten localities sampled in Costa Rica. Rivers and tributaries are shown in gray and localities are denoted by black dots. Localities were sampled between 2005 and 2007. Image generated with ArcGIS.
Figure 3. Landmark placement used to analyze gonopodium shape in X. umbratilis . Landmarks were placed as follows: (1) origin of the gonopodium; (2) terminus of the gonopodium; (3) point of curvature at the tip of the shaft; (4) midpoint between landmarks one and two; (5) midpoint between landmarks two and three on the terminus; (6) midpoint between landmarks three and five; and (7) midpoint between landmarks five and two. Landmarks one and two are homologous; landmark three is a pseudo-landmark; and landmarks four, five, six, and seven are sliding landmarks.
Figure 3. Landmark placement used to analyze gonopodium shape in X. umbratilis . Landmarks were placed as follows: (1) origin of the gonopodium; (2) terminus of the gonopodium; (3) point of curvature at the tip of the shaft; (4) midpoint between landmarks one and two; (5) midpoint between landmarks two and three on the terminus; (6) midpoint between landmarks three and five; and (7) midpoint between landmarks five and two. Landmarks one and two are homologous; landmark three is a pseudo-landmark; and landmarks four, five, six, and seven are sliding landmarks.
Figure 4. Variation in gonopodium shape explained by centroid size. Shape deformation is represented by thin plate splines. The top thin plate spline visualizes shape at the largest centroid in this dataset and the bottom thin plate spline visualizes the shape at the smallest centroid size.
Figure 4. Variation in gonopodium shape explained by centroid size. Shape deformation is represented by thin plate splines. The top thin plate spline visualizes shape at the largest centroid in this dataset and the bottom thin plate spline visualizes the shape at the smallest centroid size.
Figure 5. Visualization of gonopodium shape variation along Relative Warp 1 (RW1) and Relative Warp 2 (RW2). Thin plate splines along the x -axis represent shape deformation across Relative Warp 1. Moving from left to right, these splines show the terminus of the gonopodium becoming more tightly curved. Thin plate splines along the y -axis represent shape deformation across Relative Warp 2. These splines show some bending in the midpoint of the gonopodium shaft and some changes in the curvature of the gonopodium tip.
Figure 5. Visualization of gonopodium shape variation along Relative Warp 1 (RW1) and Relative Warp 2 (RW2). Thin plate splines along the x -axis represent shape deformation across Relative Warp 1. Moving from left to right, these splines show the terminus of the gonopodium becoming more tightly curved. Thin plate splines along the y -axis represent shape deformation across Relative Warp 2. These splines show some bending in the midpoint of the gonopodium shaft and some changes in the curvature of the gonopodium tip.
Table 1. Population identification and location information.
Table 1. Population identification and location information.
Table 2. Variables used in each model of the multivariate linear model analysis.
Table 2. Variables used in each model of the multivariate linear model analysis.
Response Variable Random Effect Predictor Variable Model 1 Relative Warps -- Centroid Size Index Centroid Size × Index Model 2 Relative Warps -- Locality Centroid Size Centroid Size × Locality Index Locality × Index Centroid Size × Index Locality × Centroid Size × Index Model 3 Relative Warps Locality Morph Centroid Size Centroid Size × Morph Index Morph × Index Centroid Size × Index Morph × Centroid Size × Index
Table 3. Results from the multivariate linear mixed model analysis. We ran three different models with different combinations of predictor variables. Predictor variable terms that include an interaction with the index variable are those that evaluate if/how gonopodium shape changes.
Table 3. Results from the multivariate linear mixed model analysis. We ran three different models with different combinations of predictor variables. Predictor variable terms that include an interaction with the index variable are those that evaluate if/how gonopodium shape changes.
Predictor Variable Degrees of Freedom F-Value p -Value Model 1 Centroid Size 1, 702 6.44 0.0113 Index 5, 657 4.9 0.0002 Centroid Size × Index 5, 657 4.82 0.0002 Model 2 Locality 9, 794 1.02 0.4226 Centroid Size 1, 794 1.25 0.2365 Centroid Size × Locality 9, 794 1.04 0.4092 Index 5, 659 2.04 0.0718 Locality × Index 45, 1183 0.98 0.5024 Centroid Size × Index 5, 659 2.07 0.0671 Locality × Centroid Size × Index 45, 1183 0.98 0.5188 Model 3 Morph 1, 704 0.01 0.9238 Centroid Size 1, 619 5.09 0.0244 Centroid Size × Morph 1, 703 0.04 0.8391 Index 5, 653 3.26 0.0065 Morph × Index 5, 653 1.39 0.2273 Centroid Size × Index 5, 653 3.07 0.0095 Morph × Centroid Size × Index 5, 653 1.23 0.0095
Chicago/Turabian Style
Nielsen, Mary-Elise, and Jerald B. Johnson. 2023. "Quantifying Shape Variation in an Antisymmetrical Trait in the Tropical Fish Xenophallus umbratilis" Symmetry15, no. 2: 489.
https://doi.org/10.3390/sym15020489
| https://www.mdpi.com/2073-8994/15/2/489 |
xml-dev - The use of XML syntax in XML Query
The use of XML syntax in XML Query [ Lists Home | Date Index | Thread Index ] To : [email protected] Subject : The use of XML syntax in XML Query From : David Carlisle < [email protected] > Date : Thu, 3 Jan 2002 11:46:52 GMT Cc : [email protected] I am very surprised that the W3C is proposing to standardise a language
that uses syntactic constructs such as
<...> ... </...>
&#...;
<!-- ... -->
<![CDATA[ ... ]>
in a format which is _not_ XML.
This just seems guaranteed to ensure user confusion.
Xquery is claimed to be the "human readable" syntax as opposed to the
XML syntax of XqueryX, however this human readable syntax has now
adopted so many XML features I suggest that it should be made into an
XML format in its own right. There is still a use case for an XML
syntax that "fully expands" the Xpath expression syntax into an XML tree,
but that does not mean that XQuery, like XSLT, could not be defined as
layered over an XML parser.
One of the main benefits of using XML as a syntax for a new text based
format is that lots of tricky i18n and encoding issues are dealt with at
that level. By choosing not to be XML, Xquery loses these benefits and,
as far as I can see in the drafts, proposes no alternative.
A couple of small examples, although it is easy to generate more:
*
Xquery includes a production CharRef which allows the syntax é
As far as I can see the meaning of this construct is not specified but
one assumes that it means the same as in XML, and denotes an e-acute.
In XSLT I can write my stylesheet in any encoding I want, but still
query the full range of XML documents. For example
<xsl:value-of select="é"/>
would return the value of the element with name e-acute.
In Xquery, as in Xpath, you can not use & within a Qname and so there
is no equivalent to this XSLT construct in Xquery, one has to write out
the Qname with character data, which means that the encoding of the
query document has to include these characters. (Perhaps all Xquery
documents are in utf8? in which case this is not an issue technically
but might still be inconvenient for users. However I can see no mention
of the possible encodings of a query document within the current draft so
it's hard to be sure what is proposed here.
*
The introduction states that any expression that is both a valid
Xpath2 and Xquery1 expression will generate the same result in both
languages. There is a technical sense in which this is true but the fact
that Xpath is most commonly used in XSLT, ie in XML, and Xquery is not
XML, means that the user perception will be that many expressions are
valid in both contexts but have wildly different results.
It is very common to XML-quote the apostrophes used to delimit Xpath
strings in order to fit the expression into an XML attribute, but note
this is using the XML entity or character reference syntax on Xpath
delimiters, something that is not permitted in Xquery.
'a'=&39;b'
is, as far as I can make out, valid as
a "raw" Xpath expression
in which case it has value a string of length 13
but usually when people write Xpaths they write them as they appear in
XML/XSLT in which case the above is a legal Xpath which is just
an XML-encoded version of 'a'='b' which is a legal expression with value
boolean false().
However Xquery introduces (as far as I can tell) a new incompatible
interpretation of this string, namely as a single string a'='b
of length 5.
Given that Xpaths (and one assumes in the future, Xqueries) are often
written by XML tools such as XSLT which don't give the user a lot of
control over the serialisation of character data, the non-XML
interpretation of XML character references by Xquery seems very
worrying to me.
Changing Xquery to be an XML format would not require so many changes in
the document. The parts of the grammar copied from the XML grammar could be
removed. Incidentally those parts highlight another problem with
copying rather than using XML, they use the character productions from
XML 1.0 but XML 1.1 is (perhaps) going to change them. If Xquery
referenced XML it would be a lot more straightforward managing the
issues related to unicode 3.x characters in QNames. (At least it would
be XML's problem rather than Xquery's)
Xquery would then need to introduce specific constructs to generate XML
comments (cf xsl:comment) as <!-- would no longer be a reliable
mechanism. Also, probably, you'd want a top level element in some Xquery
namespace just to wrap the query up as a well formed document.
David
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Immune Modulation by Parenteral Lipids - Full Text View - ClinicalTrials.gov
Immune Modulation by Parenteral Lipids
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: NCT00734916 Recruitment Status :
Completed First Posted : August 14, 2008 Last Update Posted : February 4, 2010
Sponsor:
Radboud University Medical Center
Study Details
Study Description
Brief Summary:
Immune modulating properties of parenteral lipid emulsions seem to contribute to the increased risk for infections which remains associated with the use of total parenteral nutrition. Emulsions based on soy bean oil (SO) are the oldest and still most widely used lipid source in TPN formulations but their high content of omega-6 polyunsaturated fatty acids (PUFAs) may be a drawback. Fish oil-based lipid emulsions (FO), rich in omega-3 PUFAs, has been approved for parenteral nutrition in many countries. Mainly retrospective studies on clinical outcomes in septic and postoperative patients have suggested clinical benefits with the inclusion of FO in parenteral nutrition regimens. The exact mechanisms behind the beneficial immunological effects of parenteral FO have, however, not yet been elucidated.
Objective:
To evaluate the effects of intravenous infusion of a FO-based lipid emulsion and a SO-based emulsion on immune function as evidenced by effects on peripheral blood leukocyte counts and functions and on the susceptibility to oxidative stress.
Study design:
Randomized placebo controlled cross-over pilot study with healthy volunteers.
Condition or disease Intervention/treatment Phase Infections Total Parenteral Nutrition Dietary Supplement: Parenteral lipid emulsion (Omegaven) Dietary Supplement: Parenteral lipid emulsion (Intralipid) Dietary Supplement: Parental lipid emulsion (Saline 0.9%) Not Applicable
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Estimated Enrollment : 8 participants Allocation: Randomized Intervention Model: Crossover Assignment Masking: Triple (Participant, Investigator, Outcomes Assessor) Primary Purpose: Treatment Official Title: Immune Modulation by Omega-3 Versus Omega-6 Based Parenteral Lipids in Healthy Volunteers Study Start Date : August 2008 Actual Primary Completion Date : August 2009 Actual Study Completion Date : February 2010
Arm Intervention/treatment Active Comparator: 1 Omegaven 10% Dietary Supplement: Parenteral lipid emulsion (Omegaven) Omegaven 10%, 0.2g/kg/hr i.v.during 1 hour on 3 consecutive days Other Name: Omegaven 10%, Fresenius Kabi, Bad Homburg Germany Active Comparator: 2 Intralipid 10% Dietary Supplement: Parenteral lipid emulsion (Intralipid) Intralipid 10%, 0.2g/kg/hr i.v. during 1 hour on 3 consecutive days Other Name: Intralipid 10%, Fresenius Kabi, Bad Homburg Germany Placebo Comparator: 3 Placebo Dietary Supplement: Parental lipid emulsion (Saline 0.9%) Placebo (Saline 0.9%), same volume/hr as lipid emulsions Other Name: lipid free control
Outcome Measures
Primary Outcome Measures
:
leukocyte counts [ Time Frame: T=0, T=4 days, T=11 days ]
leukocyte functions [ Time Frame: T=0, T=4 days and T=11 days ]
(anti-)oxidant status [ Time Frame: T=0, T=4 days, T=11 days ]
Secondary Outcome Measures
:
plasma and leukocyte cell membrane (phospho)lipid composition. [ Time Frame: T=0, t=4 and T=11 days ]
Eligibility Criteria
Layout table for eligibility information Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Adult (>18 yrs of age)
Healthy
Willingness to give written informed consent
Exclusion Criteria:
Smoking > 5 cigarettes/day
Diet with > 2 portions of fatty fish per day
Use of oral fish oil or vitamin substrates
History of metabolic disorder (especially diabetes or lipid disorders)
History of allergic, inflammatory of immunological disease
History of pulmonary, cardiovascular, renal or hematological disease
Medication use
Layout table for location information Netherlands Radboud University Nijmegen Medical Centre Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University Medical Center
Investigators
Layout table for investigator information Study Director: Geert JA Wanten, MD, MSc, PhD Radboud University Medical Center
Layout table for additonal information Responsible Party: M.W.J. Versleijen, MD, MSc and G.J.A. Wanten, MD, MSc, PhD, Radboud University Nijmegen Medical Centre ClinicalTrials.gov Identifier: NCT00734916 History of Changes Other Study ID Numbers: GW/MV/20307 CMO 2008/140 First Posted: August 14, 2008 Key Record Dates Last Update Posted: February 4, 2010 Last Verified: February 2010
Keywords provided by Radboud University Medical Center:
total parenteral nutrition infections Infectious complications related to parenteral nutrition
| https://clinicaltrials.gov/show/NCT00734916 |
of nasal polyposis pathophysiology and monoclonal antibody targets | Download Scientific Diagram
Download scientific diagram | of nasal polyposis pathophysiology and monoclonal antibody targets from publication: Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed? | This review article aims to outline what is known in the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) and describe the mechanism of the biologic agents being investigated for this disease. Chronic rhinosinusitis with nasal polyposis is an... | Therapeutic Antibodies, Monoclonal Antibodies and Head | ResearchGate, the professional network for scientists.
of nasal polyposis pathophysiology and monoclonal antibody targets
Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed?
This review article aims to outline what is known in the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) and describe the mechanism of the biologic agents being investigated for this disease. Chronic rhinosinusitis with nasal polyposis is an inflammatory disease of the nasal and paranasal mucosa, which causes symptoms of nas...
Background:
Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidat...
Citations
... Etokimab is a HuMAb with a good safety profile that has a high affinity to human IL-33 and inhibits its activity [151]. AMG 282 is an anti-ST2 Mab that inhibits the binding of IL-33 to the ST2 receptor
[152]
. Other anti-IL-33 drugs (GSK3772847, SAR440340) are already tested in asthma, COPD and other diseases. ...
Perspectives in Therapy of Chronic Rhinosinusitis
Jacek Brzost
Katarzyna Czerwaty
Karolina Dżaman
Nils Ludwig
Mirosław J. Szczepański
The recent classification of chronic rhinosinusitis (CRS) focusses on investigating underlying immunopathophysiological mechanisms. Primary CRS is subdivided based on endotype dominance into type 2 (that relates mostly to the Th2 immune response with high levels of IL-5, IL-13, and IgE), or non-type 2 (that corresponds to the mix of type 1 and type 3). The treatment selection of CRS is dependent on endotype dominance. Currently, the majority of patients receive standardized care—traditional pharmacological methods including local or systemic corticosteroids, nasal irrigations or antibiotics (for a selected group of patients). If well-conducted drug therapy fails, endoscopic sinus surgery is conducted. Aspirin treatment after aspirin desensitization (ATAD) with oral aspirin is an option for the treatment in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) patients. However, in this review the focus is on the role of biological treatment—monoclonal antibodies directed through the specific type 2 immune response targets. In addition, potential targets to immunotherapy in CRS are presented. Hopefully, effective diagnostic and therapeutic solutions, tailored to the individual patient, will be widely available very soon.
... Die CRSwNP wird auch als Polyposis nasi et sinuum bezeichnet und ist mit dem endoskopischen und/oder radiologischen Nachweis von polypös-hyperplastischem Gewebe in Nasenhaupthöhle und/oder Nasennebenhöhlen verbunden. Die CRSwNP ist eine immunologisch ausgelöste chronisch-inflammatorische Erkrankung von Schleimhaut und subepithelialem Gewebe, für die erst im letzten Jahrzehnt spezifische, am Endotyp orientierte immunologische Therapien entwickelt wurden
[9,
10,11,12], während Immuntherapien [13,14,15,16,17] für exogen-allergische Nasenschleimhauterkrankungen seit langem therapeutischer Standard sind. ...
Dokumentation von Biologika-Therapien bei chronischer Rhinosinusitis mit Polyposis nasi (CRSwNP): Dupilumab, Omalizumab und Mepolizumab: Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC)
Ludger Klimek
Ulrike Förster-Ruhrmann
Achim G. Beule
Adam M. Chaker
Sven Becker
Hintergrund: Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung der paranasalen Schleimhäute, der als Endotyp meistens eine Typ-2-Inflammation zugrunde liegt. Mittlerweile sind drei Antikörper (Dupilumab, Omalizumab und Mepolizumab) für die Therapie der schweren CRSwNP zugelassen. Eine Dokumentation der Erkrankungsschwere im Behandlungsverlauf ist unverzichtbar.
Methoden: In einer Literaturrecherche in Medline, Pubmed sowie den nationalen und internationalen Studien- und Leitlinienregistern und der Cochrane Library wurde die Immunologie der CRSwNP analysiert und die Evidenz zur Wirkung von Dupilumab, Omalizumab und Mepolizumab bei dieser Erkrankung ermittelt. Hieraus wurden drei Positionspapiere durch unsere Autorengruppe erstellt, die Grundlage dieser zusammenfassenden Übersichtsarbeit sind.
Ergebnisse: Basierend auf den Angaben aus der internationalen Literatur werden von einem Expertengremium Empfehlungen für die Anwendung von Dupilumab, Omalizumab und Mepolizumab bei CRSwNP im deutschen Gesundheitssystem gegeben.
Schlussfolgerung: Dupilumab, Omalizumab und Mepolizumab sind zugelassen für Patienten ab 18 Jahren mit schwerer CRSwNP als Zusatztherapie zu intranasalen Glukokortikosteroiden (INCS), wenn, bei Dupilumab und Mepolizumab, durch eine Therapie mit systemischen Glukokortikosteroiden und/oder chirurgischem Eingriff keine ausreichende Krankheitskontrolle erzielt werden kann. Eine Therapie mit Omalizumab ist angezeigt, wenn eine Therapie mit INCS keine suffiziente Kontrolle der Erkrankung ergibt. Es werden dezidierte Empfehlungen zur Dokumentation der Anwendung im Deutschen Gesundheitssystem gegeben, die auf den hierzu bereits publizierten Positionspapieren unserer Autorengruppe basieren.
Zitierweise: Klimek L, Förster-Ruhrmann U, Beule AG, Chaker AM, Hagemann J, Klimek F, Casper I, Huppertz T, Hoffmann TK, Dazert S, Deitmer T, Olze H, Strieth S, Wrede H, Schlenter W, Welkoborsky H-J, Wollenberg B, Bergmann C, Cuevas M, Beutner C, Gröger M, Becker S. Indicating biologics for chronic rhinosinusitis with nasal polyps (CRSwNP): Recommendations by German Allergy and ORL-societies AeDA and DGHNO for Dupilumab, Omalizumab and Mepolizumab. Allergo J Int 2022;31:149-60
https://doi.org/10.1007/s40629-022-00220-x
... 7 There are many studies in the literature showing that biologic agents given to patients with type 2 phenotype asthma based on the pathogenesis of inflammation are also effective in the treatment of nasal polyps. [8]
[9]
[10] Efficacy of omalizumab, an anti-Ig E antibody, which is a treatment option in severe allergic asthma, was shown in nasal polyps in randomized, clinical, phase 3 trials but data on real-life efficacy are limited, especially in CRSwNP patients without asthma. 8 So, in this study, we aimed to report our real-life experience with omalizumab in CRSwNP patients with or without asthma. ...
Omalizumab is effective in nasal polyposis with or without asthma, a real-life study
Tuğba Songül Tat
Background
Chronic rhinosinusitis with nasal polyposis (CRSwNP) can be recalcitrant in some patients despite medical therapies and surgery and has higher morbidity. Omalizumab is a new treatment option for patients with CRSwNP. The aim of this study is to evaluate the efficacy and safety of omalizumab (anti-IgE antibody) in patients with CRSwNP.
Methods
The efficiency and adverse effects of omalizumab were evaluated based on the data extracted from medical records of patients with CRSwNP. Patients were evaluated monthly for efficacy and adverse reactions. Treatment efficacy was evaluated by visual analog scale (VAS) for rhinorrhea, postnasal drip, sneeze, smell, and nasal stuffiness complaints, sinonasal outcome test-22 (SNOT-22), and nose obstruction symptom evaluation (NOSE) score.
Results
17 patients with CRSwNP formed our cohort. The mean (SD) age, weight, and total IgE level were 41.9 (9.4) years, 78.6 (15) kg, and 198.8 (169.2) IU/mL, respectively. 3 patients had mild, 6 had moderate and 1 had severe asthma as comorbidity. The mean (SD) duration of omalizumab treatment and polypectomy numbers were 9.2 (13.3) months and 2.9 (1.5), respectively. All patients had at least one polyp surgery. All sinonasal outcome parameters were significantly improved by the omalizumab treatment, also in subgroups with and without asthma. The median changes from baseline at the last visit date for omalizumab treatment were as follows: SNOT-22 score decreased from 98 to 19, NOSE score decreased from 100 to 20, the VAS for postnasal drip, rhinorrhea, nasal stuffiness, smell and sneeze decreased from 8 to 2, 8 to 2, 10 to 3, 10 to 2, 6 to 1, respectively (P < 0.001). Patients experienced no adverse reaction with omalizumab treatment.
Conclusion
Omalizumab was an effective treatment in patients with recalcitrant CRSwNP with or without asthma.
... CRSwNP is also called polyposis nasi et sinuum and is associated with endoscopic and/or radiological evidence of polypous-hyperplastic tissue in the nasal cavity and/or paranasal sinuses. CRSwNP is an immunologically triggered chronic inflammatory disease of mucosa and subepithelial tissue, for which specific endotype-oriented immunologic therapies have been developed only in the last decade
[9]
[10][11][12], whereas immunotherapies [13][14][15][16][17] for exogenous-allergic nasal mucosal diseases have been therapeutic standard for a long time. ...
Indicating biologics for chronic rhinosinusitis with nasal polyps (CRSwNP)
Full-text available
Jul 2022
Ludger Klimek
Ulrike Förster-Ruhrmann
Achim G. Beule
Adam M. Chaker
Sven Becker
Background
Chronic rhinosinusitis with nasal polyps (CRSwNP), an inflammatory disease of the paranasal mucosa, is primarily characterized by type 2 inflammation. Three antibodies (dupilumab, omalizumab, and mepolizumab) are now approved for the treatment of severe CRSwNP. Documentation of disease severity during the course of treatment is essential.
Methods
A literature search of Medline, PubMed, and the national and international trial and guideline register, and the Cochrane Library was performed to analyze the immunology of CRSwNP and determine the evidence for the effect of dupilumab, omalizumab, and mepolizumab in this disease. This has resulted in 3 position papers prepared by our group of authors, which form the basis of this summarizing review.
Results
Based on the information from the international literature, recommendations for the use of dupilumab, omalizumab, and mepolizumab in CRSwNP in the German health care system are given by an expert panel.
Conclusion
Dupilumab, omalizumab, and mepolizumab are approved for patients 18 years of age and older with CRSwNP as add-on therapy to intranasal corticosteroids when, for dupilumab and mepolizumab, therapy with systemic corticosteroids and/or surgery does not achieve sufficient disease control. Therapy with omalizumab is indicated when therapy with intranasal corticosteroids does not result in sufficient disease control. Dedicated recommendations for the documentation of the use in the German health care system are given, which are based on the position papers of our author group already published on this topic.
... Recent epidemiological studies reported that CRS affected approximately 5.5-28% of the global population, and the prevalence continues to increase [2][3][4]. Based on the presence of nasal polyps, CRS is grouped into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP)
[5]
. CRSwNP with dominant T helper 2 (Th2) inflammation can be further categorized into eosinophilic (eCRSwNP) and noneosinophilic (neCRSwNP) types determined by the degree of eosinophil infiltration in the nasal mucosa. ...
Predictive Values of Serum IL-33 and sST2 in Endotypes and Postoperative Recurrence of Chronic Rhinosinusitis with Nasal Polyps
MEDIAT INFLAMM
Yanni Zhang
Kang Zhu
Jingguo Chen
Cui Xia
Xiaoyong Ren
Background:
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disease with high heterogeneity and postoperative recidivation. The IL-33/ST2 axis is known to be involved in Th2 immune responses. This study is aimed at exploring levels of serum IL-33 and soluble ST2 (sST2) in CRSwNP patients and their potential for predicting CRSwNP endotypes and postoperative recurrence.
Methods:
The present study recruited 149 CRSwNP patients, 80 of whom were noneosinophilic (neCRSwNP) and 69 eosinophilic (eCRSwNP), as well as 60 healthy controls (HCs). Serum samples were collected from all participants, and sST2 and IL-33 concentrations were measured using ELISA. Multivariate analysis, receiver operating characteristic (ROC) curves, and Kaplan-Meier curves were used to evaluate the value of serum sST2 and IL-33 levels in distinguishing CRSwNP endotypes and predicting postoperative recurrence.
Results:
The levels of serum sST2 and IL-33 in CRSwNP patients were significantly higher than those in HCs, especially in the eCRSwNP group. Increased sST2 and IL-33 levels were associated with eosinophil counts and percentages in both tissue and blood. Multivariate regression and ROC curve analysis showed that serum sST2 and IL-33 exhibited potential for distinguishing CRSwNP endotypes, and the combination of serum IL-33 and sST2 showed even more predictive power. Finally, 124 CRSwNP patients completed the entire 3-year follow-up. Multivariate analysis and Kaplan-Meier curves showed that serum sST2 and IL-33 levels were associated with recurrence; serum sST2 and IL-33 each exhibited potential for predicting postoperative recurrence, and combining serum sST2 and IL-33 exhibited better accuracy and practicability.
Conclusion:
Our results suggested that serum sST2 and IL-33 levels were upregulated in CRSwNP patients and related to the degree of mucosal eosinophil infiltration and postoperative recurrence. Serum sST2 and IL-33 might serve as objective biomarkers for distinguishing phenotypes and predicting recurrence in CRSwNP, and their combined use outperformed either marker alone.
... A single reslizumab injection improved the nasal polyp score in half of the patients with CRSwNP, and the number of eosinophils in the serum and nasal secretions decreased significantly within 8 weeks after treatment. Although there has been no trial of reslizumab for nasal polyposis, a phase III trial of reslizumab for CRS is currently in the recruitment stage
[46]
. ...
Therapeutic Strategies of Biologics in Chronic Rhinosinusitis: Current Options and Future Targets
INT J MOL SCI
Junhu Tai
Munsoo Han
Taehoon Kim
Chronic rhinosinusitis is a chronic inflammatory disease of the upper airways, for which treatment options include medical or surgical therapy. However, there are limitations to conservative treatment strategies, such as the relapse of nasal polyps. In this review, we discuss the rising role of biomolecular mechanisms associated with various biologics that have been approved or are undergoing clinical trials to treat chronic rhinosinusitis. We also highlight the potential molecular therapeutic targets for managing and treating chronic rhinosinusitis.
... CRSwNP is also referred to as polyposis nasi et sinuum and is asso-ciated with endoscopic and/or radiologic evidence of polypoid hyperplastic tissue in the nasal cavity and/or paranasal sinuses. CRSwNP is an immunologically triggered chronic inflammatory disease of the mucosa and subepithelial tissues for which specific endotype-based immunologic therapies have been developed only in the last decade [4,
13,
14,15,16], whereas immunotherapies [17,18,19,20,21] or avoidance measures [22,23] for exogenous allergic nasal mucosal diseases have been a therapeutic standard for a long time. ...
Epithelial immune regulation of inflammatory airway diseases: Chronic rhinosinusitis with nasal polyps (CRSwNP)
Ludger Klimek
Jan Hagemann
Hans-Jürgen Welkoborsky
Mandy Cuevas
| https://www.researchgate.net/figure/of-nasal-polyposis-pathophysiology-and-monoclonal-antibody-targets_fig2_333010488 |
1971 Dodge Challenger Convertible specifications, technical data, performance
1971 Dodge Challenger Convertible - full technical specs sheet, including performance data, economy and emissions, dimensions, weight and engine particulars.
Dodge Challenger Convertible , 1971 MY JH27
Challenger
The Dodge Challenger Convertible is a 2 door convertible/cabriolet-bodied automobile with a front located engine powering the rear wheels.
Its 6.3 litre engine is a naturally aspirated, overhead valve, 8 cylinder that develops 300 bhp (304 PS/224 kW) of power at 4800 rpm, and maximum torque of 556 N·m (410 lb·ft/56.7 kgm) at 3400 rpm.
A 3 speed manual 'box supplies the power to the driven wheels. Full specs
Key facts
What body style? 2 door convertible/cabriolet with 2+2 seats How long? 4859 mm What drivetrain? naturally aspirated petrol What size engine? 6.3 litre, 6292 cm 3 How many cylinders? 8, V How much power? 304 PS / 300 bhp / 224 kW @ 4800 rpm How much torque? 556 Nm / 410 ft.lb / 56.7 kgm @ 3400 rpm
1971 Dodge Challenger Convertible
1971 Dodge Challenger Convertible Language Français Deutsch Nederlands Italiano Español English Carrosserie Carrosserie 2+2 seater convertible/cabriolet Nombre de portes 2 Designer Dimensions et poids Empattement 2794 110 Voies AV 1516 59.7 Voies AR 1565 61.6 Longueur 4859 191.3 Largeur 1887 74.3 Hauteur 1293 50.9 Garde au sol 1.74 Poids avec pleins Répartition poids AV Réservoir à essence 68.2 litres 15 [18] UK [US] gal. Caractéristiques aérodynamique Coefficient de pénétration maître-couple SCx naturally aspirated petrol Constructeur du moteur Dodge Type moteur Cylinders V 8 in 90° vee Cylindrée 6.3 litre 6292 cc (383.961 cu in ) Alésage × Course 108 × 85.85 mm 4.25 × 3.38 in Rapport alésage / course 1.26 Distribution overhead valve (OHV) 2 Soupapes par cylindre 16 Total vannes Puissance maximale (gross) 304 PS (300 bhp ) (224 kW ) à 4800 tr/mn Couple maximale (gross) 556 Nm (410 ft·lb ) (56.7 kgm ) à 3400 tr/mn Specific output (gross) 35.6 kW/litre 48.3 ps/litre 47.7 bhp/litre 0.78 bhp/cu in (gross) 88.37 Nm/litre 1.07 ft·lb/cu 3 Construction carter Carter humide Taux de compression 8.5:1 Carburant 1 carburettor bmep (brake mean effective pressure) 1110.4 kPa (161.1 psi ) Régime maximal Nombre de paliers de vilebrequin 5 Refroidissement Water Cylindrée Unitaire 786.5 cc Aspiration Normal Compressor N/A Intercooler None Catalyseur N Performances 0-80km/h 0-60mph 0-100km/h 0-160km/h 0-400m 0-1000m Vitesse Power-to-weight ratio Weight-to-power ratio Consommation Consommation universal fuel consumption (calculated from the above) litres/100km km/litre UK MPG US MPG Emissions de CO₂ Carfolio Calculated CO 2 ? VED band (UK) CO 2 Effizienz (DE) Châssis Emplacement de moteur front Engine layout longitudinal Traction rear wheel drive Répartition du couple N/A Direction turns lock-to-lock Turning circle Suspension AV Suspension AR Roues AV 5½JJ x 14 Roues AR 5½JJ x 14 Pneumatiques AV F78 x 14 Pneumatiques AR F78 x 14 Freins AV/AR Dr/Dr Diamètre des freins AV 254 mm Diamètre des freins AR 254 mm Braked area Transmission 3 Rapport de démultiplication supérieure 1 Rapport de pont 3.23 Généralités Carfolio.com ID 674806 Production total Type mines JH27 RAC rating 57.9 Insurance classification No information available Tax band No information available 1971 Dodge Challenger Convertible added 2020-06-06. Last modified 2020-06-06.
Dodge Challenger models
1972 Dodge Challenger
2 door fixed-head coupé FR 3M 3680 cm 3 /224.6 cuin 112 PS 110 bhp 82 kW 1436 kg
1972 Dodge Challenger
2 door fixed-head coupé FR 3M 5210 cm 3 /317.9 cuin 152 PS 150 bhp 112 kW 1460 kg
1972 Dodge Challenger
2 door fixed-head coupé FR 3M 5565 cm 3 /339.6 cuin 243 PS 240 bhp 179 kW
1972 Dodge Challenger Rallye
2 door fixed-head coupé FR 3M 5210 cm 3 /317.9 cuin 152 PS 150 bhp 112 kW 1506 kg
1972 Dodge Challenger Rallye
2 door fixed-head coupé FR 3M 5565 cm 3 /339.6 cuin 243 PS 240 bhp 179 kW 1567 kg
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 4M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 4M 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 3M 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 3M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 3M 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 3A 6292 cm 3 /384.0 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger JL21
2 door fixed-head coupé FR 4M 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Automatic JL21
2 door fixed-head coupé FR 3A 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Automatic JL21
2 door fixed-head coupé FR 3A 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Automatic JL21
2 door fixed-head coupé FR 3A 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger Convertible JH27
2 door convertible/cabriolet FR 3A 6292 cm 3 /384.0 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Convertible JH27
2 door convertible/cabriolet FR 4M 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Convertible JH27
2 door convertible/cabriolet FR 3M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Convertible JH27
2 door convertible/cabriolet FR 3M 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger Convertible JH27
2 door convertible/cabriolet FR 4M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Convertible Automatic JH27
2 door convertible/cabriolet FR 3A 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Convertible Automatic JH27
2 door convertible/cabriolet FR 3A 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Convertible Automatic JH27
2 door convertible/cabriolet FR 3A 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 3M 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 4M 6292 cm 3 /384.0 cuin 304 PS 300 bhp 224 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 3A 6292 cm 3 /384.0 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 3M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 4M 5565 cm 3 /339.6 cuin 279 PS 275 bhp 205 kW
1971 Dodge Challenger Hardtop JH23
2 door fixed-head coupé FR 3M 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1971 Dodge Challenger Hardtop Automatic JH23
2 door fixed-head coupé FR 3A 5210 cm 3 /317.9 cuin 233 PS 230 bhp 172 kW
1970 AMC Javelin SST Automatic 7070 7079-7
2 door fixed-head coupé FR 3A 5894 cm 3 /359.7 cuin 294 PS 290 bhp 216 kW
1970 AMC Rebel Hardtop 7010 7019-0
2 door sedan/saloon FR 3A 5894 cm 3 /359.7 cuin 294 PS 290 bhp 216 kW
1970 AMC Rebel SST Hardtop 7010 7019-7
2 door sedan/saloon FR 3A 5894 cm 3 /359.7 cuin 294 PS 290 bhp 216 kW
1970 Chevrolet Camaro 12487
2 door fixed-head coupé FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1504 kg
1969 Chevrolet Camaro Convertible SS 350 12300-12400 12467
2 door convertible/cabriolet FR 3M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro Convertible SS 350 12300-12400 12467
2 door convertible/cabriolet FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro Convertible SS 350 Powerglide 12300-12400 12467
2 door convertible/cabriolet FR 2A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro Convertible SS 350 Turbo Hydra-Matic 12300-12400 12467
2 door convertible/cabriolet FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro SS 350 12300-12400 12437
1969 Chevrolet Camaro SS 350 12300-12400 12437
2 door fixed-head coupé FR 3M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro SS 350 Powerglide 12300-12400 12437
2 door fixed-head coupé FR 2A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Camaro SS 350 Turbo Hydra-Matic 12300-12400 12437
2 door fixed-head coupé FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1970 Chevrolet Camaro Turbo Hydra-Matic 12487
2 door fixed-head coupé FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1515 kg
1969 Chevrolet Chevelle 300 Deluxe Coupé 13300-13400 13427
2 door fixed-head coupé FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Coupé 13300-13400 13427
2 door fixed-head coupé FR 3M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Coupé Powerglide 13300-13400 13427
2 door fixed-head coupé FR 2A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Coupé Turbo Hydra-Matic 13300-13400 13427
2 door fixed-head coupé FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Sport Coupé 13300-13400 13437
2 door fixed-head coupé FR 3M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Sport Coupé 13300-13400 13437
2 door fixed-head coupé FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Sport Coupé Powerglide 13300-13400 13437
2 door fixed-head coupé FR 2A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Chevrolet Chevelle 300 Deluxe Sport Coupé Turbo Hydra-Matic 13300-13400 13437
2 door fixed-head coupé FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1971 Chevrolet Chevelle Malibu Convertible SS454 13667
2 door convertible/cabriolet FR 4M 7446 cm 3 /454.4 cuin 289 PS 285 bhp 213 kW 1692 kg
1971 Chevrolet Chevelle Malibu Convertible SS454 Automatic 13667
1971 Chevrolet Chevelle Malibu Sport Coupé SS454 13637
2 door fixed-head coupé FR 4M 7446 cm 3 /454.4 cuin 289 PS 285 bhp 213 kW 1670 kg
1971 Chevrolet Chevelle Malibu Sport Coupé SS454 Automatic 13637
2 door fixed-head coupé FR 3A 7446 cm 3 /454.4 cuin 289 PS 285 bhp 213 kW 1694 kg
1970 Chevrolet Chevelle Sport Coupé 13437
2 door fixed-head coupé FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1553 kg
1970 Chevrolet Chevelle Sport Coupé Powerglide 13437
2 door fixed-head coupé FR 2A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1549 kg
1970 Chevrolet Chevelle Sport Coupé Turbo Hydra-Matic 13437
2 door fixed-head coupé FR 3A 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1562 kg
1970 Chevrolet Malibu Convertible 13667
2 door convertible/cabriolet FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW 1592 kg
1970 Chevrolet Malibu Convertible Powerglide 13667
1969 Ford Mustang Hardtop 65A
1970 Ford Mustang Hardtop
1969 Ford Mustang Hardtop 65A
1971 Ford Mustang Hardtop 351
1971 Ford Mustang Hardtop 351 Automatic
1970 Ford Mustang Hardtop Automatic
1969 Ford Mustang Hardtop Automatic 65A
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Ford Mustang Mach 1 63C
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Ford Mustang Mach 1 63C
2 door fixed-head coupé FR 3M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1970 Ford Mustang Mach 1 351
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW
1970 Ford Mustang Mach 1 351
2 door fixed-head coupé FR 3M 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW
1970 Ford Mustang Mach 1 351 Automatic
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW
1969 Ford Mustang Mach 1 Automatic
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW 1620 kg
1970 Ford Mustang Sportsroof
1970 Ford Mustang Sportsroof
2 door fixed-head coupé FR 3M 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW 1610 kg
1969 Ford Mustang SportsRoof 63A
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Ford Mustang SportsRoof 63A
2 door fixed-head coupé FR 3M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1970 Ford Mustang Sportsroof Automatic
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW
1969 Ford Mustang SportsRoof Automatic 63A
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Ford Torino Hardtop
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Ford Torino Hardtop
1969 Ford Torino Hardtop Automatic
1969 Holden Monaro GTS 350 HT
2 door fixed-head coupé FR 4M 5733 cm 3 /349.8 cuin 304 PS 300 bhp 224 kW
1969 Iso Lele
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 304 PS 300 bhp 224 kW 1380 kg
1971 Jensen Interceptor FF Mk III
2 door fixed-head coupé FA 3A 6286 cm 3 /383.6 cuin 304 PS 300 bhp 224 kW 1973 kg
1971 Jensen Interceptor Mk III
2 door fixed-head coupé FR 3A 6286 cm 3 /383.6 cuin 304 PS 300 bhp 224 kW 1814 kg
1972 Jensen Interceptor Mk III S4
2 door fixed-head coupé FR 3A 7206 cm 3 /439.7 cuin 288 PS 284 bhp 212 kW 1814 kg
1973 Maserati Indy 4.9 AM116/A49
2 door fixed-head coupé FR 5M 4930 cm 3 /300.8 cuin 320 PS 315.5 bhp 235 kW 1680 kg
1973 Maserati Indy Automatic AM116/A49
2 door fixed-head coupé FR 3A 4931 cm 3 /300.9 cuin 320 PS 316 bhp 236 kW
1969 Mercury Cougar Convertible
2 door convertible/cabriolet FR 3M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Mercury Cougar Convertible
2 door convertible/cabriolet FR 4M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Mercury Cougar Convertible Automatic
2 door convertible/cabriolet FR 3A 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Mercury Cougar Hardtop
2 door fixed-head coupé FR 3M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Mercury Cougar Hardtop
2 door fixed-head coupé FR 4M 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Mercury Cougar Hardtop Automatic
2 door fixed-head coupé FR 3A 5766 cm 3 /351.9 cuin 294 PS 290 bhp 216 kW
1969 Oldsmobile Cutlass S Convertible 350 V8 HC 33600
2 door convertible/cabriolet FR 3M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Convertible 350 V8 HC 33600 3667
2 door convertible/cabriolet FR 4M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Convertible 350 V8 HC Automatic 33600 3667
2 door convertible/cabriolet FR 3A 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Holiday Coupé 350 V8 HC 33600 3687
2 door fixed-head coupé FR 3M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Holiday Coupé 350 V8 HC 33600 3687
2 door fixed-head coupé FR 4M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Holiday Coupé 350 V8 HC Automatic 33600 3687
2 door fixed-head coupé FR 3A 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Sports Coupé 350 V8 HC 33600 3677
2 door fixed-head coupé FR 4M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Sports Coupé 350 V8 HC 33600 3677
2 door fixed-head coupé FR 3M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile Cutlass S Sports Coupé 350 V8 HC Automatic 33600 3677
2 door fixed-head coupé FR 3A 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile F-85 Sports Coupé 33200 3277
2 door fixed-head coupé FR 4M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile F-85 Sports Coupé 33200 3277
2 door fixed-head coupé FR 3M 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1969 Oldsmobile F-85 Sports Coupé 33200 3277
2 door fixed-head coupé FR 3A 5737 cm 3 /350.1 cuin 314 PS 310 bhp 231 kW
1970 Plymouth AAR 'Cuda FB2 BS23
2 door fixed-head coupé FR 4M 5563 cm 3 /339.5 cuin 294 PS 290 bhp 216 kW 1594 kg
| https://www.carfolio.com/dodge-challenger-convertible-674806?l=fr |
IJMS | Free Full-Text | Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO2
We have prepared four new Cu(II) complexes containing valine moieties with imidazole ligands at the fourth coordination sites and examined their photo-induced reactions with TiO2 in order of understanding the reaction mechanisms. Under a nitrogen atmosphere, the intermolecular electron transfer reactions (essentially supramolecular interactions) of these systems, which resulted in the reduction of Cu(II) species to Cu(I) ones, occurred after UV light irradiation. In this study, we have investigated the conditions of the redox reactions in view of substituent effects of aldehyde moieties. The results of cyclic voltammetry (CV) on an rotating ring-disk electrode (RRDE) suggested that the substitution effects and redox potentials were correlated. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were also performed to simulate the UV–Vis and circular dichroism (CD) spectra; the results revealed a reasonably good correlation between the substituent effects and the highest occupied molecular orbitals and the lowest unoccupied molecular orbitals (HOMO-LUMO) gaps associated with the most intense transition bands. In addition, we summarized the substitution effects of Cu(II) complexes for their corresponding UV light-induced reactions.
Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO 2
by Yuki Takeshita , Kazuya Takakura and Takashiro Akitsu *
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2015 , 16 (2), 3955-3969; https://doi.org/10.3390/ijms16023955
Received: 15 January 2015 / Revised: 27 January 2015 / Accepted: 5 February 2015 / Published: 12 February 2015
Abstract
:
We have prepared four new Cu(II) complexes containing valine moieties with imidazole ligands at the fourth coordination sites and examined their photo-induced reactions with TiO
2
in order of understanding the reaction mechanisms. Under a nitrogen atmosphere, the intermolecular electron transfer reactions (essentially
supramolecular interactions
) of these systems, which resulted in the reduction of Cu(II) species to Cu(I) ones, occurred after UV light irradiation. In this study, we have investigated the conditions of the redox reactions in view of substituent effects of aldehyde moieties. The results of cyclic voltammetry (CV) on an rotating ring-disk electrode (RRDE) suggested that the substitution effects and redox potentials were correlated. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were also performed to simulate the UV–Vis and circular dichroism (CD) spectra; the results revealed a reasonably good correlation between the substituent effects and the highest occupied molecular orbitals and the lowest unoccupied molecular orbitals (HOMO-LUMO) gaps associated with the most intense transition bands. In addition, we summarized the substitution effects of Cu(II) complexes for their corresponding UV light-induced reactions.
Keywords:
Schiff base complexes
;
copper(II) complexes
;
UV–Vis spectra
;
TD-DFT
;
TiO 2
Inorganic nanoparticles such as TiO 2 have been used in cosmetics for a long time because their optical absorption and scattering of UV light are remarkable. By controlling the nanoparticle size, it is typically possible to control the wavelength of light absorption and emission for many nanomaterials such as CdSe. Basic materials studies have been widely carried out in the field of cosmetology to search for materials and/or conditions to reduce UV light damage to the skin. Previous studies on inorganic oxides have mainly focused on chemical stability, UV absorption, and the uniform synthesis of nanoparticles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].
Conversely, the absorption properties of metal complexes employed as UV light absorption agents to prevent UV damage can be easily controlled compared to their conventional organic counterparts. Indeed, organic dyes are not expected to absorb a wide wavelength range of UV light. In addition, biological and medical problems related to UV light, such as compatibility and incompatibility with proteins (polypeptide or amino acids), toxicity to the human body, and chemical stability of biological molecules like nucleic acids responsible for genetic information may also be important.
To take advantage of these inorganic nanoparticles and metal complexes such as UV absorbers, it is possible to control their absorption wavelengths and strongly absorbed UV light to react with TiO
2
by compositing the metal complexes. And it can also be a dye. Therefore it is possible to develop UV protection dye complexes to improve conventional sunscreen material.
In this manner, we have previously reported that some copper(II) complexes, especially Schiff base complexes with l -amino acid moieties, showed photo-induced electron transfer reactions with TiO 2 after UV light irradiation [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Although limited spectral and electrochemical data could be obtained, the optimal reaction conditions along with the tuning of redox properties by molecular design are not yet fully understood. Herein, we prepared four new related Cu(II) complexes containing valine moieties ( Figure 1 ) with imidazole ligands at the fourth coordination sites and examined their photo-induced reactions with TiO 2 to understand their reaction mechanism.
Figure 1. Molecular structures of Cu(II) complexes ( 1 – 4 ). Crystalline solvents (water molecules) are omitted for clarity.
Figure 1. Molecular structures of Cu(II) complexes ( 1 – 4 ). Crystalline solvents (water molecules) are omitted for clarity.
2. Results and Discussion
2.1. Crystal Structures
The molecular structures of 1 , 2 , and 4 are depicted in Figure 2 , Figure 3 and Figure 4 , respectively. These compounds display slightly distorted square planar coordination geometries with umbrella conformations.
Figure 2. Crystal structure of 1 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Figure 2. Crystal structure of 1 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Figure 3. Crystal structures of 2 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Figure 3. Crystal structures of 2 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Figure 4. Crystal structures of 4 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Figure 4. Crystal structures of 4 with selected atoms labeled. Hydrogen atoms are omitted for clarity.
Selected bond distances (Å) and bond or torsion angles (°) for
1
are as follows: Cu1–O1 = 1.9167 (14), Cu1–O2 = 1.9755 (14), Cu1–N1 = 1.9585 (18), Cu1–N2 = 1.9244 (17), O1–Cu1–O2 = 171.27 (7), O1–Cu1–N1 = 91.61 (7), O1–Cu1–N2 = 94.11 (7), N1–Cu1–N2 = 172.37 (7).
Selected bond distances (Å) and bond or torsion angles (°) for
2
are as follows: Cu1–O1 = 1.916 (2), Cu1–O2 = 1.9705 (19), Cu1–N1 = 1.931 (2), Cu1–N2 = 1.958 (2), O1–Cu1–O2 = 170.94 (9), O1–Cu1–N1 = 94.00 (8), O1–Cu1–N2 = 91.61 (9), N1–Cu1–N2 = 172.65 (10).
Selected bond distances (Å) and bond or torsion angles (°) for
4
are as follows: Cu1–O1 = 1.919 (3), Cu–O2 = 1.981 (3), Cu1–N1 = 1.932 (3), Cu1–N2 = 1.959 (3), O1–Cu1–O2 = 172.29 (13), O1–Cu1–N1 = 93.56 (12), O1–Cu1–N2 = 92.23 (13), N1–Cu1–N2 = 171.46 (13).
Most of these values are within the normal ranges expected for the analogous Schiff base Cu(II) complexes [ 18 , 19 ]. The molecular packing in the solid state is essentially formed by weak van der Waals forces.
2.2. UV–Vis and CD Spectra
Figure 5 depicts the UV–Vis and CD spectra of 1 – 4 for systematic comparison and discussion. All spectra predominantly exhibited intraligand π–π* and n–π* bands around 260–390 nm and relatively weak d–d bands around 500 nm due to the d 9 electronic configuration of Cu(II) complexes. The assignment of the bands [ 20 ] in the experimental spectra is qualitatively in agreement with and supported by the computational results (see Section 2.4. ). The electron-withdrawing halogen and methoxy substituent groups resulted in remarkable shifts in the UV–Vis peaks observed at 382 nm for 2 , 384 nm for 3 , and 400 nm for 4 .
Figure 5. UV–Vis ( top ) and CD ( bottom ) spectra of 1 – 4 solutions in methanol.
Figure 5. UV–Vis ( top ) and CD ( bottom ) spectra of 1 – 4 solutions in methanol.
2.3. Redox Potential
All complexes exhibited electrochemically reversible redox behavior based on the differences between the anode and cathode potentials. The CV results revealed that the redox potentials were E = 0.078, 0.014, 0.011, and −0.001 V for 1 , 2 , 3 , and 4 , respectively; among them, only 4 exhibited a negative redox potential ( E ). The four-coordinate valine derivative complexes in this study exhibited the same redox potential tendency (the order of E as –H > –Br > –OMe) as the analogous six-coordinated arginine derivative-Schiff base Cu(II) complexes (the order of E was also –H > –Br > –OMe) [ 21 ]. As known for highly electron-donating methoxy groups, the low E of 4 tends to stabilize the Cu(II) oxidation state.
2.4. Computational Results
Figure 6 , Figure 7 , Figure 8 , and Figure 9 show the UV–Vis and CD spectra for 1 – 4 simulated by Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations (whose 6-311+G(d,p) basis set provided similar results with ZINDO (Zerner’s Intermediate Neglect of Differential Overlap). The exchange-correlation function ωB97XD [ 22 ] was used, which included the long-range correction. The basis set used was 6-31+G(d,p), similar to general procedures. Considerable red shifts of the π–π* bands were observed for the simulated spectra of 1 – 4 , which may be attributed to the stabilization of the levels of the excited states by the polar methanol solvent. However, the band assignment was qualitatively reliable for all complexes.
Figure 6. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 1 calculated by TD-DFT and determined experimentally for comparison.
Figure 6. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 1 calculated by TD-DFT and determined experimentally for comparison.
Figure 7. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 2 calculated by TD-DFT and determined experimentally for comparison.
Figure 7. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 2 calculated by TD-DFT and determined experimentally for comparison.
Figure 8. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 3 calculated by TD-DFT and determined experimentally for comparison.
Figure 8. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 3 calculated by TD-DFT and determined experimentally for comparison.
Figure 9. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 4 calculated by TD-DFT and determined experimentally for comparison.
Figure 9. UV–Vis spectra ( top ) and CD spectra ( bottom ) of 4 calculated by TD-DFT and determined experimentally for comparison.
2.5. UV Light-Induced Reactions
The UV–Vis spectra of the solutions of Cu(II) complexes ( 1 – 4 ) dissolved in methanol exhibited only slight changes after UV light irradiation, similar to those of the analogous four-coordinated [ 20 ] and six-coordinated [ 21 , 23 ] Cu(II) complexes. Conversely, UV light-induced reactions could be induced in the presence of TiO 2 microparticles ( Figure 10 , Figure 11 , and Figure 12 ). Decreases in the intensities of the d–d bands around 600 nm suggested the reduction of d 9 Cu(II) species ( 1 – 3 ) into d 10 Cu(I) ones (the latter potentially incur charge transfer transitions by absorbing UV light). However, few spectral changes in the d–d bands are observed for Figure 13 ; this is due to negative E value of 4 , which causes it to react differently than the complexes with positive E values. Therefore, it is possible to control the reduction reactivity of the Cu(II) complexes by slight chemical modification of the ligands. Moreover, for the first time, the absorption intensities of the Cu(II) complexes around 360 nm (π–π* bands) were observed to decrease in suspensions of TiO 2 particles; this may be ascribed to electron transfer reactions, which absorb extra UV light.
Figure 10. The UV–Vis spectral changes of 1 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 10. The UV–Vis spectral changes of 1 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 11. The UV–Vis spectral changes of 2 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 11. The UV–Vis spectral changes of 2 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 12. The UV–Vis spectral changes of 3 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 12. The UV–Vis spectral changes of 3 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 13. The UV–Vis spectral changes of 4 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
Figure 13. The UV–Vis spectral changes of 4 in the presence of TiO 2 microparticles subjected to UV irradiation every 10 min.
3. Experimental Section
3.1. General Procedures
Chemicals of the highest commercial grade available were purchased from Aldrich (St. Louis, MO, USA), Wako (Osaka, Japan), and TCI (Tokyo, Japan) and used as received without further purification.
3.2. Preparations
3.2.1. Preparation of 1
After reacting a methanol solution (50 mL) of l -valine (0.12 g, 1.0 mmol) and salicylaldehyde (0.12 g, 1.0 mmol) for 3 h at 333 K, Cu(CH 3 COO) 2 (0.18 g, 1.0 mmol) was added. A solution of imidazole (0.13 g, 1.0 mmol) in methanol was then added and stirred for 2 h to yield a green precipitate by evaporation and filtration. The resulting crude compound was filtered and purified by recrystallization in methanol.
Yield 50.5%. Anal. Calc. for C 15 H 17 CuN 3 O 3 : C, 51.50; H, 4.61; N, 12.01%. Found: C, 51.35; H, 4.88; N, 11.98%. IR (infrared) (KBr, cm −1 ): 544 s, 626 w, 656 s, 738 m, 761 m, 852 m, 956 w, 1071 m, 1101 w, 1149 m, 1240 w, 1283 w, 1324 m, 1378 m, 1407 w, 1448 s, 1533 w, 1589 s, 1635 s (C=N), 2868 w, 2953 w, 3029 w, 3114 w, 3459 w. UV–Vis (diffuse reflectance): 606 nm (d–d), 354 nm (π–π*). ESR (electron spin resonance) (X-band, 1 mM methanol, 77 K): g = 2.007.
3.2.2. Preparation of 2
After reacting a methanol solution (50 mL) of l -valine (0.12 g, 1.0 mmol) and 5-chlorosalicylaldehyde (0.16 g, 1.0 mmol) for 3 h at 333 K, Cu(CH 3 COO) 2 (0.18 g, 1.0 mmol) was added. A solution of imidazole (0.13 g, 1.0 mmol) in methanol was added and stirred for 2 h to yield a green precipitate by evaporation and filtration. The resulting crude compound was filtered and purified by recrystallization in methanol.
Yield 55.5%. Anal. Calc. for C 15 H 16 ClCuN 3 O 3 : C, 46.93; H, 4.07; N, 10.82%. Found: C, 46.76; H, 4.19; N, 11.03%. IR (KBr, cm −1 ): 555 s, 623 w, 657 s, 804 m, 826 s, 953 w, 1071 m, 1169 m, 1240 w, 1280 w, 1315 m, 1378 m, 1454 s, 1542 w, 1590 s, 1633 s (C=N), 2870 w, 2960 w, 3145 w, 3427 w. UV–Vis (diffuse reflectance): 608 nm (d–d), 354 nm (π–π*). ESR (X-band, 1 mM methanol, 77 K): g = 2.034.
3.2.3. Preparation of 3
After reacting a methanol solution (50 mL) of l -valine (0.12 g, 1.0 mmol) and 5-bromosalicylaldehyde (0.20 g, 1.0 mmol) for 3 h at 333 K, Cu(CH 3 COO) 2 (0.18 g, 1.0 mmol) was added. A solution of imidazole (0.13 g, 1.0 mmol) in methanol was added and stirred for 2 h to yield a green precipitate by evaporation and filtration. The resulting crude compound was filtered and purified by recrystallization in methanol.
Yield 42.2%. Anal. Calc. for C 15 H 16 BrCuN 3 O 3 : C, 41.92; H, 3.75; N, 9.78%. Found: C, 41.99; H, 3.44; N, 9.05%. IR (KBr, cm −1 ): 550 s, 623 w, 656 s, 814 m, 826 s, 953 w, 1070 m, 1166 m, 1232 w, 1275w, 1312 m, 1371 m, 1453 s, 1540 w, 1589 s, 1633 s (C=N), 2863 w, 2958 w, 3149 w, 3430 w. UV–Vis (diffuse reflectance) 609 nm (d–d), 354 nm (π–π*). ESR (X-band, 1 mM methanol, 77 K): g = 2.028.
3.2.4. Preparation of 4
After reacting a methanol solution (50 mL) of l -valine (0.12 g, 1.0 mmol) and 2-hydroxy-5-metoxybenzaldehyde (0.15 g, 1.0 mmol) for 3 h at 333 K, Cu(CH 3 COO) 2 (0.18 g, 1 mmol) was added. A solution of imidazole (0.13 g, 1.0 mmol) in methanol was added and stirred for 2 h to yield a green precipitate by evaporation and filtration. The resulting crude compound was filtered and purified by recrystallization in methanol.
Yield 44.8%. Anal. Calc. for C 16 H 19 CuN 3 O 4 : C, 50.45; H, 5.03; N, 11.03%. Found: C, 50.56; H, 4.88; N, 10.92%. IR (KBr, cm −1 ): 545 , 621 w, 650 s, 745 m, 776 m, 853 m, 956 w, 1070 m, 1101 w, 1155 m, 1278 w, 1289 w, 1320 m, 1390 m, 1405 w, 1450 s, 1523 w, 1590 s, 1632 s (C=N), 2890 w, 2952 w, 3021 w, 3110 w, 3470w. UV–Vis (diffuse reflectance): 612 nm (d–d), 358 nm (π–π*). ESR (X-band, 1 mM methanol, 77 K): g = 2.033.
3.3. Physical Measurements
Elemental analyses (C, H, N) were carried out with a Perkin-Elmer 2400II CHNS/O analyzer (Foster City, CA, USA) at Tokyo University of Science. Infrared spectra were recorded on a JASCO FT-IR 4200 plus spectrophotometer (JASCO Corporation, Tokyo, Japan) using KBr pellets in the range of 4000–400 cm
−1
at 298 K. Absorption electronic spectra were measured on a JASCO V-570 spectrophotometer in the range of 900–200 nm at 298 K. Circular dichroism (CD) spectra were measured on a JASCO J-725 spectropolarimeter in the range of 900–200 nm at 298 K. X-band ESR spectra were measured with a JEOL JES-FA200 spectrometer (JEOL, Tokyo, Japan) at 77 K. Spectroelectrochemical measurements were carried out on BAS SEC2000-UV/CVIS and ALS2323 systems (BAS, Tokyo, Japan) with Ag/AgCl electrodes in aqueous solutions. Cyclic voltammetry (CV) measured with RRDE electrodes as Nafion films of ethanol solution of the complexes. The UV and visible light sources were Hayashi LA-310UV and LA-251Xe (Hayashi Watch Works, Tokyo, Japan), respectively, with visible (λ > 350 nm) and UV (λ < 350 nm) cut filters, respectively.
3.4. X-ray Crystallography
Deep-greenish prismatic single crystals of
1
,
2
, and
4
were glued on top of a glass fiber and coated with a thin layer of epoxy resin to measure the diffraction data. Intensity data were collected on a Bruker APEX2 CCD diffractometer with graphite monochromated Mo Kα radiation (λ = 0.71073 Å). Data analysis was carried out using the SAINT program package [
24
]. The structures were solved by direct methods with SHELXS-97 [
25
], expanded by Fourier techniques, and refined by full-matrix least-squares methods based on
F
2
using the program SHELXL-97. An empirical absorption correction was applied by the program SADABS [
26
]. All non-hydrogen atoms were readily located and refined by anisotropic thermal parameters. All hydrogen atoms were located at geometrically calculated positions and refined using riding models. Unfortunately, single crystals of
3
could not be obtained.
3.4.1. Crystallographic Data for 1
C 15 H 17 CuN 3 O 3 , crystal size 0.28 mm × 0.21 mm × 0.19 mm, M w = 350.86, tetragonal, space group P 2 1 (#4), a = 5.3136(7) Å, b = 8.8313(11) Å, c = 16.190(2) Å, V = 759.70(17) Å 3 , Z = 2, D calc = 1.534 mg/m 3 , F (000) = 394, R 1 = 0.0221, wR 2 = 0.0530 (3514 reflections), S = 0.625, Flack parameter = 0.020(10) (where R 1 = ∑ || F o | − | F c ||/∑ |F o |, R w = (∑ w (| F o | − | F c |) 2 /∑ w | F o | 2 ) 1/2 , w = 1/(σ 2 ( F o ) + (0.1 P ) 2 ), P = ( F o2 + 2 F c2 )/3).
3.4.2. Crystallographic Data for 2
C 15 H 16 ClCuN 3 O 3 , crystal size 0.14 mm × 0.13 mm × 0.09 mm, M w = 385.30, tetragonal, space group P 2 1 2 1 2 1 (# 19 ) , a = 5.2964(16) Å, b = 8.759(3) Å, c = 34.915(10) Å, V = 1619.8(8) Å 3 , Z = 4, D calc = 1.580 mg/m 3 , F(000) = 788, R 1 = 0.0292, wR 2 = 0.0909 (3287 reflections), S = 0.625, Flack parameter = 0.028(13). (where R 1 = ∑ || F o | − | F c ||/∑ |F o |, R w = (∑ w (| F o | − |F c |) 2 /∑ w | F o | 2 ) 1/2 , w = 1/(σ 2 ( F o ) + (0.1 P ) 2 ), P = ( F o2 + 2 F c2 )/3).
3.4.3. Crystallographic Data for 4
C 16 H 19 CuN 3 O 4 , crystal size 0.18 mm × 0.15 mm × 0.12 mm, M w = 380.88, tetragonal, space group P 2 1 (#4), a = 5.3748(5) Å, b = 8.8801(9) Å, c = 17.2714(17) Å, V = 824.34(14) Å 3 , Z = 2, D calc = 1.350 mg/m 3 , F (000) = 394, R 1 = 0.0271, wR 2 = 0.0745 (4626 reflections), S = 0.625, Flack parameter = 0.006(7) (where R 1 = ∑ || F o | − | F c ||/∑ | F o |, R w = (∑ w (| F o | − | F c |) 2 /∑ w | F o | 2 ) 1/2 , w = 1/(σ 2 ( F o ) + (0.1 P ) 2 ), P = ( F o2 + 2 F c2 )/3).
3.5. Computational Methods
All calculations were performed using the Gaussian 09W software Revision D.01 (Gaussian, Inc., Wallingford, CT, USA) [ 27 ]. The vertical excitation energy was calculated using the TD-DFT method based on the singlet ground state geometry. The exchange functional, the correlation functional, and the basis set were ωB97XD/6-31+G(d,p). With the exception of 3 , crystal structure data were used as the initial structures.
4. Conclusions
We have synthesized
1
–
4
and investigated their photo-induced reactions with TiO
2
. The Cu(II) complexes alone showed no changes after UV light irradiation. However, composite systems (Cu(II) complexes + TiO
2
) showed characteristic intermolecular electron transfer reactions that depended on the ligands.
Composite systems containing
1
,
2
, and
3
showed decreases in d–d and π–π* band intensities, while the composite system of
4
only exhibited a decrease in the π–π* band intensity (no change in the d–d band). The CV and redox potential results were in accordance with the decreases in the absorption intensities of the d–d bands. Only
4
exhibited a negative redox potential, and the intensity of its d–d band decreased less than those of
1
,
2
, and
3
, which exhibited positive redox potentials. Complex
4
contains a methoxy group, which acts as a strong electron-donating agent; therefore,
4
tends to stabilize the Cu(II) state. This lowers the redox potential, suppressing the decrease in the intensity of the d–d band.
We have found that combining TiO
2
and suitable metal complexes results in the occurrence of electron transfer reactions, which absorb extra UV light. Moreover, as demonstrated by the negative redox potential of the composite of
4
, photo-induced electron transfer can be controlled by the structures of Cu(II) complexes. Therefore, by taking advantage of molecular design, more functional applications (UV-color change and stable chemical species) of metal complexes can be expected.
Supplementary Information
CCDC 1036495, 1036496, and 1036495 contain the supplementary crystallographic data for 1 , 2 , and 4 , respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html , or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (+44) 1223-336-033; or E-Mail: [email protected] .
Acknowledgments
This work was partly supported by The Cosmetology Research Foundation. This work was performed under the Cooperative Research Program of the “Network Joint Research Centre for Materials and Devices”. The computation was mainly carried out using the computer facilities at the Research Institute for Information Technology, Kyushu University.
Author Contributions
Yuki Takeshita (experiments); Kazuya Takakura (calculations); Takashiro Akitsu (editing paper, idea).
Conflicts of Interest
The authors declare no conflict of interest.
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MDPI and ACS Style
Takeshita, Y.; Takakura, K.; Akitsu, T. Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO 2. Int. J. Mol. Sci. 2015, 16, 3955-3969.
https://doi.org/10.3390/ijms16023955
AMA Style
Takeshita Y, Takakura K, Akitsu T. Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO 2. International Journal of Molecular Sciences. 2015; 16(2):3955-3969.
https://doi.org/10.3390/ijms16023955
Chicago/Turabian Style
Takeshita, Yuki, Kazuya Takakura, and Takashiro Akitsu. 2015. "Multifunctional Composites of Chiral Valine Derivative Schiff Base Cu(II) Complexes and TiO 2" International Journal of Molecular Sciences16, no. 2: 3955-3969.
https://doi.org/10.3390/ijms16023955
| https://www.mdpi.com/1422-0067/16/2/3955/xml |
Metformin improves vascular and metabolic insulin action in insulin-resistant muscle in: Journal of Endocrinology Volume 243 Issue 2 (2019)
Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.
Abstract
Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.
Keywords:insulin resistance;glucose metabolism;metformin;nutrition;muscle
Introduction
Metformin is the most common first-line oral glucose-lowering pharmacological therapy for people with type 2 diabetes (Bailey & Turner 1996,Gunton & Twigg 2003,Inzucchiet al.2015a,b). It is primarily known for its role in supressing hepatic glucose production (Bailey & Turner 1996,Hundalet al.2000). More recently, metformin has been demonstrated to promote the secretion of incretins such as glucagon-like peptide-1 (DeFronzoet al.2016,Preisset al.2017) and increase glucose disposal to skeletal muscle (Magalhaeset al.2006,Kristensenet al.2014). Thus, the actions of metformin to lower blood glucose are multifactorial and despite its clinical use for the past 60 years, the mechanisms involved are still not fully understood (Marshall 2017,Renaet al.2017).
Glucose and insulin delivery via the vasculature is important in regulating skeletal muscle glucose uptake (Barrettet al.2009,Kubotaet al.2013,Keskeet al.2016). In this regard, one of the mechanisms by which insulin increases muscle glucose disposal is through greater blood flow through capillaries in skeletal muscle to facilitate delivery of glucose and insulin to myocytes (Barrettet al.2009,Kubotaet al.2013,Keskeet al.2016). Insulin’s ability to increase microvascular blood flow in muscle is responsible for ~40% of insulin-stimulated glucose disposal by skeletal muscle using physiological relevant doses of insulin and exposure times (similar to postprandial levels) during a euglycaemic–hyperinsulinaemic clamp in both animals and humans (Vincentet al.2004,Zhanget al.2004,Egglestonet al.2013). The ingestion of a mixed meal (which stimulates endogenous insulin production) increases microvascular blood flow to a similar extent as exogenously infused insulin (Vincentet al.2006,Keskeet al.2009,Liuet al.2009,Russellet al.2018). Acute inhibition of this important physiological action of insulin with agents such as tumour necrosis factor alpha and vasoconstrictors is accompanied by a corresponding reduction in insulin-stimulated muscle glucose uptake (Rattiganet al.1999,Youdet al.2000,Clarket al.2003,Vincentet al.2003,Zhanget al.2003,Bradleyet al.2013,Premilovacet al.2018). The reliance of muscle glucose uptake and/or whole-body glucose homeostasis on appropriate microvascular blood flow responses also holds true in animal models of insulin resistance (St-Pierreet al.2010,Kubotaet al.2011,Sjoberget al.2015), human obesity (Clerket al.2006,Keskeet al.2009,Ketelet al.2011,Meijeret al.2015) and type 2 diabetes (Walliset al.2002,Russellet al.2017). Moreover, recent data strongly suggest that loss of microvascular insulin responsiveness is an early event in the pathogenesis of insulin resistance (Kubotaet al.2011,Premilovacet al.2013,2014,Zhaoet al.2015). Consequently, improving muscle microvascular flow also improves insulin-mediated skeletal muscle glucose uptake in muscle (Rattiganet al.2001,Fuet al.2013,Premilovacet al.2014,Bradleyet al.2015,Sjoberget al.2017). While insulin-stimulated microvascular blood flow is markedly impaired in insulin-resistant states (Walliset al.2002,St-Pierreet al.2010,Russellet al.2017), these deficits do not impede the ability of muscle contraction to stimulate microvascular blood flow and glucose uptake in muscle (Wheatleyet al.2004,St-Pierreet al.2012,Russellet al.2017). Therefore, microvascular blood flow in insulin-resistant skeletal muscle has the capacity to be increased, but not in response to insulin. This dichotomy suggests that the mechanisms of contraction and insulin-stimulated increases in microvascular blood flow are distinct from each other and indicate that targeting improved microvascular insulin action in skeletal muscle may be a novel mechanism for restoring skeletal muscle glucose uptake. Whether metformin impacts on muscle microvascular blood flow to decrease glucose concentrations in pre-diabetes and type 2 diabetes is not known and warrants investigation given its widespread clinical use.
Previous work has shown that metformin improves brachial artery endothelial function (flow-mediated dilation) in people with type 1 diabetes (Pitoccoet al.2013) and polycystic ovarian syndrome (Jensterleet al.2008). Metformin has also been reported to augment forearm blood flow and muscle glucose disposal in people with type 2 diabetes in response to a 75 g oral glucose load (Magalhaeset al.2006), although it is not clear whether this restores glucose disposal to values found in healthy muscle. However, it is now clear that although insulin increases total muscle blood flow, the extent of insulin-mediated glucose uptake is more closely related to increased microvascular blood flow than total blood flow (Rattiganet al.1997,Vincentet al.2004,Zhanget al.2004). To our knowledge, there are no reports of metformin’s effects on the microvasculature in skeletal muscle. Given the dependence of insulin-stimulated glucose uptake on the delivery of glucose and insulin to the myocyte (Laaksoet al.1990,Clarket al.2003,Keskeet al.2016,2017), the aim of the current study was to determine whether metformin improves skeletal muscle insulin responsiveness via augmentation of metabolic and microvascular insulin action in insulin-resistant high-fat diet-fed rats.
Materials and methods
Animal care
All procedures were approved by the University of Tasmania Animal Ethics Committee in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes – 2013, 8th Edition. Male Sprague–Dawley rats (4–5 weeks of age) were randomly assigned into two groups and provided either a normal diet (ND) (4.8% fat wt/wt.; Specialty Feeds, Glen Forest, VIC, Australia) or high-fat diet (HFD) (22% fat wt/wt.; Specialty Feeds)ad libitumfor 4 weeks. A subset of the HFD group was treated with metformin hydrochloride (HFD + MF) (LKT Laboratories Inc., St. Paul, MN, USA) during the final 2 weeks of the HFD intervention. Metformin was dissolved in drinking water, with the concentration adjusted according to rat water consumption and body weight three times per week, to achieve a dose of ~150 mg/kg/day per rat. Animals were housed at 21 ± 2°C with a 12 hour light/darkness cycle.
Surgical procedure
Rats fasted overnight (no food or metformin) and were anesthetised with an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt.). Complete surgical details are described previously (Rattiganet al.1997,St-Pierreet al.2010,Bradleyet al.2015). An ultrasonic flow probe (VB series 0.5 mm; Transonic Systems, Ithaca, NY, USA) was positioned around the femoral artery. Mean arterial blood pressure (MAP), femoral artery blood flow (FBF) and heart rate (HR) were recorded continuously using WINDAQ data acquisition software (DATAQ Instruments, Akron, OH, USA). The rats were maintained under anaesthesia by continuous infusion of pentobarbital sodium (0.6 mg/min/kg) via the jugular vein and the body temperature was maintained at 37°C using a heated pad.
Experimental protocol
The experimental protocol is shown inFig. 1. Following postsurgical stabilisation (~60 min) a 2-h infusion of either saline or insulin (10 mU/min/kg without a primed infusion; Humulin R, Eli Lilly) was administered via the jugular vein. Blood glucose concentration was monitored every 10–15 min using a glucose analyser (YSI Model 2300, Yellow Springs Instruments, OH, USA). In the experiments where rats received insulin, 30% (wt./vol.) glucose solution was co-infused at a variable rate to maintain basal blood glucose.
Figure 1
Experimental protocol. Following surgical preparation and ~60 min of equilibration, a constant infusion of saline or insulin (10 mU/min/kg) was commenced at 0 min and continued for 120 min. Glucose (30% wt./vol.) infusion, initiated shortly after the commencement of insulin infusion, was administered at a rate required to maintain euglycaemia as determined from arterial blood glucose assessment (black teardrops). At 55 min, a bolus injection of allopurinol (10 µmol/kg) was made followed by infusions of 1-methylxanthine (1-MX, 0.4 mg/min/kg) for 60 min. Constant infusions are indicated by the bars. At 75 min a bolus of 2-DG (20 µCi) was administered and radioactive plasma samples were collected at 80, 85, 90, 105 and 120 min to determine the plasma 2-DG clearance. Arterial and femoral vein samples (A-V) were taken 120 min to determine 1-MX metabolism. Calf muscles were freeze clamped and stored at −80°C at the end of the experiment for subsequent determination of muscle glucose uptake (R′g) and AKT and AMPK phosphorylation.
Citation: Journal of Endocrinology 243, 2;10.1530/JOE-19-0067
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Figure 1
Experimental protocol. Following surgical preparation and ~60 min of equilibration, a constant infusion of saline or insulin (10 mU/min/kg) was commenced at 0 min and continued for 120 min. Glucose (30% wt./vol.) infusion, initiated shortly after the commencement of insulin infusion, was administered at a rate required to maintain euglycaemia as determined from arterial blood glucose assessment (black teardrops). At 55 min, a bolus injection of allopurinol (10 µmol/kg) was made followed by infusions of 1-methylxanthine (1-MX, 0.4 mg/min/kg) for 60 min. Constant infusions are indicated by the bars. At 75 min a bolus of 2-DG (20 µCi) was administered and radioactive plasma samples were collected at 80, 85, 90, 105 and 120 min to determine the plasma 2-DG clearance. Arterial and femoral vein samples (A-V) were taken 120 min to determine 1-MX metabolism. Calf muscles were freeze clamped and stored at −80°C at the end of the experiment for subsequent determination of muscle glucose uptake (R′g) and AKT and AMPK phosphorylation.
Citation: Journal of Endocrinology 243, 2;10.1530/JOE-19-0067
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Plasma biochemistries
Fasting blood and plasma glucose concentrations were assessed using a glucose analyser (YSI, Yellow Springs Instruments). Fasting and end point plasma insulin concentrations were determined by ELISA (Mercodia, Uppsala, Sweden). Fasting plasma free fatty acid (FFA) concentrations were determined using an enzymatic assay kit (Wako Pure Chemical Industries, Osaka, Japan).
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR, index of insulin resistance) was calculated using the following formula:
Muscle microvascular blood flow
Microvascular blood flow was determined by measuring metabolism of infused 1-methylxanthine (1-MX, Sigma-Aldrich), a substrate targeted for xanthine oxidase, that is located predominantly in capillary endothelium in rat leg muscle (Jaraschet al.1986). This is a technique we have used extensively in the past to measure microvascular blood flow (Rattiganet al.1997,1999,Youdet al.2000,Clerket al.2002,Vincentet al.2003,Zhanget al.2003,2004,Wheatleyet al.2004,Walliset al.2005,St-Pierreet al.2010,2012,Premilovacet al.2013,2014). A bolus of allopurinol (10 µmol/kg, Sigma-Aldrich) was administered 5 min prior to 1-MX infusion. Allopurinol is required to partially inhibit the activity of xanthine oxidase (reduce the Kmand Vmaxof this enzyme), which enables a steady-state arterial level of 1-MX (~20 µmol/L). At the end of the experiment, arterial and hindleg venous plasma (100 µL) were collected, added to 2 M perchloric acid (20 µL) to precipitate proteins and centrifuged for 10 min. The supernatant was used to determine 1-MX concentrations by reverse phase high-performance liquid chromatography (HPLC) as previously described (Rattiganet al.1997). Microvascular blood flow expressed as 1-MX metabolism was calculated from arterio-venous plasma 1-MX difference multiplied by FBF at the end of the experiment and expressed as nmol/min.
Skeletal muscle glucose uptake
At 45 min before the completion of the experiment, a 20 µCi bolus dose of [1-14C]2-deoxy-d-glucose (2-DG) (specific activity 1.85-2.29 GBq/mmol; American Radiolabeled Chemicals, Inc., Saint Louis, MO, USA) was administered via the venous cannula. The clearance of 2-DG from the blood was determined from plasma samples (25 µL) collected at 5, 10, 15, 30 and 45 min after administration of the 2-DG bolus. At the conclusion of the experiment, the calf muscle group (soleus, plantaris, gastrocnemius) was freeze clamped and stored at −80°C. Frozen muscles were powdered under liquid nitrogen and homogenised. Free and phosphorylated 2-DG were separated using an anion exchange column (AG-1X8; Bio-Rad Laboratories). Biodegradable counting scintillant (Amersham) was added to each sample and radioactivity was measured using a scintillation counter (Tri-Carb 2800TR; Perkin Elmer). From this measurement and the specific activity of 2-DG in the plasma, muscle glucose uptake (R′g) was calculated as previously described by others (Kraegenet al.1985).
Skeletal muscle AKT and AMPK signalling
The extent of muscle Ser473AKT and Thr172AMPKα phosphorylation in all groups was assessed using Western blot. Calf muscles were ground into a fine powder under liquid nitrogen and sonicated (3 × 30 s cycles at 360 W; Bioruptor, Diagenode, Liege, Belgium) in ice-cold solubilising buffer (1:6 wt/vol). The homogenate was centrifuged at 16,500 gfor 10 min at 4°C and supernatant protein concentrations were determined using the Bio-Rad Protein Assay (Bio-Rad Laboratories). Aliquots containing 10 µg of protein were added to bolt LDS sample buffer (catalogue id: B0008; Thermo Fischer Scientific) and heat-treated at 70°C for 5 min. Following this, 20 µL of each sample was subjected to gel electrophoresis (4-12% Bis-Tris Protein Gel; catalogue id: NP0321BOX; Thermo Fischer Scientific) for 45 min at 180 volts (constant voltage). Proteins were transferred from gel to nitrocellulose membranes overnight at 30 volts (constant voltage) at 4°C. Following transfer, membranes were blocked with 70 mM Tris-buffered saline (pH 7.6), 5% non-fat dry milk powder, 0.1% Tween 20. Primary antibodies were diluted 1:1000 in blocking buffer and membranes were probed overnight at 4°C for either Ser473-AKT (catalogue id: #9272; Cell Signalling Technology) or Thr172AMPKα (catalogue id: #2535; Cell Signalling Technology). The following day, membranes were probed with a horse radish peroxidase-linked secondary antibody (1:1000; catalogue id: #7074, Cell Signalling Technology) for 60 min at room temperature. The membranes were then bathed in West Pico Chemiluminescent Substrate (Thermo Fischer Scientific) for 5 min and band intensity densities were quantified using ImageJ (National Institutes of Health). After imaging, membranes were exposed to stripping buffer (catalogue id: 46430; Thermo Fischer Scientific) for 15 min at room temperature to remove the phosphorylated antibodies. After stripping, the membranes were again blocked with 70 mM Tris-buffered saline (pH 7.6), 5% non-fat dry milk powder, 0.1% Tween 20 for 60 min. After blocking, membranes were incubated overnight at 4°C with primary antibodies for total AKT (diluted 1:1000 in blocking buffer; catalogue id: #9271 Cell Signalling Technology) or total AMPKα (diluted 1:1000 in blocking buffer; catalogue id: #2531 Cell Signalling Technology). The following day, membranes were probed with a horse radish peroxidase-linked secondary antibody (1:1000; catalogue id: #7074, Cell Signalling Technology) for 60 min at room temperature and then bathed in West Pico Chemiluminescent Substrate for 5 min. As described earlier, band intensity densities were quantified using ImageJ.
HPLC: analysis of metformin in plasma
Plasma samples at time = 0 min, prior to beginning infusion of insulin for the insulin clamps were used for HPLC. Following deproteinisation with 2 M perchloric acid and centrifugation at 10,000 g, 50 μL of un-neutralised supernatant was subjected to HPLC analysis for metformin. Details of the separation column and HPLC equipment were as used previously (Rattiganet al.1997) except that the mobile phase consisted of 75 mM ammonium dihydrogen orthophosphate (pH 5.5), 4 mM sodium heptanesulphonate and 13% v/v acetonitrile isocratic pumped at 1.5 ml/min. Metformin was identified by elution time (8.0 min) and quantified by absorbance at 233 nm.
Statistical analysis
All data are presented as means ± s.e.m. Comparisons between the ND, HFD and HFD + MF for the physical and biochemical characteristics were made using a one-way ANOVA. Comparisons of time course measurements in each group were performed using a two-way repeated-measures ANOVA. Comparisons of end point measurements in each group were made using a two-way ANOVA. When a significant difference (P < 0.05) was found, pairwise comparisons by the Student–Newman–Keuls (SNK) test was used to assess treatment differences. Pearson bivariate correlations were used to evaluate associations. All tests were performed using SigmaStat™ (Systat Software, Inc., San Jose, CA, USA).
Results
Physical and biochemical characteristics
The physical characteristics and plasma biochemistries of ND, HFD and HFD + MF rats are shown inTable 1. At the conclusion of the 4-week dietary intervention, body weight, epididymal fat pad weight, fasting plasma FFA and fasting plasma insulin were significantly (P < 0.05) elevated in the HFD group compared with the ND group. The calculated HOMA-IR was higher in HFD compared with the ND group (11.0 ± 1.1 vs 5.3 ± 0.5,P < 0.001). Body weight, fasting plasma FFA and fasting plasma insulin were significantly reduced by metformin treatment in the HFD + MF group. Thus, the HOMA-IR was lower in rats treated with MF compared with the HFD group (8.4 ± 0.8 vs 11.0 ± 1.1,P < 0.05). The fasting blood and plasma glucose values were not statistically different between any of the three dietary intervention groups (Table 1).
Table 1
Characteristics of rats treated with normal diet (ND), high-fat diet (HFD) or high-fat diet + metformin (HFD + MF) for 4 weeks and then fasted overnight.
ND (n = 25)HFD (n = 27)HFD + MF (n = 25)
Body weight (g)269 ± 8299 ± 6a276 ± 6a,b
Epididymal fat pad (g)0.66 ± 0.041.14 ± 0.05a1.05 ± 0.05a
Plasma FFA (mmol/L)0.55 ± 0.020.62 ± 0.01a0.54 ± 0.02b
Plasma glucose (mmol/L)7.3 ± 0.17.3 ± 0.27.4 ± 0.2
Blood glucose (mmol/L)3.7 ± 0.13.7 ± 0.23.8 ± 0.1
Plasma insulin (pmol/L)110 ± 10230 ± 20a170 ± 10a,b
Data are means ± s.e.m. One-way ANOVA and SNKpost hoctest.
a(P < 0.05) vs ND,b(P < 0.05) HFD vs HFD + MF.
FFA, free fatty acids.
Whole-body glucose metabolism
Blood glucose concentrations were clamped to basal fasting levels during the 2-h insulin infusion in all groups (Fig. 2B). The glucose infusion rate (GIR) required to maintain euglycaemia during insulin infusion was significantly lower (~23%) over the last hour of the experiment in HFD compared with ND (Fig. 2A; 18.1 ± 0.8 vs 23.3 ± 0.6 mg/kg/min,P < 0.001). The HFD + MF group displayed a significantly higher (46%) GIR compared with HFD (26.4 ± 0.9 vs 18.1 ± 0.8 mg/kg/min,P < 0.001), which was also 13% higher than the ND group. These differences in GIR occurred despite equivalent plasma insulin concentrations between the ND, HFD or HFD + MF groups at the conclusion of the 2-h insulin infusion (1300 ± 70 vs 1440 ± 70 vs 1270 ± 70 pmol/L, respectively,Fig. 3).
Figure 2
Glucose infusion rate (GIR) (panel A) required to maintain fasting blood glucose levels (panel B) during a euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) for normal diet (ND), high-fat diet (HFD) and high-fat diet + metformin (HFD + MF)-treated rats. Data are means ± s.e.m.forn = 14–17 rats in each group. *P < 0.05 ND vs HFD,#P < 0.05 HFD vs HFD + MF,†P < 0.05 ND vs HFD + MF. Two-way repeated-measures ANOVA and SNKpost hoctest.
Citation: Journal of Endocrinology 243, 2;10.1530/JOE-19-0067
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Figure 2
Glucose infusion rate (GIR) (panel A) required to maintain fasting blood glucose levels (panel B) during a euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) for normal diet (ND), high-fat diet (HFD) and high-fat diet + metformin (HFD + MF)-treated rats. Data are means ± s.e.m.forn = 14–17 rats in each group. *P < 0.05 ND vs HFD,#P < 0.05 HFD vs HFD + MF,†P < 0.05 ND vs HFD + MF. Two-way repeated-measures ANOVA and SNKpost hoctest.
Citation: Journal of Endocrinology 243, 2;10.1530/JOE-19-0067
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Figure 3
Plasma insulin levels before (0 min) and at the end (120 min) of the euglycaemic | https://joe.bioscientifica.com/view/journals/joe/243/2/JOE-19-0067.xml?result=353&rskey=MqGI3N |
Population Count Data for Fairbanks North Star Borough, AK - Population on the Open Data Network
The population count of Fairbanks North Star Borough, AK was 99,653 in 2018.API
Population Change API
Demographics and Population Datasets Involving Fairbanks North Star Borough, AK API
Uninsured Population Census Data CY 2009-2014 Human Services
This data is pulled from the U.S. Census website. This data is for years Calendar Years 2009-2014. Product: SAHIE File Layout Overview Small Area Health Insurance Estimates Program - SAHIE Filenames: SAHIE Text and SAHIE CSV files 2009 – 2014 Source: Small Area Health Insurance Estimates Program, U.S. Census Bureau. Internet Release Date: May 2016 Description: Model‐based Small Area Health Insurance Estimates (SAHIE) for Counties and States File Layout and Definitions The Small Area Health Insurance Estimates (SAHIE) program was created to develop model-based estimates of health insurance coverage for counties and states. This program builds on the work of the Small Area Income and Poverty Estimates (SAIPE) program. SAHIE is only source of single-year health insurance coverage estimates for all U.S. counties. For 2008-2014, SAHIE publishes STATE and COUNTY estimates of population with and without health insurance coverage, along with measures of uncertainty, for the full cross-classification of: •5 age categories: 0-64, 18-64, 21-64, 40-64, and 50-64 •3 sex categories: both sexes, male, and female •6 income categories: all incomes, as well as income-to-poverty ratio (IPR) categories 0-138%, 0-200%, 0-250%, 0-400%, and 138-400% of the poverty threshold •4 races/ethnicities (for states only): all races/ethnicities, White not Hispanic, Black not Hispanic, and Hispanic (any race). In addition, estimates for age category 0-18 by the income categories listed above are published. Each year’s estimates are adjusted so that, before rounding, the county estimates sum to their respective state totals and for key demographics the state estimates sum to the national ACS numbers insured and uninsured. This program is partially funded by the Centers for Disease Control and Prevention's (CDC), National Breast and Cervical Cancer Early Detection ProgramLink to a non-federal Web site (NBCCEDP). The CDC have a congressional mandate to provide screening services for breast and cervical cancer to low-income, uninsured, and underserved women through the NBCCEDP. Most state NBCCEDP programs define low-income as 200 or 250 percent of the poverty threshold. Also included are IPR categories relevant to the Affordable Care Act (ACA). In 2014, the ACA will help families gain access to health care by allowing Medicaid to cover families with incomes less than or equal to 138 percent of the poverty line. Families with incomes above the level needed to qualify for Medicaid, but less than or equal to 400 percent of the poverty line can receive tax credits that will help them pay for health coverage in the new health insurance exchanges. We welcome your feedback as we continue to research and improve our estimation methods. The SAHIE program's age model methodology and estimates have undergone internal U.S. Census Bureau review as well as external review. See the SAHIE Methodological Review page for more details and a summary of the comments and our response. The SAHIE program models health insurance coverage by combining survey data from several sources, including: •The American Community Survey (ACS) •Demographic population estimates •Aggregated federal tax returns •Participation records for the Supplemental Nutrition Assistance Program (SNAP), formerly known as the Food Stamp program •County Business Patterns •Medicaid •Children's Health Insurance Program (CHIP) participation records •Census 2010 Margin of error (MOE). Some ACS products provide an MOE instead of confidence intervals. An MOE is the difference between an estimate and its upper or lower confidence bounds. Confidence bounds can be created by adding the margin of error to the estimate (for the upper bound) and subtracting the margin of error from the estimate (for the lower bound). All published ACS margins of error are based on a 90-percent confidence level.
2013-2017 American Community Survey Detailed Census Tract Data
DETAILED CHARACTERISTICS OF PEOPLE AND HOUSING FOR INDIVIDUAL 2010 CENSUS TRACT PORTIONS INSIDE OR OUTSIDE KCMO - Some demographic data are from the 2010 Census while other data are from the 2013-2017 American Community Survey (ACS). The ACS replaces what until 2000 was the Long Form of the census; both have been based on surveys of a partial sample of people. The ACS sample is so small that surveys from five years must be combined to be reliable. The 2013-2017 ACS is the most recent grouping of 5 years of data. ACS data have been proportioned to conform with 2010 Census total population and total households.
2015-2019 American Community Survey Detailed Census Tract Data
data.kcmo.org
DETAILED CHARACTERISTICS OF PEOPLE AND HOUSING FOR INDIVIDUAL 2010 CENSUS TRACT PORTIONS INSIDE OR OUTSIDE KCMO - Some demographic data are from the 2010 Census while other data are from the 2015-2019 American Community Survey (ACS). The ACS replaces what until 2000 was the Long Form of the census; both have been based on surveys of a partial sample of people. The ACS sample is so small that surveys from five years must be combined to be reliable. The 2015-2019 ACS is the most recent grouping of 5 years of data. ACS data have been proportioned to conform with 2010 Census total population and total households.
2015-2019 American Community Survey Basic Census Tract Data
BASIC CHARACTERISTICS OF PEOPLE AND HOUSING FOR INDIVIDUAL 2010 CENSUS TRACT PORTIONS INSIDE OR OUTSIDE KCMO - Some demographic data are from the 2010 Census while other data are from the 2015-2019 American Community Survey - ACS. The ACS replaces what until 2000 was the Long Form of the census; both have been based on surveys of a partial sample of people. The ACS sample is so small that surveys from five years must be combined to be reliable. The 2015-2019 ACS is the most recent grouping of 5 years of data. ACS data have been proportioned to conform with 2010 Census total population and total households.
Point In Time Homeless Survey Data
The County of Sonoma conducts an annual homeless count for the entire county. The survey data is derived from a sample of about 600 homeless persons countywide per year. The resulting information is statistically reliable only for the county as a whole, not for individual locations. The exception is the City of Santa Rosa, where the sample taken within the city is large enough to be predictive of the overall homeless population in that city.
| https://opendatanetwork.herokuapp.com/entity/0500000US02090/Fairbanks_North_Star_Borough_AK/demographics.population.count?year=2018 |
Of Dog Guides and White Canes
OF DOG GUIDES AND WHITE CANES by Cheri Heppe
This fall, at our National Federation of the Blind of Connecticut Sate Convention we will be afforded a special opportunity to learn more about traveling effectively as blind people. One of the workshops will focus on good travel, with Fred Schroeder as presenter. Among his qualifications, Fred Schroeder has a Masters Degree in Orientation and is completing a Doctorate in Education at San Francisco State, so he can speak the language of "the field," and has some practical knowledge in traveling as a totally blind person.
Many of us still hold to the notion that only a few, somehow specially gifted people, can achieve smooth, competent travel skills. Many also believe that long cane travel and dog guide ownership have nothing in common. However, more and more of us are discovering the paradoxes and false thinking reflected in these views.
For example, no one of us starts out knowing how to get around. Sighted or blind, we all have to learn to crawl as babies, then take our first wobbly steps with family members holding our hands and encouraging us. I know of no one who has an instinctual capability to get on a two-wheeled bicycle and ride it perfectly the first time.
And consider the attention given to driver's education in high schools. We need proper training as blind people to be able to travel comfortably and effectively in our day-to-day lives. The good travelers have spent time and effort practicing and polishing their travel skills and have retained open minds to learn from others. The first time I traveled using a long cane, I felt awkward and out of place, not because my cane use was so bad, but because others I knew who were sighted did not use a cane and I felt different. I wanted to corn- form and be just like the other people. In time, I discovered that my means of getting around worked well for me and gave me an edge over my previous, uneducated place.We who travel with dog guides need to examine our underlying motivations for owning a dog guide and perhaps, refresh our skills in long cane use. Many of us took to working with a dog guide because we experienced agency philosophy or training in combination with less effective agency canes. Many of us chose a dog as a buffer between what we or our families considered a crime-ridden and frightening unknown world and ourselves. Unfortunately, the insecurity of the owner transfers to the dog and results in nervousness, aggressive or uncontrolled behavior and lack of direction. Dogs need to look to their human owner for instruction, guidance, discipline and direction. The dog that does not find this in the owner will take the dominant part in the relationship. In the 1920's when dog guide training first came to the U.S., there was no way for blind people to travel effectively, except on the arm of a sighted friend or companion, or, perhaps, a paid guide. The dog guide schools did need to take people very soon after the onset of blindness, before poor attitudes and lack of exercise and training destroyed the individual's initiative.
Time and experience pointed to the success of the dog guide. The public marveled that a blind person could walk down the street, re-learn skills to keep a home and hold a job. Agencies for the blind envied the way the dog guide schools attracted the financial support of the public and the loyalty and respect of both recipients and the public. Some agencies made an effort to gain control of the dog guide programs and the dog guide schools, being largely performance oriented and practical, remained autonomous. Word then began to be circulated about the various inconveniences and drawbacks of dog guide ownership. Also, some owners did not maintain their training and added fuel to such criticisms by the evidence of their poor handling.
The Veteran's Administration worked to develop the long cane and its use in the mid 1940's. This opened the door for everyone who was blind and wanted to travel independently to be able to do so. However, the long cane travel training fell almost entirely to agencies and service providers, not to practitioners who were blind. So, many of limiting attitudes of the agencies reflected themselves in the way cane travel was taught.
We in the NFB have developed a practical, usable and effective long cane, as well as various folding canes. More importantly, we are developing a philosophy of using and traveling with a cane that makes all the difference in how we get around. The world has become more sophisticated and demands more of us, because we, as blind people, expect more of ourselves.
All of us, dog guide owners as well as cane travelers, are encouraged to come to the travel seminar at our state convention to learn more about good traveling. Someone has said that knowledge is power. The more we know, the better we can all deal with the joys and challenges of living our lives to a full and complete degree.
| https://nfb.org/sites/nfb.org/files/images/nfb/publications/fr/fr7/issue1/f070116.html |
HESS - A general framework for understanding the response of the water cycle to global warming over land and ocean
A general framework for understanding the response of the water cycle to global warming over land and ocean
M. L. Roderick ,
F. Sun ,
W. H. Lim ,
and G. D. Farquhar
Abstract.Climate models project increases in globally averaged atmospheric specific humidity that are close to the Clausius–Clapeyron (CC) value of around 7% K −1whilst projections for mean annual global precipitation ( P) and evaporation ( E) are somewhat muted at around 2% K −1. Such global projections are useful summaries but do not provide guidance at local (grid box) scales where impacts occur. To bridge that gap in spatial scale, previous research has shown that the "wet get wetter and dry get drier" relation, Δ( P− E) ∝ P− E, follows CC scaling when the projected changes are averaged over latitudinal zones. Much of the research on projected climate impacts has been based on an implicit assumption that this CC relation also holds at local (grid box) scales but this has not previously been examined. In this paper we find that the simple latitudinal average CC scaling relation does not hold at local (grid box) scales over either ocean or land. This means that in terms of P− E, the climate models do not project that the "wet get wetter and dry get drier" at the local scales that are relevant for agricultural, ecological and hydrologic impacts. In an attempt to develop a simple framework for local-scale analysis we found that the climate model output shows a remarkably close relation to the long-standing Budyko framework of catchment hydrology. We subsequently use the Budyko curve and find that the local-scale changes in P− Eprojected by climate models are dominated by changes in Pwhile the changes in net irradiance at the surface due to greenhouse forcing are small and only play a minor role in changing the mean annual P− Ein the climate model projections. To further understand the apparently small changes in net irradiance we also examine projections of key surface energy balance terms. In terms of global averages, we find that the climate model projections are dominated by changes in only three terms of the surface energy balance: (1) an increase in the incoming long-wave irradiance, and the respective responses (2) in outgoing long-wave irradiance and (3) in the evaporative flux, with the latter change being much smaller than the former two terms and mostly restricted to the oceans. The small fraction of the realised surface forcing that is partitioned into Eexplains why the hydrologic sensitivity (2% K −1) is so much smaller than CC scaling (7% K −1). Much public and scientific perception about changes in the water cycle has been based on the notion that temperature enhances E. That notion is partly true but has proved an unfortunate starting point because it has led to misleading conclusions about the impacts of climate change on the water cycle. A better general understanding of the potential impacts of climate change on water availability that are projected by climate models will surely be gained by starting with the notion that the greater the enhancement of E, the less the surface temperature increase (and vice versa). That latter notion is based on the conservation of energy and is an underlying basis of climate model projections.
How to cite.
Roderick, M. L., Sun, F., Lim, W. H., and Farquhar, G. D.: A general framework for understanding the response of the water cycle to global warming over land and ocean, Hydrol. Earth Syst. Sci., 18, 1575–1589, https://doi.org/10.5194/hess-18-1575-2014, 2014.
| https://hess.copernicus.org/articles/18/1575/2014/ |
Mitral Prosthesis and Methods for Implantation Tuval; Yosi ; et al. [Medtronic Ventor Technologies Ltd.]
Mitral Prosthesis and Methods for Implantation
Tuval; Yosi ; et al.
uspto.report › patents ›
Medtronic Ventor Technologies Ltd. ›
Patent 12/914611 Assignee
uspto.report › patents ›
Ben-Hamou; Eli › Patent 12/914611
Inventors
uspto.report › patents › Hariton; Ilia
› Patent 12/914611 Inventors
uspto.report › patents ›
Kovalsky; Igor › Patent 12/914611
Inventors
uspto.report › patents › Tuval; Yosi ›
Patent 12/914611 Inventors
Patent Application Summary
U.S. patent application number 12/914611 was filed with the patent office on 2011-08-25 for
mitral prosthesis and methods for implantation
.
This patent application is currently assigned to Medtronic Ventor Technologies Ltd.. Invention is credited to Eli Ben-Hamou, Ilia Hariton, Igor Kovalsky, Yosi Tuval.
Application Number 20110208297 12/914611
Document ID /
Family ID 44477163
Filed Date 2011-08-25
United States Patent
Application 20110208297
Kind Code A1
Tuval; Yosi ; et
al. August 25, 2011
Mitral Prosthesis and Methods for Implantation
Abstract
Apparatus and methods are provided including a mitral valve
prosthesis. The prosthesis includes an inner support structure
having downstream and upstream sections, the upstream section
having a cross-sectional area greater than the downstream section.
The inner support structure is configured to be positioned on an
atrial side of the native valve complex, and to prevent the
prosthesis from being dislodged into the left ventricle. A
prosthetic valve having prosthetic valve leaflets is coupled to the
inner support structure. An outer support structure has engagement
arms, downstream ends of the engagement arms being coupled to the
inner support structure. The prosthesis is configured such that,
upon implantation thereof: downstream ends of the native valve
leaflets, downstream ends of the engagement arms, and downstream
ends of the prosthetic leaflets, are disposed at a longitudinal
distance from one another of less than 3 mm. Other embodiments are
also described.
Inventors: Tuval; Yosi ; (Even Yehuda,
IL) ; Hariton; Ilia ; (Zichron Yaackov, IL) ;
Kovalsky; Igor ; (Givatamin, IL) ; Ben-Hamou; Eli ; (Tel Aviv, IL)
Assignee: Medtronic Ventor Technologies
Ltd.
Minneapolis
MN
Family ID: 44477163
Appl. No.: 12/914611
Filed: October 28, 2010
Related U.S. Patent Documents
Application
Number Filing Date Patent Number
61307743 Feb 24, 2010
Current U.S.
Class: 623/2.17
Current CPC
Class: A61F 2230/008 20130101;
A61F 2220/0075 20130101; A61F 2230/005 20130101; A61F 2220/0016
20130101; A61F 2230/0069 20130101; A61F 2/2418 20130101; A61F
2230/0067 20130101; A61F 2/2412 20130101; A61F 2250/006 20130101;
A61F 2220/0008 20130101; A61F 2250/0039 20130101; A61F 2230/0013
20130101; A61F 2/2436 20130101
Class at
Publication: 623/2.17
International
Class: A61F 2/24 20060101
A61F002/24
Claims
1. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section
and an upstream section, the upstream section having a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
prevent the prosthesis from being dislodged into a left ventricle
by applying an axial force directed toward the left ventricle; a
prosthetic valve having prosthetic valve leaflets coupled to the
inner support structure; and an outer support structure having two
or more engagement arms, downstream ends of the engagement arms
being coupled to the inner support structure, the prosthesis being
configured such that, upon implantation thereof: downstream ends of
native valve leaflets of the native mitral valve complex, the
downstream ends of the engagement arms, and downstream ends of the
prosthetic leaflets, are disposed at a longitudinal distance from
one another of less than 3 mm, the longitudinal distance being
measured in a direction of a longitudinal axis of the
prosthesis.
2. The apparatus according to claim 1, wherein the downstream ends
of the engagement arms are coupled to the inner support structure
within 3 mm of a downstream end of the inner support structure.
3. The apparatus according to claim 1, wherein the prosthesis is
configured such that, upon implantation thereof, no portion of the
prosthesis protrudes into a left ventricle of the subject by more
than 3 mm.
4. The apparatus according to claim 1, wherein the engagement arms
are integrally formed with the inner support structure.
5. The apparatus according to claim 1, wherein the prosthesis is
configured such that, upon implantation thereof: the downstream
ends of native valve leaflets of the native mitral valve complex,
the downstream ends of the engagement arms, and the downstream ends
of the prosthetic leaflets, are disposed at a longitudinal distance
from one another of less than 1 mm, the longitudinal distance being
measured in a direction of a longitudinal axis of the
prosthesis.
6. The apparatus according to claim 5, wherein the prosthesis is
configured such that, upon implantation thereof, no portion of the
prosthesis protrudes into a left ventricle of the subject by more
than 1 mm.
7. The apparatus according to claim 5, wherein the downstream ends
of the engagement arms are coupled to the inner support structure
within 1 mm of a downstream end of the inner support structure.
8. The apparatus according to claim 1, wherein for each engagement
arm, along at least 30% of a length of the engagement arm, the
engagement arm is at a distance of at least 0.5 mm from an outer
surface of the inner support structure.
9. The apparatus according to claim 8, wherein the distance is at
least 1 mm.
10. The apparatus according to claim 9, wherein the distance is at
least 4 mm.
11. The apparatus according to claim 8, wherein the engagement arm
is at the distance from the outer surface of the inner support
structure along at least 50% of the length of the engagement
arm.
12. The apparatus according to claim 11, wherein the engagement arm
is at the distance from the outer surface of the inner support
structure along at least 70% of the length of the engagement
arm.
13. The apparatus according to claim 1, wherein the outer support
structure further comprises a connecting frame, the connecting
frame of the outer support structure being configured to be coupled
to the inner support structure.
14. The apparatus according to claim 13, wherein the inner support
structure is shaped to define a plurality of cells, and wherein the
connecting frame of the outer support structure is shaped to define
a plurality of cells having shapes and sizes that match cells of
the inner support structure.
15. The apparatus according to claim 1, wherein the prosthesis is
configured, upon implantation thereof, to reduce motion of the
native valve leaflets, by holding the leaflets inside the
engagement arms.
16. The apparatus according to claim 15, wherein the prosthesis is
configured to immobilize the native valve leaflets, by holding the
leaflets inside the engagement arms.
17. The apparatus according to claim 15, wherein the prosthesis is
configured to prevent systolic anterior motion of the native valve
leaflets, by holding the leaflets inside the engagement arms.
18. The apparatus according to claim 15, wherein the prosthesis is
configured to prevent the native leaflets from interfering with
LVOT, by holding the leaflets inside the engagement arms.
19. The apparatus according to claim 15, wherein the outer support
structure further comprises covers for covering the engagement
arms, the covers being configured to reduce the motion of the
native leaflets.
20. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section,
and an upstream section, wherein the upstream section has a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
apply an axial force directed toward a left ventricle; and an outer
support structure having posterior and anterior engagement arms
configured to be placed over, respectively, posterior and anterior
leaflets of the native mitral valve complex, wherein the engagement
arms are coupled to the inner support structure, wherein a ratio of
a length of the anterior engagement arm to a length of the
posterior arm is between 1.1:1 and 15:1.
21. The apparatus according to claim 20, wherein the ratio is
between 1.3:1 and 2:1.
22. The apparatus according to claim 20, wherein the length of the
anterior engagement arm is between 2 mm and 35 mm.
23. The apparatus according to claim 22, wherein the length of the
anterior engagement arm is between 15 mm and 25 mm.
24. The apparatus according to claim 20, wherein the length of the
posterior engagement arm is between 2 mm and 35 mm.
25. The apparatus according to claim 24, wherein the length of the
posterior engagement arm is between 7 mm and 23 mm.
26. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section,
and an upstream section, wherein the upstream section has a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
apply an axial force directed toward a left ventricle; and an outer
support structure having posterior and anterior engagement arms
configured to be placed over native leaflets of the native mitral
valve complex, wherein the engagement arms are coupled to the inner
support structure, the engagement arms being configured to define
first configurations thereof during implantation of the prosthesis,
and to change shape so as to define second configurations thereof,
subsequent to being placed over the native leaflets of the native
mitral valve complex, each of the engagement arms spanning a width
of less than 12 mm in the first configuration thereof, and spanning
a width of more than 15 mm when in the second configuration
thereof.
27. The apparatus according to claim 26, wherein, in the first
configuration thereof, the engagement arms are configured to span a
width of less than 8 mm.
28. The apparatus according to claim 26, wherein, in the second
configuration thereof, the engagement arms are configured to span a
width of more than 35 mm.
29. The apparatus according to claim 26, wherein, in the first
configuration thereof, the engagement arms are configured to
facilitate functioning of the native valve complex during
implantation of the prosthesis.
30. The apparatus according to claim 26, wherein, in the first
configuration thereof, the engagement arms are configured to fit
between papillary muscles of the native valve complex.
31. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section
and an upstream section, the upstream section having a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
prevent the prosthesis from being dislodged into a left ventricle
by applying an axial force directed toward the left ventricle; an
outer support structure having two or more engagement arms,
downstream ends of the engagement arms being coupled to the inner
support structure, and a prosthetic valve having prosthetic valve
leaflets coupled to the inner support structure such that
downstream ends of the prosthetic valve leaflets are within 3 mm of
the downstream ends of the engagement arms; a longitudinal distance
from a downstream end to an upstream end of each of the engagement
arms being less than 18 mm, the longitudinal distance being
measured in a direction of a longitudinal axis of the
prosthesis.
32. The apparatus according to claim 31, wherein the prosthetic
valve leaflets are coupled to the inner support structure such that
downstream ends of the prosthetic valve leaflets are within 1 mm of
the downstream ends of the engagement arms.
33. The apparatus according to claim 31, wherein the longitudinal
distance from the downstream end to the upstream end of each of the
engagement arms is less than 12 mm.
34. The apparatus according to claim 33, wherein the longitudinal
distance from the downstream end to the upstream end of each of the
engagement arms is less than 10 mm.
35. The apparatus according to claim 31, wherein the downstream
ends of the engagement arms are coupled to the inner support
structure within 3 mm of a downstream end of the inner support
structure.
36. The apparatus according to claim 35, wherein the downstream
ends of the engagement arms are coupled to the inner support
structure within 1 mm of a downstream end of the inner support
structure.
37. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section
and an upstream section, the upstream section having a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
prevent the prosthesis from being dislodged into a left ventricle
by applying an axial force directed toward the left ventricle; a
prosthetic valve having prosthetic valve leaflets coupled to the
inner support structure; and an outer support structure having two
or more engagement arms, the engagement arms being coupled to the
inner support structure, the prosthesis being configured such that,
upon implantation thereof: downstream ends of native valve leaflets
of the native mitral valve complex, and downstream ends of the
engagement arms are disposed at a longitudinal distance from one
another of less than 3 mm, the longitudinal distance being measured
in a direction of a longitudinal axis of the prosthesis, and a
downstream end of the inner support structure and downstream ends
of the prosthetic valve leaflets are at a longitudinal distance of
at least 4 mm upstream of the downstream ends of the native valve
leaflets, the longitudinal distance being measured in a direction
of a longitudinal axis of the prosthesis.
38. The apparatus according to claim 37, wherein the prosthesis is
configured such that, upon implantation thereof, the downstream end
of the inner support structure and the downstream ends of the
prosthetic valve leaflets are at a longitudinal distance of at
least 10 mm upstream of the downstream ends of the native valve
leaflets.
30. Apparatus comprising a mitral valve prosthesis for implantation
at a native mitral valve complex of a subject, the prosthesis
comprising: an inner support structure having a downstream section
and an upstream section, the upstream section having a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
prevent the prosthesis from being dislodged into a left ventricle
by applying an axial force directed toward the left ventricle; an
outer support structure having two or more engagement arms, the
engagement arms being coupled to the inner support structure, and a
prosthetic valve having prosthetic valve leaflets coupled to the
inner support structure such that downstream ends of the prosthetic
valve leaflets are at least 4 mm upstream of the downstream ends of
the engagement arms.
40. The apparatus according to claim 39, wherein the prosthetic
valve leaflets are coupled to the inner support structure such that
the downstream ends of the prosthetic valve leaflets are at least
10 mm upstream of the downstream ends of the engagement arms.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application 61/307,743, filed Feb. 24, 2010, entitled,
"Mitral prosthesis and methods for implantation," which is
incorporated herein by reference.
FIELD OF EMBODIMENTS OF THE INVENTION
[0002] Some applications of the present invention generally relate
to implantable medical apparatus. Specifically, some applications
of the present invention relate to apparatus and methods associated
with prosthetic heart valves.
BACKGROUND
[0003] The mitral valve exhibits two types of pathologies
regurgitation and stenosis. Regurgitation is the more common of the
two defects. Either defect may be treated by surgical repair. Under
certain conditions, the mitral valve must be replaced. Standard
approaches to mitral valve replacement require cutting open the
left side of the heart to access the native mitral valve.
[0004] US 2008/0071368 to Tuval describes a prosthesis for
implantation at a native semilunar valve of a native valve complex.
The prosthesis includes a distal fixation member, configured to be
positioned in a downstream artery, and shaped so as to define
exactly three proximal engagement arms that are configured to be
positioned at least partially within respective ones of semilunar
sinuses, and, in combination, to apply, to tissue that defines the
semilunar sinuses, a first axial force directed toward a ventricle.
The prosthesis further includes a proximal fixation member coupled
to the distal fixation member, the proximal fixation member
configured to be positioned at least partially on a ventricular
side of the native semilunar valve, and to apply, to the
ventricular side of the native valve complex, a second axial force
directed toward the downstream artery, such that application of the
first and second forces couples the prosthesis to the native valve
complex.
[0005] US 2009/0276040 to Rowe describes a prosthetic mitral valve
assembly and method of inserting the same. In certain embodiments,
the prosthetic mitral valve assembly has a flared upper end and a
tapered portion to fit the contours of the native mitral valve. The
prosthetic mitral valve assembly can include a stent or outer
support frame with a valve mounted therein. The assembly is
described as being adapted to expand radially outwardly and into
contact with the native tissue to create a pressure fit. One
embodiment is described including positioning the mitral valve
assembly below the annulus such that the annulus itself can
restrict the assembly from moving in an upward direction towards
the left atrium. The mitral valve assembly is also described as
being positioned so that the leaflets of the mitral valve hold the
assembly to prevent downward movement of the assembly towards the
left ventricle.
[0006] US 2010/0217382 to Chau describes a prosthetic mitral valve
assembly and method of inserting the same. In certain embodiments,
the prosthetic mitral valve assembly includes a stent and valve
combination. The stent is designed so that the anchoring portion is
positioned above the annulus of the mitral valve and in the left
atrium. The stent is radially expandable so that it can expand into
position against the walls of the left atrium and accommodate a
wide range of anatomies. Contact between the stent and the native
tissue in the left atrium is described as reducing paravalvular
leakage and preventing migration of the stent once in place.
[0007] US 2009/0005863 to Goetz describes a replacement valve for
implantation centrally within the orifice of a malfunctioning
native heart valve. The valve is designed for minimally invasive
entry through an intercostal opening in the chest of a patient and
an opening in the apex of the human heart. The replacement valve
includes either a separate anchor or a combined anchor that folds
around the malfunctioning native valve leaflets, sandwiching them
in a manner so as to securely anchor the replacement valve in a
precise, desired location.
[0008] US 2009/0216312 to Straubinger describes a stent for the
positioning and anchoring of a valvular prosthesis in an
implantation site in the heart of a patient. Specifically, the
Straubinger application relates to an expandable stent for an
endoprosthesis used in the treatment of a narrowing of a cardiac
valve and/or a cardiac valve insufficiency. The stent is described
as comprising at least one fastening portion via which the valvular
prosthesis is connectable to the stent, so as to ensure that no
longitudinal displacement of a valvular prosthesis fastened to a
stent will occur relative the stent in the implanted state of the
stent, even given the peristaltic motion of the heart. The stent
further comprises positioning arches and retaining arches, whereby
at least one positioning arch is connected to at least one
retaining arch via a first connecting web. The stent moreover
comprises at least one auxiliary retaining arch which connects the
respective arms of the at least one retaining arch connected to the
at least one positioning arch.
[0009] US 2008/0255660 to Guyenot describes a medical device for
treating a heart valve insufficiency, with an endoprosthesis which
can be introduced into a patient's body and expanded to secure a
heart valve prosthesis in the patient's aorta. In an embodiment,
the endoprosthesis has a plurality of positioning arches configured
to be positioned with respect to a patient's aorta and a plurality
of retaining arches to support a heart valve prosthesis. The
endoprosthesis includes a first collapsed mode during the process
of introducing it into the patient's body and a second expanded
mode when it is implanted.
[0010] The following references may be of interest [0011] US
2010/0030330 to Bobo [0012] US 2009/0216313 to Straubinger [0013]
US 2009/0216310 to Straubinger [0014] US 2008/0255661 to
Straubinger [0015] US 2008/0208328 to Antocci [0016] US
2008/0071369 to Tuval [0017] US 2008/0071363 to Tuval [0018] US
2008/0071366 to Tuval [0019] US 2008/0071362 to Tuval [0020] US
2008/0071361 to Tuval [0021] US 2003/0036791 to Bonhoeffer [0022]
WO 04/019825 to Figulla
SUMMARY OF EMBODIMENTS
[0023] For some applications of the present invention, mitral valve
prostheses and methods for implanting the prostheses are provided.
The prostheses are typically implanted transcatheterally, for
example, transapically (i.e., through the apex of the heart),
transatrially (i.e., through the left atrium of the heart), and/or
transseptally (i.e., through the septum of the heart). The
prostheses typically include inner and outer support structures,
the outer support structure including engagement arms. A valve
prosthesis is typically sutured to the inner support structure.
[0024] Typically, the prostheses are placed on the native mitral
valve complex such that the native leaflets are disposed between
the inner support structure and the engagement arms. For some
applications, such a configuration prevents the native leaflets
from obstructing flow through the left ventricular outflow tract
(LVOT), prevents the native leaflets from interacting with the
prosthetic leaflets, recruits the native leaflets in minimizing
peri-valvular leaks, maintains proper alignment of the valve
prosthesis, avoids systolic anterior mobility, and/or maintains
valve stability by preventing migration of the valve into the
atrium or ventricle. For some applications, the design of the
prosthesis is similar to the native valve and supports a non-round
in vivo configuration, which reflects native valve function.
[0025] There is therefore provided, in accordance with some
applications of the present invention, apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0026] an inner support structure having a downstream section and
an upstream section, the upstream section having a cross-sectional
area greater than the downstream section, the inner support
structure being configured to be positioned at least partially on
an atrial side of the native valve complex, and to prevent the
prosthesis from being dislodged into a left ventricle by applying
an axial force directed toward the left ventricle;
[0027] a prosthetic valve having prosthetic valve leaflets coupled
to the inner support structure; and
[0028] an outer support structure having two or more engagement
arms, downstream ends of the engagement arms being coupled to the
inner support structure,
[0029] the prosthesis being configured such that, upon implantation
thereof: [0030] downstream ends of native valve leaflets of the
native mitral valve complex, [0031] the downstream ends of the
engagement arms, and [0032] downstream ends of the prosthetic
leaflets,
[0033] are disposed at a longitudinal distance from one another of
less than 3 mm, the longitudinal distance being measured in a
direction of a longitudinal axis of the prosthesis.
[0034] For some applications, the downstream ends of the engagement
arms are coupled to the inner support structure within 3 mm of a
downstream end of the inner support structure.
[0035] For some applications, the prosthesis is configured such
that, upon implantation thereof, no portion of the prosthesis
protrudes into a left ventricle of the subject by more than 3
mm.
[0036] For some applications, the engagement arms are integrally
formed with the inner support structure.
[0037] For some applications, the prosthesis is configured such
that, upon implantation thereof: [0038] the downstream ends of
native valve leaflets of the native mitral valve complex, [0039]
the downstream ends of the engagement arms, and [0040] the
downstream ends of the prosthetic leaflets,
[0041] are disposed at a longitudinal distance from one another of
less than 1 mm, the longitudinal distance being measured in a
direction of a longitudinal axis of the prosthesis.
[0042] For some applications, the prosthesis is configured such
that, upon implantation thereof, no portion of the prosthesis
protrudes into a left ventricle of the subject by more than 1
mm.
[0043] For some applications, the downstream ends of the engagement
arms are coupled to the inner support structure within 1 mm of a
downstream end of the inner support structure.
[0044] For some applications, for each engagement arm, along at
least 30% of a length of the engagement arm, the engagement arm is
at a distance of at least 0.5 mm from an outer surface of the inner
support structure.
[0045] For some applications, the distance is at least 1 mm.
[0046] For some applications, the distance is at least 4 mm.
[0047] For some applications, the engagement arm is at the distance
from the outer surface of the inner support structure along at
least 50% of the length of the engagement arm.
[0048] For some applications, the engagement arm is at the distance
from the outer surface of the inner support structure along at
least 70% of the length of the engagement arm.
[0049] For some applications, the outer support structure further
includes a connecting frame, the connecting frame of the outer
support structure being configured to be coupled to the inner
support structure.
[0050] For some applications, the inner support structure is shaped
to define a plurality of cells, and the connecting frame of the
outer support structure is shaped to define a plurality of cells
having shapes and sizes that match cells of the inner support
structure.
[0051] For some applications, the prosthesis is configured, upon
implantation thereof, to reduce motion of the native valve
leaflets, by holding the leaflets inside the engagement arms.
[0052] For some applications, the prosthesis is configured to
immobilize the native valve leaflets, by holding the leaflets
inside the engagement arms.
[0053] For some applications, the prosthesis is configured to
prevent systolic anterior motion of the native valve leaflets, by
holding the leaflets inside the engagement arms.
[0054] For some applications, the prosthesis is configured to
prevent the native leaflets from interfering with LVOT, by holding
the leaflets inside the engagement arms.
[0055] For some applications, the outer support structure further
includes covers for covering the engagement arms, the covers being
configured to reduce the motion of the native leaflets.
[0056] There is further provided, in accordance with some
applications of the present invention apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0057] an inner support structure having a downstream section, and
an upstream section, wherein the upstream section has a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
apply an axial force directed toward a left ventricle; and
[0058] an outer support structure having posterior and anterior
engagement arms configured to be placed over, respectively,
posterior and anterior leaflets of the native mitral valve complex,
wherein the engagement arms are coupled to the inner support
structure,
[0059] wherein a ratio of a length of the anterior engagement arm
to a length of the posterior arm is between 1.1:1 and 15:1.
[0060] For some applications, the ratio is between 1.3:1 and
2:1.
[0061] For some applications, the length of the anterior engagement
arm is between 2 mm and 35 mm.
[0062] For some applications, the length of the anterior engagement
arm is between 15 mm and 25 mm.
[0063] For some applications, the length of the posterior
engagement arm is between 2 mm and 35 mm.
[0064] For some applications, the length of the posterior
engagement arm is between 7 mm and 23 mm.
[0065] There is additionally provided, in accordance with some
applications of the present invention, apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0066] an inner support structure having a downstream section, and
an upstream section, wherein the upstream section has a
cross-sectional area greater than the downstream section, the inner
support structure being configured to be positioned at least
partially on an atrial side of the native valve complex, and to
apply an axial force directed toward a left ventricle; and
[0067] an outer support structure having posterior and anterior
engagement arms configured to be placed over native leaflets of the
native mitral valve complex, wherein the engagement arms are
coupled to the inner support structure,
[0068] the engagement arms being configured to define first
configurations thereof during implantation of the prosthesis, and
to change shape so as to define second configurations thereof,
subsequent to being placed over the native leaflets of the native
mitral valve complex,
[0069] each of the engagement arms spanning a width of less than 12
mm in the first configuration thereof, and spanning a width of more
than 15 mm when in the second configuration thereof.
[0070] For some applications, in the first configuration thereof,
the engagement arms are configured to span a width of less than 8
mm.
[0071] For some applications, in the second configuration thereof,
the engagement arms are configured to span a width of more than 35
mm.
[0072] For some applications, in the first configuration thereof,
the engagement arms are configured to facilitate functioning of the
native valve complex during implantation of the prosthesis.
[0073] For some applications, in the first configuration thereof,
the engagement arms are configured to fit between papillary muscles
of the native valve complex.
[0074] There is additionally provided in accordance with some
applications of the present invention apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0075] an inner support structure having a downstream section and
an upstream section, the upstream section having a cross-sectional
area greater than the downstream section, the inner support
structure being configured to be positioned at least partially on
an atrial side of the native valve complex, and to prevent the
prosthesis from being dislodged into a left ventricle by applying
an axial force directed toward the left ventricle;
[0076] an outer support structure having two or more engagement
arms, downstream ends of the engagement arms being coupled to the
inner support structure, and
[0077] a prosthetic valve having prosthetic valve leaflets coupled
to the inner support structure such that downstream ends of the
prosthetic valve leaflets are within 3 mm of the downstream ends of
the engagement arms;
[0078] a longitudinal distance from a downstream end to an upstream
end of each of the engagement arms being less than 18 mm, the
longitudinal distance being measured in a direction of a
longitudinal axis of the prosthesis.
[0079] For some applications, the prosthetic valve leaflets are
coupled to the inner support structure such that downstream ends of
the prosthetic valve leaflets are within 1 mm of the downstream
ends of the engagement arms.
[0080] For some applications, the longitudinal distance from the
downstream end to the upstream end of each of the engagement arms
is less than 12 mm.
[0081] For some applications, the longitudinal distance from the
downstream end to the upstream end of each of the engagement arms
is less than 10 mm.
[0082] For some applications, the downstream ends of the engagement
arms are coupled to the inner support structure within 3 mm of a
downstream end of the inner support structure.
[0083] For some applications, the downstream ends of the engagement
arms are coupled to the inner support structure within 1 mm of a
downstream end of the inner support structure.
[0084] There is further provided, in accordance with some
applications of the present invention apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0085] an inner support structure having a downstream section and
an upstream section, the upstream section having a cross-sectional
area greater than the downstream section, the inner support
structure being configured to be positioned at least partially on
an atrial side of the native valve complex, and to prevent the
prosthesis from being dislodged into a left ventricle by applying
an axial force directed toward the left ventricle;
[0086] a prosthetic valve having prosthetic valve leaflets coupled
to the inner support structure; and
[0087] an outer support structure having two or more engagement
arms, the engagement arms being coupled to the inner support
structure,
[0088] the prosthesis being configured such that, upon implantation
thereof: [0089] downstream ends of native valve leaflets of the
native mitral valve complex, and downstream ends of the engagement
arms are disposed at a longitudinal distance from one another of
less than 3 mm, the longitudinal distance being measured in a
direction of a longitudinal axis of the prosthesis, and [0090] a
downstream end of the inner support structure and downstream ends
of the prosthetic valve leaflets are at a longitudinal distance of
at least 4 mm upstream of the downstream ends of the native valve
leaflets, the longitudinal distance being measured in a direction
of a longitudinal axis of the prosthesis.
[0091] For some applications, the prosthesis is configured such
that, upon implantation thereof, the downstream end of the inner
support structure and the downstream ends of the prosthetic valve
leaflets are at a longitudinal distance of at least 10 mm upstream
of the downstream ends of the native valve leaflets.
[0092] There is additionally provided in accordance with some
applications of the present invention apparatus including a mitral
valve prosthesis for implantation at a native mitral valve complex
of a subject, the prosthesis including:
[0093] an inner support structure having a downstream section and
an upstream section, the upstream section having a cross-sectional
area greater than the downstream section, the inner support
structure being configured to be positioned at least partially on
an atrial side of the native valve complex, and to prevent the
prosthesis from being dislodged into a left ventricle by applying
an axial force directed toward the left ventricle;
[0094] an outer support structure having two or more engagement
arms, the engagement arms being coupled to the inner support
structure, and
[0095] a prosthetic valve having prosthetic valve leaflets coupled
to the inner support structure such that downstream ends of the
prosthetic valve leaflets are at least 4 mm upstream of the
downstream ends of the engagement arms.
[0096] For some applications, the prosthetic valve leaflets are
coupled to the inner support structure such that the downstream
ends of the prosthetic valve leaflets are at least 10 mm upstream
of the downstream ends of the engagement arms.
[0097] The present invention will be more fully understood from the
following detailed description of embodiments thereof, taken
together with the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0098] FIGS. 1A-D are schematic illustration of respective views of
a mitral valve prosthesis, in accordance with some applications of
the present invention;
[0099] FIGS. 2A-D are schematic illustrations of respective views
of a mitral valve prosthesis, in accordance with some applications
of the present invention;
[0100] FIG. 3 is a schematic illustration of an inner expandable
support structure of the prosthesis, in accordance with some
applications of the present invention;
[0101] FIGS. 4A-F are schematic illustrations of mitral prostheses,
in accordance with some applications of the present invention;
[0102] FIGS. 5A-B are schematic illustrations of the inner
expandable support structure of the prosthesis, in accordance with
some applications of the present invention;
[0103] FIGS. 6A-D are schematic illustrations of the inner
expandable support structure of the prosthesis, in accordance with
some applications of the present invention;
[0104] FIGS. 7A-F are schematic illustrations of respective steps
of a transapical implantation procedure of the mitral valve
prosthesis, in accordance with some applications of the present
invention;
[0105] FIGS. 8A-F are schematic illustrations of respective steps
of a transatrial implantation procedure of the mitral valve
prosthesis, in accordance with some applications of the present
invention;
[0106] FIG. 9 is a schematic illustration of an implanted mitral
valve prosthesis, in accordance with some applications of the
present invention;
[0107] FIGS. 10A-D are schematic illustrations of the engagement
arms of the mitral valve prosthesis, in accordance with respective
applications of the present invention;
[0108] FIGS. 11A-D are schematic illustrations of an engagement arm
assembly, in accordance with some applications of the present
invention;
[0109] FIG. 12 is a schematic illustration of the mitral valve
prosthesis, in accordance with some applications of the present
invention;
[0110] FIG. 13 is a schematic illustration of the mitral valve
prosthesis, in accordance with some applications of the present
invention;
[0111] FIGS. 14A-B are schematic illustrations of the mitral valve
prosthesis, in accordance with some applications of the present
invention; and
[0112] FIGS. 15A-B are schematic illustrations of the mitral valve
prosthesis, in accordance with some applications of the present
invention.
DETAILED DESCRIPTION OF EMBODIMENTS
[0113] Reference is now made to FIGS. 1A-D, which are schematic
illustrations of respective views of a mitral valve prosthesis 100,
in accordance with some applications of the present invention.
[0114] Mitral valve prosthesis 100 includes an inner support
structure 102 and an outer support structure 104. Outer support
structure 104 includes outer engagement arms (i.e., outer support
arms) 106. As shown, mitral valve prosthesis 100 typically includes
two outer engagement arms 106 to anatomically match the native
mitral valve leaflets 107 (shown in FIG. 1B).
[0115] Sutured to inner support structure 102 is a prosthetic valve
118. For some applications, valve 118 is coupled to inner support
structure 102, and/or to engagement arms 106 in accordance with
techniques described in US 2008/0071368 to Tuval, which is
incorporated herein by reference. Valve 118 can be formed of a
biocompatible synthetic material, synthetic polymer, an autograft
tissue, xenograft tissue, or other alternative materials. Valve 118
is a bi-leaflet bovine pericardium valve, a tri-leaflet valve, or
any other suitable valve (e.g., a valve having a different number
of leaflets).
[0116] Mitral-valve prosthesis 100 is typically placed at the
subject's native mitral valve complex 128, as shown in FIG. 1D. As
used herein, including in the claims, the "native mitral valve
complex" includes the native valve leaflets, the annulus of the
valve, chordae tendineae, and papillary muscles. Inner support
structure 102 and engagement arms 106 facilitate fixation of the
mitral valve prosthesis with respect to native mitral valve complex
128. Prosthetic valve 118 functions in a generally similar manner
to a healthy native mitral valve, i.e., the prosthetic valve:
[0117] opens during diastole to permit the flow of blood from the
subject's left atrium to the subject's left ventricle, and [0118]
closes during systole to prevent the backflow of blood in the
upstream direction from the subject's left ventricle to the
subject's left atrium.
[0119] FIG. 1C shows prosthetic valve 118 in a closed state thereof
(i.e., during systole). The prosthetic valve shown in FIG. 1C has
three leaflets, although as described hereinabove, for some
applications, valve 118 has a different number of leaflets.
[0120] As shown in FIG. 1B, upon implantation, mitral valve
prosthesis 100 is placed such that native mitral valve leaflets 107
are disposed between outer engagement arms 106 and inner support
structure 102. The outer engagement arms embrace, without
squeezing, leaflets of the native valve. Typically there is a space
between the engagement arms and the inner support structure, such
that native valve leaflets are not squeezed. For example, along at
least 30% of length L of the engagement arm, the engagement arm is
separated from the inner support structure by a distance D of at
least 0.5 mm. For some applications, the engagement arm is
separated from the inner support structure by a distance 13 of at
least 0.5 mm along at least 50% or 70% of length L of the
engagement arm. For some applications, the aforementioned distance
D by which the engagement arm is separated from the inner support
structure is greater than 1 mm or greater than 4 mm.
[0121] Each outer engagement arm 106 is typically downwardly
concave (i.e., concave in a downstream direction) at the region of
the outer engagement arm that is adjacent to a downstream section
112 of inner support structure 102, when viewed from outside of the
outer support structure, as shown in FIG. 1B, for example. The
downstream ends of the engagement arms typically meet at commissure
posts 108 (shown in FIG. 1A). For some applications, the engagement
arms are coupled to the inner support structure at the commissure
posts. Alternatively or additionally, the engagement arms, and/or
the inner support structure is coupled to prosthetic valve 118 at
the commissure posts, for example, in accordance with techniques
described in US 2008/0071368 to Tuval, which is incorporated herein
by reference. For some applications, mitral valve prosthesis 100
includes three engagement arms 106, three leaflets, and/or three
commissure posts 108, or a different number of the aforementioned
components.
[0122] Typically, engagement arms 106 facilitate the anchoring
and/or orientation of the mitral valve prosthesis at the desired
implantation site. In particular, the engagement arms prevent
mitral valve prosthesis 100 from being dislodged upstream of native
mitral valve complex 128 (e.g., when valve 118 is closed during
systole and an upstream force is exerted on prosthesis 100). This
is achieved, because, in response to upstream-directed blood flow
pushing the valve prosthesis in the upstream direction (e.g.,
during systole), tissue of leaflets 107 of the native mitral valve
complex exerts a downstream-directed force F1 (shown in FIG. 1B) on
the engagement arms. For some applications (e.g., for the
configuration of prosthesis 100 shown in FIGS. 4E-F), downstream
ends of the native valve leaflets exert the downstream directed
force on downstream portions of the engagements arms, i.e., at the
portion of the engagement arms at which the engagement arms form
shoulders with inner support structure 102.
[0123] Typically, downstream ends 105 of engagement arms 106 are
within 3 mm (e.g., within 1 mm) of downstream ends 119 of
prosthetic leaflets 118 (see FIG. 1A), when measured in the
direction of the longitudinal axis of the prosthesis. Further
typically, upon implantation of the prosthesis, downstream ends 105
of engagement arms 106 are within 3 mm (e.g., within 1 mm) of
downstream ends of the native valve leaflets 107 (see FIG. 1B).
Thus, downstream ends of the engagement arms, downstream ends of
the native valve leaflets, and downstream ends of the prosthetic
valve leaflets are all typically within 3 mm (e.g., within 1 mm) of
each other, when measured in the direction of the longitudinal axis
of the prosthesis. Typically, this is achieved because (a) the
prosthetic valve leaflets are coupled to the inner support
structure such that downstream ends of the prosthetic valve
leaflets are within 3 mm (e.g., within 3 mm) of the downstream ends
of the engagement arms, and (b) longitudinal distance D1 (shown in
FIG. 1B) from a downstream end 105 to an upstream end 109 of each
of the engagement arms is less than 18 mm (e.g., less than 12 mm,
or less than 10 mm), the longitudinal distance being measured in a
direction of a longitudinal axis of the prosthesis. Further
typically, the downstream ends of the engagement arms are coupled
to the inner support structure within 3 mm (e.g., within 1 mm) of a
downstream end of the inner support structure.
[0124] Inner support structure 102 includes a downstream section
112, and an upstream section 116. Inner support structure 102 is
typically non-cylindrical. In accordance with respective
applications, downstream section 112 of inner support structure 102
is formed in a straight fashion (i.e., cylindrical and parallel to
the longitudinal axis of prosthesis 100), or in a flared fashion
(i.e., diverging away from the longitudinal axis of prosthesis
100). Upstream section 116 of the inner support structure typically
curves outwardly from the longitudinal axis of the prosthesis, such
that the upstream section has a cross-sectional area that is
greater than the cross-sectional area of downstream section 116.
The upstream section of the inner support structure is typically
wider than the native valve segment at the native annular
level.
[0125] Typically, the non-cylindrical shape of the inner support
structure facilitates the anchoring and/or orientation of the
mitral valve prosthesis at the desired implantation site. In
particular, the upstream section of the inner support structure
being wider than the native valve segment at the native annular
level prevents the mitral valve prosthesis from being dislodged
downstream of native mitral valve complex 128. This is achieved,
because in response to downstream-directed blood flow pushing the
valve prosthesis in a downstream direction, tissue of native mitral
valve complex 128 exerts an upstream-directed force F2 (shown in
FIG. 1B) on the upstream section of the inner support
structure.
[0126] For some applications, the upstream section of the inner
support structure being wider than the native valve segment at the
native annular level improves sealing of prosthesis 100 against the
atrial wall. For some applications, the inner support structure
additionally exerts a radially-directed force on tissue of native
mitral valve complex 128 that facilitates the anchoring and/or
orientation of the prosthetic valve at the desired implantation
site. For some applications, upstream section 116 of the inner
support structure exerts the radially-directed force on tissue of
native mitral valve complex 128.
[0127] Typically, when valve prosthesis 100 is implanted in native
mitral valve complex 128, there are variations with time in the
mechanical stress exerted on the inner support structure, caused by
anatomical and pathological variations of surrounding structures.
For some applications, relative to a more cylindrically-shaped
inner support structure, non-cylindrical inner support structure
resists changes in its shape due to mechanical stress that is
exerted on the inner support structure. Typically, by resisting
changes in its shape, the inner support structure facilitates the
proper functioning of prosthetic valve 118.
[0128] Typically, inner support structure 102 is expandable (e.g.,
self-expandable). For example, the inner support structure may be
formed of a memory alloy, such as nitinol, or another biocompatible
metal. Similarly, outer support structure 104 may be formed of a
memory alloy, such as nitinol, or another biocompatible metal. In
accordance with respective applications, inner support structure
102 and outer support structure 104 are integrally formed, or
comprise separate modular components that are attached to one
another, as described in further detail hereinbelow.
[0129] For some applications, inner support structure 102 is
designed to flex and deform in response to the natural cardiac
movements of the heart through the cardiac cycle. Alternatively,
inner support structure 102 is generally rigid, to avoid flexing or
deformation during the cardiac cycle.
[0130] For some applications, inner support structure 102 includes
one or more sections that are configured to expand to a restricted
or preset diameter rather than expanding until restrained by
surrounding anatomical structures. Thus, a portion of (or the
entirety of) inner support structure 102 may have a predetermined
configuration, irrespective of the surrounding anatomy. Typically,
the predetermined configuration is such that the support structure
expands so as to come into contact with the tissue of the native
valve complex, but does not exert substantial pressure on the
tissue of the native valve complex. For some applications, the
controlled expansion diameter of the inner support structure
improves the valve geometry, relative to a mitral valve prosthesis
having an inner support structure that expands until restrained by
the surrounding anatomy. Typically, at least a portion of inner
support structure 102 (and further typically, all of the inner
support structure) expands until restrained by the surrounding
anatomy.
[0131] As shown (in FIGS. 1A, 1C and 1D, for example), for some
applications, downstream section 112 and upstream section 116 of
inner support structure 102 include generally-diamond-shaped cells
103, which are described in further detail hereinbelow, with
reference to FIG. 3. Alternatively, other shapes and configurations
of the cells 103 are employed, for example, as described
hereinbelow. For some applications, the locations of junctions of
members of a cell with those of adjacent cells are positioned
asymmetrically, and/or cells are shaped asymmetrically. For some
applications, structural members of the cells are shaped
curvilinearly. Alternatively, structural members of the cells are
formed in a generally zigzag configuration to form symmetrical or
asymmetrical cells. For some applications, using structural members
that are shaped in a zigzag configuration distributes the stress
associated with radial expansion and contraction of the support
member to a plurality of points between junctions. In accordance
with respective applications, the inner support structure includes
heterogeneous patterns of cells, or homogeneous patterns, or
both.
[0132] Typically, the ratio of the cell height (H) to cell width
(W) (H and W shown in FIGS. 1A and 1C) of cells 103 is greater than
0.5:1 and/or less than 3:1, e.g., 0.5:1 to 3:1. For example, the
ratio may be greater than 1.5:1 and/or less than 2.5:1, e.g. 1.5:1
to 2.5:1. For example, the ratio may be greater than 1.75:1 and/or
less than 2.25:1, e.g., 1.75:1 to 2.25:1. For some applications,
having cells having the aforementioned ratios of cell height to
cell width facilitates the expansion and/or the maintenance of the
structure of inner support structure 102.
[0133] Reference is now made to FIGS. 2A-D, which are schematic
illustrations of respective views of mitral valve prosthesis 100,
in accordance with some applications of the present invention. For
some applications, a length L2 (shown in FIG. 2B) of an anterior
engagement arm 106A is greater than a length L3 of a posterior
engagement arm 106P. For some applications, the different lengths
of the anterior and posterior engagement arms correspond to the
anatomy of most people, most people having a native anterior mitral
valve leaflet having a greater length than their native posterior
mitral valve leaflet. In all other aspects, the mitral valve
prosthesis shown in FIGS. 2A-D is generally similar to the mitral
valve prosthesis described with reference to FIGS. 1A-D.
[0134] Typically, length L2 of the anterior engagement arm is
greater than 2 mm and less than 35 mm, e.g., 15 mm to mm. Further
typically, length L3 of the posterior engagement arm is greater
than 2 mm and less than 35 mm, e.g., 7 mm to 23 mm. Still further
typically, for applications in which the anterior and posterior
engagement arms have different lengths, the ratio of the length of
the anterior engagement arm to the length of the posterior
engagement arm is greater than 1.1:1, and/or less than 15:1, e.g.,
1.3:1 to 2:1.
[0135] Reference is now made to FIG. 3, which is a schematic
illustration of inner support structure 102 of mitral valve
prosthesis 100, in accordance with some applications of the present
invention. As shown in FIG. 3, for some applications, cells 103 of
the inner support structure have respective characteristics at
different longitudinal locations along the inner support
structure.
[0136] For some applications, downstream section 112 of the inner
support structure includes cells that have relatively short
heights, and relatively high strut width relative to height. In
addition, the cells typically define relatively high angles. For
some applications, cells having the aforementioned characteristics
provide the downstream section of the support structure with a high
radial force area to maintain circularity of the valve, and/or
fatigue resistance against high pressure gradients. Typically, the
downstream section of the support structure is relatively short, so
as to minimize protrusion of the inner support structure into the
ventricle beyond the annular plane.
[0137] For some applications, upstream section 116 of inner support
structure includes an intermediate section 116A, and an
upstream-most section 116B, intermediate section 116B being
disposed between upstream-most section 116A and downstream section
112 of the support structure. The cells of intermediate section
116A and upstream-most section 116B have respective
characteristics.
[0138] Cells 103 of intermediate section 116A typically have
relatively short heights, and relatively high strut width relative
to height. In addition, the cells typically define relatively high
angles. For some applications, cells having the aforementioned
characteristics provide the intermediate section of the support
structure with high pinching resistance. The intermediate section
of the support structure is typically shaped so as to facilitate
annular sealing on the atrial side of the mitral valve complex,
above the annulus. Alternatively or additionally, the intermediate
section of the support structure is shaped so as to prevent
downstream migration of mitral valve prosthesis 100.
[0139] Cells 103 of upstream-most section 116B typically have large
heights. The shape of the cells of the upstream-most portion
typically exert relatively low radial pressure on the surrounding
anatomy, such that the upstream-most section of the support
structure enhances sealing of the native valve complex, by
conforming to the atrial anatomy. Furthermore, by conforming to the
atrial anatomy, the upstream-most section preserves atrial
contraction. The upstream-most section of the support structure
typically has a relatively large cross-sectional area, which
typically prevents downstream migration of mitral valve prosthesis
100.
[0140] Reference is now made to FIGS. 4A-F, which are schematic
illustrations of mitral prosthesis 100, in accordance with some
applications of the present invention. As shown in FIGS. 4A-D, for
some applications, inner support structure 102 of mitral valve
prosthesis 100 does not extend to the downstream end of the
prosthesis. For example, as shown, the inner support structure may
extend from an upstream end 120 to substantially halfway between
upstream and downstream ends of the prosthesis, such that the
downstream end of the inner support structure is between 2 mm and
15 mm from downstream ends 119 of prosthetic leaflets 118.
Alternatively, inner support structure 102 of mitral valve
prosthesis 100 does extend substantially to the downstream end of
the prosthesis, for example, such that the downstream end of the
inner support structure is within 1 mm of downstream ends 119 of
prosthetic leaflets 118 (a shown in FIG. 10, for example).
[0141] For some applications, outer support structure 104 includes
outer engagement arms 106 that are coupled to upstream ends of
commissure post 108, rather than being coupled to downstream ends
of the commissure posts, as described with reference to FIGS. 1A-D.
As shown in FIG. 4B, for some applications, commissure post 108
extends downstream from the ends of engagement arms 106. For such
applications, the downstream ends of commissure posts 108 are level
with the ends of prosthetic valve leaflets 118. In all other
respects, prosthesis 100 of FIG. 4B is generally similar to
prosthesis 100 as described hereinabove with reference to FIGS.
1-3.
[0142] For some applications, not having the inner support
structure extend to the downstream end of the prosthesis, allows
for prosthesis 200 to be constructed of less material, and/or
reduces the weight of prosthesis 200.
[0143] As shown in FIGS. 4E-F, for some applications, engagement
arms 106 and prosthetic valve 118 are coupled to inner support
structure 102 such that downstream ends 119 of the prosthetic valve
leaflets are at a longitudinal distance D2 upstream of the
downstream ends 105 of the engagement arms. Thus, prosthesis 100 is
configured such that upon implantation thereof, the downstream end
of the inner support structure 102 and downstream ends 119 of the
prosthetic valve leaflets 118 are at a longitudinal distance D2
upstream of the downstream ends of the native valve leaflets 107.
Typically, distance D2 is at least 4 mm, e.g., at least mm. Further
typically, upon implantation of the prosthesis, downstream ends of
native valve leaflets of the native mitral valve complex, and
downstream ends 105 of the engagement arms are disposed at a
longitudinal distance from one another of less than 3 mm.
[0144] Reference is now made to FIGS. 5A-B, which are schematic
illustrations of inner expandable support structure 104 of mitral
valve prosthesis 100, in accordance with some applications of the
present invention. As shown, for some applications, apices of the
inner support structure at the upstream end of the support
structure are rounded. FIG. 5B shows slightly rounded apices, and
FIG. 5A shows more rounded apices. For some applications, using
apices that are rounded reduces trauma to the atrial endocardium,
and/or enhances local radial stiffness of the inner support
structure, relative to using an inner support structure having a
non-rounded upstream end. For some applications, the downstream end
of the inner support structure also has rounded cell-apices. In
alternative applications, the apices of the cells at the downstream
end of the inner support structure are non-rounded (as shown in
FIGS. 5A-B), or the apices of the cells at both ends of the inner
support structure are non-rounded (as shown in FIG. 1A).
[0145] Reference is now made to FIGS. 6A-D, which are schematic
illustrations of inner expandable support structure 102 of
prosthesis 100, in accordance with some applications of the present
invention.
[0146] Prosthesis 100 shown in FIGS. 6A-B is generally similar to
the prosthesis described hereinabove, the prosthesis including
inner support structure 102 and outer support structure 104.
However, the shape of inner support structure 102 differs from the
shape of inner support structure 102 of FIG. 1A. Specifically,
upstream section 116 of inner support structure 102 is formed
asymmetrically to accommodate the anterior horn of the atrium
(which is associated anatomically with the position of the aortic
valve), as shown in FIG. 6B, which shows the prosthesis implanted
inside the subject's heart. For example, as shown in FIG. 6A, the
length of prosthesis 100 from downstream section 112 to upstream
section 116 is increased at an area corresponding to the anterior
horn of the atrium. This area also extends radially farther from
the longitudinal axis of the prosthesis, in order to accommodate
the anterior horn. As described hereinabove, upstream section 116
is generally wider than the native valve segment at the native
annular level. Such a configuration prevents migration of
prosthesis 100 into the ventricle and improves sealing of
prosthesis 100 against the atrial wall.
[0147] For some applications, as shown, downstream section 112 of
the inner support structure has a circular cross-section, while
upstream section 116 has a non-circular cross-section. Typically,
for applications in which inner support structure is shaped to
accommodate the anterior horn of the atrium, the cross-section of
inner support structure 102 is a non-uniform, non-circular shape,
for example, a D-shape, or oval.
[0148] FIG. 6B is a sagittal cut through a human heart 124
depicting the implanted mitral valve prosthesis 100 of FIG. 6A.
Chordae tendineae 126, which are disposed in left ventricle 127,
connect native mitral valve 128 to papillary muscles 130.
Engagement arms 106 wrap around leaflets 107 of native mitral valve
128. As shown in FIG. 6B, upstream section 116 has a non-circular,
asymmetric shape to accommodate the anterior horn of atrium 132,
which is associated anatomically with the position of aortic valve
134. The shape of upstream section 116 facilitates axial fixation,
facilitates prevention of outflow obstruction, and/or facilitates
sealing of prosthesis 100 against the wall of left atrium 132.
[0149] Prosthesis 100 shown in FIGS. 6C-D is generally similar to
the prosthesis described hereinabove, the prosthesis including
inner support structure 102 and outer support structure 104.
However, in accordance with some applications of the invention,
upstream section 116 of the inner support structure includes
fixation members 190 (e.g., barbs, as shown, hooks, anchors, or
clips) to provide further fixation support and to prevent migration
of prosthesis 100 into the ventricle.
[0150] FIG. 6D is a sagittal cut through a human heart 124,
depicting an implanted mitral valve prosthesis 100. As shown in
FIG. 6D, upstream section 116 has a non-circular, asymmetric shape
to accommodate the anterior horn of left atrium 132. The shape of
upstream section 116 facilitates axial fixation, facilitates
prevention of outflow obstruction, and/or facilitates sealing of
prosthesis 100 against the wall of left atrium 132. Further, barbs
190 penetrate to the mitral annulus and serve as a locking
mechanism to prevent migration of prosthesis 100 into left
ventricle 127.
[0151] Reference is now made to FIGS. 7A-F, which are schematic
illustrations of respective steps of a transapical implantation
procedure of mitral valve prosthesis 100 (described hereinabove
with reference to any of FIGS. 1-6), in accordance with some
applications of the present invention.
[0152] As shown in FIG. 7A, a trocar (i.e., an overtube) 730 is
inserted into the left ventricle 127 through an incision created in
the apex 724 of a patient's heart 124. A dilator 732 is used to aid
in the insertion of trocar 730. In this transapical approach, the
native mitral valve 128 is approached from the downstream
direction. As shown in FIG. 7B, subsequently, trocar 730 is
retracted sufficiently to release the self-expanding engagement
arms 106 of the mitral valve prosthesis. Typically, dilator 732 is
presented between leaflets of valve 128. Trocar 730 can be rotated
and adjusted as necessary to align the valve prosthesis so that
engagement arms 106 are positioned so as to be placed around
leaflets of native valve 128.
[0153] As shown in FIG. 7C, subsequently, trocar 730 and the valve
prosthesis are advanced forward, such that outer engagement arms
106 embrace without squeezing leaflets of native valve 128. As
shown in FIG. 7D, subsequently, dilator 732 is advanced into the
left atrium to further expose inner support structure 102, and more
specifically, to begin disengaging upstream section 116 from
dilator 732, FIG. 7E shows upstream section 116 released from
dilator 732, and expanded to press against the interior wall of
native mitral valve 128, (For some applications, upstream section
116 does not expand against the interior wall of the native valve
so as to exert a substantial radial force on the inner wall of the
valve. Rather, the upstream section is configured to prevent the
prosthesis from migrating into the left ventricle, as described
hereinabove.) Subsequently, trocar 730 is withdrawn from heart 124,
and the incision in apex 724 is closed, as shown in FIG. 7F.
[0154] It is noted that in the transition from FIG. 7C to FIG. 7E,
the width W1 that is spanned by each of the engagement arms
increases. Typically, during placement of the engagement arms on
the native valve leaflets, each of the engagement arms spans a
width that is less than 12 mm, e.g. less than 8 mm, as shown in
FIG. 7C. Typically, this prevents the engagement arms from coming
into contact with the papillary muscles, since the engagement arms
span a sufficiently narrow width so as to be placed between the
papillary muscles. Further typically, this allows the native valve
to continue functioning at least in part, since there are portions
of the leaflets that are outside the engagement arms that may
continue to open and close, at least partially. Subsequently, the
engagement arms expand (typically, due to the expansion of the
inner support structure) such that each of the engagement arms
spans a width of more than 15 mm, e.g., more than 35 mm, as shown
in FIG. 7E.
[0155] Reference is now made to FIGS. 8A-F, which are schematic
illustrations of respective steps of a transatrial implantation
procedure of mitral valve prosthesis 100 (described hereinabove
with reference to any of FIGS. 1-6), in accordance with some
applications of the present invention.
[0156] As shown in FIG. 8A, dilator 732 and trocar 730 are inserted
through an incision 840 made in the wall of the left atrium of
heart 124. Dilator 732 and trocar 730 are advanced through the
native mitral valve 128 and into the left ventricle of heart 124.
As shown in FIG. 8B, subsequently, dilator 732 is withdrawn from
trocar 732. Subsequently, a guide wire 842 is advanced through
trocar 730 to the point where mitral valve prosthesis 100 comes to
the end of trocar 730, as shown in FIG. 8C. As shown in FIG. 8D,
subsequently, mitral valve prosthesis 100 is advanced sufficiently
to release the self-expanding engagement arms 106 from trocar 730.
Trocar 730 is typically rotated and adjusted as necessary to
properly align the valve prosthesis with native valve 128.
Subsequently, trocar 730 is withdrawn slightly so as to place
engagement arms 106 around the outside of leaflets of native valve
128, as shown in FIG. 8E. Subsequently, trocar 730 is completely
withdrawn from heart 124 such that mitral valve prosthesis 100
self-expands into position and assumes the function of native
mitral valve 128, as shown in FIG. 8F.
[0157] For some applications (not shown), prosthesis 100 (described
hereinabove with reference to any of FIGS. 1-6) is implanted
transseptally. For such applications, the prosthesis is advanced
via the femoral vein, into the right atrium. An incision is made in
the septum of the heart to provide access to the left atrium. The
prosthesis is then advanced through the incision in the septum and
is implanted through a technique similar to the one described
hereinabove with reference to FIGS. 8C-8F. Such a method typically
includes some or all of the following: making an incision in a
femoral vein; inserting a trocar through the incision in the
femoral vein and advancing the trocar into the right atrium of the
heart; making an incision in the septum of the heart; advancing the
trocar through the incision in the septum of the heart and into the
left atrium; advancing a mitral valve prosthesis through the trocar
and into the left atrium of the heart; advancing the trocar past
the native mitral valve and into the left ventricle of the heart;
releasing the engagement arms from the trocar; retracting the
trocar such that the engagement arms are placed around the outer
surface of the native mitral valve leaflets; releasing the inner
support structure from the trocar; closing the incision in the
septum; and withdrawing the trocar from the heart.
[0158] Reference is now made to FIG. 9, which is a schematic
illustration of implanted mitral valve prosthesis 100 (described
hereinabove with reference to any of FIGS. 1-6), in accordance with
some applications of the present invention. Mitral valve prosthesis
100 has engagement arms 106 that are placed around leaflets of
native valve 128. Typically, downstream ends of engagement arms
define a rotational gap. When valve prosthesis 100 is implanted in
the native mitral valve, the commissures of the native mitral
valve, and the regions of the native leaflets adjacent to the
commissures are squeezed within the gap between the two ends of
outer engagement arms 106. The leaflets are squeezed within the gap
such that the regions of the anterior and posterior leaflets that
are adjacent to the commissures are squeezed against one another
and seal the commisures.
[0159] Reference is now made to FIGS. 10A-D, which are schematic
illustrations of engagement arms 106 of mitral valve prosthesis
100, in accordance with respective applications of the present
invention. In accordance with respective applications, engagement
arms 106 form a U-shaped troughs 110 (FIG. 10A), circular-shaped
troughs 111 (FIG. 10B), bulging flask-shaped troughs 113 (FIG.
100), and/or undulating, bottle-nipple shaped trough 115 (FIG.
10D). For some applications (not shown), the engagement arms are
shaped to include two or more parallel arches.
[0160] Reference is now made to FIGS. 11A-D, which are schematic
illustrations of outer support structure 104, in accordance with
some applications of the present invention. FIG. 11A shows a single
continuous structure that includes engagement arms 106, the
engagement arms emerging from respective points of a connecting
frame 121 of the outer support structure. As shown in FIG. 11B, the
outer support structure is placed over inner support structure 102,
and is coupled to the inner support structure. For some
applications, using a single continuous structure from which the
engagement arms emerge ensures that the engagement arms are placed
symmetrically on the prosthesis, facilitates assembly of the
prosthesis, and/or enhances the overall frame strength of the
prosthesis.
[0161] As shown in FIG. 11A, for some applications, the engagements
arms include a leaflet capturing element 123 (e.g., additional
struts, as shown) to reduce motion of the native valve leaflets, to
immobilize the native valve leaflets, and/or to prevent systolic
anterior motion of the leaflets. Typically, by preventing systolic
anterior motion of the leaflets, the engagement arms prevent the
native leaflets from blocking or interfering with the LVOT. For
some applications, engagement arms 106, as described with reference
to FIGS. 11A-D, or elsewhere in the present application, prevent
systolic anterior motion of the native leaflets even in the absence
of the leaflet capturing element or any other additional
element.
[0162] As shown in FIGS. 11C-D, for some applications, the whole of
outer support structure 104 (FIG. 11C), or a portion thereof (FIG.
11D), is covered with a biocompatible cloth 145 (e.g., polyester).
Typically, the cover helps to prevent systolic anterior motion of
the native leaflets through engagement arms 106, and/or to reduce
metal to metal abrasion between the outer and inner support
structures. For some applications, the cover generally may help
capture calcific, thrombotic, or other material which might be
dislodged from the native valve or the surrounding tissue.
[0163] Reference is now made to FIG. 12, which is a schematic
illustration of the mitral valve prosthesis 100, in accordance with
some applications of the present invention. Prosthesis 100, as
shown in FIG. 12, is generally similar to prosthesis 100 described
hereinabove, except that the downstream ends of engagement arms 106
of prosthesis 100 as shown in FIG. 12 are connected directly to
inner support structure 102. As shown in FIG. 12, engagement arms
106 are attached to inner support structure 102 at downstream
section 112 of the inner support structure. In accordance with some
applications, engagement arms 106 are directly attached to inner
support structure 102 at any suitable location, including but not
limited to downstream section 112, intermediate section 116A,
and/or upstream-most section 116B (the aforementioned sections
typically being as described hereinabove with reference to FIG. 3).
For some applications, the engagement arms are integrally formed
with the inner support structure.
[0164] Reference is now made to FIG. 13, which is a schematic
illustration of mitral valve prosthesis 100, in accordance with
some applications of the present invention. Prosthesis 100, as
shown in FIG. 13, is generally similar to prosthesis 100 described
with reference to FIG. 12. However, relative to the prosthesis
shown in FIG. 12, the prosthesis shown in FIG. 13 includes a
shorter downstream section 112 of more than 1 mm and/or less than
20 mm, e.g., 1-20 mm (for example, more than 10 mm and/or less than
14 mm, e.g., 10-14 mm). In addition, relative to the prosthesis
shown in FIG. 12, engagement arms 106 of the prosthesis shown in
FIG. 13 are attached to inner support structure 102 closer to the
downstream end of the prosthesis. For some applications, use of a
shorter prosthesis improves the maneuverability of the prosthesis
when loaded on a delivery catheter, thereby facilitating
implantation of such devices and reducing the time required to
perform the implantation procedure, relative to the use of a longer
prosthesis. For some applications, use of a shorter prosthesis
reduces interference of the prosthesis with the left ventricular
outflow tract (LVOT), relative to a longer prosthesis.
[0165] Reference is now made to FIGS. 14A-B, which are schematic
illustrations of portions of mitral valve prosthesis 100, in
accordance with some applications of the present invention. FIGS.
14A-B shows a single outer support structure 104 that includes
engagement arms 106, the engagement arms emerging from respective
points of the continuous structure. Connecting frame 123 of the
outer support structure includes struts that are geometrically
similar in structure to the corresponding struts on the inner
support structure 102. For some applications, using struts that are
similar to the corresponding struts on the inner support structure
enhances the frame strength of the prosthesis, when the inner and
outer support structures are coupled to one another.
[0166] In accordance with respective applications, engagement arms
106 are coupled to connecting frame 123 of outer support structure
104, or the engagement arms and the connecting frame form a single
continuous structure. As described hereinabove with reference to
FIGS. 11A-B, for some applications, using a single continuous
structure from which the engagement arms emerge ensures that the
engagement arms are placed symmetrically on the prosthesis,
facilitates assembly of the prosthesis, and/or enhances the overall
frame strength of the prosthesis.
[0167] As shown in FIG. 14B, for some applications, at least a
portion of outer support structure 104 is covered with a
biocompatible cloth 145 (e.g., polyester). Typically, the cover
helps to prevent systolic anterior motion of the native leaflets
through engagement arms 106, and/or to reduce metal to metal
abrasion between the outer and inner support structures. For some
applications, the cover generally may help capture calcific,
thrombotic, or other material which might be dislodged from the
native valve or the surrounding tissue.
[0168] Reference is now made to FIGS. 15A-B, which are schematic
illustrations of mitral valve prosthesis 100, in accordance with
some applications of the present invention. For some applications,
during the construction of the mitral valve prosthesis, engagement
arms 106 are cut as integral parts of inner support structure 102.
Engagement arms 106 are folded into position with respect to inner
support structure 102 using heat treatment, FIG. 15B shows the
engagement arms having been folded into position, with respect to
the inner support structure.
[0169] Features of mitral valve prosthesis 100 described with
reference to respective figures are not limited to the prostheses
shown in those figures. Rather, features of the prosthesis shown in
any of the figures could be used in combination with any of the
other features described herein, mutatis mutandis. Examples of the
features that may be combined with each other include, but are not
limited to: [0170] structures of the cells of inner support
structure 102 [0171] asymmetrical engagement arms 106 of FIGS.
2A-D, [0172] the features of inner support structure 102 and outer
support structure 104 described with reference to FIGS. 4A-F [0173]
the features of inner support structure 102 described with
reference to FIGS. 5A-B [0174] the asymmetric inner support
structure, and fixation barbs of the inner support structure, as
described with reference to FIGS. 6A-D [0175] features of the outer
support structure, and/or the engagement arms described with
reference to FIGS. 9-15B.
[0176] Further, any of the surgical techniques described herein can
be used for implantation of prosthesis 100, including but not
limited to, methods of implanting the mitral valve prosthesis
transapically, transatrially, and transseptally, for example, as
described hereinabove with reference to FIGS. 7-8.
[0177] As used herein, the terms "upstream" and "downstream" are
used to refer to the upstream and downstream directions of the
blood flow when mitral valve prosthesis 100 is implanted inside the
subject's heart. The terms "upstream" and "downstream" should be
interpreted as being interchangeable, respectively, with the terms
"proximal" and "distal."
[0178] The techniques described herein may be combined with the
techniques described in one or more of the following applications,
all of which applications are incorporated herein by reference:
[0179] US 2008/0071368 to Tuval [0180] US 2009/0281618 to Hill
[0181] US 2010-0036479 to Hill
[0182] It will be appreciated by persons skilled in the art that
the present invention is not limited to what has been particularly
shown and described hereinabove. Rather, the scope of the present
invention includes both combinations and subcombinations of the
various features described hereinabove, as well as variations and
modifications thereof that are not in the prior art, which would
occur to persons skilled in the art upon reading the foregoing
description.
* * * * * | https://uspto.report/patent/app/20110208297 |
AC generators, of an output 75-375 kVA | OEC - The Observatory of Economic Complexity
null
AC generators, of an output 75-375 kVA
850162 (Harmonized System 1992 for 6-digit)
2021 World Trade : $1.05B , Rnk 2079 / 4641
2021 Top Exporter | Top Importer : $279M | $173M , United States | United States
2021 Product Complexity : 0.57 , Rnk 1521 / 4648
2020 - 2021 Export Growth (CAGR) : -6.22% , Rnk 4324 / 4641
2018 Mean Tariff : 6.99% , Rnk 3250 / 6538
2021 Share of World Trade : <0.01% , Rnk 2079 / 4641
OverviewThis page contains the latest trade data of AC generators, of an output 75-375 kVA. In 2021, AC generators, of an output 75-375 kVAwere the world's 2079th most traded product, with a total trade of $1.05B. Between 2020 and 2021 the exports of AC generators, of an output 75-375 kVAdecreased by -6.22%, from $1.12B to $1.05B. Trade in AC generators, of an output 75-375 kVArepresent 0.00005% of total world trade.
AC generators, of an output 75-375 kVA are a part ofElectric Motors.
ExportsIn 2021 the top exporters of AC generators, of an output 75-375 kVAwereUnited States($279M),Singapore($125M),China($120M),Germany($102M), andUnited Kingdom($100M).
ImportsIn 2021 the top importers of AC generators, of an output 75-375 kVAwereUnited States($173M),France($110M),Germany($86.5M),China($71.1M), andUnited Kingdom($61.5M).
TariffsIn 2018 the average tariff for AC generators, of an output 75-375 kVAwas 6.99%, making it the 3250th lowest tariff using the HS6 product classification.
Ranking AC generators, of an output 75-375 kVAranks 1521st in the Product Complexity Index (PCI).
DescriptionAn ac generator is a device that converts mechanical energy into electrical energy. Large generators typically produce AC power at a voltage of 120 V and a frequency of 60 Hz. The common uses of an output 75-375 kva are for supplying power to electric grids, powering large industrial sites, and providing backup power for small communities.
Latest Trends
Latest Data
Color caret-down Trade Value Index Index (YoY) Growth Growth (YoY)
The following visualization shows the latest trends on AC generators, of an output 75-375 kVA. Countries are shown based on data availability.
For a full breakdown of trade patterns, visit the trend explorer or the product in country profile.
* Using January 2020 exchange rates when trade data is reported in local currency.
Historical Data
Exporters and Importers
Trade By Country
Year caret-down 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
Top Origin (2021) : United States , $279M
Top Destination (2021) : United States , $173M
AC generators, of an output 75-375 kVAare the world's 2079th most traded product.
In 2021, the top exporters of AC generators, of an output 75-375 kVAwereUnited States($279M),Singapore($125M),China($120M),Germany($102M), andUnited Kingdom($100M).
In 2021, the top importers of AC generators, of an output 75-375 kVAwereUnited States($173M),France($110M),Germany($86.5M),China($71.1M), andUnited Kingdom($61.5M).
Market Dynamics
Trade by country
Starting caret-down 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
Ending caret-down 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
Color Growth Growth %
Top Origin Growth (2020 - 2021) : Singapore , $31.4M
Top Destination Growth (2020 - 2021) : China , $35.9M
Between 2020 and 2021, the exports of AC generators, of an output 75-375 kVAgrew the fastest inSingapore($31.4M),India($13.8M),Russia($13M),China($8.43M), andSpain($8.36M).
Between 2020 and 2021, the fastest growing importers of AC generators, of an output 75-375 kVAwereChina($35.9M),Spain($17.3M),Australia($12.2M),Turkey($11.3M), andRussia($10.4M).
Market Concentration
Cumulative market share
Value Value Share
This chart shows the evolution of the market concentration of exports of AC generators, of an output 75-375 kVA.
In 2021, market concentration measured using Shannon Entropy, was 3.77. This means that most of the exports of AC generators, of an output 75-375 kVAare explained by 13 countries.
Net Trade
Year caret-down 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
TOP NET EXPORTER (2021) : Singapore , $109M
TOP NET IMPORTER (2021) : France , $58.9M
This map shows which countries export or import more of AC generators, of an output 75-375 kVA. Each country is colored based on the difference in exports and imports of AC generators, of an output 75-375 kVAduring 2021.
In 2021, the countries that had a largest trade value in exports than in imports of AC generators, of an output 75-375 kVAwereSingapore($109M),United States($106M),China($49.2M),United Kingdom($38.6M), andCzechia($30.3M).
In 2021, the countries that had a largest trade value in imports than in exports of AC generators, of an output 75-375 kVAwereFrance($58.9M),United Arab Emirates($51M),Turkey($27.1M),Spain($25M), andCanada($23.3M).
Country Comparison
Continents caret-down All Africa Antarctica Asia Europe North America Oceania South America
Flow Imports Exports
Measure Rate Value Growth (%)
Ranking Top 10 Bottom 10
This visualization shows the countries that have an important ratio of their trade related to AC generators, of an output 75-375 kVA.It is possible to select the main countries that export or import AC generators, of an output 75-375 kVAin the world, or by continent, as well as select the measure of interest.
Product Complexity
Diversification Frontier
Specialization All RCA ≤ 1 RCA > 1
Year caret-down 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
The Complexity-Relatedness diagram compares the risk and the strategic value of a product's potential export opportunities. Relatedness is predictive of the probability that a country increases its exports in a product. Complexity, is associated with higher levels of income, economic growth potential, lower income inequality, and lower emissions.
| https://oec.world/en/profile/hs/ac-generators-of-an-output-75-375-kva |
Judges 19 KJV KJV Parallel
KJV Parallel KJV [BSB CSB ESV HCS
KJV ISV NAS NET NIV NLT HEB]
King James Bible King James Bible
1 And it came to pass in those days, when there was no king in Israel, that there was a certain Levite sojourning on the side of mount Ephraim, who took to him a concubine out of Bethlehemjudah.
1 And it came to pass in those days, when there was no king in Israel, that there was a certain Levite sojourning on the side of mount Ephraim, who took to him a concubine out of Bethlehemjudah.
2 And his concubine played the whore against him, and went away from him unto her father's house to Bethlehemjudah, and was there four whole months. 2 And his concubine played the whore against him, and went away from him unto her father's house to Bethlehemjudah, and was there four whole months.
3 And her husband arose, and went after her, to speak friendly unto her,
and to bring her again, having his servant with him, and a couple of asses: and she brought him into her father's house: and when the father of the damsel saw him, he rejoiced to meet him.
3 And her husband arose, and went after her, to speak friendly unto her,
and to bring her again, having his servant with him, and a couple of asses: and she brought him into her father's house: and when the father of the damsel saw him, he rejoiced to meet him.
4 And his father in law, the damsel's father, retained him; and he abode with him three days: so they did eat and drink, and lodged there. 4 And his father in law, the damsel's father, retained him; and he abode with him three days: so they did eat and drink, and lodged there.
5 And it came to pass on the fourth day, when they arose early in the morning, that he rose up to depart: and the damsel's father said unto his son in law, Comfort thine heart with a morsel of bread, and afterward go your way. 5 And it came to pass on the fourth day, when they arose early in the morning, that he rose up to depart: and the damsel's father said unto his son in law, Comfort thine heart with a morsel of bread, and afterward go your way.
6 And they sat down, and did eat and drink both of them together: for the damsel's father had said unto the man, Be content, I pray thee, and tarry all night, and let thine heart be merry. 6 And they sat down, and did eat and drink both of them together: for the damsel's father had said unto the man, Be content, I pray thee, and tarry all night, and let thine heart be merry.
7 And when the man rose up to depart, his father in law urged him: therefore he lodged there again. 7 And when the man rose up to depart, his father in law urged him: therefore he lodged there again.
8 And he arose early in the morning on the fifth day to depart: and the damsel's father said, Comfort thine heart, I pray thee. And they tarried until afternoon, and they did eat both of them. 8 And he arose early in the morning on the fifth day to depart: and the damsel's father said, Comfort thine heart, I pray thee. And they tarried until afternoon, and they did eat both of them.
9 And when the man rose up to depart, he, and his concubine, and his servant, his father in law, the damsel's father, said unto him, Behold, now the day draweth toward evening, I pray you tarry all night: behold, the day groweth to an end, lodge here, that thine heart may be merry; and to morrow get you early on your way, that thou mayest go home. 9 And when the man rose up to depart, he, and his concubine, and his servant, his father in law, the damsel's father, said unto him, Behold, now the day draweth toward evening, I pray you tarry all night: behold, the day groweth to an end, lodge here, that thine heart may be merry; and to morrow get you early on your way, that thou mayest go home.
10 But the man would not tarry that night, but he rose up and departed, and came over against Jebus, which is
Jerusalem; and
there were with him two asses saddled, his concubine also was
with him.
10 But the man would not tarry that night, but he rose up and departed, and came over against Jebus, which is
Jerusalem; and
there were with him two asses saddled, his concubine also was
with him.
11 And when they
were by Jebus, the day was far spent; and the servant said unto his master, Come, I pray thee, and let us turn in into this city of the Jebusites, and lodge in it.
11 And when they
were by Jebus, the day was far spent; and the servant said unto his master, Come, I pray thee, and let us turn in into this city of the Jebusites, and lodge in it.
12 And his master said unto him, We will not turn aside hither into the city of a stranger, that
is not of the children of Israel; we will pass over to Gibeah.
12 And his master said unto him, We will not turn aside hither into the city of a stranger, that
is not of the children of Israel; we will pass over to Gibeah.
13 And he said unto his servant, Come, and let us draw near to one of these places to lodge all night, in Gibeah, or in Ramah. 13 And he said unto his servant, Come, and let us draw near to one of these places to lodge all night, in Gibeah, or in Ramah.
14 And they passed on and went their way; and the sun went down upon them
when they were
by Gibeah, which belongeth to Benjamin.
14 And they passed on and went their way; and the sun went down upon them
when they were
by Gibeah, which belongeth to Benjamin.
15 And they turned aside thither, to go in and to lodge in Gibeah: and when he went in, he sat him down in a street of the city: for there was no man that took them into his house to lodging.
15 And they turned aside thither, to go in and to lodge in Gibeah: and when he went in, he sat him down in a street of the city: for there was no man that took them into his house to lodging.
16 And, behold, there came an old man from his work out of the field at even, which was
also of mount Ephraim; and he sojourned in Gibeah: but the men of the place
were Benjamites.
16 And, behold, there came an old man from his work out of the field at even, which was
also of mount Ephraim; and he sojourned in Gibeah: but the men of the place
were Benjamites.
17 And when he had lifted up his eyes, he saw a wayfaring man in the street of the city: and the old man said, Whither goest thou? and whence comest thou? 17 And when he had lifted up his eyes, he saw a wayfaring man in the street of the city: and the old man said, Whither goest thou? and whence comest thou?
18 And he said unto him, We are
passing from Bethlehemjudah toward the side of mount Ephraim; from thence am I: and I went to Bethlehemjudah, but I am now going to the house of the LORD; and there is
no man that receiveth me to house.
18 And he said unto him, We are
passing from Bethlehemjudah toward the side of mount Ephraim; from thence am I: and I went to Bethlehemjudah, but I am now going to the house of the LORD; and there is
no man that receiveth me to house.
19 Yet there is both straw and provender for our asses; and there is bread and wine also for me, and for thy handmaid, and for the young man which is with thy servants:
there is
no want of any thing.
19 Yet there is both straw and provender for our asses; and there is bread and wine also for me, and for thy handmaid, and for the young man which is with thy servants:
there is
no want of any thing.
20 And the old man said, Peace be with thee; howsoever
let all thy wants lie
upon me; only lodge not in the street.
20 And the old man said, Peace be with thee; howsoever
let all thy wants lie
upon me; only lodge not in the street.
21 So he brought him into his house, and gave provender unto the asses: and they washed their feet, and did eat and drink. 21 So he brought him into his house, and gave provender unto the asses: and they washed their feet, and did eat and drink.
22 Now as they were making their hearts merry, behold, the men of the city, certain sons of Belial, beset the house round about, and
beat at the door, and spake to the master of the house, the old man, saying, Bring forth the man that came into thine house, that we may know him.
22 Now as they were making their hearts merry, behold, the men of the city, certain sons of Belial, beset the house round about, and
beat at the door, and spake to the master of the house, the old man, saying, Bring forth the man that came into thine house, that we may know him.
23 And the man, the master of the house, went out unto them, and said unto them, Nay, my brethren,
nay , I pray you, do not so wickedly; seeing that this man is come into mine house, do not this folly.
23 And the man, the master of the house, went out unto them, and said unto them, Nay, my brethren,
nay , I pray you, do not so wickedly; seeing that this man is come into mine house, do not this folly.
24 Behold, here is
my daughter a maiden, and his concubine; them I will bring out now, and humble ye them, and do with them what seemeth good unto you: but unto this man do not so vile a thing.
24 Behold, here is
my daughter a maiden, and his concubine; them I will bring out now, and humble ye them, and do with them what seemeth good unto you: but unto this man do not so vile a thing.
25 But the men would not hearken to him: so the man took his concubine, and brought her forth unto them; and they knew her, and abused her all the night until the morning: and when the day began to spring, they let her go. 25 But the men would not hearken to him: so the man took his concubine, and brought her forth unto them; and they knew her, and abused her all the night until the morning: and when the day began to spring, they let her go.
26 Then came the woman in the dawning of the day, and fell down at the door of the man's house where her lord was , till it was light.
26 Then came the woman in the dawning of the day, and fell down at the door of the man's house where her lord was , till it was light.
27 And her lord rose up in the morning, and opened the doors of the house, and went out to go his way: and, behold, the woman his concubine was fallen down at the door of the house, and her hands
were upon the threshold.
27 And her lord rose up in the morning, and opened the doors of the house, and went out to go his way: and, behold, the woman his concubine was fallen down at the door of the house, and her hands
were upon the threshold.
28 And he said unto her, Up, and let us be going. But none answered. Then the man took her
up upon an ass, and the man rose up, and gat him unto his place.
28 And he said unto her, Up, and let us be going. But none answered. Then the man took her
up upon an ass, and the man rose up, and gat him unto his place.
29 And when he was come into his house, he took a knife, and laid hold on his concubine, and divided her,
together with her bones, into twelve pieces, and sent her into all the coasts of Israel.
29 And when he was come into his house, he took a knife, and laid hold on his concubine, and divided her,
together with her bones, into twelve pieces, and sent her into all the coasts of Israel.
30 And it was so, that all that saw it said, There was no such deed done nor seen from the day that the children of Israel came up out of the land of Egypt unto this day: consider of it, take advice, and speak
your minds .
30 And it was so, that all that saw it said, There was no such deed done nor seen from the day that the children of Israel came up out of the land of Egypt unto this day: consider of it, take advice, and speak
your minds .
King James Bible, text courtesy of
BibleProtector.com .
King James Bible, text courtesy of
BibleProtector.com .
Bible Hub | https://biblehub.com/p/kjv/kjv/judges/19.shtml |
1 H NMR spectrum of b (TFA-D, 298 K, 600 MHz). | Download Scientific Diagram
Download scientific diagram | 1 H NMR spectrum of b (TFA-D, 298 K, 600 MHz). from publication: Data of 1H/13C NMR spectra and degree of substitution for chitosan alkyl urea | The data shown in this article are related to the subject of an article in Carbohydrate Polymers, entitled “Synthesis and characterization of chitosan alkyl urea” [1]. 1H NMR and 13C NMR spectra of chitosan n-octyl urea, chitosan n-dodecyl urea and chitosan cyclohexyl urea... | Chitosan, Urea and Spectra | ResearchGate, the professional network for scientists.
1 H NMR spectrum of b (TFA-D, 298 K, 600 MHz).
Source publication
Data of 1H/13C NMR spectra and degree of substitution for chitosan alkyl urea
Ji-Zhou Jiang
The data shown in this article are related to the subject of an article in Carbohydrate Polymers, entitled “Synthesis and characterization of chitosan alkyl urea” [1]. 1H NMR and 13C NMR spectra of chitosan n-octyl urea, chitosan n-dodecyl urea and chitosan cyclohexyl urea are displayed. The chemical shifts of proton and carbon of glucose skeleton...
Contexts in source publication
Context 1
... total integral of the seven hydrogens of glucose skeleton of chitosan is designated as 7.00 (Fig. 4), other integrals match corresponding hydrogen numbers. Therefore, the DS of n-dodecyl on b is almost ...
Context 2
... on Figs. 4 and 5, the chemical shifts of proton and carbon in glucose skeleton of chitosan n-dodecyl urea (b) are listed in Table 2. The peak of the hydrogen in -CH-of cyclohexyl group overlapped with that of seven hydrogens on glucose skeleton of chitosan, and the total integral of these eight hydrogens is assumed as 8.00 (Fig. 6). The DS of ...
Citations
... In sample C, a set of peaks at 3.10, 1.59 and 0.82 ppm were attributed to the hydrogen atoms on tripropyl (h, i, and j). New peaks at 3.34, 1.54, 1.23 and 0.81 ppm were ascribed to the protons h, i, j and k of -N + (CH2CH2CH2CH3)3 on compound D, respectively [31,
32]
. In conclusion, the above 1 H NMR spectrum analysis indicated the successful preparation of cationic chitooligosaccharide derivatives bearing pyridinium and trialkyl ammonium through the nucleophilic substitution reaction of COS-N and BPTABs with different alkyl chain lengths. ...
Cationic Chitooligosaccharide Derivatives Bearing Pyridinium and Trialkyl Ammonium: Preparation, Characterization and Antimicrobial Activities
Aili Jiang
In this study, chitooligosaccharide-niacin acid conjugate was designed and synthesized through the reaction of chitooligosaccharide and nicotinic acid with the aid of N,N′-carbonyldiimidazole. Its cationic derivatives were prepared by the further nucleophilic substitution reaction between the chitooligosaccharide-niacin acid conjugate and bromopropyl trialkyl ammonium bromide with different alkyl chain lengths. The specific structural characterization of all derivatives was identified using Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR), and the degree of substitution was obtained using the integral area ratio of the hydrogen signals. Specifically, the antibacterial activities against Escherichia coli, Staphylococcus aureus, Pseudoalteromonas citrea and Vibrio harveyi were evaluated using broth dilution methods. In addition, their antifungal activities, including Botrytis cinerea, Glomerella cingulate and Fusarium oxysporum f. sp. cubense were assayed in vitro using the mycelium growth rate method. Experimental data proved that the samples showed antibacterial activity against four pathogenic bacteria (MIC = 1–0.125 mg/mL, MBC = 8–0.5 mg/mL) and enhanced antifungal activity (50.30–68.48% at 1.0 mg/mL) against Botrytis cinerea. In particular, of all chitooligosaccharide derivatives, the chitooligosaccharide derivative containing pyridinium and tri-n-butylamine showed the strongest antibacterial capacity against all of the test pathogenic bacteria; the MIC against Vibrio harveyi was 0.125 mg/mL and the MBC was 1 mg/mL. The experimental results above showed that the introduction of pyridinium salt and quaternary ammonium salt bearing trialkyl enhanced the antimicrobial activity. In addition, the cytotoxicity against L929 cells of the chitooligosaccharide derivatives was evaluated, and the compounds exhibited slight cytotoxicity. Specifically, the cell viability was greater than 91.80% at all test concentrations. The results suggested that the cationic chitooligosaccharide derivatives bearing pyridinium and trialkyl ammonium possessed better antimicrobial activity than pure chitooligosaccharide, indicating their potential as antimicrobial agents in food, medicine, cosmetics and other fields.
... ppm. 39 The simultaneous appearance of signals due to C�O
55
39 These results showed the formation of chitosan TSCs with partial introduction of the TSC group in chitosan. ...
Pyridine-Based NNS Tridentate Chitosan Thiosemicarbazones and Their Copper(II) Complexes: Synthesis, Characterization, and Anticancer Activity
Chitosan-functionalized pyridine-based thiosemicarbazones and their copper(II) complexes have been found to own a substantial antiproliferative activity against the tumorigenic Madin Darby canine kidney (MDCK) and MCF-7 cancer cell lines. In the current study, chitosan oligosaccharide (CS) (87% DDA, Mw < 3000 Da) and crab shell chitosan (CCS) (67% DDA, M w 350 kDa) were functionalized as chitosan pyridine-2-thiosemicarbazones and chitosan 2-acetyl pyridine-2-thiosemicarbazones, and their copper(II) complexes were synthesized. The formation of chitosan thiosemicarbazones and their NNS tridentate behavior to give the square planar copper(II) chitosan thiosemicarbazone complexes were established by spectroscopic studies, powder X-ray diffraction, elemental analysis, and magnetic moment measurements. The thermal study showed a marked stability of these derivatives before the outset of chitosan backbone degradation at 200 °C. The colorimetric MTT assay revealed a higher activity of CS thiosemicarbazones, viz., CSTSC series (IC50 375-381 μg mL-1 in the MDCK cell line and 281-355 μg mL-1 in the MCF-7 cell line) than that of high-molecular-weight CCS thiosemicarbazones, viz., CCSTSC series (IC50 335-400 μg mL-1 in the MDCK cell line and 365-400 μg mL-1 in the MCF-7 cell line), showing an enhanced activity with a decrease in Mw and an increase in DDA of constituent chitosan, a higher activity of both of these series of thiosemicarbazones than that of their native chitosan, viz., CS (IC50 370 μg mL-1 in the MCF-7 cell line and >400 μg mL-1 in the MDCK cell line) and CCS (IC50 > 400 μg mL-1 in both cell lines), and a higher activity of the Cu-CSTSC complexes (IC50 322-342 μg mL-1 in the MDCK cell line and 278-352 μg mL-1 in the MCF-7 cell line) and Cu-CCSTSC complexes (IC50 274-400 μg mL-1 in the MDCK cell line and 231-352 μg mL-1 in the MCF-7 cell line) than that of their respective ligands.
... A sharp signal at 4.78 ppm was identified to be of the solvent D 2 O [75][76][77] and the signal at 1.81 ppm can be due to the left-over acetic acid (solvent) in the reaction mixture. The degree of substitution of NHMA moiety on CS is calculated by (A/2) × 100%
[78]
where 'A' signifies the total integral of the peak (CH 2 group of NHMA) at 4.5 ppm, in which there are two hydrogens. Hence, degree of substitution was found to be (0.72/2) × 100 = 36%. ...
Synthesis, characterization and application of chitosan-N-(4-hydroxyphenyl)-methacrylamide derivative as a drug and gene carrier
Article
Dec 2021
INT J BIOL MACROMOL
Shefali Jaiswal
Pradip Kumar Dutta
Santosh Kumar
Joonseok Koh
Pankaj Garg
The aim of this study was to develop a green method to fabricate a novel CS modified N-(4-hydroxyphenyl)- methacrylamide conjugate (CSNHMA) and to evaluate its biomedical potential. CSNHMA has been prepared by a simple method via aza Michael addition reaction between CS and N- (4-hydroxyphenyl)-methacrylamide (NHMA) in ethanol. Its structural and morphological properties were characterized by various analysis techniques. The obtained results confirmed that a highly porous network structure of CSNHMA was successfully synthesized via aza Michael addition reaction. Consequently, it was analyzed as a drug and gene carrier. CSNHMA/pGL3 showed an enhanced buffering capacity due to the presence of NHMA moiety leading to higher transfection efficiency in all cancer cells (A549, HeLa and HepG2) as compared to native CS and Lipofectamine®. Therefore, these findings clearly support the possibility of using CSNHMA as a good transfection agent. For in vitro drug release study, we prepared CSNHMA nanoparticles (NPs) and curcumin loaded CSNHMA NPs of size <230 nm respectively via the non-toxic ionic gelation route and the encapsulation efficiency of drug was found to be 77.03%. In vitro drug release studies demonstrated a faster and sustained release of curcumin loaded CSNHMA NPs at pH 5.0 compared to physiological pH.
... FT-IR and 1 H NMR analyses provide useful information about the successful modification of chitosan by MR. These methods are among the most accurate and useful techniques to characterize and calculate the DDA and the DS of chitosan (Dong et al., 2001;Lavertu et al., 2003;Vandevelde & Kiekens, 2004;
Wang, Jiang, Chen, & Bai, 2016)
. Indeed, all studies showed that the FT-IR analysis of chitosan derivatives obtained by MR exhibited a new absorption band between 1630 and 1650 cm − 1 assigned to the Schiff base (-C--N-) linkage (Arata Badano et al., 2019;Duan et al., 2019;Gullón et al., 2016;Hafsa & Smach, 2019;Kosaraju, Weerakkody, & Augustin, 2010;Li et al., 2011;Sun et al., 2017;Wu et al., 2014;Xu et al., 2019;Ying et al., 2011;Zhang et al., 2015;Zheng et al., 2019b). ...
Functional properties of chitosan derivatives obtained through Maillard reaction: A novel promising food preservative
FOOD CHEM
Jawhar Hafsa
Mohamed ali Smach
Reda ben Mrid
Mansour Sobeh
This review provides an insight about the functional properties of chitosan obtained through Maillard reaction to enhance the shelf life and food quality. Maillard reaction is a promising and safe method to obtain commercial water-soluble chitosan’s through Schiff base linkage and Amadori or Heyns rearrangement. Likewise, chitosan derivatives exert an enhanced antimicrobial, antioxidant, and emulsifying properties due to the development of Maillard reaction products (MRPs) like reductones and melanoidins. Additionally, the application of chitosan-MRPs effectively inhibited the microbial spoilage, reduced lipid oxidative, and extended the shelf life and the quality of fresh food products. Therefore, understand the potential of chitosan-MRPs derivatives as a functional biomaterial to improve the postharvest quality and extending the shelf life of food products will scale up its application as a food preservative.
... The lyophilized compounds were dissolved in CDCl3 for NMR measurement. The degree of substitution (DS) was determined by integral analysis of 1 H NMR spectra based on a reported method with slight modifications (Supplementary Table 1)
(Wang, Jiang, Chen, & Bai, 2016)
. ...
... The 13 C NMR spectrum of the prepared CHN-DNSA nanoparticles is displayed in Fig. 1b. The chemical shifts of CHN (C 1 -C 6 ) are consistent with that published in the literature
(Wang et al. 2016
). An intense peak at appeared at 49.21 ppm (C 7 ) is attributed to the carbon in the methylenic bridge of Ar-NH-CH 2 . ...
... The 13 C NMR of the CSPAN nano polymer particle is shown in Fig. 1b. The C1 and C2 chemical shift of acrylonitrile moiety is observed at 30.52 ppm and 122.13 ppm [42] while the minor peaks at 59.7 ppm and 102.5 ppm corresponds to the chemical shift of C1 and C2, respectively of chitosan unit of the polymer nanoparticle as reported elsewhere
[43]
... The 13 C NMR spectrum of the prepared CN/DA is shown in Fig. 2. The chemical shifts of CN (C 1 -C 6 ) are matching with the bases of published elsewhere
(Wang et al., 2016)
. The intense peak at 49.21 ppm (C 7 ) ascribed to the methylenic carbon bridge of Ar-NH-CH 2 moiety. ...
(Wang, Jiang, Chen, & Bai, 2016)
(Wang, Jiang, Chen, & Bai, 2016)
. 'A' denotes the total integral of the peak (CH 3 group of MMA) ranging from 1.97 to 1.99, in which there are three hydrogens. ...
| https://www.researchgate.net/figure/1-H-NMR-spectrum-of-b-TFA-D-298-K-600-MHz_fig14_301236421 |
Organic Electro-Optics and Photonics: Molecules, Polymers and Crystals | Request PDF
Request PDF | Organic Electro-Optics and Photonics: Molecules, Polymers and Crystals | This definitive guide to modern organic electro-optic and photonic technologies provides critical insight into recent advances in organic... | Find, read and cite all the research you need on ResearchGate
Organic Electro-Optics and Photonics: Molecules, Polymers and Crystals
August 2015
DOI: 10.1017/CBO9781139043885
ISBN: 9780521449656
Authors:
Zurich University of Applied Sciences
O-Pil Kwon
Abstract
This definitive guide to modern organic electro-optic and photonic technologies provides critical insight into recent advances in organic electro-optic materials, from the underlying quantum and statistical concepts through to the practical application of materials in modern devices and systems. Introduces theoretical and experimental methods for improving organic electro-optic and photonic technologies. Reviews the central concepts of nonlinear optics, focusing on multi-scale theoretical methods. Provides clear insight into the structure and function relationships critical to optimizing the performance of devices based on organic electro-optic materials. Serving as a primer for the systematic nano-engineering of soft matter materials, this is an invaluable resource for those involved in the development of modern telecommunication, computing, and sensing technologies depending on electro-optic technology. It is also an indispensable work of reference for academic researchers and graduate students in the fields of chemistry, physics, electrical engineering, materials science and engineering, and chemical engineering. © 2015, Larry R. Dalton, Peter Günter, Mojca Jazbinsek, O-Pil Kwon, and Philip A. Sullivan. All rights reserved.
... In recent decades, the design and development of new promising organic single crystals (co-crystal, salt and hydrated salt) with high nonlinear susceptibility and ultrafast response time have gained much interest due to their potential optical applicability in the field of nonlinear optics, photonics and optoelectronics [1,
2]
. The organic molecular crystal generally has specific properties such as high charge mobility, high nonlinear response and photochemical stability due to the delocalization of the π-electron system and presence of intermolecular hydrogen bond interactions [3]. ...
... Where one water molecule (A) is connected to another water molecule (B) via hydrogen bond, H37⋅⋅⋅⋅O39 interaction with bond distance 1.838 Å. Further, the DNB molecule (C) interacts with three molecules: (1) with the water molecule (B) with O ̶ ⋅⋅⋅⋅H-O type interaction (O ̶ ⋅⋅⋅⋅H bond distance ¼ 1.877 Å),
(2)
with TAP molecule (D) having H⋅⋅⋅⋅O ̶ and H⋅⋅⋅⋅O distance of 2.012 and 2.109 Å, respectively and (3) with water molecule (E), forming O-H⋅⋅⋅⋅O type interaction with H⋅⋅⋅⋅O bond distance, 1.796 Å, unlike that observed between the C (DNB) and B (water) molecule. The same bond distance is observed between the water (E) and water (F) molecules as in the case of water (A) to water (B) molecules. ...
Experimental and computational investigation of novel dihydrated organic single crystal of 2,4,6-triaminopyrimidine and 3,5-dintrobenzoic acid: Linear and nonlinear optical response with limiting performance
May 2021
Mohd Mehkoom
Ziya Afroz
Shabbir Ahmad
Newly synthesized dihydrated organic crystal (TAPþDNB.2H2O) of 2,4,6-triaminopyrimidine (TAP) with 3,5- dinitrobenzoic acid (DNB) was grown by slow evaporation technique and this crystal belongs to monoclinic P-1 space group. Infrared spectroscopy combined with DFT calculation has been used to confirm the presence of the expected functional group of the titular crystal. Further, the UV–Vis absorption spectroscopy has been utilized to determine various optical parameters such as excitation wavelength, optical band gap, and extinction coefficient from the point of view of optical application. In addition to this, TD-DFT/B3LYP computational theory was also applied to simulate the UV–Vis absorption spectrum for supporting the experimental result. The effect of complex formation from its constituents has been explored using frontier molecular orbitals analysis. Furthermore, the mapping of the 3D Hirshfeld surface and its related fingerprint plots were used for qualitative and quantitative analysis of the intermolecular interactions which involve among different molecular moiety in the synthesized crystal. The third-order nonlinear optical response of this molecular complex (TAPþDNB.2H2O) have been investigated in detail using the z-scan technique with CW diode laser (520 nm). Also, theoretical nonlinear optical parameters have been investigated by the DFT method. The thermal characteristic of the growth dihydrate crystal has been studied by thermal gravimetric-differential thermal analysis (TG-DTA).
... Second-order organic nonlinear optical (NLO) materials are important candidates for application in optical communication; their properties are conditioned by thermally resistant and photochemically stable push-pull chromophores introduced into the polymer material. These chromophores provide the molecular origin of the electro-optic (EO) response
[1,
2]. The design of new D-π-A systems is an important task for the development in this field. ...
Push-pull chromophores with π-deficient benzoazine and π-excessive thiophene cores in conjugated bridge as sources of quadratic nonlinear optical activity of composite polymer materials and molecular glasses
Apr 2023
DYES PIGMENTS
Alexey A. Shustikov
Alexey Alexandrovich Kalinin
... Many materials have nonlinear optical behavior. Among these, organic compounds are interesting to researchers due to their high polarization ability and synthetic diversity, which facilitates structural changes and consequently nonlinear optical properties
[12]
[13][14]. In addition, organic compounds with an extensive conjugate system containing electron donor and acceptor groups are of great interest in this field due to their unique intramolecular charge-transfer (ICT), intrinsic electron excitation, and the inherent ultra fast response times. ...
Linear and nonlinear optical properties of 1-(2-methoxyphenyl)-3-(4-chlorophenyl) triazene
Article
Full-text available
May 2022
INT J MATER RES
Fatameh Mostaghni
Homa Shafiekhani
Nosrat madadi mahani
In this research, 1-(2-methoxyphenyl)-3-(4-chlorophenyl) triazene was studied as a compound with high nonlinear optical properties for use in optical devices. For this purpose, the compound was synthesized and its structure was identified by melting point and infrared and nuclear magnetic resonance spectroscopy. Then, the bandgap energy of the title compound was determined to be 2.4 eV using the Tauc relation. Density functional theory and time-dependent methods were used for calculations of magnetic moment, natural band orbital, analysis of frontier molecular orbitals, first and second order hyperpolarizability. The results showed a dipole moment of 2.45 Debye for the molecule. The calculation of the hyperpolarizability showed the values of −109.6, 128.9 and −3694 a.u. for the first, second and third order polarizability respectively. Finally, the experimental and computational results showed that the compound has significant nonlinear optical properties and will be suitable for nonlinear optics studies and applications in optical devices.
... Coordination compounds with second-order nonlinear optical (NLO) properties represent a topic of growing interest as molecular inorganic-organic hybrid materials for emerging optoelectronic and optical signal processing [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Compared to purely organic compounds [16][17]
[18]
, they have the advantage of possessing both inorganic and organic elements with a lot of different electronic structures related to the metal oxidation state and coordination sphere, which can give rise to fascinating tunable electronic and photophysical properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Also, metals serve as perfect templates to construct three-dimensional structures, affording dipolar and octupolar molecules [10,19]. ...
A Chiral Bis(salicylaldiminato)zinc(II) Complex with Second-Order Nonlinear Optical and Luminescent Properties in Solution
Article
Full-text available
Apr 2020
Paola Matozzo
Alessia Colombo
Claudia Dragonetti
Daniele Marinotto
Whereas there is an increasing amount of reports on the second-order nonlinear optical (NLO) and luminescence properties of tetradentate [N2O2] Schiff base–zinc complexes, the study of zinc complexes having two bidentate [NO] Schiff-base ligands is relatively unexplored from an NLO point of view. This work puts in evidence that the known chiral bis{2-[(R)-(+)-1-phenylethyliminomethyl]phenolato-N,O}zinc(II) complex is a fascinating multifunctional molecular inorganic–organic hybrid material characterized by interesting second-order NLO and luminescent properties in solution. The emissive properties of the organic 2-(R)-(+)-1-phenylethyliminomethyl]phenol proligand are greatly enhanced upon coordination to the inorganic Zn(II) center.
... [6][7][8] To date, a wide range of NLO-responsive materials have been investigated; among these, organic materials have received much focus due to their excellent optical and electronic properties, which can be further tailored through structural modification to achieve better characteristics to improve the nonlinear optical activity of the materials for industrial processing. [9][10][11]
[12]
The synthesis of organic materials that contain electrondonor (D) and electron-acceptor (A) units linked through a p-conjugated bridge (D-p-A molecules as push-pull systems) has been a subject of considerable interest. [13][14][15][16] In these materials, the first-order hyperpolarizability depends on the conjugated-electronic structure, viz., its length and shape and on the specific character of the donor and acceptor groups. ...
Synthesis, structural characterization and computational study of NLO responsive chromophores and second order coefficients of thermally crosslinked polymers
Article
Aug 2019
Nandini A. Pattanashetti
Radha Doddamani
Padma Rachipudi
Mahadevappa Y. Kariduraganavar
This paper emphasizes on the preparation of nonlinear optical (NLO) responsive chromophores and their corresponding polymers. Initially, the carboxyl acid groups based precursors of the chromophores containing strong acceptors like...
Plasmonic organic hybrid electro-optic modulators as a platform for process optimization towards extraordinary nonlinearity and exceptional stability enabling commercial applications
Conference Paper
Mar 2023
Scott R. Hammond
Kevin M. O'Malley
Delwin L. Elder
Lewis E Johnson
Structural design and characterization of a new chalcone molecular derivative crystal DMNC with high second-order nonlinear coefficient
Article
Mar 2023
CHINESE J STRUC CHEM
Siyuan Hu
Xueting Mu
Degao Zhong
Jinkang Ma
Optical and terahertz characterisation of efficient NLO single crystal: (E)-2-(4-(dimethyl amine) styryl)-1,1,3-trimethyl-1H-benzo[e]indol-3-ium iodide (P-BI)
Article
Jan 2023
PRAMANA-J PHYS
Palaniyasan Eniya
Kalyana Sundar Jeyaperumal
P. Naveen Kumar
A.K Chaudhary
We report the terahertz (THz)-based characterisation of a highly efficient non-linear optical compound (E)-2-(4-(dimethyl amino) styryl)-1,1,3-trimethyl-1H-benzo[e]indol-3-ium iodide (P-BI) single crystal. The crystallographic structure of the grown crystal was confirmed by single-crystal X-ray diffraction analysis. Based on the obtained diffraction analysis, the title crystal belongs to the space group P21 and possesses good optical transmission between 700 and 1500 nm. The most important impedance spectroscopy-based parameters such as dielectric constant and dielectric losses show lower values which are an essential requirement for general non-linear optical (NLO) materials. The femtosecond oscillator has helped us to ascertain the transmission/absorption and generation in the 0.2–2.0 THz range. The obtained experimental data were used for the measurement of real and imaginary parts of the refractive index and absorption coefficients of the crystal. Finally, the crystal was subjected to the femtosecond laser amplifier for measuring the efficiency, maximum generated power and effect of vertical rotation of the crystal on THz radiation. The output power was measured using a pyroelectric detector and the generated maximum power was of the order of 1.9 µW at 150 mW incident pump power. The corresponding efficiency of the generated THz signal is of the order of 1.26 × 10–3%.
Quadratic Nonlinear Optical Response of Composite Polymer Materials Based on Push-pull Quinoxaline Chromophores with Various Groups in Aniline Donor Moiety
Article
Full-text available
Jan 2023
Sirina M. Sharipova
Alexey Alexandrovich Kalinin
Liliya N. Islamova
Marina Balakina
Composite polymer materials doped with original push-pull choromophores with quinoxaline core in conjugated bridge have been developed. Chromophores with various substituents in aniline donor moiety and tricyanofuran acceptor are characterized...
Design Novel Chalcone Crystals for Enhancement of Nonlinear Optical Activity and Higher Molecular Structural Stability
Article
Dec 2022
Kai Xu
Tianhua Wang
Rui Chen
Bing Teng
New paradigms in materials and devices for hybrid electro-optics and optical rectification
Conference Paper
Aug 2021
Lewis E Johnson
Delwin L. Elder
Huajun Xu
Larry Dalton
Molecular Structure Design, Crystal Growth, and Characterization of New Types of Organic Nonlinear Optical Chalcone Crystals
Article
Jun 2022
Kai Xu
Rui Chen
Jinkang Ma
Haitao Wu
Chalcone structures obtained by structural tailoring are an important class of molecular organic nonlinear optics (NLO) crystals that can be used for multiple purposes. In this work, two novel chalcone compound crystals with non-centrosymmetric structures, 6MN3MPP (C21H18O3, Pca21) and 6MN4MPP (C21H18O3, Pn), were designed and grown by extending the π-conjugation and structure-modifying strategy. On this basis, the second harmonic generation (SHG) efficiency, thermal stability, transmission spectra, dielectric constant, and photoluminescence properties of the crystal were characterized, and the hyperpolarizability of the crystal was theoretically calculated. The results show that the synthesized crystals exhibit higher crystal transparency (≥70%), higher melting point, and lower dielectric constant (ϵr≈ 6.5) compared with other reported chalcone NLO crystals. In particular, the SHG intensity of the 6MN3MPP crystal is 4.3 times higher than that of the KDP crystal. All of the results show that the two newly synthesized compounds have good application prospects as NLO crystals.
Organic–Inorganic Hybrid Noncentrosymmetric (Morpholinium) 2 Cd 2 Cl 6 Single Crystals: Synthesis, Nonlinear Optical Properties, and Stability
Article
Full-text available
May 2022
Defu Sun
Duanliang Wang
Yangyang Dang
Chuanying Shen
To design nonlinear optical (NLO) materials, we focused on combinations of d10 metal cation (Cd2+)-based chloride and morpholine molecules to form organic-inorganic hybrids. The O of morpholine containing lone-pair electrons can be integrated with Cd2+ by a ligand-to-metal charge transfer (LMCT) strategy to build acentric structures benefiting from the second-order Jahn-Teller effect. Introduction of the high-electronegativity chlorine can make polyhedrons of acentric crystals more distorted and conducive to a strong second harmonic generation (SHG) response. Therefore, (Morpholinium)2Cd2Cl6 crystals were constructed and synthesized by a solvent evaporation method. (Morpholinium)2Cd2Cl6 belongs to the orthorhombic P212121 space group and shows a one-dimensional (1D) structure with distorted [CdCl6] and [CdCl4O2] octahedrons. The short cutoff edge of (Morpholinium)2Cd2Cl6 was determined to be about 230 nm. The SHG response of (Morpholinium)2Cd2Cl6 exhibited an intensity of approximately 0.73 × KDP as estimated by the powder second harmonic generation technique. Furthermore, related theoretical calculations were performed to study the relationship of the band structure, refractive anisotropy, electronic state, and nonlinear optical response. Besides, (Morpholinium)2Cd2Cl6 showed relatively good thermal stability. This work can serve as a guide for the design and synthesis of new large NLO hybrid crystals with d10 transition metals.
New D-π-A chromophores incorporating (5,5-dimethylcyclohex-2-en-1-ylidene)- or (6-methyl-4H-pyran-4-ylidene)-malononitrile moiety
Article
Feb 2022
A. N. Vasyanin
Igor V. Lunegov
Daria Slobodinyuk
George Abashev
New D-π-A-type chromophores that simultaneously incorporate N,N-dimethylaminophenyl moiety as the terminal electron-donating group and either (5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile (DCM-1) or (6-methyl-4H-pyran-4-ylidene)malononitrile (DCM-2) unit as the terminal electron-withdrawing group were synthesized. Vinylene moiety and azo group served as the π-spacer. A comparative analysis of optical and electrochemical properties of the synthesized chromophores revealed that the replacement of the DCM-1 unit with the DCM-2 moiety led to chromophore band gap broadening and a decrease in the molar extinction coefficient value; while the replacement of the DCM-1 unit with the DCM-2 one in the chromophores bearing the vinylene π-spacers led to a sharp increase in the fluorescence quantum yield.
Assessment of alkali and alkaline earth metals doped cubanes as high performance nonlinear optical materials by first-principles study
Article
Apr 2022
Javaria Naeem
Rehana Bano
Khurshid Ayub
Mazhar Gilani
Novel organic materials have played a tremendous role in the development of high performance nonlinear optical materials. Herein, the geometric, electronic and nonlinear optical properties of designed alkali (Li, Na, and K) and alkaline earth metals (Be, Mg, and Ca) doped cubane (C8H8) complexes have been explored by using density functional theory. Excess electrons generated by doping alkali/alkaline earth metals have significantly enhanced the NLO properties by reducing the crucial excitation energy of cubane. The HOMO-LUMO energy gap of doped complexes is reduced up to 4.43 eV. It is revealed that the reduction in HOMO-LUMO energy gap results from the development of new highest occupied molecular orbital, which is confirmed by the density of state (DOS) analysis. The NBO analysis is carried out to confirm the charge transfer between metal atoms and cubane ring. Further, the NCI and QTAIM analyses confirmed the nature of intramolecular interaction. The remarkable first hyperpolarizability (βₒ) of 3.01×10⁴ au is observed for [email protected] Moreover, frequency dependent first hyperpolarizability (β (ω)), second harmonic generation β (-2ω; ω,ω), electro-optic Pockel’s effect β (-ω; ω,0), hyper-Rayleigh scattering coefficient (βHRS), second hyperpolarizability (γ (ω)), electric field-induced second harmonic generation γ(-2ω; ω, ω,0) electro-optic Kerr effect γ(-ω; ω,0,0), and nonlinear refractive indices (n2) were also studied. The highest dc-Kerr 2.69×10¹⁰ au and EFISHG 3.69×10⁹ au values observed for [email protected] along with large n2 (1.73×10⁻⁹ au) justify the large NLO response. These intriguing outcomes will be advantageous for promoting possible utilization of designed complexes in the field of high performance NLO materials.
Organic electro-optic materials combining extraordinary nonlinearity with exceptional stability to enable commercial applications
Conference Paper
Mar 2022
Scott R. Hammond
Kevin M. O'Malley
Huajun Xu
Lewis E Johnson
Synthesis and optical properties of chromophores with a methoxyphenylindolizine moiety
Conference Paper
Feb 2022
G. M. Fazleeva
Timur Burganov
Alexey Alexandrovich Kalinin
Marina Balakina
Chromophores with 2-methoxyphenyl-1(3)methylindolizine donor and tricyanofuran acceptor moiety linked by octatetraene n-bridge have been synthesized and their linear and nonlinear optical properties were investigated. Chromophores exhibited large solvatochromic shifts (∼100 nm) when passing from dioxane to DMSO solutions and their absorption maxima shifted from visible to near-IR region. An additional narrow intensive absorption band at ca. 921–954 nm appeared in DMSO solution resulting from the crossing of cyanine limit. Density functional theory was used to calculate the first hyperpolarizability (β) of the chromophores.
Organic Electro-Optics and Optical Rectification: From Mesoscale to Nanoscale Hybrid Devices and Chip-Scale Integration of Electronics and Photonics
Article
Jan 2022
Larry Dalton
Delwin L. Elder
A Reversible Change in the Nonlinear Optical Properties of Polymer Electret Films Based on Methacrylic Copolymers
Article
Dec 2021
E. O. Mityshkin
A. I. Gaisin
Artemiy Shmelev
V. S. Lobkov
Plasmonic-Organic-Hybrid (POH) Modulators - a Powerful Platform for Next-Generation Integrated Circuits
Conference Paper
Jan 2021
Claudia Hoessbacher
Patrick Habegger
Marcel Destraz
Wolfgang Heni
We present reliability studies of plasmonic-organic-hybrid modulators for high-speed optical communications. By exclusion of oxygen and water, demanding thermal environments and high optical power levels can be tolerated.
Highly Nonlinear Optical Organic Crystals for Efficient Terahertz Wave Generation, Detection, and Applications
Article
Sep 2021
Bongjoo Kang
Seung‐Jun Kim
Uroš Puc
O-Pil Kwon
Organic π‐conjugated crystals with second‐order optical nonlinearity are considerably attractive materials for diverse terahertz (THz) wave photonics. An overview of the research of organic nonlinear optical (NLO) crystals for THz wave generation, detection, and applications is provided here. First, the status of organic NLO crystals compared to other alternative THz materials is described. Second, the basic theory and requirements for organic THz generators and detectors are explained. Third, with a primary focus on the organic NLO crystals that have been developed during the last decade, various molecular engineering approaches are discussed from the perspective of THz photonics. Finally, various types of high‐power broadband coherent THz sources and their applications in THz nonlinear optics are discussed. Organic nonlinear optical crystals are promising terahertz (THz) active materials for efficient THz wave generation and detection. Various molecular engineering techniques for the development of organic THz generators and detectors are presented. In addition, high‐power broadband THz generators and their applications are discussed.
Experimental and theoretical investigations of propyl para-hydroxybenzoate crystal for optical applications
Article
Full-text available
Oct 2021
J MATER SCI-MATER EL
K. Kumar
Samikkannu Rajathi
V. Charles Vincent
G. Vinitha
Propyl para-hydroxybenzoate (PHB) known as Propylparaben is an organic family that single crystal is grown by solvent evaporation process with a solvent like methanol. The value of unit cell geometry and the crystalline system with space group nature are estimated from the single-crystal XRD study. From the optical spectra, the lower absorption wavelength edge is measured using the visible optical spectrum of range 200–1200 nm. From the absorption edge value, different optical parameters such as band gap, extinction coefficient with absorption, optical and electrical conductivity, Urbach energy, and susceptibility values are measured. Also, the grown PHB crystals’ different dispersion parameters and strength of oscillator are also evaluated by using Wemple Di-Domenico single oscillator method. Third-order nonlinear parameters such as refractive index, nonlinear absorption coefficient, and nonlinear susceptibility are evaluated as 5.99 × 10−9cm2/W, 3.41 × 10−4 cm/W, and 5.76 × 10−6 esu by using the z-scan method. The microhardness analysis and different mechanical properties such as elastic stiffness constant, yield strength, fracture toughness, and Brittleness index are also estimated. The basic important solid-state properties such as the energy of plasma, Penn, and Fermi gap and the value of molecular electronic polarizability are measured and compared from various methods as the coupled dipole method, Clausius–Mossotti relation, and Lorentz equation. The intermolecular interaction of the PHB molecule is confirmed by the Hirshfeld surface study, and their percentage is evaluated by using a fingerprint plot.
Composing NLO chromophore as a puzzle: electrochemistry‐based approach to the design and effectiveness
Article
Sep 2021
Yulia H Budnikova
Yulia B. Dudkina
Alexey Alexandrovich Kalinin
Marina Balakina
A series D‐π‐A, D‐π‐D′‐π‐A, D‐π‐A′‐π‐A nonlinear optical chromophores with vinylene π‐electron bridges or bridges with π‐deficient/π‐excessive heterocyclic moieties along with the corresponding precursors D‐vinylene, D‐π‐D′, D′‐π‐A, D‐π‐A′ and A′‐π‐A are obtained and studied both experimentally and computationally. The effect of heterocycle in π‐electron bridge on the oxidation/reduction potentials and the energy gaps, ΔE el , is specially investigated. The properties of the D‐π‐A′(D′)‐π‐A chromophores are shown to correlate with those of building blocks: oxidation potential is determined by the D‐vinylene, and reduction potential is determined by A′(D′)‐π‐A truncated compounds. The contribution of the acceptor to the oxidation potential of chromophores in comparison with those of the precursors was estimated and analyzed in terms of electronic communication between the end groups. A good correlation between the ΔE el and the chromophores first hyperpolarizability is revealed.
Birefringence, dimensionality, and surface influences on organic hybrid electro-optic performance
Conference Paper
Aug 2021
Lewis E Johnson
Stephanie Benight
Bruce H. Robinson
Delwin L. Elder
Highly efficient THz generation by optical rectification of mid-IR pulses in DAST
Article
Full-text available
Mar 2021
Claudia Gollner
Mostafa Shalaby
Corinne Brodeur
Audrius Pugzlys
We report on efficient THz generation in DAST by optical rectification of intense mid-IR pulses centered at (i) 3.9μm and (ii) its sec-ond harmonic at 1.95μm. Suppression of multi-photon absorption shifts the onset of saturation of the THz conversion efficiency to pumpenergy densities, which are almost an order of magnitude higher as compared to conventional pump schemes at 1.5μm. Despite strong linearabsorption at 3.9μm, DAST exhibits a high optical-to-THz conversion efficiency, which we attribute to resonantly enhanced nonlinearityand advantageous phase matching of the THz phase velocity and group velocity of the driving pulse. At 1.95μm, we find that low linear andmulti-photon absorption in combination with cascaded optical rectification lead to record optical-to-THz conversion efficiencies approach-ing 6%. The observed high sensitivity of the THz generation to the parameters of the mid-IR driving pulses motivates an in-depth study ofthe underlying interplay of nonlinear wavelength- and intensity-dependent effects
Facile Synthesis, Crystal Structure, Spectral Characterization, Quantum Chemical Calculations, and Hirshfeld Surface Analysis of 5‐Chloro‐3‐Methoxy‐4‐Hydroxybenzaldehyde
Article
Jun 2021
P. Nagapandiselvi
This article deals with synthesis, growth, structure, and characterization of 5‐chloro‐3‐methoxy‐4‐hydroxybenzaldehyde (5CMHBA or 5‐chlorovanillin) single crystals. A facile one‐pot method is employed for the chlorination of vanillin using N‐chlorosuccinimide. After chlorination, the single crystals of 5CMHBA are grown by slow evaporation solution growth technique. Grown crystals are subjected to single crystal X‐ray diffraction (SXRD), Fourier Transform Infrared (FTIR), and Thermogravimetric‐Differential Thermal Analysis (TG‐DTA). 5CMHBA crystallizes in the tetragonal crystal system with the space group P42/n. Vibrational characteristics are studied using FTIR. Further, thermal studies of the crystal are carried out using simultaneous TG‐DTA thermal analyzer. The molecular structure and its intermolecular interactions are studied by applying time–dependent density functional theory (TD‐DFT) using Gaussian 09 program and Hirshfeld surface analysis. A lesser energy gap of the 5CMHBA compared to that of vanillin shows the high reactivity of the molecule. Dipole moment, polarizability, and hyper‐polarizability are calculated in the molecular level and found to have greater polarizability than vanillin and also higher in order than that of standard urea molecule. This reveals the suitability of the molecule for nonlinear optical applications. The intermolecular interactions and porosity are analyzed and compared with vanillin and its polymorphs by Hirshfeld surface analysis. Vanillin is chlorinated using N‐chlorosuccinimide by simple single step procedure. Single crystals are grown from chlorinated vanillin. The position of chlorine in chlorovanillin is confirmed by elucidating its crystal structure from single crystal X‐ray diffraction technique. The chlorinated vanillin exhibits greater molecular dipole moment, polarizability, and hyperpolarizability than vanillin and urea identified by applying time dependent density functional theory.
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High‐Density Organic Electro‐Optic Crystals for Ultra‐Broadband THz Spectroscopy
Article
Full-text available
Jun 2021
Jin-Hong Seok
Uroš Puc
Seung‐Jun Kim
O-Pil Kwon
Ultra‐broadband THz photonics covering the 0.3–20 THz range provides a very attractive foundation for a wide range of basic research and industrial applications. However, the lack of ultra‐broadband THz devices has yet to be overcome. In this work, high‐density organic electro‐optic crystals are newly developed for efficient THz wave generation in a very broad THz spectral range and are successfully used for a broadband THz time‐domain spectroscopy. The new organic THz generator crystals, namely the OHP‐TFS crystals, have very low void volume, high density, and are shown to cover the ultra‐broadband THz spectrum up to about 15 THz, which cannot be easily accessed with the more widely used inorganic‐based THz generators. In addition to the very favorable broadband properties, the generated THz electric‐field amplitude at the pump wavelength of 1560 nm is about 40 times higher than that generated by a commercial inorganic THz generator (ZnTe crystal). By using the newly developed OHP‐TFS as generation crystal in a compact table‐top all‐organic THz time‐domain spectrometer based on a low‐cost telecom fiber laser, the optical characteristics of a model material are successfully determined in the broad 1.5–12.5 THz range with high accuracy. New high‐density organic electro‐optic crystals are developed for efficient ultra‐broadband THz wave generation up to about 15 THz. Using the newly developed crystals, ultra‐broadband all‐organic THz time‐domain spectroscopy is successfully demonstrated.
Polar in-plane surface orientation of a ferroelectric nematic liquid crystal: Polar monodomains and twisted state electro-optics
Article
Full-text available
Jun 2021
Xi Chen
Eva Korblova
Matthew A Glaser
Noel Clark
Significance
The devices of the portable computing revolution are being made possible by nematic liquid crystal display (LCD) technology. The optical changes viewed in a dynamic LCD image are based on reorienting molecules by coupling electronically generated electric fields to molecular dielectric anisotropy. This takes place in appropriate fluid electro-optic structures stabilized by nonpolar orientational coupling of molecules to surfaces. The recent observation of ferroelectric nematics having spontaneous macroscopic electric polarization density has introduced a much stronger polar coupling of electric field to molecular reorientation in nematics. This development opens opportunities for advanced electro-optics, but these will require polar control of molecular orientation by surfaces. The generation of polar-structured surfaces and their coupling to nematic polarity is demonstrated in this paper.
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V-shaped Pyranylidene/Triphenylamine-based Chromophores with Enhanced Photophysical, Electrochemical and Nonlinear Optical Properties
Article
Full-text available
Jan 2021
Sergio Gámez
David Neusser
Carlos Benitez-Martin
M. Carmen Ruiz Delgado
We report the synthesis and comprehensive study of two chromophores based on 4H-pyranylidene moiety as a part of the π-conjugated spacer. Triphenylamine (TPA) acts as donor and tricarbonitrile-based electron-accepting groups...
New benzothiazolium crystals with very large off-diagonal optical nonlinearity
Article
May 2021
DYES PIGMENTS
Seung‐Jun Kim
In Cheol Yu
Ji-Ah Lee
O-Pil Kwon
In this study, we develop new organic benzothiazolium crystals possessing very large off-diagonal optical nonlinearity. In these crystals, benzothiazolium-based 2-(4-(4-(hydroxymethyl)piperidin-1-yl)styryl)-3-methylbenzothiazol-3-ium (PMB) cations with large molecular optical nonlinearity are incorporated with two anions: 4-(trifluoromethoxy)benzenesulfonate (TFO) with an orthogonal non-planar shape and 5-bromothiophene-2-sulfonate (BTS) with a planar shape. Both PMB-TFO and PMB-BTS crystals exhibit state-of-the-art off-diagonal effective hyperpolarizability (∼105 × 10⁻³⁰ esu) that results from the V-shape and X-shape alignments of PMB chromophores, respectively. Newly developed PMB crystals indicate excellent characteristics for second-order nonlinear optical applications such as difference-frequency generation (e.g. optical rectification) and sum-frequency generation (e.g. second-harmonic generation), which are comparable to current benchmark organic crystals.
Twisted One-Dimensional Charge Transfer and Related Y-Shaped Chromophores with a 4H-Pyranylidene Donor: Synthesis and Optical Properties
Article
Full-text available
Feb 2021
J ORG CHEM
Víctor Tejeda-Orusco
Raquel Andreu
Jesús Orduna
Alba Civera
Three series of push-pull derivatives bearing 4H-pyranylidene as electron donor group and a variety of acceptors were designed. On one hand, one-dimensional chromophores with a thiophene ring (series 1H) or 5-dimethylaminothiophene moiety (series 1N) as an auxiliary donor, non-coplanar with the π-conjugated system, were synthesized. On the other hand, related two-dimensional (2D) Y-shaped chromophores (series 2) were also prepared to compare how the diverse architectures affect the electrochemical, linear, and second-order nonlinear optical (NLO) properties. The presence of the 5-dimethylaminothiophene moiety in the exocyclic C═C bond of the pyranylidene unit gives rise to oxidation potentials rarely low, and the protonation (with an excess of trifluoroacetic acid) of its derivatives results in the apparition of a new blue-shifted band in the UV-visible spectra. The analysis of the properties of derivatives with and without the additional thiophene ring shows that this auxiliary donor leads to a higher NLO response, accompanied by an enhanced transparency. Y-shaped chromophores of series 2 present a blue-shifted absorption, higher molar extinction coefficients, and higher Eox values compared to their linear twisted counterparts. As concerns NLO properties, 2D Y-shaped architecture gives rise to somewhat lower μβ values (except for thiobarbiturate derivatives).
The study of dipolar relaxation in chromophore-containing methacrylic copolymers using thermally stimulated depolarization current measurements
Conference Paper
Dec 2020
Anvar S. Mukhtarov
Maksim A. Smirnov
Marina Balakina
Taniyana Vakhonina
In this work the relaxation processes of chromophores containing copolymers are considered. These processes were studied using the method of thermostimulated depolarization technique. Thermograms for linear and branched azo-chromophore containing methacrylic copolymers were obtained and explained. A comparison of the obtained results demonstrates an increase in the activation energy of relaxation processes for branched copolymers.
Ultra‐Broadband and High Dynamic Range THz‐TDS System Based on Organic Crystal Emitter and Detector in Transmission and Reflection Geometry
Article
Full-text available
Dec 2020
Uroš Puc
Tobias Bach
Peter Günter
Mojca Jazbinsek
The terahertz range of the electromagnetic spectrum reveals important insights when studying material properties. We present an ultra‐broadband terahertz time‐domain spectroscopy system based on state‐of‐the‐art, high‐stability organic nonlinear optical crystals used both as THz‐wave generator and detector. In the transmission geometry, we achieve a broad spectrum exceeding 20 THz and a high dynamic range of more than 80 dB by using a compact 100 MHz femtosecond laser working at telecom wavelengths 1560 nm. In the normal‐incidence reflection geometry we report a similar bandwidth with a dynamic range surpassing 60 dB. The experimental results are supported by a complete theoretical model, which includes the pump pulse duration, THz phonon and vibrational modes of the organic crystals and optical/THz beam path optimizations. The effectiveness of the newly developed system is demonstrated by measuring pharmaceutical samples with distinct THz features in the ultra‐broadband THz range and by measuring narrow water vapor lines at a spectral resolution of 2.7 GHz (0.090 cm‐1) resulting in an excellent accuracy with a frequency deviation of less than 0.05% from the reference values.
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Solid‐State Molecular Motions in Organic THz Generators
Article
Dec 2020
Jongtaek Kim
Young Choon Park
Jin-Hong Seok
O-Pil Kwon
Organic nonlinear optical salt crystals are widely used as efficient broadband THz generators. Although solid state molecular motions of organic crystals can greatly influence THz generation characteristics, their origin and effects on THz photonics are not clearly identified. In this work, the origin of solid‐state molecular motions of the state‐of‐the‐art nonlinear optical organic salt crystals and their effects on THz generation characteristics are theoretically investigated. A model crystal, HMQ‐TMS (2‐(4‐hydroxy‐3‐methoxystyryl)‐1‐methylquinolinium 2,4,6‐trimethylbenzenesulfonate) with large macroscopic optical nonlinearity, which is very attractive for intense broadband and narrowband THz wave generation, is chosen. The solid‐state molecular vibrations of HMQ‐TMS crystals can be classified in three frequency regions: phonon mode region, intramolecular motion region, and their mixing region. For the first time for ionic organic crystalline THz generators, the contributions of cationic chromophores and anionic matchmakers on each of vibrational modes are quantitatively separated. In addition, the influence of solid‐state molecular vibrations of HMQ‐TMS crystals on the generated THz spectra is investigated. These results provide an essential information for design of new organic nonlinear optical salt crystals for THz generators as well as detectors and for optimization of THz generation performance.
Synthesis, growth, structure analysis and performance characterization of DOST crystal: a nonlinear functional material with a wide range of applications
Article
Oct 2020
CRYSTENGCOMM
Zhe Yu
Tianhua Wang
Guanjun Wang
Bing Teng
Novel organic nonlinear optical crystals of 4-N,N-dimethylamino-4′-N′-methyl-stilbazolium 3,4-dimethoxysulfonate (DOST) with high quality were grown by a spontaneous nucleation method. The crystal quality, defect types and growth mechanism were studied by a chemical etching method and synchrotron radiation X-ray topography. The non-centrosymmetric P21 space group of the crystal was confirmed by single-crystal XRD, and the HOMO–LUMO orbital diagram and molecular electrostatic potential (ESP) surface were drawn. Spectroscopy studies have shown that the DOST crystal has high optical transmittance (≥70%), a wide transmission range and an energy bandwidth of 2.43 eV. As a kind of nonlinear optical (NLO) material, the crystal has an extremely high second-order nonlinear effect. The second-harmonic generation (SHG) efficiency is about 4 times that of DAST, which exceeds the SHG efficiency of most second-order nonlinear materials that have been reported. The dielectric and ferroelectric properties of the DOST crystal under different temperature and frequency conditions are measured. In addition, it is proved by PL and TG-DSC tests that the DOST crystal also has green light emission characteristics and good thermal stability.
Comparative analysis of the optical and electrochemical properties of new D-π-A chromophores containing (5,5-dimethylcyclohex-2-en-1-ylidene)propanedinitrile or (6-methyl-4H-pyran-4-ylidene)propanedinitrile fragments
Conference Paper
Full-text available
Oct 2020
Daria Slobodinyuk
Yu. A. Strelkova
Elena V. Shklyaeva
George Abashev
A series of new D-π-A chromophores containing a triphenylamine fragment as a terminal electron-donating group, as well as (5,5-dimethylcyclohex-2-en-1-ylidene) propanedinitrile or (6-methyl-4H-pyran-4-ylidene) propanedinitrile fragments as an acceptor. A comparative analysis of the optical and electrochemical properties of the obtained compounds is carried out. It was found that the replacement of the (5,5-dimethylcyclohex-2-en-1-ylidene) propanedinitrile fragment with a (6- methyl-4H-pyran-4-ylidene) propanedinitrile fragment leads to a slight increase in the bandgap of the compound, while the coefficient increases significantly molar absorption, as well as the quantum yield of luminescence.
The Effect of Molecular Structure on Second-order Nonlinear Optical Properties of Stilbazolium Derivative Single Crystals: A review
Article
Full-text available
Oct 2020
| https://www.researchgate.net/publication/290275940_Organic_electro-optics_and_photonics_Molecules_polymers_and_crystals |
Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial | Blood Advances | American Society of Hematology
Key Points. Decitabine increased platelet counts of patients with RPIT after allogeneic HCT.Decitabine also increased survival of patients with RPIT.
Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial
Clinical Trials & Observations
Key Points
Decitabine increased platelet counts of patients with RPIT after allogeneic HCT.
Decitabine also increased survival of patients with RPIT.
Visual Abstract
Abstract
Refractory prolonged isolated thrombocytopenia (RPIT) is an intractable complication after allogeneic hematopoietic cell transplantation (HCT), which often leads to poor prognosis. A clinical study was designed to validate the efficacy and safety of low-dose decitabine for RPIT after HCT and explore the related underlying mechanisms. Eligible patients were randomly allocated to receive 1 of 3 interventions: arm A, low-dose decitabine (15 mg/m 2daily IV for 3 consecutive days [days 1-3]) plus recombinant human thrombopoietin (300 U/kg daily); arm B, decitabine alone; or arm C, conventional treatment. The primary end point was the response rate of platelet recovery at day 28 after treatment. Secondary end points included megakaryocyte count 28 days after treatment and survival during additional follow-up of 24 weeks. Among the 91 evaluable patients, response rates were 66.7%, 73.3%, and 19.4% for the 3 arms, respectively ( P< .001). One-year survival rates in arms A (64.4% ± 9.1%) and B (73.4% ± 8.8%) were similar ( P= .662), and both were superior to that in arm C (41.0% ± 9.8%; P= .025). Megakaryocytes, endothelial cells (ECs), and cytokines relating to megakaryocyte migration and EC damage were improved in patients responding to decitabine. This study showed low-dose decitabine improved platelet recovery as well as overall survival in RPIT patients after transplantation. This trial was registered atwww.clinicaltrials.govas #NCT02487563.
Subjects:
Clinical Trials and Observations
Platelets and Thrombopoiesis
,
Transplantation
Topics:
arm
,
decitabine
,
thrombocytopenia
,
cytokine
,
follow-up
,
megakaryocytes
,
blood platelets
,
endothelial cells
,
transplantation
Introduction
Allogeneic hematopoietic cell transplantation (HCT) is a widely used treatment for hematologic malignancies with the potential for cure. 1Prolonged isolated thrombocytopenia that is refractory to conventional treatments has remained a critical complication after allogeneic HCT since its recognition for 35 years. 2-4The frequency of prolonged refractory thrombocytopenia after allogeneic HCT has been reported to be 20% to 37%, but the defining criteria of this disorder have been inconsistent. 3,5Prolonged isolated thrombocytopenia post-HCT is usually associated with other post-HCT complications, including relapse of underlying disease, infection, graft-versus-host disease (GVHD), and thrombotic microangiopathy. 4-6However, there are other patients with prolonged isolated thrombocytopenia without an identified cause who are often resistant to conventional treatments for thrombocytopenia, such as glucocorticoids, IV immunoglobulin, rituximab, interleukin-11 (IL-11), and recombinant human thrombopoietin (rhTPO) or TPO receptor agonists. 2,3We define these patients by a platelet count <30 × 10 9/L for >60 days post-HCT that is not associated with relapse of the underlying disease, severe GVHD, infection, or other recognized etiology and that is unresponsive to conventional treatments for thrombocytopenia. We describe these patients as having refractory prolonged isolated thrombocytopenia (RPIT). The cause of RPIT may be decreased platelet production. 2,3Prognosis for these patients is poor.
Platelet production is a consecutive process beginning with the commitment of hematopoietic stem cells to the megakaryocyte lineage and ending with the fragmentation of megakaryocyte cytoplasm into platelets. Effective hematopoiesis depends on the bone marrow microenvironment where hematopoietic stem cells reside and interact with supportive cells. 7,8Cross-talk between megakaryocytes and bone marrow endothelial cells (BMECs) in the marrow vascular microenvironment regulates megakaryocyte maturation and thrombopoiesis. In patients undergoing HCT, the interruption of homeostasis in the bone marrow microenvironment caused by the intensive conditioning treatments and alloreactivities associated with allogeneic transplantation may contribute to the etiology of thrombocytopenia. 9,10Previous studies documented impaired BMECs, both in quantity and function, in patients with thrombocytopenia post-HCT. 10
The pathogenesis of RPIT remains unclear, and effective treatment is lacking. It has been demonstrated that decitabine, a hypomethylating agent, 11may increase platelet counts in mice by enhancing platelet release and megakaryocyte maturation. 12In addition, decitabine may ameliorate endothelial progenitor cell (EPC) impairment and moderate immune dysfunction in hematopoietic microenvironment. 13,14
We previously reported a pilot study demonstrating the effectiveness of low-dose decitabine in increasing platelet counts in transplant recipients with RPIT. 15We have now conducted a randomized multicenter trial to validate the efficacy and safety of low-dose decitabine in patients with RPIT after HCT, and we have further explored the underlying mechanisms.
Methods
Patient recruitment
This prospective, open-label, 3-arm clinical trial was designed by investigators at the First Affiliated Hospital of Soochow University (Suzhou, China) and conducted at 6 hematology centers in China. The inclusion criteria were: (1) platelet count <30 × 10 9/L for >60 days post-HCT, (2) recovered neutrophil and hemoglobin concentrations, (3) donor chimerism >95% detected by short tandem repeat polymerase chain reaction, and (4) no response to conventional treatments for thrombocytopenia (rhTPO alone or combined with IV immunoglobulin, rituximab, IL-11, or glucocorticoid) for at least 4 weeks. Exclusion criteria were: (1) relapse or progression of underlying disease, (2) active infection, (3) grade 3 to 4 acute GVHD or severe chronic GVHD according to National Institutes of Health criteria, 16,17(4) severe organ damage (cardiac, renal, and/or hepatic dysfunction grade >2 according to the Common Terminology Criteria for Adverse Events [version 5.0]), (5) thrombosis requiring treatment, and (6) decitabine for any indication after the current transplantation. In addition, enrolled participants would be withdrawn from this trial if judged as having relapse or progression of the underlying disease before initial response evaluation at day 28.
Study design
After enrollment, patients were randomly assigned to 1 of 3 intervention arm: arm A, 15 mg/m 2of decitabine (Chia Tai Tianqing Pharma, Lianyungang, China) daily IV for 3 consecutive days (days 1-3) followed by 300 U/kg of rhTPO (SanSheng Pharma, Shenyang, China) daily subcutaneously from day 4 until response or initial evaluation (day 28); arm B, 15 mg/m 2of decitabine daily IV for 3 consecutive days (days 1-3) alone; or arm C, conventional therapies with recommended options, including IV immunoglobulin, IL-11, and glucocorticoids, alone or in combination. Decitabine was administered for 1 cycle in both arms A and B, followed by 28 days of evaluation and additional 24 weeks of follow-up. Dosage adjustment of rhTPO in arm A was not permitted unless participants withdrew from this study.
Hematologic adverse events (AEs) were assessed by both duration and maximum deviation from baseline level of white blood cells and hemoglobin. Nonhematologic AEs were graded according to Common Terminology Criteria for Adverse Events (version 5.0), and severe AEs were defined as grade ≥3 AEs or AEs resulting in unplanned hospital stays. From day 1, all patients were evaluated for safety every day until the day of evaluation (day 28).
Donors for allogeneic HCT were selected based on the results of HLA typing, age, sex, and health status. Generally, HLA-matched related younger male donors were preferred. HLA haploidentical donors and HLA-matched unrelated donors were selected according to institutional guidelines.
The protocol was approved by the institutional review board at each participating center. All participants provided written informed consent. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Megakaryocyte counts and ploidy distribution in bone marrow
Bone marrow aspirate was performed at baseline and day 28 after treatment. The total number of megakaryocytes as well as the platelet-shedding megakaryocytes of bone marrow smears (per cm 2) was counted and cross-checked by blinded observers as previously described. 18To measure ploidy distribution, megakaryocytes were labeled with PE-Cy5–conjugated CD41 (BD Biosciences) and incubated with propidium iodide (Abcam). The samples were then evaluated using an ACEA NovoCyte flow cytometer.
Endothelial cells and related cytokines
Data from preliminary experiments performed before this trial suggested that patients with RPIT had decreased EPCs, BMECs, and related cytokines reflecting the function of BMECs. These included vascular endothelial growth factor (VEGF), endothelia-1, C-X-C chemokine receptor type 4 (CXCR4), stromal cell–derived factor-1 (SDF-1), and fibroblast growth factor-4 (FGF-4). Endogenous nitric oxide (NO), another biomarker of BMEC impairment, was increased. Therefore, the levels of these cytokines and chemokines were measured for patients enrolled in this trial. EPCs and BMECs were detected in mononuclear cells and stained with mouse anti-human CD45, CD34, CD133, and VEGF receptor monoclonal antibodies (BD Biosciences). SDF-1, VEGF, endothelial-1, and endogenous NO levels were assessed by ELISA kits (R&D Systems) and CXCR4 and FGF-4 by reverse transcription polymerase chain reaction (Thermo Fisher Scientific).
Assessments
Evaluation of the primary end point was conducted at day 28; platelet response was defined as sustained increase (stable or increasing level) of at least 30 × 10 9/L independent of transfusion for 3 days. 15Counts of blood cells were monitored daily during the first 4 weeks after decitabine treatment and every 4 weeks until the 28th week. Secondary end points included megakaryocyte counts 4 weeks after decitabine treatment and survival during follow-up of 24 weeks. Additional follow-up after 24 weeks was conducted to observe long-term survival. Overall survival was calculated from the date of enrollment to date of death or end of follow-up.
Sample size calculation and statistical analysis
According to the previous study, among the 3 arms, we supposed the biggest effective rate to be 80% ( P max) and the lowest rate to be 35% ( P min). Under the condition of α = 0.05 (2 tailed), β = 0.20 (1 tailed), and ν = 2, so λ = 9.63, the theoretic sample size for each group was calculated with the following formula: n = λ/(2[arcsin √ P max− arcsin √ P min] 2) = 9.63/(2[arcsin √0.80 − arcsin √0.35] 2) = 21.42. Considering an expulsion rate of 20%, the sample size for each group was at least 25.Completely randomized block design method was performed to assign patients to 1 of the 3 arms. For each study site, we produced the random series and corresponding assigning arms A, B, and C, in which the block equaled 5 and length equaled 6. If the length was ≤2, the arm was A; if length was 3 to 4, arm was B; and if length was 5 to 6, arm was C. Numeric data are presented as medians with interquartile ranges (IQRs), and categorical data are shown as proportions. One-way analysis of variance was used to compare the difference of numeric variables among 3 treatment arms, and χ 2or Wilcoxon rank test was used to compare the categorized variables. Survival was estimated by Kaplan-Meier method and compared by log-rank test. Cox and logistic regression models were used to evaluate the impact of variables on outcomes. Significance level was set as a 2-tailed Pvalue of <.05. All analyses used SPSS (version 19.0; SPSS, Inc.).
Results
Patient characteristics
From October 2015 to April 2019, of 2616 allogeneic transplant recipients screened at 6 participating centers, 256 patients were identified as having thrombocytopenia (platelet count <30 × 10 9/L) for >60 days post-HCT (Figure 1). Ninety-seven patients met the inclusion and exclusion criteria and were randomly allocated to arm A (n = 32), B (n = 33), or C (n = 32;Figure 1). Subsequently, 2 patients in arm A, 3 in arm B and 1 in arm C were excluded because of relapse before initial evaluation. Therefore, 30 patients in arm A, 30 in arm B, and 31 in arm C were included in the analyses. The main treatments for RPIT after HCT in arm C included glucocorticoids, rhTPO, and immunoglobulin, alone or in combination. Baseline characteristics were comparable among the 3 arms (Table 1).
Figure 1.
CONSORT diagram for the study.A total of 97 patients were enrolled in the trial, and 91 patients were evaluated. aPlatelet count <30 × 10 9/L. bNeutrophil count <1.0 × 10 9/L and/or red blood cells transfusion dependent.
Figure 1.
CONSORT diagram for the study.A total of 97 patients were enrolled in the trial, and 91 patients were evaluated. aPlatelet count <30 × 10 9/L. bNeutrophil count <1.0 × 10 9/L and/or red blood cells transfusion dependent.
Table 1.
Baseline characteristics of patients in 3 arms
. Arm A (n = 30) . Arm B (n = 30) . Arm C (n = 31) .
Age, y
Median 30 36 36
IQR 23-43 27-46 28-51
Sex
Male 25 (83) 18 (60) 16 (52)
Female 5 (17) 12 (40) 15 (48)
Diagnosis
ALL 8 (27) 10 (33) 11 (35)
AML 15 (50) 14 (47) 12 (39)
CML 0 (0) 2 (7) 1 (3)
MDS 5 (17) 4 (13) 4 (13)
NHL 2 (7) 0 3 (10)
Transplant donor
Haploidentical 23 (77) 20 (67) 21 (68)
Matched related 5 (17) 8 (27) 6 (19)
Matched unrelated 2 (7) 2 (7) 4 (13)
ABO compatibility
Matched 15 (50) 13 (43) 18 (58)
Mismatched 15 (50) 17 (57) 13 (42)
Conditioning
BU/CY 26 (87) 27 (90) 29 (94)
Other* 4 (13) 3 (10) 2 (6)
MNCs, × 10 8 /kg
Median 9.78 10.50 9.40
IQR 6.18-11.52 7.77-12.55 6.46-11.40
NE recovery, d
Median 12 12 13
IQR 11-13 12-14 12-14
Enrollment time post-HCT, d
Median 103 105 79
IQR 71-149 78-184 63-129
PLTs at enrollment, × 10 9 /L
Median 14 12 17
IQR 11-17 9-17 9-22
MK counts at enrollment, per smear
Median 11 8 6
IQR 2-17 2-20 3-23
Concurrent GVHD
Acute 10 7 9
Grade 1 5 3 5
Grade 2 5 4 4
Chronic 4 6 3
. Arm A (n = 30) . Arm B (n = 30) . Arm C (n = 31) . Age, y Median 30 36 36 IQR 23-43 27-46 28-51 Sex Male 25 (83) 18 (60) 16 (52) Female 5 (17) 12 (40) 15 (48) Diagnosis ALL 8 (27) 10 (33) 11 (35) AML 15 (50) 14 (47) 12 (39) CML 0 (0) 2 (7) 1 (3) MDS 5 (17) 4 (13) 4 (13) NHL 2 (7) 0 3 (10) Transplant donor Haploidentical 23 (77) 20 (67) 21 (68) Matched related 5 (17) 8 (27) 6 (19) Matched unrelated 2 (7) 2 (7) 4 (13) ABO compatibility Matched 15 (50) 13 (43) 18 (58) Mismatched 15 (50) 17 (57) 13 (42) Conditioning BU/CY 26 (87) 27 (90) 29 (94) Other* 4 (13) 3 (10) 2 (6) MNCs, × 10 8 /kg Median 9.78 10.50 9.40 IQR 6.18-11.52 7.77-12.55 6.46-11.40 NE recovery, d Median 12 12 13 IQR 11-13 12-14 12-14 Enrollment time post-HCT, d Median 103 105 79 IQR 71-149 78-184 63-129 PLTs at enrollment, × 10 9 /L Median 14 12 17 IQR 11-17 9-17 9-22 MK counts at enrollment, per smear Median 11 8 6 IQR 2-17 2-20 3-23 Concurrent GVHD Acute 10 7 9 Grade 1 5 3 5 Grade 2 5 4 4 Chronic 4 6 3
Data are n (%) unless otherwise noted.
ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BU/CY, busulfan/cyclophosphamide; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; MK, megakaryocyte; MNC, mononuclear cell; NE, neutrophil; NHL, non-Hodgkin lymphoma; PLT, platelet.
*Other conditioning regimens included fludarabine/cytarabine/busulfan and total-body irradiation/cyclophosphamide.
Initial evaluation of response
Patients in arms A and B had a significant increase in platelet count beginning in the third week after initiation of treatment (Figure 2A). Response rates were similar between arms A (n = 20 patients; 66.7%) and B (n = 22; 73.3%; P= .779); both arms A and B were superior to arm C (n = 6; 19.4%; P< .001). For the intention-to-treat data set (n = 97 participants in total), response rates in arms A (62.5%) and B (66.7%) were both higher than that in arm C (18.8%; P< .001). Median response durations for responding patients were comparable among arms A (25 weeks; IQR, 1-26 weeks), B (24 weeks; IQR, 1-27 weeks), and C (25 weeks; IQR, 3-27 weeks; P= .471 for comparison among 3 arms; P= .314 between arms A and B). Median use of platelet transfusions was 3, 3, and 5 units per week in arms A, B and C, respectively ( P= .001).
Figure 2.
Significantly improved platelet and megakaryocyte (MK) counts were observed in patients receiving decitabine treatment.(A) Platelet counts increased significantly in arms A and B during third week after decitabine administration. (B) Total MKs (per cm 2), platelet-shedding MKs (per cm 2), and MK polyploidy (%) in patients in arms A and B increased remarkably after treatment compared with those in arm C. (C) Representative microscopic images (Wright-Giemsa staining) of bone marrow biopsy in case 29 in arm A at week 0 (left) and week 4 (right) after treatment. Arrows indicate MKs. * P< .05. ns, not significant.
Figure 2.
Significantly improved platelet and megakaryocyte (MK) counts were observed in patients receiving decitabine treatment.(A) Platelet counts increased significantly in arms A and B during third week after decitabine administration. (B) Total MKs (per cm 2), platelet-shedding MKs (per cm 2), and MK polyploidy (%) in patients in arms A and B increased remarkably after treatment compared with those in arm C. (C) Representative microscopic images (Wright-Giemsa staining) of bone marrow biopsy in case 29 in arm A at week 0 (left) and week 4 (right) after treatment. Arrows indicate MKs. * P< .05. ns, not significant.
Total megakaryocyte counts, platelet-shedding megakaryocytes, and megakaryocyte polyploidy of patients in arms A ( P= .017, .027, and .015, respectively) and B ( P= .042, .013, and .017, respectively) were significantly elevated after treatment (Figure 2B), suggesting improved megakaryocyte proliferation and maturation in patients who received decitabine. There was no increase of these megakaryocyte parameters in arm C ( P= .836, .875, and .485, respectively). The increase in megakaryocytes after decitabine was also visually apparent on bone marrow biopsies (Figure 2C).
All variates described inTable 1were tested in risk factor analyses for response, which revealed the trial intervention (decitabine) to be the only significant variate. Compared with arm C, both arms A (hazard ratio [HR], 8.333; 95% confidence interval [CI], 2.585-26.864; P< .001) and B (HR, 11.458; 95% CI, 3.439-38.181; P< .001) led to better response rates (Table 2).
Table 2.
Risk analyses for response and OS in the whole cohort
. Response . OS . HR . 95% CI . P . HR . 95% CI . P .
Intervention arm
C <.001 .037
A 8.333 2.585-26.864 <.001 2.000 0.960-4.167 .064
B 11.458 3.439-38.181 <.001 2.597 1.164-5.814 .018
Diagnosis
Other .746 .936
ALL 0.646 0.211-1.979 .444 1.136 0.482-2.677 .771
AML 0.765 0.267-2.192 .618 0.997 0.460-2.160 .993
Age 0.945 0.414-2.156 .893 0.784 0.413-1.485 .454
Sex 0.844 0.356-1.997 .699 0.675 0.355-1.281 .229
Time of enrollment 1.000 0.998-1.002 .870 0.999 0.998-1.001 .310
Donor
MUD .843 .102
MMRD 1.207 0.277-5.253 .802 2.215 0.906-5.414 .081
MRD 0.900 0.172-4.699 .901 3.203 1.069-9.603 .038
ABO compatibility 0.800 0.351-1.825 .596 0.963 0.514-1.806 .907
Conditioning 1.974 0.443-8.802 .373 0.273 0.037-1.994 .201
MNCs 2.812 0.901-6.585 .107 1.134 0.604-2.127 .696
NE recovery 0.902 0.764-1.066 .227 1.012 0.895-1.143 .855
MKs before treatment 1.005 0.986-1.025 .588 1.003 0.989-1.017 .718
Response 3.076 1.565-6.047 .001
. Response . OS . HR . 95% CI . P . HR . 95% CI . P . Intervention arm C <.001 .037 A 8.333 2.585-26.864 <.001 2.000 0.960-4.167 .064 B 11.458 3.439-38.181 <.001 2.597 1.164-5.814 .018 Diagnosis Other .746 .936 ALL 0.646 0.211-1.979 .444 1.136 0.482-2.677 .771 AML 0.765 0.267-2.192 .618 0.997 0.460-2.160 .993 Age 0.945 0.414-2.156 .893 0.784 0.413-1.485 .454 Sex 0.844 0.356-1.997 .699 0.675 0.355-1.281 .229 Time of enrollment 1.000 0.998-1.002 .870 0.999 0.998-1.001 .310 Donor MUD .843 .102 MMRD 1.207 0.277-5.253 .802 2.215 0.906-5.414 .081 MRD 0.900 0.172-4.699 .901 3.203 1.069-9.603 .038 ABO compatibility 0.800 0.351-1.825 .596 0.963 0.514-1.806 .907 Conditioning 1.974 0.443-8.802 .373 0.273 0.037-1.994 .201 MNCs 2.812 0.901-6.585 .107 1.134 0.604-2.127 .696 NE recovery 0.902 0.764-1.066 .227 1.012 0.895-1.143 .855 MKs before treatment 1.005 0.986-1.025 .588 1.003 0.989-1.017 .718 Response 3.076 1.565-6.047 .001
MMRD, mismatched related donor; MRD, matched related donor; MUD, matched unrelated donor; OS, overall survival.
Follow-up
During follow-up of additional 24 weeks after the initial evaluation, 4 patients had delayed platelet recovery (at the 6th, 11th, 14th, and 18th week during follow-up, respectively) in arm A, 3 in arm B (at the 5th, 10th, and 17th week during follow-up, respectively), and 6 in arm C (at the 5th, 10th, 11th, 18th, 25th, and 26th week during follow-up, respectively). No statistical difference was found in comparison among the 3 arms ( P= .655).
At the end of 28 weeks after treatment, survival was 80.0% for arm A, 83.3% for arm B, and 58.1% for arm C ( P= .057). Because survival rates in arms A and B were similar ( P> .99), we combined arms A and B and found superior 28-week survival for patients treated with decitabine compared with those receiving conventional treatments (82.5% vs 60.0%; P= .22). With a median total follow-up of 11 months, the estimated 1-year survival rate was 64.4% ± 9.1% for arm A, 73.4% ± 8.8% for arm B, and 41.0% ± 9.8% for arm C ( P= .025;Figure 3A). Decitabine treatment (arms A + B) was associated with significantly greater 1-year survival (68.2% ± 6.4% vs 41.0% ± 9.8%; P= .008;Figure 3B).
Figure 3.
Decitabine treatment is associated with better overall survival.(A) One-year overall survival rates in arms A, B, and C were 64.4% ± 9.1%, 73.4% ± 8.8%, and 41.0% ± 9.8%, respectively ( P= .025). (B) One-year overall survival rates for patients in arms A and B (decitabine ± rhTPO; 68.2% ± 6.4%) were higher than those for patients in arm C (conventional treatment; 41.0% ± 9.8%; P= .008).
Figure 3.
Decitabine treatment is associated with better overall survival.(A) One-year overall survival rates in arms A, B, and C were 64.4% ± 9.1%, 73.4% ± 8.8%, and 41.0% ± 9.8%, respectively ( P= .025). (B) One-year overall survival rates for patients in arms A and B (decitabine ± rhTPO; 68.2% ± 6.4%) were higher than those for patients in arm C (conventional treatment; 41.0% ± 9.8%; P= .008).
Six patients relapsed before the primary end point evaluation (day 28) and were therefore excluded from this study. An additional 3 patients in arm A, 2 in arm B, and 2 in arm C relapsed during long-term follow-up (median, 11 months). No difference in overall incidence of relapse was found among the 3 arms ( P= .807).
Thirty-five patients died during follow-up, including 10 in arm A, 8 in arm B, and 17 in arm C. More patients died as a result of bleeding (n = 6 [35.3%] of 17) in arm C compared with arms A (n = 2 [20.0%] of 10) and B (n = 1 [12.5%] of 8), although the difference was not statistically significant ( P= .543). Other causes of death were severe GVHD (n = 1 in arm A, 2 in B, and 3 in C), infection/sepsis (n = 3, 3, and 5, respectively), relapse (n = 3, 2, and 2, respectively), and multiple organ failure (n = 1, 0, and 1, respectively).
Risk factor analyses in patients receiving decitabine
Univariate analysis revealed that the trial intervention and platelet response were related to survival (Table 2). Because the intervention was strongly associated with response, we excluded platelet response from multivariate analysis for survival to avoid a conjugation interaction. As a result, the intervention was the only independent factor affecting survival for all patients.
Factors related to response and survival in patients in arms A and B were further analyzed (supplemental Table 1). We did not identify the predictor for response after analyzing the impact of the combination of rhTPO, diagnosis, age, sex, time of enrollment, ABO compatibility, conditioning, cell counts in graft, neutrophil recovery, and megakaryocytes before treatment. Similarly, none of these variates showed an independent impact on survival in Cox regression, except response to decitabine, which was associated with prolonged survival with marginal significance (HR, 2.316; 95% CI, 0.964-5.556; P= .060).
Endothelial cells and related cytokines
Percentages of EPCs and BMECs in bone marrow increased significantly in arms A ( P= .001 and .006, respectively) and B ( P= .024 and .045, respectively) compared with arm C ( P= .635 and .869, respectively; supplemental Figure 1A). After decitabine treatment, secreted endothelin-1 ( P= .004 and .011) and VEGF ( P= .003 and .006) levels increased and endogenous NO level ( P= .01 and .019) decreased significantly in patients in arms A and B, respectively (supplemental Figure 1B). Cytokines and chemokines reflecting megakaryocyte migration and adhesion, including SDF-1 ( P= .003 and .01), CXCR4 ( P= .014 and .04), and FGF-4 ( P= .016 and .007) were also increased after treatment in both arms A and B, respectively (supplemental Figure 1C).
AEs
The main AEs were hematologic and related toxicities, including neutropenia, anemia, infection, and bleeding events (Table 3). Slight fluctuations in white blood cells and hemoglobin were observed in arm C, although no cytotoxic agents were administered to these patients. Greater myelosuppression was found in arms A and B, presenting as more severe and prolonged leukopenia and anemia, when compared with arm C, but the incidence of infection was similar among the 3 arms. Despite the increased platelet counts in arms A and B, the frequency of bleeding events was comparable. Other AEs included fatigue, decreased liver function, and chest pain, but few of these events were grade ≥3. Nonhematologic toxicities were not different among the 3 arms ( P= .702).
Table 3.
AEs
AEs * . Arm A . Arm B . Arm C . P .
Duration of decreased WBCs from baseline, d <.001
Median 18.5 15.0 4.0
Range 11.0-25.0 10.8-21.5 0.0-9.0
Maximum deviation of WBCs from baseline, × 10 9 /L .001
Median 2.03 1.84 0.37
Range 1.33-2.74 1.06-3.21 0.0-1.65
Maximum deviation of NEs from baseline, × 10 9 /L) .139
Median 0.98 1.17 0.71
Range 0.52-1.83 0.52-2.13 0.22-1.41
Duration of decreased Hb from baseline, d .041
Median 11.0 9.5 4.0
Range 5.0-17.0 2.8-22.3 0.0-7.0
Maximum deviation of Hb from baseline, × g/L .029
Median 12.0 10.0 4.0
Range 4.0-17.0 1.8-16.3 0.0-11.0
Bleeding events †
All 4 3 3 .919
Moderate/severe 1 1 0 .546
New infections
Any grade 2 0 3 .364
Grade ≥3 2 0 2 .541
Hypohepatia ‡ 2 1 1 .843
Chest distress ‡ 1 1 0 .546
Anorexia ‡ 1 0 0 .659
Fatigue ‡ 2 1 1 .843
Headache ‡ 1 0 0 .659
Nausea ‡ 1 0 0 .659
Fever ‡ 1 2 1 .843
Blurred vision ‡ 0 1 0 .659
Hyperuricemia ‡ 0 1 0 .659
Erythra ‡ 0 1 1 >.99
Shock 1 0 1 >.99
AEs * . Arm A . Arm B . Arm C . P . Duration of decreased WBCs from baseline, d <.001 Median 18.5 15.0 4.0 Range 11.0-25.0 10.8-21.5 0.0-9.0 Maximum deviation of WBCs from baseline, × 10 9 /L .001 Median 2.03 1.84 0.37 Range 1.33-2.74 1.06-3.21 0.0-1.65 Maximum deviation of NEs from baseline, × 10 9 /L) .139 Median 0.98 1.17 0.71 Range 0.52-1.83 0.52-2.13 0.22-1.41 Duration of decreased Hb from baseline, d .041 Median 11.0 9.5 4.0 Range 5.0-17.0 2.8-22.3 0.0-7.0 Maximum deviation of Hb from baseline, × g/L .029 Median 12.0 10.0 4.0 Range 4.0-17.0 1.8-16.3 0.0-11.0 Bleeding events † All 4 3 3 .919 Moderate/severe 1 1 0 .546 New infections Any grade 2 0 3 .364 Grade ≥3 2 0 2 .541 Hypohepatia ‡ 2 1 1 .843 Chest distress ‡ 1 1 0 .546 Anorexia ‡ 1 0 0 .659 Fatigue ‡ 2 1 1 .843 Headache ‡ 1 0 0 .659 Nausea ‡ 1 0 0 .659 Fever ‡ 1 2 1 .843 Blurred vision ‡ 0 1 0 .659 Hyperuricemia ‡ 0 1 0 .659 Erythra ‡ 0 1 1 >.99 Shock 1 0 1 >.99
Data are number of events unless otherwise noted.
Hb, hemoglobin; WBC, white blood cell.
*
Nonhematologic AEs were based on Common Terminology Criteria for Adverse Events (version 5.0).
†
Bleeding events were assessed according to the previous study by Nevo et al. 31
‡
Any grade.
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Discussion
Isolated thrombocytopenia is a frequent and severe complication of HCT that is associated with worse outcomes. 4Thrombocytopenia post-HCT has been attributed to the recurrence of underlying disease, treatment history, transplant donor, and transplantation complications, such as GVHD or infection. 4,5However, the pathogenesis of thrombocytopenia in patients without an identified risk factor remains uncertain. Because of the lack of a consistent definition for prolonged isolated thrombocytopenia, published studies have enrolled diverse patients according to various criteria, which makes it difficult to evaluate incidence, treatment efficacy, and long-term outcomes.
After transplantation, relapse and transplantation complications such as GVHD, infection, or microangiopathy may lead to incomplete platelet recovery, which requires appropriate interventions to resolve the underlying conditions. For those without an identified cause, supportive treatments for increasing platelet counts are usually administered. Therefore, in our study, we enrolled patients with isolated thrombocytopenia after 60 days post-HCT to allow conventional treatments for thrombocytopenia to be effective so as to ensure that the recruited patients were refractory to the usual treatments. As recommended by the 2019 immune thrombocytopenia guideline of the American Society of Hematology, patients with platelet count <30 × 10 9/L were enrolled, because these patients have a significantly higher risk of severe bleeding. 19Therefore, RPIT in our study was defined as platelet count <30 × 10 9/L after 60 days post-HCT without an identified cause and refractoriness to conventional supportive treatments. Patients with RPIT deserve more intensive interventions, because both our data on patients in arm C and previously published data suggest that these patients have poor outcomes despite continuous administration of conventional treatments. 3,5
Patients with RPIT after HCT had lower megakaryocyte counts and abnormal megakaryocyte maturation, 2which may be correlated with the damaged bone marrow microenvironment, including endothelial cells and cytokines, which are required to support megakaryocytopoiesis and platelet production. It has been reported that the administration of vascular disrupting agents could lead to prolonged and selective thrombocytopenia after chemotherapy, which continued even if other hematopoietic lineages were restored. 20Damage to microvascular endothelial cells is unavoidable for HCT patients because of the radiochemotherapy conditioning regimen administered before transplantation as well as the potential immune disorders caused by alloreactivities. 9,21,22Endothelial-associated adhesion molecules such as SDF-1 and CXCR4 have an essential role in regulating megakaryocyte migration and platelet release. 23,24A previous study indicated that administration of SDF-1 and FGF-4 caused a threefold increase in platelet count as a result of enhanced interactions between megakaryocyte progenitors and the bone marrow vascular endothelium in thrombocytopenic, TPO-deficient mice. 25In posttransplantation settings, impaired EPCs and related chemokines have been found in patients with poor graft function. 10
Optimal treatment remains a challenge for patients with RPIT after HCT. Decitabine, a well-recognized hypomethylating agent, has been reported to induce megakaryocyte differentiation and maturation in vitro. 12In vivo, a 30% platelet count increase in mice after the injection of decitabine was observed, suggesting rapid platelet release from the bone marrow. 12Recently, a multicenter study in refractory immune thrombocytopenia patients demonstrated that low-dose decitabine (3.5 mg/m 2IV for 3 consecutive days per cycle for 3 cycles, with a 4-week interval between cycles) improved the platelet count in 51% participants, 26possibly by increasing the number of mature polyploid megakaryocytes and promoting platelet production. Moreover, there is evidence suggesting that hypomethylating agents may help alleviate endothelial damage 13and modulate the microenvironment in niche by upregulating CXCR4, the SDF-1 ligand on CD34 +cells. 27In accordance with previous observations, we found that RPIT patients responding to decitabine had increased levels of EPCs, BMECs, and chemokines related to megakaryocyte migration, as well as improved megakaryocyte maturation status (data supplement).
rhTPO and TPO receptor agonists (eltrombopag and romiplostim) are alternative approaches to treat thrombocytopenia caused by various settings, including allogeneic HCT. 28-30TPO has proved to be the principal physiologic cytokine for megakaryogenesis. Our previous study showed rhTPO after allogeneic HCT could promote platelet engraftment and significantly improve the prognosis of patients with myelodysplastic syndrome and aplastic anemia. 29Because neither eltrombopag nor romiplostim were available in China when this trial began, we designed a combined regimen of decitabine and rhTPO (arm A) to investigate the potential synergistic effect. No benefit of this combination was apparent when compared with decitabine alone.
For patients with RPIT after HCT, it remains to be investigated whether additional decitabine may be beneficial. Delayed recovery of platelets was also observed in all 3 arms, although it is difficult to determine whether this was a delayed response to treatment (either decitabine or control) or spontaneous platelet recovery. Meanwhile, death during follow-up may have contributed to bias when analyzing this group of patients, because there was a competing risk between death and delayed recovery.
Superior survival was found in patients receiving decitabine of both arms A and B, which may be attributed to the improved bone marrow microenvironment that facilitates platelet recovery and immune reconstitution. Because of the poor platelet recovery in arm C, more patients died as a result of bleeding compared with patients in arms A and B. Although the difference was not significant, probably because of the small number of patients, this result suggests that the reduced survival in arm C can be mainly attributed to increased fatal hemorrhage, because other causes of death (eg, GVHD, infection, and relapse) were comparable among the 3 groups. Although the antitumor property of decitabine potentially contributed to the prolonged overall survival, relapse incidence was comparable among the 3 arms during long-term follow-up.
Limitations of our study include the small and diverse sample and heterogeneous treatment options in arm C. Although our data suggests that decitabine can increase megakaryocyte numbers and function, additional studies are required to accurately define the effect of decitabine on platelet production. Our data suggest that the benefit of decitabine can be attributed to the promotion of megakaryocyte maturation and migration, as well as the repair of endothelial cells. Additional studies are warranted to determine the role of decitabine regarding EPCs and megakaryocytes.
In conclusion, this multicenter randomized study demonstrates the efficacy and safety of decitabine for patients with RPIT after HCT, with improved response and prolonged survival.
Requests for data sharing should be e-mailed to the corresponding author [email protected].
Acknowledgments
The authors thank James George and Lijun Xia for their critical reading and comments, as well as Yu Hu at Wuhan Union Hospital (Wuhan, China), Xiaojun Huang at Peking University People’s Hospital (Beijing, China), and Ming Hou at Qilu Hospital of Shandong University (Jinan, China) for assistance with developing the clinical trial protocol.
This work was supported by grants from the National Natural Science Foundation of China (81873432, 81670132, 81730003, and 81700173), National Key R&D Program of China (2019YFC0840604), National Science and Technology Major Project (2017ZX09304021), Jiangsu Province of China (18KJA320006, SBE2016740635, BE2019798, and ZDRCA2016047), and Priority Academic Program Development of Jiangsu Higher Education Institutions.
Authorship
Contribution: Y.H. and D.W. designed the study; Q.L., X.F.H., F.C., T.Y., X.M., X.W., S.H., X.C., X.H., J.H., and Y.L. recruited patients; Q.L., Y.H., D.W., and C.R. provided administrative support; Y.T., J.C., T.C., T.P., J.L., J.Q., and Y.S. collected the data and performed the analyses; Y.T., J.C., and Y.H. interpreted the data and wrote the manuscript; and all authors contributed to data interpretation, reviewed and provided their comments on the manuscript, and approved the final version.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Yue Han, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China; e-mail:[email protected]; and Depei Wu, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China; e-mail:[email protected].
References
1.
Appelbaum FR
.
Hematopoietic-cell transplantation at 50
2.
Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation: associations with impaired platelet production and increased platelet turnover
3.
Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes
4.
Author notes
Y.T., J.C., and Q.L. contributed equally to this study.
Supplemental data
Supplement File 1 - pdf file
| https://ashpublications.org/bloodadvances/article/5/5/1250/475338/Low-dose-decitabine-for-refractory-prolonged?searchresult=1 |
Facts about "Casablanca" : Classic Movie Hub (CMH)
Browse Fun Facts and Trivia about at Classic Movie Hub (CMH).
Facts>By Film> Casablanca >
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Casablanca
"As Time Goes By" was written by lifelong bachelorHerman Hupfeldand debuted in 1931's Broadway show "Everybody's Welcome", sung byFrances Williams, It had been a personal favorite of playwright and high school teacherMurray Burnettwho, seven years later, visited Vienna just after the Nazis had entered. Later, after visiting a café in south France where a black pianist had entertained a mixed crowd of Nazis, French and refugees, Burnett was inspired to write the melodrama "Everybody Comes to Rick's", which was optioned for production byMartin GabelandCarly Wharton, and later, Warners. After the film's release, "As Time Goes By" stayed on radio's "Hit Parade" for 21 weeks. However, because of the coincidental musicians' union recording ban, the 1931Rudy Valleeversion became the smash hit. (It contains the rarely-sung introductory verse, not heard in the film.)Max Steiner, in a 1943 interview, admitted that the song "must have had something to attract so much attention".
"Here's looking at you, kid" was improvised byHumphrey Bogartin the Parisian scenes and worked so well that it was used later on again in the film. He originally used the same line inMidnight. It is also rumored that during breaks,Ingrid Bergmanwould play poker with other cast members. Since she was still learning English, Bogart would occasionally watch the game, and he added "Here's looking at you" to her poker repertoire.
"Rick's Café Américain" was modeled after Hotel El Minzah in Tangiers.
Humphrey Bogarthad to wear platform shoes to play alongsideIngrid Bergman.
Humphrey Bogart,Ingrid BergmanandPaul Henreidlater reprised their roles for a radio performance of on the CBS radio program "The Screen Guild Players", a war benefit show on April 26, 1943.
Humphrey Bogart's wifeMayo Methotcontinually accused him of having an affair withIngrid Bergman, often confronting him in his dressing room before a shot. Bogart would come onto the set in a rage. In fact, despite the undeniable on-screen chemistry between Bogart and Bergman, they hardly spoke, and the only time they bonded was when the two had lunch withGeraldine Fitzgerald. According to Fitzgerald, "the whole subject at lunch was how they could get out of that movie. They thought the dialogue was ridiculous and the situations were unbelievable... I knew Bogart very well, and I think he wanted to join forces with Bergman, to make sure they both said the same things." For whatever reasons, Bogart and Bergman rarely spoke after that.
S.Z. Sakall, who plays the maitre d' at Rick's Cafe, actually has more screen time thanPeter LorreorSydney Greenstreet.
Madeleine Lebeau, who plays Yvonne, andMarcel Dalio, who plays croupier Emil, were husband and wife at the time of filming. They had not long before escaped the Nazis by fleeing their native France.
Dooley Wilson(Sam) was a professional drummer who faked playing the piano. As the music was recorded at the same time as the film, the piano playing was actually a recording of a performance byElliot Carpenterwho was playing behind a curtain but who was positioned such that Dooley could watch, and copy, his hand movements.
Dooley Wilsonwas borrowed from Paramount at $500 a week.
Dooley Wilsonwas, in fact, the only member of the cast to have ever actually visited the city of Casablanca.
Joy Page, who played the young Bulgarian wife, was the stepdaughter of studio headJack L. Warner. She,Humphrey BogartandDooley Wilsonwere the only American-born people in the credited cast. This film was her debut.
Hal B. Wallisdidn't wantHumphrey Bogartwearing a hat too often in the film, as he thought it made Bogart look like a gangster.
Hal B. Wallis's first choice for director wasWilliam Wyler.
Sydney Greenstreetwanted to wear something more ethnic to show that his character had assimilated into the Moroccan lifestyle. This idea was nixed by producerHal B. Walliswho insisted that he wear his now-iconic white suit.
Ingrid BergmanandPaul Henreidmake their first appearance 24 minutes into the film.
Ingrid Bergmanconsidered her left side as her better side, and to the extent possible that was the side photographed throughout the film, so she is almost always on the right side of the screen looking towards the left regardless of who is in the shot with her. However, there are several shots where she is to the left andHumphrey Bogartis on the right, including the flashbacks to the street scene in Paris (0:41:50) and the scene at the window (0:43:40). There are also several scenes where Bergman is centered betweenPaul Henreidand Bogart, suggesting the triangle nature of their relationship; in these shots Henreid is usually to the left and Bogart is usually on the right, including the scene where she and Henreid enter the café at just before the famous "Battle of the Anthems" (1:07:40); the scene where Captain Renault arrests Victor Laszlo (1:34:00); and at the end of the final airport scene (1:39:00).
Ingrid Bergman's contract was owned by producerDavid O. Selznick, and producerHal B. Wallissent the film's writers,Philip G. EpsteinandJulius J. Epstein, to persuade Selznick to loan her to Warner Bros. for the picture. After 20 minutes of describing the plot to Selznick, Julius gave up and said, "Oh, what the hell! It's a lot of shit likeAlgiers!" Selznick nodded and agreed to the loan.
Ingrid Bergman's line "Victor Laszlo is my husband, and was, even when I knew you in Paris" was almost cut from the film because during that time it was deemed inappropriate for a film to depict or suggest a woman romancing with another man if she were already married. However, it was pointed out that later in the film she explains that she had thought Laszlo was dead at the time, and the censors allowed the line to stay in.
Howard Hawkshad said in interviews that he was supposed to directCasablancaandMichael Curtizwas supposed to directSergeant York. The directors had lunch together, where Hawks said he didn't know how to make this "musical comedy", while Curtiz didn't know anything about "those hill people." They switched projects. Hawks struggled on how to direct the scenes that involved singing, namely the "La Marseillaise" scene. It is ironic to note that most of his other films involved at least one singing scene.
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LC: Speech by SLW in moving the Second Reading of the Occupational Deafness (Compensation)(Amendment) Bill 2009
LC: Speech by SLW in moving the Second Reading of the Occupational Deafness (Compensation)(Amendment) Bill 2009
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Following is the speech (English translation) by the Secretary for Labour and Welfare, Mr Matthew Cheung Kin-chung, in moving the Second Reading of the Occupational Deafness (Compensation) (Amendment) Bill 2009 in the Legislative Council meeting today (June 3):President,I move the Second Reading of the Occupational Deafness (Compensation) (Amendment) Bill 2009 (the Bill).The main objective of this Bill is to adjust the overall rate and proportions of distribution of the Employees' Compensation Insurance Levy (the Levy) and to improve the Occupational Deafness Compensation Scheme (ODC Scheme).At present, for every Employees' Compensation Insurance (ECI) policy, employers are required to pay a levy at the rate of 6.3% on the premium of that policy to the Employees' Compensation Insurance Levies Management Board (ECILMB). The Levy so collected will then be distributed to three statutory bodies, namely, the Occupational Deafness Compensation Board (ODCB), the Employees Compensation Assistance Fund Board (ECAFB) and the Occupational Safety and Health Council, in accordance with the proportions stipulated under the law. The Levy is the main source of income of these statutory bodies.Among these three statutory bodies, the financial situation of ECAFB has been tight in the past few years. It is necessary to increase the rate of distribution of the Levy to ECAFB to ensure its long-term financial viability and its ability to perform various statutory functions. On the other hand, the ODCB has over the years accumulated a healthy reserve. The number of applications for compensation and the amount of compensation paid each year have more or less stabilised. It has continuously been operating with a surplus. In view of the financial positions of these two statutory bodies, we suggest that the rate of the Levy for distribution to ECAFB be increased from 2.5% to 3.1% and that of the ODCB be reduced from 1.8% to 0.7%. By effecting these adjustments, the overall Levy rate can be reduced from 6.3% to 5.8%.The ODC Scheme was set up under the Occupational Deafness Compensation Ordinance to provide compensation for employees who suffer from noise-induced deafness by reason of employment. At present, the ODC Scheme provides compensation to employees with sensorineural hearing loss of at least 40 dB in both ears. Moreover, these employees are entitled to reimbursement of expenses relating to the hearing assistive devices (HADs) up to a specified amount. Upon reviewing the financial position of the ODCB and taking into account the views of relevant groups, it is proposed that the following improvement measures should be introduced to the ODC Scheme:-(i) extending the coverage of compensation to employees who have developed noise induced deafness in only one ear because of their employment;(ii) increasing the maximum reimbursable amount for the expenses incurred relating to HADs from $18,000 to $36,000; and(iii) providing further compensation for employees whose hearing loss deteriorates as a result of continued employment in noisy occupations.The proposed amendments, if implemented, would enable the relevant statutory bodies to maintain their financial viability and to perform their statutory functions. Employers will benefit from a reduction of the overall Levy rate when taking out ECI policies. With improvements made to the ODC Scheme, benefits for employees with occupational deafness will also be improved. Although the three proposed improvement items to the ODC Scheme will increase the annual expenditure of the ODCB, given its accumulated fund and the proposed Levy rate of 0.7%, the ODCB should be able to absorb the additional expenditure comfortably.President, both employers and employees would stand to benefit from the proposed amendments. The ODCB and ECAFB supported the proposals. The Labour Advisory Board and the Legislative Council Panel on Manpower also agreed to the proposals. I hope that Honourable Members would support the Bill so that it can be passed early for the benefit of employees.Thank you. President.
| http://www.info.gov.hk/gia/general/200906/03/P200906030234.htm |
DSM-V and transgender people – Transgender Map
DSM-V and transgender people
The Diagnostic and Statistical Manual of Mental Disorders(DSM) is a document published by theAmerican Psychiatric Association(APA). It has been one of the most influential documents in the pathologization of sex and gender minorities.
The fight over the fifth revision (DSM-V) came at a major turning point in transgender activism. After the APA announced non-psychiatristsKenneth ZuckerandRay Blanchardwould be involved in writing the sections that affected our community, we staged protests and campaigns to minimize their involvement and the promotion of their ideology in the revision.
Every trans person fighting the academic exploitation of our community got involved. Kelley Winters had a leading role through her GID Reform project, books, and presentations.
James (2010)
Below is what I submitted to the American Psychiatric Association regarding the highly problematic proposed revisions for the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Comments are due April 20.
I’m grateful to those diplomatically working on damage control regarding this ill-fated DSM-V revision. Its negative effects will harm sex and gender minorities well into the 2020s. It will particularly harm an entire generation of transgender youth and intersex people.
My comments below are not diplomatic. I am noting for the record that those responsible missed their historic opportunity. They rejected the depathologization of sex and gender minorities in 2013. The DSM-V is on track to be remembered for how the responsible parties reinforced and even expanded the pathologization of sex and gender minorities, rather than taking the courageous and historically inevitable step of depathologization.
DSM-IV editor Allen Frances observed that this group has proposed two of the most troubling DSM-V revisions. Since the actual number of problems makes an exhaustive yet brief commentary impossible, I will focus on the worst of the worst:
“Paraphilia”
The worst decision in this fiasco will be to continue treating “paraphilia” as a mental disorder rather than as a sexual orientation. It is clear that the listed sexual interests cannot be “cured” any more than those orientations currently deemed non-disordered by the APA. What should be diagnosed for treatment is not the underlying interest, but the thoughts and actions related to the interest. These are no different than any other forms of impulse control issues. Any behavior can be taken to a level that could become problematic.
Most “paraphilias” involve consensual behaviors and should not be considered disorders. Characterizing these as “erotic target location errors” or diseases echoes now-outmoded “clinical wisdom” on homosexuality. We are about to see a broad expansion of “disordered” sexualities, a doubling of the types. This is being promulgated by those who think creating new “paraphilias” through iatrogenic artifact is their bid for immortality (Blanchard), or who don’t think peddling “cures” to self-hating crossdressers and what-not (Kafka) is a direct conflict of interest with the aims of this revision.
As for nonconsensual sexual interests, they are not mental disorders, either. Consent is a legal concept, not a medical one. Arousal studies suggest that many people with interests deemed illegal never act on those interests, and in fact they may face a lifetime of silent struggle not to act on these interests because of the medico-juridical climate surrounding these interests. Diagnoses support criminal statutes and vice versa: in most jurisdictions where homosexuality is illegal, it is also considered a disease.
“Experts” leverage the moral panic about intergenerational sexuality and age of consent to get funding and job security, in the same way the moral panic about homosexuality created a cottage industry. What politician wants to say they voted against funding to “cure” pedophilia? Anyone who questions any aspect of current protocols is immediately considered sexually suspect themselves, akin to earlier moral panics about communism, terrorism, and again, homosexuality. It’s clear that doctors have an important role in preventing non-consensual sexual behavior. What they are treating is not the underlying interest, but the ability to control the impulses to act on those interests.
Unconventional sexual behavior that is consensual can reach a level where impulse control needs to be managed, but that should not be thought of as “curing” the interest itself. There’s no need to diagnose or “cure” harmless sexual interests. It’s sad to see that we are well into the 21st century, yet some experts still cling to the idea that “transvestic fetishism” or other forms of consensual kink are disorders.
“Disorders of sex development”
It was inevitable that DSD would make its way into these revisions, since the term is such a huge step backwards for sex minorities. That this disorder is intermingled with gender minorities in these proposed revisions was also inevitable. From the moment I heard the term “disorders of sex development” being bandied about by self-styled ethicists, I know this is where we would end up. Their short-sighted advocacy will now result in a generation of people with natural human variations in sex anatomy to be de facto mentally disordered as well as physically disordered. This term implies that these people have a form of retardation (developmental disorder), and we will see an uptick in “cures” for both fetuses and neonates thanks to the term DSD.
The pathologization of sex diversity through the term “disorders of sex development,” which was railroaded through in a sham “consensus,” should not be codified in the DSM. To use one of Zucker’s favorite analogies (racism), policing racial distinctions is the same thing as policing sex and gender distinctions. The DSM-V should avoid engaging in this sort of policing activity: it’s politics, not science.
“Gender identity disorder”
“Gender identity disorder” and “disorders of sex development” have at their hearts the same problem: diversity is not disorder. I have lobbied long and hard against both concepts because both DSD and GID emerged from the same mindset that sees the world through a medical lens of sickness. It has troubling overlap with heterosexist reproductive ideologies as well, where those who can’t procreate are less able or even less human.
There are some trans people, especially older trans people, who argue that disease models validate their identities and allow treatment. They want GID to stay because they fear trans health services will become less available. Some also wish GID to remain because they consider themselves disabled because of GID and collect government benefits based on this alleged disability. Their self-interests should not affect the scientific debate at hand.
Most transgender people do not seek out transition-related medical services. Of those who do, most people are doing things the way we did before the rise of the “gender clinics.” Gender clinics function as gatekeepers and thus want to keep “gender identity disorder” in place. Ritual documents like the DSM encourage regressive protocols that few trans people have the patience to endure. These regressive gender clinics like CAMH in Toronto have turned down as many as 90% of patients in the past, leaving them to seek higher-risk options like medical tourism at their own expense. They then get drugs and surgery from exotic locales and/or unqualified providers unless they have the money to seek less risky treatment. Gender clinics that engage in regressive gatekeeping result in the opposite of harm reduction by forcing patients to find care outside the established system.
My position is simple but unpopular among some: Subsidized healthcare is not a fair trade for human dignity. If the psychopathology model of gender diversity promulgated in Toronto by American ex-pats is imported to the US via the DSM-V, it will have disastrous long-term consequences. The UK has made it clear that trans people are able to have access to trans health services without the stigma of a mental illness diagnosis. Other countries have followed. It’s time to remove gender identity disorder and look at options that do not situate a disorder within trans peoples’ minds.
Inflicting trauma and shame on gender-variant children through “GIDC”
In the years I have been raising awareness about the atrocities committed against gender-variant children at CAMH in Toronto, I have come to see in Zucker what can only be called anti-intellectualism regarding philosophy of science, history of science, the sociology of theory, and other relevant academic disciplines critical to understanding how pathological science and systemic bias seep into scientific methodology. We are expected to rely on Zucker’s “clinical wisdom” rather than objective outcome data. We are not supposed to question why 5 to 30 times as many children assigned as males have historically been targeted for “curing.” We are not supposed to ask if we can talk to any of the children Zucker “cured,” just as John Money wouldn’t divulge the status of a patient against whom he committed atrocities then lied about “curing.”
Clinicians have called Zucker and his colleague Susan Bradley’s therapeutic intervention for children “something disturbingly close to reparative therapy for homosexuals” and have noted that the goal is preventing transsexualism: “Reparative therapy is believed to reduce the chances of adult GID (i.e., transsexualism) which Zucker and Bradley characterize as undesirable.” Author Phyllis Burke wrote, “The diagnosis of GID in children, as supported by Zucker and Bradley, is simply child abuse.”
Conclusion
When Zucker was in charge of a similar ritual document for the American Psychological Association, he and his team cheerfully ignored a wide range of suggested changes. Between that farce and this process, I have lost faith in these empty gestures toward public commentary. So I’ll end here for now, since I am not confident in this process or its outcome.
We see these people ignoring legitimate scientific objections and continuing to use unscientific and inaccurate terminology like “shemales” (Blanchard) and “homosexual transsexual” (Cohen-Kettenis), both of which are considered outrageous slurs outside of the bubble in which these alleged experts live. Science and its terminology evolve with understanding, and if these experts are unable to evolve their terminology and thinking as well, they should not be placed in positions of authority.
Let’s hope we don’t have to resort to stunts like Dr. H. Anonymous to make our points. I doubt even someone of his fortitude could overcome all the problems with this proposed revision.
Andrea JamesApril 2010
Note: These views are mine only and do not necessarily reflect the views of any other organizations or individuals. If you require footnotes, I am happy to provide them after the fact, but I don’t really feel like taking the time after similar efforts were cheerfully ignored by Zucker and company on the 2007 American Psychological Association Task Force.
DSM-V sitehttp://www.dsm5.org/Pages/Default.aspx
Sexual and Gender Identity Disordershttp://www.dsm5.org/ProposedRevisions/Pages/SexualandGenderIdentityDisorders.aspx
Original URL:
http://www.tsroadmap.com/notes/index.php/site/my_comment_on_the_dsm_v_proposals/
My reading list (2009)
critical of DSM and the bio-psych merge
As Nancy Ordover points out inAmerican Eugenics: Race, Queer Anatomy, and the Science of Nationalism, attempts to graft the hard science of biology to the social science of psychology has been a major American obsession for over a century. It’s had a number of names, including eugenics, sociobiology, and evolutionary psychology. This “bio-psych merge” has profound implications for sex and gender minorities. For those interested in the topic, Ordover’s book linked above is a good place to start. The books below represent a range of views on this burgeoning problem.
Paula J. Caplan.They Say You’re Crazy: How The World’s Most Powerful Psychiatrists Decide Who’s Normal. Da Capo Press, 1996 ISBN 978-0201488326
Ethan Watters & Richard Ofshe.Therapy’s Delusions: The Myth of the Unconscious and the Exploitation of Today’s Walking Worried. Scribner, New York, 1999
Louise Armstrong.And They Call It Help: The Psychiatric Policing of America’s Children. Addison-Wesley Pub. Co., Reading, Mass., 1993
Lee Coleman, MD,The Reign of Error: Psychiatry, Authority, and Law. Beacon Press, Boston, 1984
Colin A. Ross, MD, & Alvin Pam, PhD, et al.Pseudoscience in Biological Psychiatry: Blaming the Body (Wiley Series in General and Clinical Psychiatry). John Wiley & Sons, Inc., New York, 1995
Ehrbar et al (2009)
Paper: Revision Suggestions for Gender Related Diagnoses in the DSM and ICD
At the 2009 WPATH conference in Oslo, a reformed disease model was presented based on work by Randall Ehrbar, Psy.D., Kelley Winters, Ph.D. and Nick Gorton, M.D. It reconfigures gender dysphoria as an acute form of distress that can go into “remission.”
Summary of Proposed Diagnosis:
Dx Criteria – Both A and B• A: Strong and persistent distress with physical sex characteristics, or ascribed social gender role, that is incongruent with persistent gender identity.• B: Distress is clinically significant or causes impairment in social, occupational, or other important areas of functioning, when this distress or impairment is not solely due to external prejudice or discrimination.
GD in remission• No longer meets criteria, needs treatment to maintain remission
‘Exit clause’• No longer meets criteria, doesn’t need treatment to maintain remission
Full article:http://www.gidreform.org/wpath2009/
Protest and rally (2009)
Please spread the word about theupcoming protest and rallyat the American Psychiatric Association meeting in San Francisco.
Monday, May 18, 2009Time: 6:00pm – 7:30pmLocation: Moscone Center 747 Howard St, San Francisco, CA 94103Phone: 701-885-1125Email: protestgenderdx at gmail dot com
The APA appointedKenneth ZuckerandRay Blanchardto determine how trans people will be categorized in the next version of the Diagnostic and Statistical Manual of Metal Disorder (DSM-V). On the 18th, trans community leaders will be speaking on a panel:
“In or Out?”: A Discussion About Gender Identity Diagnoses and the DSM
1. The DSM-V Revision Process: Principles and Progress William E. Narrow, M.D.2. Beyond Conundrum: Strategies for Diagnostic Harm Reduction Kelley Winters, Ph.D.3. Aligning Bodies With Minds: The Case for Medical and Surgical Treatment of Gender Dysphoria Rebecca Allison, M.D.4. The Role of Medical and Psychological Discourse in Legal and Policy Advocacy for Transgender Persons in the U.S. Shannon P. Minter, J.D.
We need to stand up and be heard! This DSM-V revision will affect an entire generation of trans people and will be a historically significant factor in how our legal status is determined during the next 15 to 20 years.
Please join this Facebook event to help us plan the event. Questions? Contact Lore M. Dickey at the contact information above.
http://www.facebook.com/profile.php?id=519725212#/event.php?eid=187297865362&ref=mf
Winters (2009)
Transvestic Disorder and Policy Dysfunction in the DSM-V
Kelley Winters notes:
At the Annual Meeting of the Society for Sex Therapy and Research this month, a “Provisional Report by the DSM-V Workgroup on Sexual and Gender Identity Disorders,” was presented by Chairman Kenneth Zucker and a panel of workgroup members. Ray Blanchard, who chairs the Paraphilias Subcommittee, summarized proposals for “Pedohebephilic Disorder” and “Transvestic Disorder” in the DSM-V. While Charles Moser, Ph.D., M.D., and others have long raised concern about all paraphilia diagnoses in the DSM, the current diagnostic category of Transvestic Fetishism is particularly stigmatizing and defamatory for male-to-female (MTF) cross-dressers as well as many transsexual women.
Dr. Winters then proceeds to dismantle these new spurious categories.
We are starting to see how the next edition of the DSM is being shaped, and how it will affect trans people until the mid-2020s.
Full article.
Transvestic Disorder and Policy Dysfunction in the DSM-V
She adds:
“I ask the elected leadership and Board of Trustees of the American Psychiatric Association to affirm in a public statement that gender identity and expression which differ from assigned birth sex do not, in themselves, constitute mental disorder and imply no impairment in judgment or competence. I ask the DSM-V Task Force to honor this principle in the DSM-V by removing the current category of Transvestic Fetishism and rejecting Dr. Blanchard’s proposal to replace it with Transvestic Disorder. Finally, I invite members, allies and affirming care providers of the transcommunity to voice their concerns by publishing comments to this essay at gidreform.wordpress.com. I will forward these postings to the APA and DSM-V Task Force at the APA Annual Meeting in May.”
Trans group: reflect all views in DSM-V revision committee
Winters (2008)
Kelley Winters at GID Reform has announced a drive to add more diversity of opinion to the American Psychiatric Association Task Force that will determine the fate of trans people in the fifth Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Headed by Arlene Istar Lev, they are calling on all professionals to write in support of expanding the group. Trans people have protested the heavy representation of people and views associated with Toronto’s Centre for Addiction and Mental Health (CAMH). The CAMH has promoted reparative therapy on trans children they felt could be cured of gender identity disorder, and they advocate a taxonomy that asserts all trans women are either homosexuals or paraphilics.
More info:
http://www.professionals.gidreform.org
Dr. Winters’ blog post:
Balancing Views on Gender Diversity in the DSM-V Process
A new group of concerned mental health and medical professionals and scholars is calling upon clinicians and researchers supportive of gender transcendent people to press for reform of gender diagnoses in the Diagnostic and Statistical Manual of Mental Disorders. Organized by author and Clinical Social Worker Arlene Istar Lev, they are urging colleagues to write the American Psychiatric Association with recommendations that new members be added to committees responsible for gender nomenclature in the upcoming fifth edition (DSM-V).
Professionals Concerned with Gender Diagnoses in the DSM urges all trans-supportive medical and mental health practitioners and researchers to write the APA DSM-V Task Force and request that the Sexual and GID Work Group be expanded to include more affirming views of gender diversity and transition care. A web resource athttp://www.professionals.gidreform.orgprovides specific recommendations for nomination with biographical information and sample letters. For more information, [email protected] Winters, Ph.D.GID Reform Advocateshttp://[email protected]
Original URL: http://www.tsroadmap.com/notes/index.php/site/2008/09/P10/
Maligning Terminology in the DSM: The Language of Oppression
Kelly Winters of GIDreform has a good post on “maligning language” and how it effaces the identities of trans people.
Maligning language contradicts the social legitimacy of transitioned individuals. It denies our humanity and contributes to an environment of intolerance, discrimination and even physical violence. Tragically, such disrespectful conduct is encouraged with the authority of the American Psychiatric Association (APA) in the diagnosis of “Gender Identity Disorder” (GID) in the Diagnostic and Statistical Manual of Mental Disorders (DSM)
*Maligning Terminology in the DSM: The Language of Oppressionhttps://web.archive.org/web/20121204100702/http://www.tsroadmap.com/notes/index.php/site/maligning_terminology_in_the_dsm_the_language_of_oppression/
Miskimen (2008)
Dr. Linda Miskimen: oppose Ken Zucker and Ray Blanchard on DSM committee
Reverend Linda Miskimen has written a position statement opposing involvement in Ken Zucker and Ray Blanchard in the Sexual and Gender Identity Disorders work group for the DSM-V revision.
Full article (PDF)zucker_APA.pdf
Reverend Linda Miskimen, Doctor of Philosophy in Religion, Circle Ministries, Bloomington MN.http://www.circleministries.org
http://www.tsroadmap.com/notes/index.php/site/comments/dr_linda_miskimen_oppose_ken_zucker_and_ray_blanchard_on_dsm_committee
Forstein (2008)
Update on the DSM-V Issue from Dr. Marshall Forstein
Viaquench zine, Dr. Marshall Forstein notes:
Before people get overly hysterical about the Gender Identity Work group for the DSM, some things need to be made clear.
The letter you are asking us to sign onto is inaccurate in many ways and does not help our cause. Let me clarify what I know as someone who has worked with the American Psychiatric Association for many years.
1- there are TWO professional associations: Both unfortunately go by A P A
a) one is the American Psychiatric Association [this is a MEDICAL society of physicians who specialize in psychiatry]
b) the other is the American Psychological Association [this is a non- medical society of psychologists who are not medical doctors but have a PhD or PsyD or EdD in psychology, either clinical or research or academic or all.]
The American PSYCHIATRIC Association is the organization that publishes the DSM. This is a guide to diagnosis and NOT to Treatment.
Dr. Zucker, although not my preferred choice to head the work group on Gender and Sexuality, does not decide himself what the American Psychiatric Association publishes in the next DSM. In fact, there is a lengthy, and complicated process of peer review based on PUBLISHED scientific literature- in fact, the way we got homosexuality OUT of the DSM [1973] was to force the scientific program committee to produce evidence that homosexuality was an illness, and then in 1989 we removed ego-dystonic homosexuality because there was no evidence to support it and we suggested that there was also ego-dystonic heterosexuality that was a phase of people coming to understand their inner nature.
Sexual orientation is NOT even an issue for the DSM committee to consider. Transgender Identity is a bit more complicated, especially in childhood. The DSM work group will struggle with these issues in coming up with criteria for what to diagnose as a true gender identity disorder. I WANT TO EMPHASIZE THAT TREATMENT RECOMMENDATIONS ARE NOT A PART OF THIS ENDEAVOR.
Any treatment recommendations that the American Psychiatric Association makes are the result of significant process of creating EVIDENCED based research.
I am currently the Chair of the Work group on Practices Guidelines on HIV Psychiatry for the American Psychiatric Association, and so am intimately aware of the process. Guidelines go through rigorous research review for controlled studies in order to make recommendations. Hundreds of people review these guidelines before publication, and the same will be true of the criteria set forth by the work group on the DSM gender identity subcommittee.
EVEN if there is literature out there that disturbs those of us who are comfortable with the concepts of transgender identity, unless it meets peer review by legitimate journals ( i.e. non religious based periodicals) it will not be considered in the development of criteria for diagnosis or treatment.
I hope that what I have written makes us pause a bit before we do something to alienate even our supporters and friends in the American Psychiatric and the American Psychological Association who have been very pro-gay and pro-trans in their deliberations so far. There will always be a vocal minority that claim otherwise, but the process is vetted by many people committed to scientific integrity and evidence.
I have alerted the Association of Gay and Lesbian Psychiatrists to the announcement of Dr Zucker’s appointment and we will be addressing the implications of this within the psychiatric and psychological professional groups. I will also be talking with the Medical Director of the American Psychiatric Association and the Director of the Research group that oversees the DSM to convey the concerns that people have about the “transphobia” that may emerge.
In good conscience, however, I cannot sign a petition that is inaccurate and misleading – it may do far more harm than good. Clarity of the scientific evidence, asking the right questions of the committee, and addressing the criteria that will be put forth for review before it is ever considered ready for publication is the only way we will be taken seriously.
Please let me know how I can help to keep the issues clear.Marshall Forstein, M.D.Associate Professor of PsychiatryHarvard Medical School Director, Adult Psychiatry Residency TrainingThe Cambridge HospitalThe Cambridge Health Alliance
Thanks toquench zinefor publishing this.
http://www.tsroadmap.com/notes/index.php/site/comments/update_on_the_dsm_v_issue_from_dr_marshall_forstein/
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IJERPH | Free Full-Text | Perceived Stigma of Sudden Bereavement as a Risk Factor for Suicidal Thoughts and Suicide Attempt: Analysis of British Cross-Sectional Survey Data on 3387 Young Bereaved Adults
The sudden death of a friend or relative, particularly by suicide, is a risk factor for suicide. People who experience sudden bereavement report feeling highly stigmatised by the loss, potentially influencing access to support. We assessed whether perceived stigma following sudden bereavement is associated with suicidal thoughts and suicide attempt. We analysed cross-sectional survey data on 3387 young adults bereaved by the sudden death of a close contact. We tested the association of high versus low perceived stigma (on the stigma sub-scale of the Grief Experience Questionnaire) with post-bereavement suicidal ideation and suicide attempt, using random effects logistic regression, adjusting for socio-demographic factors, pre-bereavement psychopathology, and mode of sudden bereavement (natural causes/unnatural causes/suicide). Subjects with high perceived stigma scores were significantly more likely to report post-bereavement suicidal thoughts (adjusted odds ratio (AOR) = 2.74; 95% confidence interval (CI) = 1.93–3.89) and suicide attempt (AOR = 2.73; 95% CI = 2.33–3.18) than those with low stigma scores. People who feel highly stigmatised by a sudden bereavement are at increased risk of suicidal thoughts and suicide attempt, even taking into account prior suicidal behaviour. General practitioners, bereavement counsellors, and others who support people bereaved suddenly, should consider inquiring about perceived stigma, mental wellbeing, and suicidal thoughts, and directing them to appropriate sources of support.
Perceived Stigma of Sudden Bereavement as a Risk Factor for Suicidal Thoughts and Suicide Attempt: Analysis of British Cross-Sectional Survey Data on 3387 Young Bereaved Adults
1
UCL Division of Psychiatry, University College London, London W1T 7NF, UK
2
Camden and Islington NHS Foundation Trust, London NW1 0PE, UK
3
Education Unit, UCL Institute of Neurology, University College London, London WC1N 3BG, UK
4
UCL Department of Primary Care and Population Health, University College London, London NW3 2PF, UK
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2017 , 14 (3), 286; https://doi.org/10.3390/ijerph14030286
Received: 30 January 2017 / Accepted: 6 March 2017 / Published: 9 March 2017
(This article belongs to the Special Issue From Understanding Suicide Risk to Preventing Suicide )
Abstract
:
The sudden death of a friend or relative, particularly by suicide, is a risk factor for suicide. People who experience sudden bereavement report feeling highly stigmatised by the loss, potentially influencing access to support. We assessed whether perceived stigma following sudden bereavement is associated with suicidal thoughts and suicide attempt. We analysed cross-sectional survey data on 3387 young adults bereaved by the sudden death of a close contact. We tested the association of high versus low perceived stigma (on the stigma sub-scale of the Grief Experience Questionnaire) with post-bereavement suicidal ideation and suicide attempt, using random effects logistic regression, adjusting for socio-demographic factors, pre-bereavement psychopathology, and mode of sudden bereavement (natural causes/unnatural causes/suicide). Subjects with high perceived stigma scores were significantly more likely to report post-bereavement suicidal thoughts (adjusted odds ratio (AOR) = 2.74; 95% confidence interval (CI) = 1.93–3.89) and suicide attempt (AOR = 2.73; 95% CI = 2.33–3.18) than those with low stigma scores. People who feel highly stigmatised by a sudden bereavement are at increased risk of suicidal thoughts and suicide attempt, even taking into account prior suicidal behaviour. General practitioners, bereavement counsellors, and others who support people bereaved suddenly, should consider inquiring about perceived stigma, mental wellbeing, and suicidal thoughts, and directing them to appropriate sources of support.
Keywords:
suicide
;
bereavement
;
stigma
;
depression
;
support
;
risk factor
1. Introduction
The search for modifiable risk factors for suicide underpins the suicide prevention research agenda. Sudden bereavement, particularly by suicide [ 1 ], is now recognised as a robust risk factor for suicide [ 2 ], but explanations for this are unclear. Studies controlling for mental illness indicate that neither heritability [ 2 , 3 ] nor assortative mating [ 4 ] completely account for the observed association. An alternative explanation is perceived stigma; the subjective awareness of others’ negative attitudes [ 5 ]. This is a common feature of sudden or violent bereavements and may influence access to support [ 1 ]. Stigma is also potentially modifiable [ 6 ]. Studies comparing grief reactions after different causes of death reveal that experiences of stigma, shame, and concealing the cause are reported after all modes of bereavement, but particularly after violent deaths [ 1 , 7 ] and specifically suicide [ 8 ]. Accounting for high levels of perceived stigma has been found to attenuate the association of suicide bereavement with suicide attempt [ 9 ], suggesting its role as a mediator of suicide risk. The implication is that anti-stigma interventions might reduce the risk of suicide attempt in people who experience sudden bereavement, perhaps by reducing distress and/or optimising support.
The means by which stigma creates barriers to help-seeking have been well-described in relation to mental illness [ 10 ], but less well in relation to sudden bereavement [ 7 , 11 , 12 , 13 ]. In people with mental illness, stigma is hypothesised to contribute to suicidality through factors such as social isolation, hopelessness, and a perception of being a burden [ 14 ]. The same might be theorised after sudden bereavement, when avoidance might arise due to embarrassment, or fear of appearing socially incompetent [ 15 ]. Feeling stigmatised by a death contributes to a sense of thwarted belongingness and poor social support; both of which may engender suicidal thoughts [ 16 ]. Our objective was to investigate whether high levels of perceived stigma after sudden bereavement are associated with suicidal behaviour. To do this, we analysed British cross-sectional survey data on adults who had experienced sudden bereavement. Our hypothesis was that high stigma scores are associated with post-bereavement suicidal behaviour and depression. To build our understanding of mechanisms, we also hypothesised that high stigma scores would be negatively associated with social support, and receipt of formal or informal support. To understand what differentiates those who attempt suicide from those who consider suicide after sudden bereavement, we hypothesised that high stigma scores are associated with suicide attempt in the sub-group of those with suicidal thoughts following bereavement [ 17 ]. Finally, we hypothesised that the effect of high stigma scores on primary outcomes would be modified by gender and by mode of bereavement, such that it would be more pronounced in women and in people bereaved by non-suicide causes.
2. Materials and Methods
2.1. Study Design
We analysed data from the UCL Bereavement Study [ 8 , 9 ]. This was a UK-wide cross-sectional survey of young adults aged 18–40 working and/or studying at UK higher education institutions (HEIs) who had experienced the sudden bereavement of a close friend or relative. This study had focused on young adults due to concerns about their risk of suicide [ 18 ] and the difficulties of engaging young suicidal men with services [ 19 ]. Full details of sampling for this closed online survey have been described elsewhere, including the survey instrument (see Supplementary Materials ) [ 8 , 9 ]. Sampling via institution-wide email lists (to all staff and students) avoided the biases associated with recruiting a help-seeking sample, and was felt to be the most efficient, comprehensive and pragmatic means of recruiting a hard-to-reach population of young adults [ 20 ]. Of 5085 respondents to the survey, we included those who consented to participate, completed a stigma score, and specified their mode of bereavement ( n = 3387).
The study was approved by the UCL Research Ethics Committee in 2010 (ref: 1975/002). All participants provided online informed consent.
2.2. Measures
Our exposure measure was high perceived stigma of the bereavement, defined using the 10-item stigma subscale of the Grief Experience Questionnaire (GEQ) [ 21 ]. The GEQ is a standardised, self-administered instrument for the assessment of the phenomenology of grief. It was originally developed in the U.S. using qualitative data from individuals bereaved by natural causes, accidental death, and suicide [ 22 ], and subsequently validated [ 21 ]. The stigma sub-scale includes items describing perceptions of others’ avoidance and lack of concern (see Box 1 ), capturing perceived rather than personal stigma. Responses to items in each subscale are rated using a 5-point Likert-style frequency scale, generating subscale scores of 5 to 25 (at 0.5 intervals). The majority of studies measuring GEQ scores use GEQ subscales rather than overall GEQ scores, allowing them to delineate specific components of grief [ 8 , 23 , 24 , 25 ]. Based on precedent [ 23 ] and the normal distribution of stigma scores in this sample, we used the mean to dichotomise stigma scores, classifying them as low (5 to 12) or high (12.5 to 25) to aid clinical interpretation.
Box 1. GEQ stigma subscale items.
Stem:
Since the death how often did you….
feel like a social outcast?
feel like no-one cared to listen to you?
feel that neighbours and friends did not offer enough concern?
feel avoided by friends?
think people were gossiping about you or the person?
think that others didn’t want you to talk about the death?
feel somehow stigmatised by the death?
feel like people were probably wondering about what kind of personal problems you and the person had experienced?
think that people were uncomfortable offering their condolences to you?
feel like the death somehow reflected negatively on you or your family?
Our primary outcomes were self-reported suicidal ideation (“Have you ever thought of taking your life, even though you would not actually do it?”) [ 26 ] and self-reported suicide attempt (“Have you ever made an attempt to take your life, by taking an overdose of tablets or in some other way?”) [ 27 ] post-bereavement. These standardised, validated measures were derived from the Adult Psychiatric Morbidity Survey (APMS) [ 28 ], a regular national population survey in England, qualified by whether each was before or after the sudden bereavement, or both, to derive an incident measure.
Our three secondary mental health outcomes were post-bereavement non-suicidal self-harm (self-poisoning and self-injury without suicidal intent) using the standardised, validated APMS measure [
27
] (adapted as above); post-bereavement suicidal and non-suicidal self-harm (aggregating the suicide attempt and non-suicidal self-harm measures, to correspond to that used in a major longitudinal study of self-harm in England [
29
]); and post-bereavement depression, using the Composite International Diagnostic Interview (CIDI) screen for lifetime depression [
30
], also validated for use in an online questionnaire [
31
] (adapted for incident cases as above).
Our three self-reported support measures were level of current social support (using a standardised ordinal measure from the APMS [
28
]); receipt of any formal bereavement support (using a binary measure developed for this study); and receipt of any informal bereavement support (using a binary measure developed for this study). Classification of formal and informal bereavement support was derived from similar British [
32
] and international [
33
] studies of service use . Self-help was excluded due to problematic categorisation in relation to formal versus informal bereavement support [
34
]. Thus, formal support was defined as that received from healthcare or social services staff; psychological therapists or counsellors; voluntary sector helplines or counsellors; police officers; funeral directors; coroners’ officers; teaching staff; school or HEI counselling services; line managers, or employer counselling services. Informal support was defined as that received from friends; family; spiritual/religious advisors, or complementary and alternative medicine practitioners.
We selected nine confounding variables on the basis of existing literature and clinical judgement: age; gender; socio-economic status (using the UK Office for National Statistics Standard Occupational Classification [
35
]); mode of sudden bereavement; kinship to the deceased; family history of suicide (excluding an index bereavement by suicide); pre-loss depression; pre-loss suicidal and non-suicidal self-harm; and years since sudden bereavement. Mode of bereavement was classified via self-report as bereavement by suicide, bereavement by sudden natural causes (e.g., cardiac arrest), and bereavement by sudden unnatural causes (e.g., accidental death). In the case of exposures to more than one mode of sudden bereavement, all those bereaved by suicide were classified as such, regardless of other exposures. Those bereaved by non-suicide death were asked to relate their responses to whichever person they had felt closest to, with exposure status classified accordingly.
Missing data for model covariates and outcomes were less than 7%.
2.3. Statistical Analysis
We investigated simple associations between the outcome variables and exposure using χ2 tests or one-way analysis of variance, as appropriate.
We investigated the relationship between outcomes and high stigma scores using multilevel regression models with HEI as random effect, to take into account the clustering effect at the HEI level. We used ordinal logistic regression to investigate the relationship between social support and high levels of perceived stigma scores. All multivariable models included the nine pre-specified confounding variables described above. Models were fitted using complete case analysis. We used the Bonferroni correction to set a significance threshold of
p
= 0.006 for multiple testing.
To test whether the effect of high stigma scores on primary outcomes varied by gender and by mode of bereavement, we added interaction terms to these models, using a less stringent
p
-value threshold (
p
= 0.1) to reflect the limited statistical power of interaction tests.
To test an additional research question about whether high perceived stigma helps differentiate those who attempt suicide after bereavement from those with suicidal ideation after bereavement, we ran our multivariable model for suicide attempt in the sub-sample of those who reported suicidal thoughts or attempts post-bereavement (
n
= 1510).
We ran a series of a priori defined sensitivity analyses to assess the robustness of our main findings when taking into account biases introduced by <7% missing data and by our sampling strategy. In the first and second analyses, we used best-case and worst-case scenarios to impute missing values by recoding all missing values on outcomes/covariates as positive (e.g., no suicidal ideation/attempt) or as negative (e.g., suicidal ideation/attempt) respectively [
36
]. In the third and fourth, we used more stringent inclusion criteria: dropping the 10 HEIs that modified the stipulated recruitment method, and the 18 HEIs with participant numbers below the median cluster size. Finally, we conducted linear regression to test whether there was a linear association between stigma scores and outcomes.
All analyses were conducted using Stata version 12 (Stata Corp. 2011. Stata Statistical Software: Release 12. College Station, TX, USA).
3. Results
3.1. Participant Characteristics
The majority of the sample were female (81%), of white ethnicity (90%), bereaved by sudden natural causes (61%), and reported the death of a relative (71%). The mean time elapsed since bereavement was 5 years (standard deviation (SD) = 5.3 years; range = 1 day to 30 years), with no group differences (
Table 1
). The age of the deceased varied from 0 (for miscarriage or stillbirth) to 100 years, and median age was significantly younger for those reporting high (median age = 45; inter-quartile range (IQR) = 22–58) versus low stigma scores (median = 50; IQR = 23–70). The group reporting high stigma scores were more likely to be women, students, those in higher social classes, and those educated to a higher level than the group with low stigma scores. They were also significantly more likely to have been bereaved by suicide, and to have had a history of suicidal or non-suicidal self-harm and of depression prior to the loss.
Amongst subjects who had made a suicide attempt since the bereavement, those who reported high stigma scores were significantly less likely to have sought help for it than those reporting low stigma scores.
Overall, 32% of the sample had received no informal support after the bereavement ( Table 2 ).
3.2. Association between High Stigma Scores and Outcomes
In an adjusted analysis ( Table 3 ), high stigma scores were associated with a significantly higher probability of post-bereavement suicidal thoughts (AOR = 2.74; 95% CI = 1.93–3.89), suicide attempt (AOR = 2.73; 95% CI = 2.33–3.18), non-suicidal self-harm (2.16; 95% CI = 1.76–2.64), any self-harm (AOR = 2.25; 95% CI = 1.85–2.74), depression (AOR = 3.84; 95% CI = 3.21–4.59).
High stigma scores were positively associated with poor social support (AOR = 2.86; 95% CI = 2.44–3.34), and use of formal bereavement support (AOR = 1.87; 95% CI = 1.60–2.19), but negatively associated with use of informal bereavement support (AOR = 0.48; 95% CI = 0.41–0.57).
In the sub-sample of
n
= 1510 individuals who reported suicidal thoughts or attempts post-bereavement, we found a significant association between high stigma scores and post-bereavement suicide attempt (AOR = 1.90; 95% CI = 1.32–2.72;
p
= 0.001).
3.3. Interactions
Gender did not modify the associations between stigma and primary outcomes, but there was an interaction with mode of bereavement, such that the magnitude of the association between high stigma and suicidal ideation was higher for those bereaved by sudden natural death (AOR = 3.08; 95% CI = 2.52–3.76) or sudden unnatural death (AOR = 3.02; 95% CI = 2.13–4.28) than for those bereaved by suicide (AOR = 1.61; 95% CI = 1.09–2.39).
3.4. Sensitivity Analysis
The magnitude and direction of adjusted odds ratios for primary outcomes were unchanged in four sensitivity analyses simulating potential biases introduced by missing data and by our sampling strategy. Conducting the analysis using linear regression showed that stigma scores were significantly associated with suicidal ideation (adjusted coefficient = 0.033; 95% CI = 0.029–0.037; p ≤ 0.001) and suicide attempt (adjusted coefficient = 0.009; 95% CI = 0.006–0.107; p ≤ 0.001). On all other measures, it also showed directions of associations consistent with those in our main analysis ( p ≤ 0.001 in all cases).
4. Discussion
4.1. Main Findings
The findings of this analysis of British cross-sectional data support our hypothesis that people who feel highly stigmatised by the sudden death of a friend or relative are at increased risk of suicidal thoughts, suicide attempt, non-suicidal self-harm, and depression. The cross-sectional nature of the data limits interpretation of the chronology of the pathways between high stigma scores and outcomes. However, associations with support measures suggested a buffering effect of social support on the negative effects of perceived stigma: those with low perceived stigma scores were more likely to report use of informal support, whereas those with high stigma scores perceived poor social support. Contrary to our hypothesis, use of formal support was more likely in people who felt highly stigmatised, perhaps because they could not rely on friends and family. It is possible that informal support plays an important role in preventing and/or redressing perceived stigma and in mitigating the effects of stigma on suicidality and depression. The results of our interaction tests are interpretable in the context of previous findings from this dataset, namely the increased risk of suicide attempt in people bereaved by suicide [
9
]. Amongst those bereaved by non-suicide causes, it was those perceiving high levels of stigma who were much more likely to report suicidal thoughts.
4.2. Results in the Context of Other Studies
Previous studies measuring the stigma of sudden bereavement have compared groups defined by cause of death [ 1 , 9 ], but none have explored whether stigma scores per se are associated with adverse outcomes. Instead, qualitative approaches have been used to describe the nature of the stigma experienced by people bereaved traumatically, and how the “death taboo” influences their and others’ avoidance of the topic [ 11 ]. Qualitative studies of the stigma perceived by people with mental illness identify the anticipation of negative consequences as a key theme in relation to help-seeking behaviour [ 10 ]. The same might apply after bereavement, particularly where the bereaved anticipate social awkwardness [ 15 ]. There is some evidence that the stigma attached to help-seeking for mental health problems [ 10 ] also applies to bereavement support groups [ 38 ], even despite social expectations for the bereaved to engage with support [ 39 ] so they can quickly “move on” with their grief [ 40 , 41 , 42 ].
4.3. Strengths and Limitations
We analysed data from a large, UK-wide sample of 3387 bereaved adults using a validated stigma measure. We tested specific hypotheses formulated on the basis of theory and clinical experience, and our models were adjusted for pre-selected potential confounders. Results were robust to sensitivity analysis simulating potential biases. We acknowledge the potential for male non-response bias, and selection bias of highly educated adults from HEIs. This, and the restricted 18–40 age range, suggest that this study’s findings may only be generalizable to highly-educated young women in the UK. All measures were potentially subject to recall bias. Although validated, our measure of lifetime depression was derived from a brief screening tool [
30
], and may have over- or under-estimated past depression where used as a potential confounder in multivariable models. Our measures of formal and informal support use were subjective, and represent both preferences and availability. Although the GEQ stigma subscale captures stigmatising aspects of the death specifically, perceived stigma may have been compounded by stigmatising depression or suicidal behaviour. As this was a cross-sectional study, it was not possible to ascertain the temporal sequence of outcomes, including whether suicidal behaviour following bereavement had preceded the awareness of stigma, or of lack of support. However, quantitative [
43
] and qualitative [
44
] studies identify perceptions of a lack of support immediately after a sudden death.
4.4. Clinical and Policy Implications
This study has identified perceived stigma after sudden bereavement as a potentially useful marker for suicidality, depression, and for poor social support. Indeed, among those who had felt suicidal following sudden bereavement, perceptions of high stigma helped differentiate attempters from ideators. Identification of people who feel highly stigmatised after bereavement creates an opportunity to intervene and prevent suicide attempt. General practitioners and bereavement counsellors who encounter bereaved people might consider inquiring about perceived stigma as a way of building a rapport before probing, where appropriate, for low mood and thoughts of self-harm and suicide. Anyone in contact with someone bereaved traumatically has a role in providing information on sources of voluntary sector bereavement support [ 45 , 46 , 47 ]. Given our findings, this is particularly important for those who feel most stigmatised. Specific resources are available for people bereaved by suicide [ 46 , 48 ], recognising their elevated risk of suicide [ 2 , 4 ] and efforts to target this group in suicide prevention strategies [ 49 , 50 ].
4.5. Future Research
The role of stigma as a putative mediator in the association between sudden bereavement and suicide-related outcomes, and the role of informal support as a moderator of this effect, would need formal testing using longitudinal approaches. If stigma is confirmed as mediating risk of suicidality, the next step would be to develop and trial individual-level or community-level anti-stigma interventions. These might address the barriers to seeking or receiving support, and potentially reduce suicide rates. Cultural dimensions of grief [ 51 ] suggest that the development of anti-stigma interventions will need to be based on the findings of qualitative studies. These should explore why bereaved people in different communities feel stigmatised, and how this influences help-seeking behaviour and mental health, but also to understand how informal networks perceive their role and what prevents them from offering adequate support.
5. Conclusions
The results of this study suggest that people who feel the most stigmatised by a sudden bereavement are at greater risk of suicidal behaviour and depression, and are more likely to feel inadequately socially supported by friends and family. High perceived stigma helps differentiate those who attempt suicide after sudden bereavement from those who consider it. Clinicians who inquire about perceived stigma are in a position to identify suicidal distress and address support needs. All those who have contact with people bereaved traumatically should direct them to appropriate sources of support, to overcome any barriers to help-seeking and the effects of perceived stigma.
Supplementary Materials
The following are available online at www.mdpi.com/1660-4601/14/3/286/s1 .
Acknowledgments
This work was supported by a Medical Research Council Population Health Scientist Fellowship to AP (G0802441). The Medical Research Council, as with other UK Research Councils, provides UCL with funds to cover open access for research papers it has funded. We would like to thank all the HEIs from England, Wales, Northern Ireland, and Scotland that consented to participate in the UCL Bereavement Study, listed below, and all the bereaved individuals who took time to respond to the online survey. Participating HEIs: Bishop Grosseteste University College Lincoln; Bournemouth University; Central School of Speech and Drama; City University; Cranfield University; Courtauld Institute; De Montfort University; University of Greenwich; King’s College London; Liverpool Institute for Performing Arts; Liverpool John Moores University; London Metropolitan University; Norwich University College of the Arts; Royal Veterinary College; School of Oriental and African Studies; St George’s, University of London; Staffordshire University; Trinity Laban Conservatoire of Music and Dance; UCL; University Campus Suffolk; University of Bedfordshire; University of Chester; University of Cumbria; University of Leeds; University of Liverpool; University of Oxford; University of Southampton; University of Worcester; University of Westminster; Queen Margaret University; Heriot-Watt University; Scottish Agricultural College; University of Dundee; Cardiff University; Cardiff Metropolitan University (formerly University of Wales Institute Cardiff); Queen’s University Belfast; University of Ulster.
Author Contributions
Alexandra Pitman conceived the study with Michael King and David Osborn, and designed the analysis plan in collaboration with Khadija Rantell, Louise Marston, Michael King and David Osborn. Alexandra Pitman conducted the data analysis. All authors interpreted data. Alexandra Pitman wrote the paper, with input from Khadija Rantell, Louise Marston, Michael King and David Osborn. Alexandra Pitman had full access to all the data in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis, and is the guarantor.
Conflicts of Interest
The authors declare no conflict of interest. The Medical Research Council had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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Table 1. Characteristics of participants by high versus low perceived stigma scores.
Table 1. Characteristics of participants by high versus low perceived stigma scores. GEQ Stigma Sub-Scale Score Low Perceived Stigma Score a ( n = 1764) High Perceived Stigma Score a ( n = 1623) Total ( n = 3387) p -Value b Socio-demographic characteristics Gender † Female n (%) 1388 (79) 1360 (84) 2748 (81) <0.001 missing n (%) 0 (0) 1 (<1) 1 (<1) Age of participant † mean (SD) 25.0 (6.2) 25.1 (6.4) 25.0 (6.3) 1.000 Self-defined ethnicity white n (%) 1598 (91) 1449 (89) 3047 (90) 0.224 non-white n (%) 165 (9) 172 (11) 337 (10) missing n (%) 1 (<1) 2 (<1) 3 (<1) Socio-economic status c † social classes 1.1 and 1.2 n (%) 551 (31) 440 (27) 991 (29) <0.001 social class 2 n (%) 586 (33) 526 (32) 1112 (33) social class 3 n (%) 209 (12) 185 (11) 394 (12) social class 4 n (%) 91 (5) 63 (4) 154 (5) social classes 5–7 and 9 n (%) 273 (16) 359 (22) 632 (19) missing n (%) 54 (3) 50 (3) 104 (3) Educational status attained up to A level equivalent leaving qualification n (%) 734 (42) 750 (46) 1484 (44) 0.008 attained undergraduate degree or above n (%) 1025 (58) 871 (54) 1896 (56) missing n (%) 5 (<1) 2 (<1) 7 (<1) Student status student n (%) 1472 (83) 1428 (88) 2900 (86) 0.001 staff n (%) 238 (13) 156 (10) 394 (12) both n (%) 54 (3) 38 (2) 92 (3) missing n (%) 1 (0) 1 (<1) 1 (<1) Characteristics of index bereavement Mode of death sudden natural causes n (%) 1184 (67) 892 (55) 2076 (61) <0.001 sudden unnatural causes n (%) 368 (21) 336 (21) 704 (21) suicide n (%) 212 (12) 395 (24) 607 (18) missing n (%) 0 (0) 0 (0) 0 (0) Kinship to the deceased † blood relative n (%) 1224 (69) 1176 (73) 2400 (71) 0.050 unrelated n (%) 533 (30) 441 (27) 974 (29) missing n (%) 7 (<1) 6 (<1) 13 (<1) Age of the deceased median (IQR) 50 (23–70) 45 (22–58) 47 (23–64) <0.001 Gender of the deceased Female n (%) 666 (38) 583 (36) 1249 (37) 0.216 missing n (%) 54 (3) 41 (3) 95 (3) Time since bereavement † mean (SD) 4.6 (5) 5.4 (6) 5 (5.3) 1.000 Clinical characteristics Family history of suicide (excluding index suicide bereavement) † Yes n (%) 109 (6) 104 (6) 213 (6) 0.829 missing n (%) 128 (7) 106 (7) 234 (7) Family history of psychiatric problems Yes n (%) 1008 (57) 1059 (65) 2067 (61) <0.001 missing n (%) 124 (7) 102 (6) 226 (7) Personality disorder screen positive d Yes n (%) 464 (26) 712 (44) 1176 (35) <0.001 missing n (%) 105 (6) 84 (5) 189 (6) Pre-loss depression † Yes n (%) 280 (16) 353 (22) 633 (19) <0.001 missing n (%) 74 (4) 54 (3) 128 (4) Pre-loss non-suicidal self-harm and suicide attempt † Yes n (%) 325 (18) 380 (23) 705 (21) <0.001 missing n (%) 127 (7) 104 (6) 231 (7) Help sought after suicide attempt post-bereavement Yes n (%) 15 (1) 54 (3) 69 (2) <0.001 No n (%) 36 (2) 101 (6) 137 (4) No suicide attempt post-bereavement n (%) 1713 (97) 1468 (91) 3181 (94)
SD = standard deviation; IQR = inter-quartile range; a using Grief Experience Questionnaire (GEQ) stigma sub-scale score dichotomised at mean into low (5 to 12) and high (12.5 to 25). † pre-specified covariate entered into adjusted models. b significance threshold of p = 0.05; not adjusted for multiple testing. c socio-economic status using the five categories from UK Office for National Statistics. d SAPAS-SR screen for personality disorder [ 37 ].
Table 2. Summary of outcomes by low versus high perceived stigma scores.
Table 2. Summary of outcomes by low versus high perceived stigma scores. GEQ Stigma sub-Scale Score Low Perceived Stigma Score a ( n = 1764) High Perceived Stigma Score a ( n = 1623) Total ( n = 3387) p -Value b Primary outcomes Post-loss suicidal thoughts Yes n (%) 582 (33) 929 (57) 1511 (45) <0.001 missing n (%) 121 (7) 100 (6) 221 (7) Post-loss suicide attempt Yes n (%) 51 (3) 155 (10) 206 (6) <0.001 missing n (%) 126 (7) 100 (6) 226 (7) Secondary outcomes Secondary mental health outcomes Post-loss non-suicidal self-harm Yes n (%) 260 (15) 473 (29) 733 (22) <0.001 missing n (%) 125 (15) 102 (6) 227 (7) Post-loss non-suicidal self-harm and suicide attempt Yes n (%) 280 (16) 519 (32) 799 (24) <0.001 missing n (%) 121 (7) 98 (6) 219 (7) Post-loss depression Yes n (%) 361 (21) 699 (43) 1060 (4) <0.001 missing n (%) 74 (4) 54 (3) 128 (4) Support measures Measure of social support c no lack of perceived social support n (%) 1228 (70) 739 (46) 1967 (58) <0.001 moderate lack of perceived social support n (%) 406 (23) 499 (31) 905 (27) severe lack of perceived social support n (%) 130 (7) 384 (24) 514 (15) missing n (%) 0 (0) 1 (<1) 1 (<1) Receipt of formal support after index bereavement Yes n (%) 553 (31) 704 (43) 1257 (37) <0.001 No n (%) 1135 (64) 861 (53) 1996 (59) missing n (%) 76 (4) 58 (4) 134 (4) Receipt of informal support after index bereavement Yes n (%) 1277 (72) 907 (56) 2184 (65) <0.001 No n (%) 411 (23) 658 (41) 1069 (32) missing n (%) 76 (4) 58 (4) 134 (4)
GEQ = Grief Experience Questionnaire, a using GEQ stigma sub-scale score. a using Grief Experience Questionnaire stigma sub-scale score dichotomised at mean into low (5 to 12) and high (12.5 to 25). b significance threshold of p = 0.05; not adjusted for multiple testing. c measure of social support from Adult Psychiatric Morbidity Survey [ 28 ].
Table 3. Estimates of the association between high stigma scores and outcomes.
Table 3. Estimates of the association between high stigma scores and outcomes. GEQ Stigma Sub-Scale Score Low Perceived Stigma Score a ( n = 1764) High Perceived Stigma Score a ( n = 1623) Primary Outcomes Odds Ratio (reference) Unadjusted Odds Ratio (95% CI) p Value b Adjusted c Odds Ratio (95% CI) p Value b post-bereavement suicidal ideation 1 3.45 (2.47–4.81) <0.001 2.74 (1.93–3.89) <0.001 post-bereavement suicide attempt 1 2.84 (2.45–3.89) <0.001 2.73 (2.33–3.18) <0.001 Secondary Measures post-bereavement non-suicidal self-harm 1 2.40 (2.01–2.86) <0.001 2.16 (1.76–2.64) <0.001 post-bereavement suicidal and non-suicidal self-harm 1 2.50 (2.11–2.96) <0.001 2.25 (1.85–2.74) <0.001 post-bereavement depression 1 2.91 (2.48–3.41) <0.001 3.84 (3.21–4.59) <0.001 low perceived social support 1 2.84 (2.45–3.28) <0.001 2.86 (2.44–3.34) <0.001 use of formal bereavement support 1 1.76 (1.52–2.04) <0.001 1.87 (1.60–2.19) <0.001 use of informal bereavement support 1 0.44 (0.37–0.51) <0.001 0.48 (0.41–0.57) <0.001
GEQ = Grief Experience Questionnaire. a using Grief Experience Questionnaire stigma sub-scale score dichotomised at mean into low (5 to 12) and high (12.5 to 25). b using corrected significance threshold of p = 0.006. c adjusted for nine pre-specified confounding variables: age; gender; socio-economic status; mode of sudden bereavement; kinship to the deceased; family history of suicide (excluding index bereavement); pre-loss depression; pre-loss suicidal and non-suicidal self-harm; and years since index bereavement.
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PART 331—SPECIAL PROVISIONS FOR DESIGNATED STATES AND TERRITORIES; AND FOR DESIGNATION OF ESTABLISHMENTS WHICH ENDANGER PUBLIC HEALTH AND FOR SUCH DESIGNATED ESTABLISHMENTS Authority: 21 U.S.C. 601–695; 7 CFR 2.18, 2.53. Source: 35 FR 19667, Dec. 29, 1970, unless otherwise noted. § 331.1 Definition of “State”.
For purposes of this part, the term “State” means any State (including the Commonwealth of Puerto Rico) or organized Territory. § 331.2 Designation of States under paragraph 301(c) of the Act.
Each of the following States has been designated, under paragraph 301(c) of the Act, as a State in which the provisions of Titles I and IV of the Act shall apply to operations and transactions wholly within such State. The Federal provisions apply, effective on the dates shown below: State Effective date of application of Federal provisions Alaska July 31, 1999. Arkansas June 1, 1981. California Apr. 1, 1976. Colorado July 1, 1975. Connecticut Oct. 1, 1975. Florida Dec. 2, 1997. Guam Jan. 21, 1972. Hawaii Nov. 1, 1995. Idaho July 1, 1981. Kentucky Jan. 14, 1972. Maryland Mar. 31, 1991 Massachusetts Jan. 12, 1976. Michigan Oct. 3, 1981. Nebraska Oct. 1, 1971. Nevada July 1, 1973. New Hampshire Aug. 6, 1978. New Jersey July 1, 1975. New Mexico Aug. 13, 2007. New York July 16, 1975. Northern Mariana Islands Oct. 29, 1979. Oregon July 1, 1972. Pennsylvania July 17, 1972. Puerto Rico June 18, 1971. Rhode Island Oct. 1, 1981. Tennessee Oct. 1, 1975. Virgin Islands of the U.S Nov. 27, 1971. Washington June 1, 1973. [35 FR 19667, Dec. 29, 1970] Editorial Note: For Federal Register citations affecting § 331.2, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at www.govinfo.gov. § 331.3 States designated under paragraph 301(c) of the Act; application of regulations.
The provisions of the regulations in this subchapter apply to operations and transactions wholly within each State designated in § 331.2 under paragraph 301(c) of the Act, except as otherwise provided in this section. (The provisions of the regulations apply in all respects to operations and transactions in or for commerce.)
(a) Each establishment located in such a designated State shall be granted inspection required under § 302.1(a)(2) of this subchapter only if it is found, upon a combined evaluation of its premises, facilities, and operating procedures, to be capable of producing products that are not adulterated or misbranded.
(b) Section 305.2 of this subchapter will apply to establishments required to have inspection under § 302.1(a)(2) of this subchapter, except that existing interconnections between official and unofficial establishments will be permitted if it is determined in specific cases that the interconnections are such that transfer of inedible product into the official establishment would be difficult or unusual, and any such transfers are strictly prohibited, except as permitted under other provisions of this subchapter. It is essential that separation of facilities be maintained to the extent necessary to assure that inedible product does not enter the official establishment contrary to the regulations in this subchapter.
(c) Sections 416.2(c), (d), (e), (f), and (h) of this chapter shall apply to such establishments.
(d) Section 314.2 of this subchapter shall apply to such establishments, except that a separate room or compartment need not be provided for inedible products if they can be handled so that they do not create insanitary conditions in any room or compartment used for edible products or otherwise render any edible products adulterated and do not interfere with the conduct of inspection. For example, intestines, paunch contents, feet, and hides might be accumulated on the kill floor in clean, watertight drums with close fitting covers if there is sufficient space to store them out of the way until the close of the day's operation.
(e) Sections 316.7, 317.3, and 412.1 of this chapter apply to such establishments, except as provided in this paragraph (e).
(1) The operator of each such establishment will, prior to the inauguration of inspection, identify all labeling and marking devices in use, or proposed for use, (upon the date of inauguration of inspection) to the Front Line Supervisor of the circuit in which the establishment is located. Temporary approval, pending formal approval under §§ 316.7, 317.3, and 412.1 of this chapter, will be granted by the Front Line Supervisor for labeling and marking devices that he determines are neither false nor misleading, provided the official inspection legend bearing the official establishment number is applied to the principal display panel of each label, either by a mechanical printing device or a self-destructive pressure sensitive sticker, and provided the label shows the true product name, an accurate ingredient statement, the name and address of the manufacturer, packer, or distributor, and any other features required by section 1(n) of the Act.
(2) The circuit supervisor will forward one copy of each item of labeling and a description of each marking device for which he has granted temporary approval to the Washington, DC, office of the Labeling and Packaging Staff and will retain one copy in a temporary approval file for the establishment.
(3) The operator of the official establishment shall promptly forward a copy of each item of labeling and a description of each marking device for which temporary approval has been granted by the Front Line Supervisor (showing any modifications required by the Front Line Supervisor) to the FSIS Labeling and Program Delivery Staff, accompanied by the formula and details of preparation and packaging for each product. Within 90 days after inauguration of inspection, all labeling material and marking devices temporarily approved by the Front Line Supervisor must receive approval as required by §§ 316.7, 317.3, and 412.1 of this chapter, or their use must be discontinued.
(4) The circuit supervisor will also review all shipping containers to insure that they do not have any false or misleading labeling and are otherwise not misbranded. Modifications of unacceptable information on labeling material by the use of self-destructive pressure sensitive tape or by blocking out with an ink stamp will be authorized on a temporary basis to permit the maximum allowable use of all labeling materials on hand. All unacceptable labeling material which is not modified to comply with the requirements of this subchapter must be destroyed or removed from the official establishment.
(f) Sections 320.1, 320.2, 320.3, 320.4, 320.5, 325.20, and 325.21 apply to operations and transactions not in or for commerce in a State designated under paragraph 301(c) only if the State is also designated under section 205 of the Act and if such provisions are applicable as shown in § 331.6.
(g) Section 321.1(a) of this subchapter will not apply to States designated under paragraph 301(c) of the Act.
(h) Parts 322 and 327 and § 325.3 of this subchapter relating to exports and imports do not apply to operations and transactions solely in or for intrastate commerce.
(i) Part 325 of this subchapter will apply to establishments required to have inspection under § 302.1(a)(2) of this subchapter and to operations and transactions solely in or for intrastate commerce, except as provided in paragraphs (h) and (j) of this section.
(j) Sections 325.4, 325.15, and 325.1(b) of this subchapter will not apply to require a certificate, or evidence thereof, for the distribution solely within any designated State of products that are U.S. inspected and passed and so marked. [35 FR 19667, Dec. 29, 1970, as amended at 36 FR 12004, June 24, 1971; 41 FR 18089, Apr. 30, 1976; 62 FR 45026, Aug. 25, 1997; 64 FR 56416, Oct. 20, 1999; 78 FR 66837, Nov. 7, 2013] § 331.4 Control and disposal of non-federally-inspected products in States designated under paragraph 301(c) of the Act.
Upon the effective date of designation of a State under paragraph 301(c) of the Act, no products can be prepared within the State unless they are prepared under inspection pursuant to the regulations in this subchapter or are exempted from the requirement of inspection under § 303.1 of this subchapter, and no unexempted products which were prepared without any inspection can lawfully be distributed within the State. For a period of 90 days from the effective date of such designation, products which were prepared and inspected and passed under the supervision of a responsible State or local inspection agency can be distributed solely within the State, provided they are not adulterated or misbranded, except that the official inspection legend is not required. Within the 90-day period, products that have been inspected by the State or local inspection agency may be further prepared and otherwise handled in official establishments required to have inspection under § 302.1(a)(2) of this subchapter or at establishments exempted from the requirements of such inspection under § 303.1 of this subchapter, and may be distributed as provided in this section but otherwise shall be handled in accordance with § 305.4 of this subchapter. Such products shall not bear any [Federal] official inspection legends. After said 90–day period, only federally inspected and passed products may be distributed within the designated State, except as provided in § 303.1 of this subchapter. § 331.5 Criteria and procedure for designating establishments with operations which would clearly endanger the public health; disposition of products; application of regulations.
(a) An establishment preparing products solely for distribution within any State shall be designated as one producing adulterated products which would clearly endanger the public health, if:
(1) Any meat or meat food product prepared at the establishment is adulterated in any of the following respects:
(i) It bears or contains a pesticide chemical, food additive, or color additive, that is “unsafe” within the meaning of sections 408, 409, or 706 of the Federal Food, Drug, and Cosmetic Act or was intentionally subjected to radiation in a manner not permitted under section 409 of said Act; or if it bears or contains any other added poisonous or added deleterious substance which may render it injurious to health or make it unfit for human food; or
(ii) It consists in whole or in part of any filthy, putrid, or decomposed substance or is for any other reason unsound, unhealthful, or unwholesome or otherwise unfit for human food (for example, it was prepared from meat or other ingredients exhibiting spoilage characteristics; or it is, or was prepared from, a carcass affected with a disease transmissible to humans and its condemnation would be required under part 309 or 310 of the Federal Meat Inspection regulations (9 CFR parts 309, 310) at federally inspected establishments; or
(iii) It has been prepared, packed or held under insanitary conditions whereby it may have become contaminated with filth or may have been rendered injurious to health (for example if insects or vermin are not effectively controlled at the establishments, or insanitary water is used in preparing meat or meat food products for human food); or
(iv) It is, in whole or in part, the product of an animal that died otherwise than by slaughter; or
(v) Its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; and
(2) Such adulterated articles are intended to be or are distributed from the establishment while capable of use as human food.
(b) When any such establishment is identified by a Program Inspector as one producing adulterated product, which would clearly endanger public health under the criteria in paragraph (a) of this section, the following procedure will be followed:
(1) The Program Inspector will informally advise the operator of the establishment concerning the deficiencies found by him and report his findings to the appropriate Regional Director for the Program. When it is determined by the Regional Director that any establishment preparing products solely for distribution within any State is producing adulterated products for distribution within such State which would clearly endanger the public health, written notification thereof will be issued to the appropriate State officials, including the Governor of the State and the appropriate Advisory Committee, for effective action under State or local law to prevent such endangering of the public health. Such written notification shall clearly specify the deficiencies deemed to result in the production of adulterated products and shall specify a reasonable time for such action under State or local law.
(2) If effective action is not taken under State or local law within the specified time, written notification shall be issued by the Regional Director to the operator of the establishment, specifying the deficiencies involved and allowing him ten days to present his views or make the necessary corrections, and notifying him that failure to correct such deficiencies may result in designation of the establishment and operator thereof as subject to the provisions of titles I and IV of the Act as though engaged in commerce.
(3) Thereafter the Program Inspector shall survey the establishment and designate it if he determines, in consultation with the Regional Director, that it is producing adulterated products, which would clearly endanger the public health, and formal notice of such designation will be issued to the operator of the establishment by the Regional Director.
(c) Products on hand at the time of designation of an establishment under this section are subject to detention, seizure and condemnation in accordance with part 329 of this subchapter: Provided,
That products that have been federally inspected and so identified and that have not been further prepared at any nonfederally inspected establishment may be released for distribution if the products appear to be not adulterated or misbranded at the time of such release.
(d) No establishment designated under this section can lawfully prepare any products unless it first obtains inspection or qualifies for exemption under § 303.1 of this subchapter. All of the provisions of the regulations shall apply to establishments designated under this section, except that the exceptions provided for in § 331.3 of this part shall apply to such establishments. [35 FR 19667, Dec. 29, 1970, as amended at 83 FR 25308, May 31, 2018] § 331.6 Designation of States under section 205 of the Act; application of sections of the Act and the regulations.
Each of the following States has been designated, effective on the date shown below, under section 205 of the Act, as a State in which the provisions of the sections of the Act and regulations specified below shall apply to operators engaged, other than in or for commerce, in the kinds of business indicated below: Sections of act and regulations Classes of operators State Effective date of designation Act, section 202; §§ 320.1, 320.2, 320.3, and 320.4 Persons engaged (not in or for commerce) in (1) the business of slaughtering any livestock or preparing, freezing, packaging or labeling any livestock carcasses or parts or products thereof, for use as human food or animal food; (2) the business of buying or selling (as a meat broker, wholesaler, or otherwise), transporting or storing any livestock carcasses or parts or products thereof; or (3) business as a renderer, or in the business of buying, selling, or transporting any dead, dying, disabled, or diseased livestock or parts of carcasses of any livestock that died otherwise than by slaughter Alaska Arkansas California Colorado Connecticut Guam Idaho Kentucky Maryland Massachusetts Michigan Nebraska July 31, 1999. Mar. 29, 1982. Apr. 1, 1976. July 1, 1975. Oct. 1, 1975. Nov. 19, 1976. Mar. 29, 1982. Apr. 18, 1973. Mar. 31, 1991. Jan. 12, 1976. Mar. 29, 1982. Jan. 31, 1975. Nevada Jan. 31, 1975. New Hampshire Oct. 29, 1979. New Jersey July 1, 1975. New York July 16, 1975. Northern Mariana Islands Oct. 29, 1979. Oregon Jan. 31, 1975. Pennsylvania May 2, 1974. Puerto Rico Nov. 19, 1976. Rhode Island Mar. 29, 1982. Tennessee Oct. 1, 1975. Virgin Islands Nov. 19, 1976. Washington Jan. 31, 1975. Act, 203; § 320.5 Persons engaged (not in or for commerce) in business as a meat broker; renderer; animal food manufacturer; wholesaler or public warehouseman of livestock carcasses, or parts or products thereof; or buying, selling, or transporting any dead, dying, disabled, or diseased livestock, or parts of carcasses of any such livestock that dies otherwise than by slaughter Alaska Arkansas California Colorado Connecticut Guam Idaho Kentucky Maryland Massachusetts July 31, 1999. Mar. 29, 1982. Apr. 1, 1976. July 1, 1975. Oct. 1, 1973. Nov. 19, 1976. Mar. 29, 1982. Apr. 18, 1976. Mar. 31, 1991. Jan. 12, 1975. Michigan Mar. 29, 1982. Nebraska Jan. 31, 1975. Nevada Jan. 31, 1975. New Hampshire Oct. 29, 1979. New Jersey July 1, 1975. New York July 16, 1973. Northern Mariana Islands Oct. 29, 1979. Oregon Jan. 31, 1974. Pennsylvania May 2, 1975. Puerto Rico Nov. 19, 1976. Rhode Island Mar. 29, 1982. Tennessee Oct. 1, 1975. Virgin Islands Nov. 19, 1976. Washington Jan. 31, 1975. Act, 204; §§ 325.20 and 325.21 Persons engaged (not in or for commerce) in the business of buying, selling or transporting any dead, dying, disabled or diseased animals, or parts of carcasses of any animals that died otherwise than by slaughter Alaska Arkansas Connecticut Guam Idaho Kentucky Maryland Massachusetts July 31, 1999. Mar. 29, 1982. Oct. 1, 1975. Nov. 19, 1976. Mar. 29, 1982. Apr. 18, 1973. Mar. 31, 1991. Jan. 12, 1976. Michigan Mar. 29, 1982. Nevada Jan. 31, 1975. New Hampshire Oct. 29, 1979. New Jersey July 1, 1975. New York July 16, 1975. Northern Mariana Islands Oct. 29, 1979. Oregon Jan. 31, 1975. Pennsylvania May 2, 1974. Puerto Rico Nov. 19, 1976. Rhode Island Mar. 29, 1982. Virgin Islands Nov. 19, 1976. Washington Jan. 31, 1975. [35 FR 19667, Dec. 29, 1970] Editorial Note: For Federal Register citations affecting § 331.6, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at www.govinfo.gov.
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<DIV5 N =" 331 " TYPE =" PART " VOLUME =" 2 " >
<HEAD >
PART 331—SPECIAL PROVISIONS FOR DESIGNATED STATES AND TERRITORIES; AND FOR DESIGNATION OF ESTABLISHMENTS WHICH ENDANGER PUBLIC HEALTH AND FOR SUCH DESIGNATED ESTABLISHMENTS
</HEAD >
<HEAD > ... </HEAD >
<AUTH >
<HED > Authority: </HED >
<PSPACE > 21 U.S.C. 601–695; 7 CFR 2.18, 2.53. </PSPACE >
</AUTH >
<AUTH > ... </AUTH >
<SOURCE >
<HED > Source: </HED >
<PSPACE >
35 FR 19667, Dec. 29, 1970, unless otherwise noted.
</PSPACE >
<PSPACE > ... </PSPACE >
</SOURCE >
<SOURCE > ... </SOURCE >
<DIV8 N =" 331.1 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD > § 331.1 Definition of “State”.
</HEAD >
<P >
For purposes of this part, the term “State” means any State (including the Commonwealth of Puerto Rico) or organized Territory.
</P >
<P > ... </P >
</DIV8 >
<DIV8 N =" 331.1 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
<DIV8 N =" 331.2 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD >
§ 331.2 Designation of States under paragraph 301(c) of the Act.
</HEAD >
<HEAD > ... </HEAD >
<P >
Each of the following States has been designated, under paragraph 301(c) of the Act, as a State in which the provisions of Titles I and IV of the Act shall apply to operations and transactions wholly within such State. The Federal provisions apply, effective on the dates shown below:
</P >
<P > ... </P >
<DIV width =" 100% " >
<DIV class =" gpotbl_div " >
<TABLE border =" 1 " cellpadding =" 1 "
cellspacing =" 1 " class =" gpotbl_table "
frame =" void " width =" 100% " >
<TR >
<TH class =" gpotbl_colhed "
scope =" col " > State </TH >
<TH class =" gpotbl_colhed " scope =" col " >
Effective date of application of Federal provisions
</TH >
<TH class =" gpotbl_colhed " scope =" col " > ... </TH >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Alaska </TD >
<TD align =" left "
class =" gpotbl_cell " > July 31, 1999. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Arkansas </TD >
<TD align =" left "
class =" gpotbl_cell " > June 1, 1981. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > California </TD >
<TD align =" left "
class =" gpotbl_cell " > Apr. 1, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Colorado </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Connecticut </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Florida </TD >
<TD align =" left "
class =" gpotbl_cell " > Dec. 2, 1997. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Guam </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 21, 1972. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Hawaii </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 1, 1995. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Idaho </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1981. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Kentucky </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 14, 1972. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Maryland </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 31, 1991 </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Massachusetts </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 12, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Michigan </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 3, 1981. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Nebraska </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1971. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Nevada </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1973. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > New Hampshire </TD >
<TD align =" left "
class =" gpotbl_cell " > Aug. 6, 1978. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > New Jersey </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > New Mexico </TD >
<TD align =" left "
class =" gpotbl_cell " > Aug. 13, 2007. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > New York </TD >
<TD align =" left "
class =" gpotbl_cell " > July 16, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Northern Mariana Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Oregon </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1972. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Pennsylvania </TD >
<TD align =" left "
class =" gpotbl_cell " > July 17, 1972. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Puerto Rico </TD >
<TD align =" left "
class =" gpotbl_cell " > June 18, 1971. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Rhode Island </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1981. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Tennessee </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Virgin Islands of the U.S </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 27, 1971. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Washington </TD >
<TD align =" left "
class =" gpotbl_cell " > June 1, 1973. </TD >
</TR >
<TR > ... </TR >
</TABLE >
<TABLE border =" 1 " cellpadding =" 1 " cellspacing =" 1 " class =" gpotbl_table " frame =" void " width =" 100% " > ... </TABLE >
</DIV >
<DIV class =" gpotbl_div " > ... </DIV >
</DIV >
<DIV width =" 100% " > ... </DIV >
<CITA TYPE =" N " > [35 FR 19667, Dec. 29, 1970] </CITA >
<EDNOTE >
<HED > Editorial Note: </HED >
<PSPACE >
For
<E T =" 04 " > Federal Register </E >
citations affecting § 331.2, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at
<I > www.govinfo.gov. </I >
</PSPACE >
<PSPACE > ... </PSPACE >
</EDNOTE >
<EDNOTE > ... </EDNOTE >
</DIV8 >
<DIV8 N =" 331.2 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
<DIV8 N =" 331.3 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD >
§ 331.3 States designated under paragraph 301(c) of the Act; application of regulations.
</HEAD >
<HEAD > ... </HEAD >
<P >
The provisions of the regulations in this subchapter apply to operations and transactions wholly within each State designated in § 331.2 under paragraph 301(c) of the Act, except as otherwise provided in this section. (The provisions of the regulations apply in all respects to operations and transactions in or for commerce.)
</P >
<P > ... </P >
<P >
(a) Each establishment located in such a designated State shall be granted inspection required under § 302.1(a)(2) of this subchapter only if it is found, upon a combined evaluation of its premises, facilities, and operating procedures, to be capable of producing products that are not adulterated or misbranded.
</P >
<P > ... </P >
<P >
(b) Section 305.2 of this subchapter will apply to establishments required to have inspection under § 302.1(a)(2) of this subchapter, except that existing interconnections between official and unofficial establishments will be permitted if it is determined in specific cases that the interconnections are such that transfer of inedible product into the official establishment would be difficult or unusual, and any such transfers are strictly prohibited, except as permitted under other provisions of this subchapter. It is essential that separation of facilities be maintained to the extent necessary to assure that inedible product does not enter the official establishment contrary to the regulations in this subchapter.
</P >
<P > ... </P >
<P >
(c) Sections 416.2(c), (d), (e), (f), and (h) of this chapter shall apply to such establishments.
</P >
<P > ... </P >
<P >
(d) Section 314.2 of this subchapter shall apply to such establishments, except that a separate room or compartment need not be provided for inedible products if they can be handled so that they do not create insanitary conditions in any room or compartment used for edible products or otherwise render any edible products adulterated and do not interfere with the conduct of inspection. For example, intestines, paunch contents, feet, and hides might be accumulated on the kill floor in clean, watertight drums with close fitting covers if there is sufficient space to store them out of the way until the close of the day's operation.
</P >
<P > ... </P >
<P >
(e) Sections 316.7, 317.3, and 412.1 of this chapter apply to such establishments, except as provided in this paragraph (e).
</P >
<P > ... </P >
<P >
(1) The operator of each such establishment will, prior to the inauguration of inspection, identify all labeling and marking devices in use, or proposed for use, (upon the date of inauguration of inspection) to the Front Line Supervisor of the circuit in which the establishment is located. Temporary approval, pending formal approval under §§ 316.7, 317.3, and 412.1 of this chapter, will be granted by the Front Line Supervisor for labeling and marking devices that he determines are neither false nor misleading, provided the official inspection legend bearing the official establishment number is applied to the principal display panel of each label, either by a mechanical printing device or a self-destructive pressure sensitive sticker, and provided the label shows the true product name, an accurate ingredient statement, the name and address of the manufacturer, packer, or distributor, and any other features required by section 1(n) of the Act.
</P >
<P > ... </P >
<P >
(2) The circuit supervisor will forward one copy of each item of labeling and a description of each marking device for which he has granted temporary approval to the Washington, DC, office of the Labeling and Packaging Staff and will retain one copy in a temporary approval file for the establishment.
</P >
<P > ... </P >
<P >
(3) The operator of the official establishment shall promptly forward a copy of each item of labeling and a description of each marking device for which temporary approval has been granted by the Front Line Supervisor (showing any modifications required by the Front Line Supervisor) to the FSIS Labeling and Program Delivery Staff, accompanied by the formula and details of preparation and packaging for each product. Within 90 days after inauguration of inspection, all labeling material and marking devices temporarily approved by the Front Line Supervisor must receive approval as required by §§ 316.7, 317.3, and 412.1 of this chapter, or their use must be discontinued.
</P >
<P > ... </P >
<P >
(4) The circuit supervisor will also review all shipping containers to insure that they do not have any false or misleading labeling and are otherwise not misbranded. Modifications of unacceptable information on labeling material by the use of self-destructive pressure sensitive tape or by blocking out with an ink stamp will be authorized on a temporary basis to permit the maximum allowable use of all labeling materials on hand. All unacceptable labeling material which is not modified to comply with the requirements of this subchapter must be destroyed or removed from the official establishment.
</P >
<P > ... </P >
<P >
(f) Sections 320.1, 320.2, 320.3, 320.4, 320.5, 325.20, and 325.21 apply to operations and transactions not in or for commerce in a State designated under paragraph 301(c) only if the State is also designated under section 205 of the Act and if such provisions are applicable as shown in § 331.6.
</P >
<P > ... </P >
<P >
(g) Section 321.1(a) of this subchapter will not apply to States designated under paragraph 301(c) of the Act.
</P >
<P > ... </P >
<P >
(h) Parts 322 and 327 and § 325.3 of this subchapter relating to exports and imports do not apply to operations and transactions solely in or for intrastate commerce.
</P >
<P > ... </P >
<P >
(i) Part 325 of this subchapter will apply to establishments required to have inspection under § 302.1(a)(2) of this subchapter and to operations and transactions solely in or for intrastate commerce, except as provided in paragraphs (h) and (j) of this section.
</P >
<P > ... </P >
<P >
(j) Sections 325.4, 325.15, and 325.1(b) of this subchapter will not apply to require a certificate, or evidence thereof, for the distribution solely within any designated State of products that are U.S. inspected and passed and so marked.
</P >
<P > ... </P >
<CITA TYPE =" N " >
[35 FR 19667, Dec. 29, 1970, as amended at 36 FR 12004, June 24, 1971; 41 FR 18089, Apr. 30, 1976; 62 FR 45026, Aug. 25, 1997; 64 FR 56416, Oct. 20, 1999; 78 FR 66837, Nov. 7, 2013]
</CITA >
<CITA TYPE =" N " > ... </CITA >
</DIV8 >
<DIV8 N =" 331.3 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
<DIV8 N =" 331.4 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD >
§ 331.4 Control and disposal of non-federally-inspected products in States designated under paragraph 301(c) of the Act.
</HEAD >
<HEAD > ... </HEAD >
<P >
Upon the effective date of designation of a State under paragraph 301(c) of the Act, no products can be prepared within the State unless they are prepared under inspection pursuant to the regulations in this subchapter or are exempted from the requirement of inspection under § 303.1 of this subchapter, and no unexempted products which were prepared without any inspection can lawfully be distributed within the State. For a period of 90 days from the effective date of such designation, products which were prepared and inspected and passed under the supervision of a responsible State or local inspection agency can be distributed solely within the State, provided they are not adulterated or misbranded, except that the official inspection legend is not required. Within the 90-day period, products that have been inspected by the State or local inspection agency may be further prepared and otherwise handled in official establishments required to have inspection under § 302.1(a)(2) of this subchapter or at establishments exempted from the requirements of such inspection under § 303.1 of this subchapter, and may be distributed as provided in this section but otherwise shall be handled in accordance with § 305.4 of this subchapter. Such products shall not bear any [Federal] official inspection legends. After said 90–day period, only federally inspected and passed products may be distributed within the designated State, except as provided in § 303.1 of this subchapter.
</P >
<P > ... </P >
</DIV8 >
<DIV8 N =" 331.4 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
<DIV8 N =" 331.5 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD >
§ 331.5 Criteria and procedure for designating establishments with operations which would clearly endanger the public health; disposition of products; application of regulations.
</HEAD >
<HEAD > ... </HEAD >
<P >
(a) An establishment preparing products solely for distribution within any State shall be designated as one producing adulterated products which would clearly endanger the public health, if:
</P >
<P > ... </P >
<P >
(1) Any meat or meat food product prepared at the establishment is adulterated in any of the following respects:
</P >
<P > ... </P >
<P >
(i) It bears or contains a pesticide chemical, food additive, or color additive, that is “unsafe” within the meaning of sections 408, 409, or 706 of the Federal Food, Drug, and Cosmetic Act or was intentionally subjected to radiation in a manner not permitted under section 409 of said Act; or if it bears or contains any other added poisonous or added deleterious substance which may render it injurious to health or make it unfit for human food; or
</P >
<P > ... </P >
<P >
(ii) It consists in whole or in part of any filthy, putrid, or decomposed substance or is for any other reason unsound, unhealthful, or unwholesome or otherwise unfit for human food (for example, it was prepared from meat or other ingredients exhibiting spoilage characteristics; or it is, or was prepared from, a carcass affected with a disease transmissible to humans and its condemnation would be required under part 309 or 310 of the Federal Meat Inspection regulations (9 CFR parts 309, 310) at federally inspected establishments; or
</P >
<P > ... </P >
<P >
(iii) It has been prepared, packed or held under insanitary conditions whereby it may have become contaminated with filth or may have been rendered injurious to health (for example if insects or vermin are not effectively controlled at the establishments, or insanitary water is used in preparing meat or meat food products for human food); or
</P >
<P > ... </P >
<P >
(iv) It is, in whole or in part, the product of an animal that died otherwise than by slaughter; or
</P >
<P > ... </P >
<P >
(v) Its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; and
</P >
<P > ... </P >
<P >
(2) Such adulterated articles are intended to be or are distributed from the establishment while capable of use as human food.
</P >
<P > ... </P >
<P >
(b) When any such establishment is identified by a Program Inspector as one producing adulterated product, which would clearly endanger public health under the criteria in paragraph (a) of this section, the following procedure will be followed:
</P >
<P > ... </P >
<P >
(1) The Program Inspector will informally advise the operator of the establishment concerning the deficiencies found by him and report his findings to the appropriate Regional Director for the Program. When it is determined by the Regional Director that any establishment preparing products solely for distribution within any State is producing adulterated products for distribution within such State which would clearly endanger the public health, written notification thereof will be issued to the appropriate State officials, including the Governor of the State and the appropriate Advisory Committee, for effective action under State or local law to prevent such endangering of the public health. Such written notification shall clearly specify the deficiencies deemed to result in the production of adulterated products and shall specify a reasonable time for such action under State or local law.
</P >
<P > ... </P >
<P >
(2) If effective action is not taken under State or local law within the specified time, written notification shall be issued by the Regional Director to the operator of the establishment, specifying the deficiencies involved and allowing him ten days to present his views or make the necessary corrections, and notifying him that failure to correct such deficiencies may result in designation of the establishment and operator thereof as subject to the provisions of titles I and IV of the Act as though engaged in commerce.
</P >
<P > ... </P >
<P >
(3) Thereafter the Program Inspector shall survey the establishment and designate it if he determines, in consultation with the Regional Director, that it is producing adulterated products, which would clearly endanger the public health, and formal notice of such designation will be issued to the operator of the establishment by the Regional Director.
</P >
<P > ... </P >
<P >
(c) Products on hand at the time of designation of an establishment under this section are subject to detention, seizure and condemnation in accordance with part 329 of this subchapter:
<I > Provided, </I >
That products that have been federally inspected and so identified and that have not been further prepared at any nonfederally inspected establishment may be released for distribution if the products appear to be not adulterated or misbranded at the time of such release.
</P >
<P > ... </P >
<P >
(d) No establishment designated under this section can lawfully prepare any products unless it first obtains inspection or qualifies for exemption under § 303.1 of this subchapter. All of the provisions of the regulations shall apply to establishments designated under this section, except that the exceptions provided for in § 331.3 of this part shall apply to such establishments.
</P >
<P > ... </P >
<CITA TYPE =" N " >
[35 FR 19667, Dec. 29, 1970, as amended at 83 FR 25308, May 31, 2018]
</CITA >
<CITA TYPE =" N " > ... </CITA >
</DIV8 >
<DIV8 N =" 331.5 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
<DIV8 N =" 331.6 " TYPE =" SECTION " VOLUME =" 2 " >
<HEAD >
§ 331.6 Designation of States under section 205 of the Act; application of sections of the Act and the regulations.
</HEAD >
<HEAD > ... </HEAD >
<P >
Each of the following States has been designated, effective on the date shown below, under section 205 of the Act, as a State in which the provisions of the sections of the Act and regulations specified below shall apply to operators engaged, other than in or for commerce, in the kinds of business indicated below:
</P >
<P > ... </P >
<DIV width =" 100% " >
<DIV class =" gpotbl_div " >
<TABLE border =" 1 " cellpadding =" 1 "
cellspacing =" 1 " class =" gpotbl_table "
frame =" void " width =" 100% " >
<TR >
<TH class =" gpotbl_colhed "
scope =" col " > Sections of act and regulations </TH >
<TH class =" gpotbl_colhed "
scope =" col " > Classes of operators </TH >
<TH class =" gpotbl_colhed "
scope =" col " > State </TH >
<TH class =" gpotbl_colhed "
scope =" col " > Effective date of designation </TH >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " >
Act, section 202; §§ 320.1, 320.2, 320.3, and 320.4
</TD >
<TD align =" left " class =" gpotbl_cell " scope =" row " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
Persons engaged (not in or for commerce) in (1) the business of slaughtering any livestock or preparing, freezing, packaging or labeling any livestock carcasses or parts or products thereof, for use as human food or animal food; (2) the business of buying or selling (as a meat broker, wholesaler, or otherwise), transporting or storing any livestock carcasses or parts or products thereof; or (3) business as a renderer, or in the business of buying, selling, or transporting any dead, dying, disabled, or diseased livestock or parts of carcasses of any livestock that died otherwise than by slaughter
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
Alaska
<br />
Arkansas
<br />
California
<br />
Colorado
<br />
Connecticut
<br />
Guam
<br />
Idaho
<br />
Kentucky
<br />
Maryland
<br />
Massachusetts
<br />
Michigan
<br />
Nebraska
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
July 31, 1999.
<br />
Mar. 29, 1982.
<br />
Apr. 1, 1976.
<br />
July 1, 1975.
<br />
Oct. 1, 1975.
<br />
Nov. 19, 1976.
<br />
Mar. 29, 1982.
<br />
Apr. 18, 1973.
<br />
Mar. 31, 1991.
<br />
Jan. 12, 1976.
<br />
Mar. 29, 1982.
<br />
Jan. 31, 1975.
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Nevada </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Hampshire </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Jersey </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New York </TD >
<TD align =" left "
class =" gpotbl_cell " > July 16, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Northern Mariana Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Oregon </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Pennsylvania </TD >
<TD align =" left " class =" gpotbl_cell " > May 2, 1974. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Puerto Rico </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Rhode Island </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 29, 1982. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Tennessee </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Virgin Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Washington </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Act, 203; § 320.5 </TD >
<TD align =" left " class =" gpotbl_cell " >
Persons engaged (not in or for commerce) in business as a meat broker; renderer; animal food manufacturer; wholesaler or public warehouseman of livestock carcasses, or parts or products thereof; or buying, selling, or transporting any dead, dying, disabled, or diseased livestock, or parts of carcasses of any such livestock that dies otherwise than by slaughter
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
Alaska
<br />
Arkansas
<br />
California
<br />
Colorado
<br />
Connecticut
<br />
Guam
<br />
Idaho
<br />
Kentucky
<br />
Maryland
<br />
Massachusetts
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
July 31, 1999.
<br />
Mar. 29, 1982.
<br />
Apr. 1, 1976.
<br />
July 1, 1975.
<br />
Oct. 1, 1973.
<br />
Nov. 19, 1976.
<br />
Mar. 29, 1982.
<br />
Apr. 18, 1976.
<br />
Mar. 31, 1991.
<br />
Jan. 12, 1975.
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Michigan </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 29, 1982. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Nebraska </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Nevada </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Hampshire </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Jersey </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New York </TD >
<TD align =" left "
class =" gpotbl_cell " > July 16, 1973. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Northern Mariana Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Oregon </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1974. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Pennsylvania </TD >
<TD align =" left " class =" gpotbl_cell " > May 2, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Puerto Rico </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Rhode Island </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 29, 1982. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Tennessee </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Virgin Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Washington </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > Act, 204; §§ 325.20 and 325.21 </TD >
<TD align =" left " class =" gpotbl_cell " >
Persons engaged (not in or for commerce) in the business of buying, selling or transporting any dead, dying, disabled or diseased animals, or parts of carcasses of any animals that died otherwise than by slaughter
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
Alaska
<br />
Arkansas
<br />
Connecticut
<br />
Guam
<br />
Idaho
<br />
Kentucky
<br />
Maryland
<br />
Massachusetts
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
<TD align =" left " class =" gpotbl_cell " >
July 31, 1999.
<br />
Mar. 29, 1982.
<br />
Oct. 1, 1975.
<br />
Nov. 19, 1976.
<br />
Mar. 29, 1982.
<br />
Apr. 18, 1973.
<br />
Mar. 31, 1991.
<br />
Jan. 12, 1976.
</TD >
<TD align =" left " class =" gpotbl_cell " > ... </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Michigan </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 29, 1982. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Nevada </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Hampshire </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New Jersey </TD >
<TD align =" left "
class =" gpotbl_cell " > July 1, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left " class =" gpotbl_cell " > New York </TD >
<TD align =" left "
class =" gpotbl_cell " > July 16, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Northern Mariana Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Oct. 29, 1979. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Oregon </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Pennsylvania </TD >
<TD align =" left " class =" gpotbl_cell " > May 2, 1974. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Puerto Rico </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Rhode Island </TD >
<TD align =" left "
class =" gpotbl_cell " > Mar. 29, 1982. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Virgin Islands </TD >
<TD align =" left "
class =" gpotbl_cell " > Nov. 19, 1976. </TD >
</TR >
<TR > ... </TR >
<TR >
<TD align =" left " class =" gpotbl_cell "
scope =" row " > </TD >
<TD align =" left " class =" gpotbl_cell " >
</TD >
<TD align =" left "
class =" gpotbl_cell " > Washington </TD >
<TD align =" left "
class =" gpotbl_cell " > Jan. 31, 1975. </TD >
</TR >
<TR > ... </TR >
</TABLE >
<TABLE border =" 1 " cellpadding =" 1 " cellspacing =" 1 " class =" gpotbl_table " frame =" void " width =" 100% " > ... </TABLE >
</DIV >
<DIV class =" gpotbl_div " > ... </DIV >
</DIV >
<DIV width =" 100% " > ... </DIV >
<CITA TYPE =" N " > [35 FR 19667, Dec. 29, 1970] </CITA >
<EDNOTE >
<HED > Editorial Note: </HED >
<PSPACE >
For
<E T =" 04 " > Federal Register </E >
citations affecting § 331.6, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at
<I > www.govinfo.gov. </I >
</PSPACE >
<PSPACE > ... </PSPACE >
</EDNOTE >
<EDNOTE > ... </EDNOTE >
</DIV8 >
<DIV8 N =" 331.6 " TYPE =" SECTION " VOLUME =" 2 " > ... </DIV8 >
</DIV5 >
<DIV5 N =" 331 " TYPE =" PART " VOLUME =" 2 " > ... </DIV5 > | https://www.ecfr.gov/api/versioner/v1/full/2023-06-06/title-9.xml?part=331 |
Patriarch Kirill Answers Questions from Ukrainian Journalists in Anticipation of his Visit to Ukraine / OrthoChristian.Com
Patriarch Kirill Answers Questions from Ukrainian Journalists in Anticipation of his Visit to Ukraine
The Primate of the Russian Orthodox Church had a discussion with representatives of the Ukrainian mass media on July 15, 2010, at his working residence in Chisty Pereulok. Before his visit to Ukraine, Patriarch Kirill answered questions from Ukrainian TV channels
Inter, Ukraine, First National,
and
Era.
I would like to welcome representatives of the Ukrainian mass media and to have a talk with you before my visit to Ukraine. As an introduction I would like to tell you about my impressions of the first visit because I was so much moved by all that I saw and felt in Ukraine.
The places I went to became my most vivid remembrances of the last year. I was struck by the fact that despite the complicated political context and the contradictions existing in the Ukrainian society, an absolute majority of the people cherish the Orthodox faith and spiritual values defined by this faith. These are the same values that are cherished in Russia, Byelorussia, Moldova and other places. These are the values that outline the parameters of a very important cultural and civilizational notion which I would describe as the Russian World.
For Ukrainians I would like to stress that the Russian World does not mean that of Russia. Even less it is a world of the Russian Federation. It is the world which has come out of our common font – the baptismal font of Kiev. It is the world which exists on the level of faith, intellect, spirituality and culture. This world is not altered by the fact that some deny it; nothing changes because this world exists, and it is an objective reality. I have come to feel this reality and the whole power of this wonderful spiritual and cultural phenomenon, which has been generated by the Orthodox Church. It is a most powerful experience.
I am again going to Ukraine with joy. I hope to visit Odessa, Dnepropetrovsk, Kiev and to pray again with my faithful people, to venerate the holy shrines, to think about much and to understand much. These trips are very important for a Primate of a Church.
I would like to use this opportunity and say that I hold Ukraine very dear for many reasons. But the most important one is the power of faith, the power of religious feeling, the purity and naturalness of the manifestation of this feeling. God grant that people preserve this faith and together with it the remarkable spiritual tradition of Kievan Rus’.
- Inter TV channel: Your Holiness, thank you for the opportunity to hear these words from you for our Ukrainian believers. It is no secret that you have closely followed the developments that have happened in Ukraine when you have been away from our country. Do you think anything has changed?
- In the first place, I would like to see what has changed. As they say, it is better to see once than to hear one hundred times. But it is clear already now that there is a political stabilization, leveling of economic indexes, development of relations with the world and the neighbours, including Russia, Europe, and with the United States of America. I believe there have been considerable qualitative changes in the life of the Ukrainian society, though it may be an outsider’s view. Precisely for this reason I would like to see and feel what is happening in Ukraine today. Well, in short, I assess positively the developments in Ukraine in the recent months.
- Inter TV channel:You have recently called upon the clergy to make a more active use of new technical means in dealing with the faithful, such as the Internet and social networks. But it cannot replace direct human contacts…
- Quite right. But what are, say, social networks today, or the Internet or e-mail? After all it is about an envelope, be it a conventional envelope in which we put our hand-written letters or an electronic form. All these are technical media which are not the point.
I have to say that I see in the development of these social networks and live journals one very positive things – the revival of the epistolary genre. If we look at the second half of the 20 thcentury, we see that it was an era of the dying epistolary genre. People stopped to write letter – all spoke with each other by telephone. But a letter disciplines the thought. Of course, if you write to a close friend and this letter is read by nobody but this friend, you can afford making mistakes in it. But any thought if committed to paper to become open for a wide range of people to read, especially if there is a feedback, when others can immediately react to this text and critically at that, would discipline one and develop the culture of setting forth one’s thoughts in writing. And the ability to set forth one’s thoughts in writing is one of the most significant indicators of one’s culture. Therefore the development of epistolary genre to reach a new stage is culturally a very important positive step.
And now concerning the participation of the clergy. Indeed, we do not reproach St. Paul for developing doctrine through correspondence. All that St. Paul created are letters. We do not reproach holy fathers and ascetics whose heritage we admire today for the fact that many of their works were also set forth in letters. Similarly, today clergy and theologians have an opportunity to convey their thoughts in writing, to share their spiritual experience, to answer to the perplexities of other people and to join in polemics. It is certainly a great challenge because when a priest signs his full name for all the rest to know that it is a priest who speaks, then the responsibility is very high. Therefore I call upon the clergy to participate in all this modern life, in this exchange of information, but only with a strong feeling of responsibility. One cannot just chat in the Internet. One cannot present one’s thoughts in the way that people take them as those of the Church. Therefore, on the one hand, I call upon the clergy to be more active in the use of these new envelops for correspondence, but on the other, considering thus growing responsibility, I suggest that one should prepare oneself both spiritually and intellectually for this kind of work.
- Inter TV channel:Your Holiness, it is no secret that both in Ukraine and Russia there are so-called social diseases. What is the role of the Church today? Can this role be much stronger to combat pride, money-grabbing and greed?
- This is precisely what the social role of the Church lies in. Today we do not limit ourselves to work with individuals, and we do not reduce the Church’s preaching only to the preaching of individual morals. Why? – Because history has shown: if we work only with the individual and neglect the social dimension, we overlook pastorally the most important thing, which is how the inner world of the individual is self-fulfilled in a socium. Certainly, evil intentions come from the heart, as Scripture says (see, Mk. 7:19). Greed, pride, anger, impatience, jealousy, envy – a great deal of spiritual problems – arise inside, in the heart, but spill out. We can see them on the scale of the country and society, like, say, in the economy when crime begins to destroy like a cancer the healthy fabric of economic life, to destroy the very society. We also see them in politics when politicians are engaged in dividing people for their narrow political purposes instead of uniting and serving them. And what is the result? The result is a blown-up national life, broken destinies, ruined families. Indeed, when an acute political crisis comes it goes through human destinies.
What is the reason for all this? – The inner state of a person. A person educated for responsibility before God will not project his inner evil into the public, political and economic life and the legislature, so closely bound up with ethics.
That is why the Church says today that she walks around the world holding the cross of the Lord. And what is a cross? It is an intersection of the vertical and horizontal dimensions. The vertical dimension is the inner dimension of man: man and God, while horizontal dimension is the participation of man societal life. Therefore one should by no means start individualistic moralism and say: All that concerns society is of no interest to us since we deal only with man. Just as one should not say otherwise, a thing which is often present in the world Christianity: We are engaged in social problems, whereas private life is one’s private life with the freedom for one to decide everything on one’s own. The Orthodox Church is by no means against the freedom of the personality but it calls upon man to develop in such a way as to realize his freedom within the framework of moral responsibility of man before God.
- The First National TV channel:Our today’s society is called a society of consumers. What does the Church do to make spiritual values prevail over material ones in man?
- You have so rightly formulated the question, that I have almost nothing to answer. Because on the one hand, material consumption is a natural desire of man: if man does not take care of the material consumption he will die. This need is laid in our instincts, as we have to eat, drink, clothe ourselves and see to it that the human race is reproduced. It is linked with human survival, and the Church by no means can adopt a detached and moralistic attitude: You see, you should not think about all that. It is inadmissible especially today when there are so many poor people in our societies, when people are sometimes even starving, when they have no money for the necessities, let alone good education, medical care, healthy rest, cultural life… For this reason the Church cannot say today: You know, all this is bad. And what are the things the Church opposed, oppose and will oppose? It opposes what holy fathers called ‘the lust of flesh’. It is when consumption comes to dominate one’s life. Then lust (and lust is a disease, a disorder of the inner balance) comes to govern one’s life. Such a person concerns himself only with things material while the spiritual dimension is gone. It is very important that man, especially, the modern man, should remember the wonderful words of the Saviour: ‘What good will it be for a man if he gains the whole world, yet forfeits his soul?’ (Mt. 16:26). These words should be written in golden letters and hung in every room, especially in cloakrooms of some rich men. Indeed, what use is it for one to acquire the world but ruin his soul?
For this reason the Church should put everything to its proper place in people’s conscience, doing it very naturally, with love, without coming down from the height of its position to teach people who sometimes live in poverty, but proclaiming spiritual values in solidarity with poor people. Then nobody will accuse the Church of hypocrisy and sanctimoniousness but people will listen to the preaching of the Church with attention.
The preaching we have just spoken about is of enormous significance for the survival of the whole human civilization because the psychology of consumption, ‘the lust of flesh’, is unviable. It will destroy the spiritual dimension of human life and turn the human being into an animal.
- The First National TV Channel:Is the mass culture,pop-culture, in your view, threatening our today’s society? What is to be done to cultivate in the youth morality and spirituality which is so shaky and so easily lost today?
- We use the words ‘mass culture’ without thinking about its meaning. It seems to us that mass culture is a culture of the masses. It is not quite so. A culture of masses is called ‘people’s culture’. The term ‘mass culture’ appeared at the same time as the term ‘the mass media’. Why? – Because the mass culture is a culture which is reproduced through the mass media and lives mostly at their expense. Take any area of the mass culture. If you remove the mass media, it vanishes.
Therefore it is very important to remember that for the mass media not every manifestation of what is called cultural life is worthy of attracting hundreds of millions of people. Culture – and I have repeatedly stated it – is called to cultivate people, to cultivate the human personality. The word ‘culture’, just as religious culture, originates from what cultivates, what links man to God, hence the word ‘cult’. So, what is very important to understand? If a culture destroys the human personality, it is not a culture but an anti-culture; it is diabolic. And if the mass media turn this into a mass phenomenon, it is a disaster. Therefore, great attention is needed here from those who have an influence on the mass media and those who support them, but first of all, the responsible mass media workers themselves. They should know how to discern spirits to avoid taking sin on their souls.
Certainly, we live an informationally-united world today. If you do not take sin on your soul in the Ukraine, some one will in another European country, but in an instant it will become known both in Ukraine and Russia. It is impossible and unnecessary to put any obstacles here, but I believe we should educate people through the mass media for them to understand what is dangerous and what is beneficial for their spiritual life.
This is the role of the Church in the first place of course. But if the Church relies on the mass media then its word will also become a mass culture.
- Radio and TV channel ‘Ukraine’:Your Holiness, some time ago, speaking of the Ukrainian politics, you said that any well-considered policy was impossible in Ukraine without harmonizing the interests of the Ukrainian society in the system of basic values. Tell me please what basic values you meant and how in your view this harmonization of Ukraine is possible?
- As far as basic values are concerned, these are the values which were born by our faith, because religious values lay in the basis of the Old Russian State from which the present day sovereign states including Ukraine have generated. It is the matrix that formed the mentality of people, their worldview and system of values and this matrix has existed for 1000 years. What a great effort was made to destroy it, especially in the post-Revolution time! Yes, and not only after the Revolution but also before it…
And when I speak of the need to preserve the basic values I state first of all that this matrix of the people’s life ought not to be destroyed. Because if we destroy it we will cease to be Russians or, as they say today, Russians, Ukrainians, Byelorussians… We will become different. It will be an enormous civilizational catastrophe, just as in the case of other nations’ losing their identity. The world will become uniform and terrible; the world will become easily manipulated. Why? – Because this spiritual culture traditional for most people is the basic criterion for discerning good and evil.
So, when we speak about today’s Ukraine and today’s Russia we should understand that there are an enormous number of challenges to these values. They are often associated with the political orientation, the cultural orientation, with the influence of other cultures on the national life. In order to preserve the people in unity (in this case we are speaking about Ukraine), it is important to preserve the basic values, and on the basis of these values, to harmonize those sections of society which absorbed later cultural influences and which, firstly, sometimes insist on these cultural differences and, secondly, wish these cultural differences to be applied to the other part of the Ukrainian society.
For a country to stay united, the kingdom should not be divided against itself (cf. Mk. 3:24). Given all the diversity of views and preferences, against what should it not be divided? – Against these basic values. Then you can deal with pluralism: some like tea with milk, others with sugar – chose whatever you like.
We preserve unity as a people. We join the family of other European nations not as those who are led and hang on the every word of the other, a stronger partner. We join it as equal partners and bearers of our own historical and cultural code.
I believe in some sense it is important today for every nation. Incidentally, the best minds in Europe and other countries understand it very well. I had an opportunity to speak in the UN, at the Council on Human Rights, and we dealt with this theme of preserving national, spiritual, cultural and religious identity. At that meeting, there were ambassadors from almost all the countries of the world who are UN members, and I did not hear any negative comment. Everybody understood that in the situation of globalization it is an enormous challenge since we have to preserve the diversity and beauty of God’s world while developing good international cooperation and peaceful relations among nations.
- Radio and TV channel ‘Ukraine’:Your Holiness, now in Italy they forbid hanging crosses in schools, in France Muslim women can no longer wear hijab in public places while in Russia, on the contrary, lessons on basic Orthodox culture are introduced. Tell me please what you think is the ideal model of co-existence between church and state?
- European countries, including Russia and Ukraine, have declared themselves today to be secular countries in which church is separated from state. We should think within this constitutional space. There are people who object to the separation of church and state and there are people whose attitude to it is very positive. But whatever private opinions may be, the fact is that modern European countries are secular. It seems to me that this term and notion are abused today in a very dangerous way.
What does secularism mean and when did it appear? It emerged as a political phenomenon in Western Europe. It was a response of the society to the clericalization of politics. A number of Western European states were ruled by bishops and representatives of the clergy including the Pope of Rome. These church rulers carried out their policy accordingly, of course, building on their own understanding of how things should be arranged. This was not always met with understanding in society and among the people and it was not without reason that such a term as tyranny appeared. The French Revolution came out against tyranny. We will not start definitions and analysis to find out what was right and what was wrong. But there was struggle including with clericalism.
What was offered in return? Instead of the participation of the clergy in state governance the principle of the Church’s non-interference in state governance was declared, as was the non-interference of the state in the governance over the Church. That’s all. It is the separation of church and state. And what is happening today? Today, under the cover of this term, a false interpretation to it is given, presupposing the ousting of religion from the public space. What we are seeing in Italy today is this attempt to oust religious tradition from the public consciousness. What does it have to do with governance? Nothing. And we do know that crosses can be not only removed from schools; they can be also sawn off churches. And where is the guarantee that tomorrow some lady or gentlemen will not appeal to the European Court to object to his children passing by a church with a cross on their way to school, or a mosque with a crescent?
We can see now another active attempt to oust Christian culture and Christian faith from the life of Europe. But remarkably such Orthodox countries as Russia, Greece, Cyprus and Catholic Lithuania and Poland and many other countries have come out in support of Italy. Therefore we should state clearly to our opponents that we are not ready to accept secularization as a synonym of a godless and non-religious world. Then it is not secularization but a triumph of one of the ideologies, the triumph of atheism. We have already lived in an atheistic society and know what it is.
As for the teaching of Basic Orthodox Culture in Russia, certainly it does not go against the principle of church-state separation because there are lessons on not only Orthodox but also Islamic, Jewish, Buddhist culture, and secular ethics and secular cultural and moral tradition are taught as the Orthodox Church has proposed. Now many choose this course and I see nothing bad in it. But it is important that all the courses should be aimed at one goal – the education of the younger generation for high morality. And all this, according to my observations, does not at all run contrary to the separation of church and state.
- Era TV and Radio Company:Your Holiness, to continue the previous question. When the influence of the Church in society is discussed, references are often made to the number of believers and parishes but seldom to their quality. The quality of a priest is revealed in his ability to govern the parish, to organize the parishioners. How to ensure that the number of parishes grows into the quality of the priest, if I may state it so?
- I would extend your question and complicate it: How to ensure that the number of parishes is reflected in the quality of people? This is the main task. It is something we all think over and work at today. Only we spoke about religious motivation and moral motivation in general. Today the religious motivation occupies a very small place in people’s life, as the choice is more often made according to pragmatic considerations. But if a believer is not guided by faith in making important decisions, then what are the implications of his faith?
A person becomes a real believer when he in his actions is motivated by his religious convictions, the ethical Christian code and the Beatitudes, to speak in purely Church language. The number of people who claim to be Orthodox in Ukraine, Russia and Belarus is much greater than that of the Orthodox who go to church. If out of the church-goers we chose those who seek to be motivated by their Orthodox morality in their specific life situations, then their number will be even smaller. I would say there is a lot of work ahead.
In your question there is something especially disturbing for me. It is the moral and spiritual condition of the clergy. The clergy are the people who should set an example. Therefore the education of a modern priest and the creation of conditions for his continuous growth is the most important task of the episcopate. Very often a young man comes to a seminary with his eyes shining and with great enthusiasm. At graduation his enthusiasm remains but the eyes no longer shine. He begins his service at a parish and his eyes no longer shine and his enthusiasm is gone…
How to ensure that the enthusiasm of a young man, who has decided to devote himself to the Lord and who is ready for certain deprivations and limitations, does not wither away but develop with time? We have the examples of such remarkable priests and ascetics. I am traveling much today to parishes and dioceses to meet with people who carry on their service with great enthusiasm in severe climatic and hard material conditions. I will tell an utterly unexpected thing for some: we stand in the great need of ascetics and we should do all possible so that such ascetics should be as many as possible. They are like small locomotives who will tow the people.
- Ukraine TV and Radio Company:Your Holiness, you have just taken a question from my lips, as we say in Ukraine. Figures show that the number of Christians in the world in proportion to the world population is steadily declining. It is understandable why. How you think Christian Churches can be encouraged to replace rivalry, which has sometimes taken terrible forms as you are aware, with joint efforts for enhancing Christian influencein the world, if it is necessary, of course?
- It is very necessary. In order to avoid rivalry among Christians who are kin in the spirit, it is important that the influence made by the political factor on religious life should be excluded. In history it has always happened so that politics would invade church life with terrible consequences. After all, the historic schism between East and West in the 11 thcentury dividing Christianity into the Orthodox East and the Catholic West was a result of political motives brought into church life. It is a classic example of what happens to a Church when it begins to be motivated by political considerations.
There is another important point. It is the desire of power if it is not linked with the spiritual life of a man. Spiritual power can have a very positive aspect. It is first of all the spiritual authority. The growth of spiritual authority is very important. But the growth of bureaucratic powers can be dangerous but more often than not, struggle in the past and perhaps also in the present is waged precisely around these bureaucratic powers.
Concerning Christian kinship in the spirit. There is another problem if we speak of the whole Christendom, namely, a part of this Christendom lives today according to a different law, the law of secular society. Not in the sense that citizens who belong to these religious groups are good and law-abiding citizens. The point is different. Christians let into their inner world the sinful elements of the world, and justify these elements if they are offered by a secular society. We see such developments in modern Protestantism. It is very dangerous when under the influence of secular liberal views of life, these secular philosophical liberal clichés are repeated in Protestant Churches and take root in religious consciousness.
This is precisely how the theme of female priesthood emerged. It was not dictated by missionary considerations. When I asked a Protestant leader, ‘Tell me, has the number of parishioners increased with the coming of women priests?’ He smiled and answered, ‘No’. – ‘It was not a missionary project?’ – ‘No, it was just respect for the rights of the personality’. That is to say, the secular notion of human rights was incorporated into theology and ecclesiastical practice contrary to the entire Christian Church tradition. The apostolic tradition excludes this practice, but to please a secular liberal standard, this practice is incorporated in church life.
Another similar problem is the attitude to homosexuality. In order to please the secular liberal standard, the very Word of God is distorted. It is written in black and white that homosexuality is a sin. And what do you think? Our brothers say, ‘No, no, it is wrong to understand it in this way. It is not at all a sin; it is, you know, simply a cultural context of the time when St. Paul wrote it’. It turns out that to please a liberal standard one can even deny the source of one’s faith.
Recently I have met with a very important ecumenical leader. I began saying to him about the fact that the developments in Protestantism take Protestants further and further away from the Orthodox and the Catholics, thus increasing the internal gap in the Christian world. And if it increases it will be difficult for us to defend Christian values. And what he told me stuck me ,and at the same time helped me to understand how profound this crisis of Christianity is. He said to me quietly, ‘Well, what is special about these developments? We have different attitudes to the problems of the Middle East; we have different attitudes toward the economic crisis, and we have different attitudes toward homosexuality as well’.
If we do not manage to change the situation through the internal dialogue between the Orthodox and Protestant worlds, then I see a very sad prospect – an even greater alienation of the Protestant world from Orthodoxy and hence a weakening of common Christian witness. Therefore the Orthodox Church faces an enormous task to bear witness to the purity of the apostolic tradition, to the purity of faith before, among others, non-Orthodox Christians.
- Ukraine TV and Radio Company:Your Holiness, just a couple of words about cooperation. As I understand it gap is not as great between Catholicism and Orthodoxy as between Protestantism and Orthodoxy?
- In the Catholic world there are also liberal tendencies. They gathered momentum in the second part of the twentieth century, and we in the Orthodox East watched these tendencies with concern. But I should say that the position of the present Pope Benedict XVI inspires us with optimism. Perhaps he is criticized so strongly for it by liberal theologians and the liberal mass media in the West, but his attitude to many public and ethical issues coincides fully with that of the Orthodox Church. It offers us an opportunity to defend Christian values together with the Catholic Church on the level of international organizations and in the international arena.
DECR
| https://orthochristian.com/36238.html |
Team Dispersion, Emergent States, and Performance in Virtual IT Service Provisioning Teams: Business & Management Journal Article | IGI Global
Team Dispersion, Emergent States, and Performance in Virtual IT Service Provisioning Teams: 10.4018/IJISSS.287577: Today, virtual teams composed by dispersed team members relying on computer-supported collaborative work are common in the information technology (IT) service
Team Dispersion, Emergent States, and Performance in Virtual IT Service Provisioning Teams
Hugo Martinelli Watanuki, Renato de Oliveira Moraes
Source Title: International Journal of Information Systems in the Service Sector (IJISSS) 14(1)
Copyright: © 2022 |
Pages: 16
DOI: 10.4018/IJISSS.287577
OnDemand: (Individual Articles) Available $29.50
$29.50
Abstract Today, virtual teams composed by dispersed team members relying on computer-supported collaborative work are common in the information technology (IT) service provisioning industry. Despite the increasing interest in virtual team research, there is a limited understanding of a multidimensional view of team dispersion and its effect on the performance of virtual teams via the team´s socioemotional states. The purpose of this paper is to investigate the influence of team distribution and variety of work practices on the performance of virtual IT service provisioning teams via the emergent states of trust and cohesiveness. To this aim, an input-process-output framework was adopted to develop a conceptual model and a survey with IT service provisioning professionals was conducted. The results suggest that a variety of work practices constitutes a barrier to the performance of virtual IT service provisioning teams; and that trust and cohesiveness are important mediators in this cause-effect relationship. Article Preview Top IntroductionComputer-supported cooperative work among dispersed individuals in the form of virtual teams has been an organizational reality in the information technology (IT) service provisioning industry for almost two decades (Alfaro & Chadrasekaran, 2015; Balint, 2015; Cater-Steel, 2009; Espinosa, DeLone, & Lee, 2006; Popoli & Popoli, 2009; Sakthivel, 2005; Siakas & Siakas, 2008). Given the global and interorganizational collaboration aspect of provisioning the services required to maintain day-to-day operations of a company’s IT systems, this industry has increasingly leveraged temporary cross-functional virtual work teams whose performance is highly dependent on the relationships developed among the dispersed team members (Alfaro & Chadrasekaran, 2015; Heitlager, Helms, & Brikkemper, 2010; Watanuki & Moraes, 2016).Despite this trend, researchers are still striving to comprehensively understand the factors that impact the performance of virtual teams (Brown, Prewett, & Grossenbacher, 2020; Clark, Manerwick, & Manerwick, 2019; De Jong, Gillespie, Williamson, & Gill, 2020; Eisenberg, Post, & DiTomaso, 2019; Prasad, DeRosa, & Beyerlein, 2017). Although virtual work can result in many potential benefits, such as increased productivity and flexibility, doubts regarding the performance of virtual teams are common in the literature because being virtual adds challenges to the already complex task of collaborating (Anh, Cruzes, & Conradi, 2012; Colazo & Fang, 2010; Dulebohn & Hoch, 2017). A considerable number of these challenges can be associated with the several discontinuities that these teams face, such as spatial, temporal, cultural, organizational or functional dispersion (Alfaro & Chadrasekaran, 2015; Anh et al., 2012; Brown et al., 2020; Colazo & Fang, 2010; Eisenberg et al., 2019; Espinosa et al., 2006; Espinosa, Nan, & Carmel, 2015; O’Leary & Cummings, 2007; Prasad et al., 2017) and their consequent implications for the socioemotional state of the team, such as trust and cohesiveness (Clark et al., 2019; De Jong et al., 2020; Paul, Drake, & Liang, 2016; Peñarroja, Orengo, Zornoza, & Hernández, 2013). Given the growing popularity of virtual teams in the IT service provisioning industry, this study is motivated by the need for a more comprehensive understanding of the effects of team dispersion on the performance of virtual teams via the team´s socioemotional states.In an attempt to provide further distinction and understanding of the effect different dimensions of team dispersion might have over the virtual team performance, this study combines findings from previous research about team dispersion (Anh et al., 2012; Chudoba, Wynn, Lu, & Watson-Manheim, 2005; Espinosa et al., 2006; O’Leary & Cummings, 2007; Prasad et al., 2017) and adopts a two-dimensional view of team dispersion along the concepts of team distribution, which encompasses the highly correlated spatial, temporal and cultural dimensions of dispersion; and variety of practices, which encompasses the highly correlated organizational and functional dimensions of dispersion.In an attempt to provide further distinction and understanding of the effect that different socioemotional states of the virtual team might have on the team´s performance, this study investigates the mediating role of trust and cohesiveness in the relationship between team dispersion and virtual team performance.
| https://www.igi-global.com/article/team-dispersion-emergent-states-and-performance-in-virtual-it-service-provisioning-teams/287577 |
JESUS V. OCCEÑA v. RAMON V. JABSON
GR No. L-44349, (1976-10-29)
DIVISION
[ GR No. L-44349, Oct 29, 1976 ]
JESUS V. OCCEÑA v. RAMON V. JABSON +
DECISION
165 Phil. 617
FIRST DIVISION
[ G.R. No. L-44349, October 29, 1976 ]
JESUS V. OCCEÑA AND EFIGENIA C. OCCEÑA, PETITIONERS, VS. HON. RAMON V. JABSON, PRESIDING JUDGE OF THE COURT OF FIRST INSTANCE OF RIZAL, BRANCH XXVI; COURT OF APPEALS AND TROPICAL HOMES, INC., RESPONDENTS. D E C I S I O N
TEEHANKEE, J.:
The Court reverses the Court of Appeals' appealed resolution. The Civil Code authorizes the release of an obligor when the service has become so difficult as to be manifestly beyond the contemplation of the parties but does not authorize the courts to
modify or revise the subdivision contract between the parties or fix a different sharing ratio from that contractually stipulated with the force of law between the parties. Private respondent's complaint for modification of the contract manifestly has no basis in law and
must therefore be dismissed for failure to state a cause of action.
On February 25, 1975 private respondent Tropical Homes, Inc. filed a complaint for modification of the terms and conditions of its subdivision contract with petitioners (landowners of a 55,330 square meter parcel of land in Davao City), making the following
allegations:
"That due to the increase in price of oil and its derivatives and the concomitant worldwide spiralling of prices, which are not within the control of plaintiff, of all commodities including basic raw materials required for such development work, the cost of development has
risen to levels which are unanticipated, unimagined and not within the remotest contemplation of the parties at the time said agreement was entered into and to such a degree that the conditions and factors which formed the original basis of said contract, Annex 'A', have been
totally changed;
"That further performance by the plaintiff under the contract, Annex 'A', will result in a situation where defendants would be unjustly enriched at the expense of the plaintiff; will cause an inequitous distribution of proceeds from the sales of subdivided lots in manifest
contravention of the original essence of the agreement; and will actually result in the unjust and intolerable exposure of plaintiff to implacable losses, all such situations resulting in an unconscionable, unjust and immoral situation contrary to and in violation of the
primordial concepts of good faith, fairness and equity which should pervade all human relations."
Under the subdivision contract, respondent "guaranteed (petitioners as landowners) as the latter's fixed and sole share and participation an amount equivalent to forty (40%) per cent of all cash receipts from the sale of the subdivision lots".
Respondent prayed of the Rizal court of first instance that "after due trial, this Honorable Court render judgment modifying the terms and conditions of the contract x x x by fixing the proper shares that should pertain to the herein parties out of the gross proceeds from the
sales of subdivided lots of subject subdivision".
Petitioners moved to dismiss the complaint principally for lack of cause of action, and upon denial thereof and of reconsideration by the lower court elevated the matter on certiorarito respondent Court of Appeals.
Respondent court in its questioned resolution of June 28, 1976 set aside the preliminary injunction previously issued by it and dismissed petition on the ground that under Article 1267 of the Civil Code which provides that
"ART. 1267. When the service has become so difficult as to be manifestly beyond the contemplation of the parties, the obligor may also be released therefrom, in whole or in part." [1]
"x x x a positive right is created in favor of the obligor to be released from the performance of an obligation in full or in part when its performance 'has become so difficult as to be manifestly beyond the contemplation of the parties'."
Hence, the petition at bar wherein petitioners insist that the worldwide increase in prices cited by respondent does not constitute a sufficient cause of action for modification of the subdivision contract. After receipt of respondent's comment, the Court in its
Resolution of September 13, 1976 resolved to treat the petition as a special civil action and declared the case submitted for decision.
The petition must be granted.
While respondent court correctly cited in its decision the Code Commission's report giving the rationale for Article 1267 of the Civil Code, to wit,
"The general rule is that impossibility of performance releases the obligor. However, it is submitted that when the service has become so difficult as to be manifestly beyond the contemplation of the parties, the court should be authorized to release the obligor in
whole or in part. The intention of the parties should govern and if it appears that the service turns out to be so difficult as have been beyond their contemplation, it would be doing violence to that intention to hold the obligor still responsible. x x
x." [2]
it misapplied the same to respondent's complaint.
If respondent's complaint were to be releasedfrom having to comply with the subdivision contract, assuming it could show at the trial that the service undertaken contractually by it had "become so difficult as to be manifestly beyond the contemplation of the
parties", then respondent court's upholding of respondent's complaint and dismissal of the petition would be justifiable under the cited codal article. Without said article, respondent would remain bound by its contract under the theretofore prevailing doctrine that
performance therewith is not excused "by the fact that the contract turns out to be hard and improvident, unprofitable or impracticable, ill advised or even foolish, or less profitable, or unexpectedly burdensome", [3]since in case a party desires to
be excused from performance in the event of such contingencies arising, it is his duty to provide therefor in the contract.
But respondent's complaint seeks notrelease from the subdivision contract but that the court "render judgment modifyingthe terms and conditions of the contract ... by fixingthe proper sharesthat should pertainto the
herein parties out of the gross proceedsfrom the sales of subdivided lots of subject subdivision". The cited article does not grant the courts this authority to remake, modify or revise the contract or to fix the division of shares between the parties as
contractually stipulated with the force of law between the parties, so as to substitute its own terms for those covenanted by the parties themselves. Respondent's complaint for modification of contract manifestly has no basis in law and therefore states no cause of
action. Under the particular allegations of respondent's complaint and the circumstances therein averred, the courts cannot even in equity grant the relief sought.
A final procedural note. Respondent cites the general rule that an erroneous order denying a motion to dismiss is interlocutory and should not be corrected by certioraribut by appeal in due course. This case however manifestly falls within the recognized
exception that certiorariwill lie when appeal would not prove to be a speedy and adequate remedy. [4]Where the remedy of appeal would not, as in this case promptly relieve petitioners from the injurious effects of the patently erroneous
order maintaining respondent's baseless action and compelling petitioners needlessly to go through a protracted trial and clogging the court dockets by one more futile case, certiorariwill issue as the plain, speedy and adequate remedy of an aggrieved
party.
ACCORDINGLY,the resolution of respondent appellate court is reversed and the petition for certiorariis granted and private respondent's complaint in the lower court is ordered dismissed for failure to state a sufficient cause of action.
With costs in all instances against private respondent.
Makasiar, Muñoz Palma, Concepcion, Jr.,and Martin, JJ.,concur.
[1]
Other Civil Code articles cited by respondent court as justifying the complaint were Articles 19 and 1159 which read:
"ART. 19. Every person must, in the exercise of his rights and in the performance of his duties, act with justice, give everyone his due and observe honesty and good faith."
xxx xxx xxx
"ART. 1159. Obligations arising from contracts have the force of law between the contracting parties and should be complied with in good faith."
[2]At p. 113, cited in Vol. IV, Padilla's Civil Code, 6th Ed., p. 476; Italics supplied.
[3]Reyes vs. Caltex (Phil.) Inc., 84 Phil. 654.
[4]Cf. 3 Moran's Rules of Court 1970 Ed., pp. 164-165, and cases cited.
tags
| https://lawyerly.ph/juris/view/c55ae |
(PDF) Effect of Long-Term Storage in TRIzol on Microarray-Based Gene Expression Profiling
PDF | Although TRIzol is widely used for preservation and isolation of RNA, there is suspicion that prolonged sample storage in TRIzol may affect... | Find, read and cite all the research you need on ResearchGate
Effect of Long-Term Storage in TRIzol on Microarray-Based Gene Expression Profiling
October 2010
Cancer Epidemiology Biomarkers & Prevention19(10):2445-52
DOI: 10.1158/1055-9965.EPI-10-0565
Authors:
Wencai Ma
Wencai Ma
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Michael Wang
university of Maimi
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Zhi-Qiang Wang
Zhi-Qiang Wang
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Luhong Sun
Luhong Sun
Abstract and Figures
Although TRIzol is widely used for preservation and isolation of RNA, there is suspicion that prolonged sample storage in TRIzol may affect array-based gene expression profiling (GEP) through premature termination during reverse transcription.
GEP on Illumina arrays compared paired aliquots (cryopreserved or stored in TRIzol) of primary samples of multiple myeloma (MM) and acute myeloid leukemia (AML). Data were analyzed at the "probe level" (a single consensus value) or "bead level" (multiple measurements provided by individual beads).
TRIzol storage does not affect standard probe-level comparisons between sample groups: different preservation methods did not generate differentially expressed probes (DEP) within MM or AML sample groups, or substantially affect the many DEPs distinguishing between these groups. Differences were found by gene set enrichment analysis, but these were dismissible because of instability with permutation of sample labels, unbalanced restriction to TRIzol aliquots, inconsistency between MM and AML groups, and lack of biological plausibility. Bead-level comparisons found many DEPs within sample pairs, but most (73%) were <2-fold changed. There was no consistent evidence that TRIzol causes premature reverse transcription termination. Instead, a subset of DEPs were systematically due to increased signals in TRIzol-preserved samples from probes near the 5' end of transcripts, suggesting better mRNA preservation with TRIzol.
TRIzol preserves RNA quality well, without a deleterious effect on GEP. Samples stored frozen with and without TRIzol may be compared by GEP with only minor concern for systematic artifacts.
The standard practice of prolonged sample storage in TRIzol is suitable for GEP.
<here is a image ddf332fab2b04a7a-b8fc9d272e375d35>
Cumulative frequency of log 2 fold-change magnitude of DEPs between MM sample pairs. Absolute values are shown for Up-DEPs (higher in Tri, dashed line) and Down-DEPs (lower in Tri, solid line). …
<here is a image a0da8cebb840e604-8cf873b561c3c0ad>
" Ratio of ratios " for pairs of probes recognizing the same transcript. 325 pairs of probes were significantly detected in all MM and AML samples, on both Tri and Cryo arrays. For each probe pair, the intensity ratios of 5' and 3' probes were calculated for each sample and preservation method, then the medians for Tri vs. Cryo compared. For the 209 probes with a higher Tri 5'/3' ratio, the Tri array ratio is divided by that of the Cryo array (dashed line). For the 116 probes with a higher Cryo 5'/3' ratio, the Cryo ratio is divided by that of the Tri array (solid line). …
Figures - uploaded by
Steven M Kornblau
<here is a image 175d1bd4b7439d95-754927124da715c1>
Effect of Long-Term Storage in TRIzol on Microarray-Based Gene
Expression Profiling
Wencai Ma 1 ,Michael Wang 1 ,Zhi-Qiang Wang 1 ,Luhong Sun 1 ,David Graber 1,2 ,Jairo
Matthews 1 , Richard Champlin 1,2,3, Qing Yi 1,3, Robert Z. Orlowski 1,3, Larry W. Kwak 1,3,
Donna M. Weber 1 ,Sheeba K. Thomas 1 ,Jatin Shah 1 ,Steven Kornblau 1,2 , andR. Eric
Davis 1,4
1 The Myeloma Tissue and Leukemia Satellite Sample Banks, Department of Lymphoma and
Myeloma, University of Texas-M. D. Anderson Cancer Center, Houston, TX
2 The Myeloma Tissue and Leukemia Satellite Sample Banks, Department of Stem Cell
Transplantation, University of Texas-M. D. Anderson Cancer Center, Houston, TX
3 Center for Cancer Immunology Research, University of Texas-M. D. Anderson Cancer Center,
Houston, TX
Abstract
Background— Although TRIzol is widely used for preservation and isolation of RNA, there is
suspicion that prolonged sample storage in TRIzol may affect array-based gene expression profiling
(GEP), via premature termination during reverse transcription (RT).
Methods— GEP on Illumina arrays compared paired aliquots (cryopreserved or stored in TRIzol)
of primary samples of multiple myeloma (MM) and acute myeloid leukemia (AML). Data were
analyzed at the “probe level” (a single consensus value) or “bead level” (multiple measurements
provided by individual beads).
Results— TRIzol storage does not affect standard probe-level comparisons between sample groups:
different preservation methods did not generate differentially-expressed probes (DEPs) within MM
or AML sample groups, or substantially affect the many DEPs distinguishing between these groups.
Differences were found by gene set enrichment analysis, but were dismissible because of instability
with permutation of sample labels, unbalanced restriction to TRIzol aliquots, inconsistency between
MM and AML groups, and lack of biological plausibility. Bead-level comparisons found many DEPs
within sample pairs, but most (73%) were <2-fold changed. There was no consistent evidence that
TRIzol causes premature RT termination. Instead, a subset of DEPs were systematically due to
increased signals in TRIzol-preserved samples from probes near the 5’ end of transcripts, suggesting
better mRNA preservation with TRIzol.
Conclusions— TRIzol preserves RNA quality well, without a deleterious effect on GEP. Samples
stored frozen with and without TRIzol may be compared by GEP with only minor concern for
systematic artifacts.
Impact— The standard practice of prolonged sample storage in TRIzol is suitable for GEP.
Keywords
gene expression profiling; RNA preservation; microarray; TRIzol
4 To whom correspondence should be sent: Department of Lymphoma and Myeloma, M. D. Anderson Cancer Center, SCRB1.2015, Box
903, 7455 Fannin St., Houston, TX 77054, [email protected], Office: (713) 745-8797, Fax: (713) 792-0332.
NIH Public Access
Author Manuscript
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
Published in final edited form as:
Cancer Epidemiol Biomarkers Prev . 2010 October ; 19(10): 2445–2452. doi:
10.1158/1055-9965.EPI-10-0565.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Introduction
The TRIzol® reagent from Invitrogen is a mono-phasic solution of phenol and guanidine
isothiocyanate, based on the single-step RNA isolation method developed by Chomczynski
and Sacchi.(1) TRIzol is widely used for the isolation of RNA, and investigators often use it
for preservation as well, placing fresh samples into TRIzol for freezing and storage at -80 °C,
then thawing the samples later for completion of the RNA isolation procedure. However, there
is undocumented suspicion that prolonged storage of tissues prior to RNA isolation, even at
-80 °C, can cause chemical modification (depurination) of RNA. In theory, this could result in
early termination during reverse transcription (RT) of mRNA molecules, potentially affecting
gene expression profiling (GEP) more strongly for transcripts with probes located farther from
the 3’ end. We decided to investigate effects of long-term TRIzol storage by comparing paired
aliquots of primary tumor samples collected for research purposes and frozen in TRIzol or
viably-frozen with dimethyl sulfoxide (DMSO).
Materials and Methods
Samples
Bone marrow aspirate samples of acute myeloid leukemia (AML) were collected and processed
by the Leukemia Sample Bank at MDACC between 1997 and 2006 under an Institutional
Review Board (IRB) approved protocol, and stored in liquid nitrogen freezers. Informed
consent was obtained in accordance with the Declaration of Helsinki. Primary tumor samples
of multiple myeloma (MM) were similarly collected for processing and storage under an IRB-
approved protocol by the Myeloma Tissue Bank since its inception in 2007. From these banks
we selected samples of AML (Ficoll-purified, CD3- and CD19-depleted) and MM (CD138+)
for which paired aliquots had been stored frozen in TRIzol (“Tri”) or cryopreservation medium
(“Cryo”, RPMI + 20% fetal calf serum + 10% DMSO) since the time of initial isolation (range,
1-9 years).
RNA isolation, cRNA generation, and microarray data generation
Cryo aliquots were quickly thawed, washed, and placed in TRIzol, then total RNA was isolated
from all aliquots as per the TRIzol manufacturer’s instructions (Invitrogen). RNA quality was
assessed with a Bioanalyzer 2100 (Agilent). RNA from 12 sample pairs (6 AML, 6 MM), all
with an RNA integrity number (RIN) > 7, was further purified with Qiagen RNAeasy columns.
From 300 ng of total RNA, the Illumina® TotalPrep RNA Amplification Kit (Ambion) was
used to generate amplified, biotinylated cRNA after RT by the Eberwine procedure. 750 ng of
cRNA was hybridized overnight to Illumina HT-12 BeadArrays, which were then washed and
stained with streptavidin-Cy3 (Amersham-Pharmacia Biotech) as per the Illumina protocol.
Arrays were scanned on a BeadArray Reader (Illumina) at the Biomarker Core Laboratory
Services at the University of Texas Health Science Center at Houston. The 6 MM Tri/Cryo
paired samples were hybridized to one HT-12 array, and the 6 AML paired samples to another
array.
Probe-level GEP data processing
Specific transcripts within the biotinylated cRNA are measured by fluorescent imaging after
direct hybridization to HT-12 bead arrays, which contain 12 arrays per slide, each with an
average of 15 beads for each of 48,803 probes measuring 37,846 annotated genes and additional
transcripts. Raw measurements of each bead’s intensity were captured directly and processed
as “bead-level” for the MM samples, as described below. For both MM and AML samples,
measurements were processed as “probe-level” data by GenomeStudio software (Illumina).
GenomeStudio checks that a probe has ≥3 beads present on the array (if not, the probe is
considered to be missing), performs a local background subtraction for each bead, then
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condenses bead-level data to a single probe-level value per probe by removing outliers greater
than 3 median absolute deviations (MADs) from the median, recalculating the mean of the
remaining values.(2) Raw probe-level values were extracted from GenomeStudio, without
using its correction or normalization options, but using its option for imputing missing values.
Values for each were then corrected using the model-based background correction (MBCB)
method, which uses values for negative control probes to estimate and remove the nonspecific
signal component for each transcript probe, with non-parametric estimation.(3) Corrected
values from the two arrays were combined into an integrated array, containing 12 Tri/Cryo
pairs, and quantile-normalized.(4) Non-significantly detected probes are defined by
GenomeStudio as having intensity no greater than that of a negative control probe (p<=0.05),
based on the normal distribution and the mean and SD of negative control probes.( 5 ) Intensities
of non-significantly detected probes in a particular sample aliquot were reset to the p = 0.05
value of the negative control distribution, i.e., the detection threshold, so that fold-change
differences between paired significant and non-significantly detected probes were kept to a
conservative minimum. We further excluded control probes and the ~20% of probes whose
sequences are not perfect or good matches to actual transcripts,(6) and log 2-transformed the
probe-level data.
Bead-level GEP data processing
To process bead level data from the MM sample array, and take advantage of the statistical
power inherent in many measurements of each transcript, i.e., one for each bead, we employed
a procedure using open-source and original software, modified from the approach of Dunning
et al.(7):
1. Extract bead level data.
2. Perform local background correction.
3. Discard outlier beads > 3 MAD from the median of transcript probes.
4. Perform MBCB correction of bead values.
5. Discard transcript probes with < 3 remaining beads.
6. Perform quantile normalization of bead values for the entire integrated array.
7. Exclude control probes (for biotin, housekeeping genes, Cy3 hybridization, labeling,
low stringency hybridization, and negative controls).
8. Exclude the ~20% of probes which are not perfect or good matches to actual
transcripts.(6)
9. Perform log 2of bead-level data.
Comparative analysis of TRIzol effect
Exploratory analysis to find differentially-expressed probes (DEPs) was done separately for
probe-level and bead-level data. Probe-level data from groups of MM and AML samples were
compared by t tests with false discovery rate (FDR) correction for multiple comparisons,(8)
and included paired t tests where appropriate. For bead-level data, comparisons were made
between Tri/Cryo pairs for each of the 6 MM samples by t tests with FDR control, excluding
probe comparisons in which the bead summary value (defined as the mean) for both arrays of
a pair was beneath the detection threshold (calculated similarly to the GenomeStudio method).
Analysis of TRIzol effect relative to probe location
For all probes, we determined the distance between the probe target sequence and the 5’ end
of its target transcript, the “5-prime end distance”, which is simply the start site nucleotide
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number of the probe (from “PROBE_START” in GenomeStudio). We also calculated the
distance between the probe target sequence and the 3’ end, the “3-prime end distance”, by
subtracting the start site nucleotide number from the full length of the mRNA (from
human.rna.gpff, downloaded from NCBI FTP). These were then used to examine a positional
effect of TRIzol by 3 methods of analysis: 1) Bead-level DEPs were divided into Up-DEPs
and Down-DEPs according to whether the bead summary value was higher or lower,
respectively, in Tri versus Cryo. The Wilcoxon rank-sum test was then used to determine
whether the distribution of 3-prime end distances differed between the Up-DEPs and Down-
DEPs.
2) Differences in probe intensity between Tri and Cryo sample pairs were examined as a
function of the probe distance from the 5’ or 3’ transcript end. For a given sample pair, absolute
differences between probe-level intensity values for all probes with at least one significantly-
detected value were summed in a running cumulative score with increasing distance from the
5’ or 3’ end.
3) Pairs of probes recognizing the same transcript were examined as to whether the ratio of
their probe-level intensities (5’/3’) for Tri arrays differed from those for the corresponding
Cryo arrays. For each gene, it was required that all 4 measurements (2 probes each for both
Tri and Cryo) were significantly detected. For genes in which there were more than 2 probes
meeting these criteria, a single comparison was made between the most 5’ probe and the most
3’ probe.
Results
TRIzol helps to preserve RNA quality
The RNA integrity number (RIN), a measure of RNA quality generated by the Agilent
Bioanalyzer 2100, was ≥9 for all 12 AML Tri, 6 of 12 AML Cryo, all 6 MM Tri, and 3 of 6
MM Cryo samples (Supplemental Table S1). 6 pairs of AML samples with high RIN values,
and all 6 MM pairs, were processed further to generate cRNA.
TRIzol does not negatively affect cRNA generation
Bioanalyzer-generated histograms assessing cRNA quality were similar for all sample aliquots,
suggesting no early termination of RT due to TRIzol (data not shown). cRNA quantity was
generally slightly higher from Tri samples, but Cryo samples also yielded well more than the
750 ng required for array hybridization (data not shown).
Probe-level comparisons show little effect of TRIzol storage
Table 1 shows the results of t and paired t tests comparing probe-level data from groups of
samples, arranged by disease (MM or AML) and preservation method (Tri or Cryo). At an
FDR of 0.1, no DEPs were found by within-disease comparisons, whether by group or paired
t tests, whereas many DEPs were found by between-disease comparisons, with substantial
overlap (Table S2). We also compared within-disease gene expression profiles between Tri
and Cryo aliquots by gene set enrichment analysis (GSEA), an increasingly-used method to
identify sets of genes that implicate biological processes or other explanations of differences,
even when fold-changes of individual genes are too low to be significant by t tests.( 9 ) Perhaps
due to this lesser requirement for fold change, a large number of gene sets were enriched among
genes more highly expressed in Tri aliquots of the 6 MM samples (data not shown), even with
an FDR of 0.25 commonly used for GSEA. However, the validity of these GSEA findings was
questioned by several observations: the enriched gene sets did not support a plausible or
consistent biological interpretation; they were substantially affected by permutation of sample
labels; no gene sets were enriched among genes less highly expressed in Tri aliquots of MM
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samples; and of the few gene sets enriched in the 6 AML samples, only 2 were also enriched
in MM samples.
We also considered the effect of length of storage in TRIzol, which for AML samples varied
from 2 to 9 years (all MM samples had been stored for < 2 years). The correlation coefficient
for pairs of AML samples, considering all eligible probes (those with at least one significantly-
detected value), ranged from 0.957 to 0.988 with no consistent effect of storage time. There
was a slight decrease in the slope of the Cryo/Tri regresssion line over time, from 0.982 to
0.956.
Bead-level comparison of MM samples shows an effect of TRIzol on GEP results
To test further whether TRIzol storage has an effect on GEP results, we then employed the
greater statistical power of comparisons based on processed bead-level data, available only for
the 6 MM samples. As shown in Table 2, we found a surprisingly large number of DEPs when
Tri/Cryo MM sample pairs were compared by t tests, for all eligible probes. Comparisons of
GEP data usually consider not just the number of DEPs but their fold-change. As shown in
Figure 1, the log 2magnitude of fold-change in DEPs between MM pairs was generally small,
with the majority being less than 1, i.e. either a 2-fold increase or decrease. Figure 1 also shows
that with some exceptions, the DEPs of highest fold-change were mostly in the Up-DEP group,
i.e. those higher in the Tri aliquot.
To assess whether these differences in bead-level were “real”, as opposed to being an artifact
of excessive statistical power, we subdivided bead-level data for eligible probes, and at least
10 beads on each array, randomly assigning the beads into 2 subarrays. Comparisons showed
many DEPs for between-sample subarrays, but not for within-sample subarrays, confirming
the difference in data between sample pairs (Table 3).
Next, to determine whether the particular DEPs observed were systematic, i.e., occurring in
multiple sample comparisons more frequently than expected from chance, we used
hypergeometric distribution tests to examine the overlap of DEPs found in pairs of sample
comparisons. The number of eligible probes used for the DEP determinations differed between
samples, and evaluation of the likelihood significance of overlap was done using the most
conservative denominator, i.e. the intersection of eligible probes from each sample. The overlap
of DEPs was highly significant for almost all pairwise comparisons of samples 1, 2, 4, and 6
(Table S3). Although further analysis showed that the number of overlapping DEPs between
these 4 samples declined considerably as the number of samples compared was increased (data
not shown), and DEPs were generally not overlapping in combinations involving samples 3 or
5 (Table S3), these results suggest that there was some systematic basis for the DEPs found by
bead-level comparisons.
In order to understand the systematic basis of DEP overlap in samples 1, 2, 4, and 6, we
examined DEP intensities with respect to probe location. The distance from the transcript 3’
end potentially provides information about the efficiency of RT, and therefore whether the
“TRIzol hypothesis” of premature termination of RT is correct. Table 2 showed that for all
sample pairs except #5, the Up-DEPs (higher in TRIzol) and Down-DEPs differed significantly
in their “3-prime end distance”. In pairs 1, 2, 4, and 6, the Up-DEPs were located farther from
the 3’ end of their target transcript. This is the opposite of what is expected if the “TRIzol
hypothesis” of premature RT termination is correct. An alternative hypothesis is that the effect
of probe location may be due to the positional tendency of mRNA degradation. This is not
straightforward, since mRNA degradation can be a specific process by which mRNA stability
is regulated in living cells, or a potentially artifactual process occurring in cells damaged during
preservation and handling. Furthermore, in living eukaryotes, general pathways of mRNA
degradation can proceed from either end, although the most frequently cited pathway involves
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initial shortening of the 3’ poly(A) tail followed by decapping of the 5’ methylguanosine cap,
exposing the mRNA body to 5’-to-3’ exonuclease digestion.(10-13) In theory, initial
shortening of the 3’ poly(A) tail would apply to all transcripts regardless of length, and the
effect on the GEP methods used here would be a global reduction on cRNA yield. However,
5’-to-3’ exonuclease digestion would have a biased effect, reducing the intensity for probes
near the 5’ transcript end. Perhaps as a result, the GEP literature generally states that mRNA
degradation starts at the 5’ end of transcripts,(14,15) and the 3’/5’ intensity ratios for
multiprobed “housekeeping” genes on Affymetrix arrays has been used for assessing RNA
quality.(16-19) These observations specify an alternate hypothesis: that there is less mRNA
degradation in TRIzol-preserved samples than in cryopreserved samples, with better
preservation of the 5’ portions of transcripts. This is consistent with the Bioanalyzer RIN
values, which were higher in the Tri samples. By this hypothesis, the preservation method with
less degradation is expected to have artifactual Up-DEPs for probes closer to the 5’ end of
transcripts, which on average are farther from the transcript 3’ end, and this is what was
observed for Tri in samples 1, 2, 4, and 6. Quantile normalization would not eliminate this
effect, although it may reduce its magnitude.
To test this alternate hypothesis further, we compared probe-level normalized intensities for
all eligible probes, as to whether the Tri or Cryo value was higher, as a function of the distance
from the 5’ end of the corresponding transcripts. A running cumulative score of the intensity
differences shows that Tri values were higher near the 5’ end for MM samples 1, 2, 4, and 6
(Figure 2), supporting the alternate hypothesis for these sample pairs. Sample 5 showed little
position effect, whereas sample 3 showed a mixed effect of position. Position effects were
inconsistent when using the 3-prime end distance, and among AML samples (data not shown).
In a third analysis of the relationship between probe position and preservation method, we
examined probe-level data for pairs of DEPs that measured the same transcript. For each sample
probe pair and preservation method (Tri or Cryo), we divided the intensity of the probe farther
from the 3’ end (5’) by that of the probe nearer to the 3’ end (3’). The rationale behind this
analysis is that the same object (i.e., the expressed transcript) is being measured by the two
probes; if the 5’/3’ ratio is different between the two preservation methods, it provides evidence
for differences in the lengths of cRNA generated from the two samples. We limited this analysis
to the 325 pairs of probes that targeted the same transcript and exceeded the detection threshold
for all 48 measurements (12 samples, 2 arrays each, 2 probes per transcript). For these 325
pairs, we computed the 5’/3’ intensity ratio for each of the 12 samples and preservation
methods, and then compared the median of the ratios of Tri arrays to that of Cryo arrays. 209
pairs had higher median ratios for Tri than Cryo, which was significantly more than the 116
pairs with higher Cryo ratios (p = 1.4E-07 by the binomial distribution). We then compared
the 5’/3’ Tri and Cryo median ratios for each of the 325 probes, creating a “ratio of ratios” (RR).
For the 209 probes with a higher Tri 5’/3’ ratio (RR 1), we divided the Tri array ratio by that
of the Cryo array, and for the 116 probes with a higher Cryo 5’/3’ ratio (RR 2), we divided the
Cryo ratio by that of the Tri array. Figure 3 shows that RR 1is consistently higher than RR 2.
Therefore, not only is the RR more often higher for Tri arrays than for Cryo arrays (209 vs.
116), the magnitude of its increases are greater than those of its decreases. Again, this is the
opposite of what is predicted by the TRIzol hypothesis of premature RT termination, and
supports the alternative hypothesis that there is less mRNA degradation in TRIzol-preserved
samples than in cryopreserved samples.
Discussion
Our results support 3 conclusions:
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1) TRIzol preservation should not produce artifactual differences in the usual way by which
gene expression profiling is done
Gene expression data are usually at the probe level, i.e., a single value per probe in each sample,
and are commonly analyzed by comparisons between groups of samples, e.g., using t tests. We
found that comparisons between groups of paired samples differing in preservation method,
even using paired t tests, failed to generate DEPs at the FDR level of 0.1. We found significant
enrichment of gene sets by GSEA, which is more sensitive to changes of low fold-change;
however, certain unusual features of these (sensitivity to permutation, lack of biological
plausibility, etc.) should serve to prevent their being interpreted as true differences.
2) TRIzol preservation may produce differences by bead-level comparisons to samples not
preserved in TRIzol, but those differences are mostly of low fold-magnitude
The number of DEPs in paired Tri vs. Cryo bead-level comparisons was surprisingly high,
although generally of low fold-magnitude. Splitting of the data confirmed that this was not the
result of high-power bead-level comparison, i.e., there were actual differences in the bead-level
data. Because we did not perform technical replicates with the same sample and preservation
method, we cannot exclude that the origin of these differences is methodologic, i.e., introduced
at or downstream of the point of RNA isolation in the GEP process. However, that seems
unlikely given the evidence, at least for some samples, that differences were related to probe
position. Therefore, our data suggest that bead-level comparisons may be made, with caution
(use of fold-change threshold, etc.) and consideration of potential position-dependent effects,
between samples irrespective of whether or not they have been preserved in TRIzol.
3) To the extent that bead-level differences between samples attributable to preservation
method (with TRIzol vs. without TRIzol) are consistent and of higher fold-magnitude, they
may be the result of better RNA preservation with TRIzol
Where we did observe a consistent TRIzol effect in bead-level comparisons, it supported the
hypothesis that TRIzol has a beneficial effect on RNA quality, with a particular effect on
enhancing the intensity of signals from probes near the 5’ end of transcripts. At the least, this
is evidence against the hypothesis of depurination and premature RT termination. We
compared TRIzol-preserved specimens to their cryopreserved counterparts, the latter of which
unavoidably had to undergo thawing and washing before being placed in TRIzol for RNA
isolation. This provided an opportunity for RNA degradation not experienced by the TRIzol-
preserved specimens, and therefore differences may have resulted from this process, rather
than during prolonged low-termperature storage. A better comparison would have been
between TRIzol aliquots vs. aliquots snap-frozen and stored without TRIzol, then thawed in
TRIzol. However, such paired samples were not available to us, and we wanted to test the
effects of long-term storage in the “real-world” context of samples from tissue banks whose
quality has been shown in studies of other types. Our results suggest that rather than being a
potential source of artifacts in GEP analysis, sample preservation in TRIzol may be an optimal
method, and should be continued by those who have been using it for many years.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Grants supporting the sample/tissue bank cores include NIH grants 2P01 CA55164-05A1 and P50 CA100632-01.
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Abbreviations
GEP gene expression profiling
Ma et al.Page 8
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Tri TRIzol
Cryo cryopreserved
AML acute myeloid leukemia
MM multiple myeloma
RT reverse transcription
DEP differentially-expressed probe
MDACC University of Texas-M. D. Anderson Cancer Center
IRB Institutional Review Board
RIN RNA integrity number
MAD median absolute deviation from the median
MBCB model-based background correction
FDR false discovery rate
Ma et al.Page 9
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Figure 1.
Cumulative frequency of log 2fold-change magnitude of DEPs between MM sample pairs.
Absolute values are shown for Up-DEPs (higher in Tri, dashed line) and Down-DEPs (lower
in Tri, solid line).
Ma et al.Page 10
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Figure 2.
Effect of preservation method on probe intensity, as a function of the distance of the probe
from the 5’ end of the targeted transcript. For each MM sample pair and eligible probe, the
intensity difference between probe level data (Tri – Cryo) is calculated, then a cumulative sum
is calculated over increasing distance.
Ma et al.Page 11
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Figure 3.
“ Ratio of ratios” for pairs of probes recognizing the same transcript. 325 pairs of probes were
significantly detected in all MM and AML samples, on both Tri and Cryo arrays. For each
probe pair, the intensity ratios of 5’ and 3’ probes were calculated for each sample and
preservation method, then the medians for Tri vs. Cryo compared. For the 209 probes with a
higher Tri 5’/3’ ratio, the Tri array ratio is divided by that of the Cryo array (dashed line). For
the 116 probes with a higher Cryo 5’/3’ ratio, the Cryo ratio is divided by that of the Tri array
(solid line).
Ma et al.Page 12
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NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Ma et al.Page 13
Table 1
Number of DEPs by found in probe-level comparisons between samples, grouped by disease and preservation method, by t tests with FDR <0.1.
t testGroup#1Group#2Down-DEPsUp-DEPsTotal probesTotal DEPs, %
Paired MM/TriMM/Cryo 00139760
Paired AML/TriAML/Cryo 00159720
Group MM/TriMM/Cryo 00139760
Group AML/TriAML/Cryo 00159720
Group MM/Tri AML/Tri 361328031599040.13
Group MM/TriAML/Cryo 334126971601637.70
Group MM/Cryo AML/Cryo 346829951597140.47
Group MM/Cryo AML/Tri370430931603342.39
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Ma et al.Page 14
Table 2
Number of DEPs by found in bead-level comparisons between paired MM samples, by t tests with FDR <0.1.
Pair Up-DEPs (%) 1 Down-DEPs (%) 1 Farther from 3’ end 2 p value 3
1 1212 (8.8)1130 (8.2)Up-DEPs<2.2e-16
2 745 (5.6)1126 (8.4)Up-DEPs1.9e-13
3 1174 (8.6)2594 (19.0)Down-DEPs<2.2e-16
4 821 (7.0)712 (6.0)Up-DEPs2.5e-5
5 164 (1.2)109 (0.8)Down-DEPs0.06
6 894 (6.6)767 (5.6)Up-DEPs<2.2e-16
1 Number of DEPs in the indicated direction; “Up” means higher mean value in Tri than in Cryo, “Down” is lower in Tri. Value in parentheses is the
percentage of DEPs among the total number of eligible filtered probes.
2 Indicates which DEP set (Up or Down) is significantly farther from the transcript 3’ end.
3 p value of the Wilcoxon rank test in comparing Up- vs. Down-DEPs in distance from the transcript 3’ end.
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript
Ma et al.Page 15
Table 3
Number of DEPs found after subviding bead-level data. For each MM sample pair, and each eligible probe with at least 10 bead values in each pair, Tri and
Cryo GEP data (designated as “1” or “2”, respectively) were each randomly assigned to either “A” or “B” subarrays. Subarrays were then compared by t
tests with FDR <0.1.
1A vs. 1B2A vs. 2B1A vs. 2A1B vs. 2A1A vs. 2B1B vs. 2B
Pair 1 00 482519619584
Pair 2 10 460506422474
Pair 3 00 1182108910931137
Pair 4 00 291268261222
Pair 5 00 17151212
Pair 6 00 370384362405
Cancer Epidemiol Biomarkers Prev . Author manuscript; available in PMC 2011 October 1.
... 9,10 Moreover, it has been demonstrated that long-term tissue storage (up to 9 years) in TRIzol does not observably impact RNA quality for gene expression assays.
11
Importantly, TRIzol has three constituents with properties that are known to inactivate bacterial and viral pathogens. However, a systematic review of the efficacy and limitations of TRIzol and of its individual constituents in inactivating pathogens is currently lacking. ...
Effectiveness of TRIzol in Inactivating Animal Pathogens
Jun 2023
<here is a image 586d80fb1c1633d2-4b4214d579d3c819> Gwen Duytschaever
<here is a image 528af8a6f64a644f-d39af8b0850606da> Patrícia R. Ströher
Kevin Fonseca
<here is a image da199536c2dfe090-4457b45c16d2ff8d> Amanda D Melin
Introduction: Safe handling of biological samples sourced from wild ecosystems is a pressing concern for scientists in disparate fields, including ecology and evolution, OneHealth initiatives, bioresources, geography, veterinary medicine, conservation, and many others. This is especially relevant given the growing global research community and collaborative networks that often span international borders. Treatments to inactivate potential pathogens of concern during transportation and analysis of biospecimens while preserving molecular structures of interest are necessary.
Objective: We provide a detailed resource on the effectiveness and limitations of TRIzol™ Reagent, a product commonly used in molecular biology to inactivate bacterial and viral pathogens found in wild animals.
Methods: By literature review, we evaluate the mode of action of TRIzol Reagent and its main components on bacterial and viral structures. We also synthesize peer-reviewed literature on the effectiveness of TRIzol in inactivating a broad range of infectious bacteria and viruses.
Key Findings: TRIzol Reagent inactivation is based on phenol, chaotropic salts, and sodium acetate. We find evidence of widespread efficacy in deactivating bacteria and a broad range of enveloped viruses. The efficacy against a subset of potential pathogens, including some nonenveloped viruses, remains uncertain.
Conclusion: Available evidence suggests that TRIzol Reagent is effective in inactivating a broad spectrum of bacteria and viruses from cells, tissues, and liquids in biological samples when the matrices are exposed to at least 10 min at room temperature to the reagent. We highlight areas that require additional research and discuss implications for laboratory protocols.
... Circulating miRNAs can be extracted directly from unfractionated biological fluids or from extracellular vesicle preparations using commercially available extraction kits (148) or TRIzol
(149)
. Upon isolation, miRNAs can be stored at -70°C and remain stable for up to 1 year (148). ...
MicroRNAs in kidney development and disease
May 2022
<here is a image 830cdbfe4b21d2ea-3a1be2f194289e85> Debora Malta Cerqueira
Maliha Tayeb
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jacqueline Ho
MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.
... Clinical characteristics of six JAK2V617F-positive cMPNs patients and six normal controls, from which bone marrow mononuclear cells were isolated, were shown in Table 1. Total RNA was extracted from bone marrow mononuclear cells using TRIzol reagent
[12]
(Invitrogen, Carlsbad, CA, USA). ...
A Comprehensive Genome-wide Analysis of Long Non-coding RNA and mRNA Expression Profiles of JAK2V617F-positive Classical Myeloproliferative Neoplasms
Article
Full-text available
Nov 2021
Jie Zhou
Hao Wu
Cheng Guo
Jian-Fei Fu
Aberrant expression of long non-coding RNAs (lncRNAs) is involved in the progression of myeloid neoplasms, but the role of lncRNAs in the JAK2V617F-positive subtype of classical myeloproliferative neoplasms (cMPNs) remains unclear. This study was conducted to clarify the expression and regulation patterns of lncRNAs in JAK2V617F-positive cMPNs, and to explore new potential carcinogenic factors of cMPNs. Bioinformatics analysis of microarray detection and wet testing verification were performed to study the expression and regulation signature of differentially expressed lncRNAs (DELs) and related genes (DEGs) in cMPNs. The expression of lncRNAs and mRNAs were observed to significantly dysregulated in JAK2V617F-positive cMPN patients compared with the normal controls. Co-expression analysis indicated that there were significant differences of the co-expression pattern of lncRNAs and mRNAs in JAK2V617F-positive cMPN patients compared to normal controls. GO and KEGG pathway analysis of DEGs and DELs showed the involvement of several pathways previously reported to regulate the pathogenesis of leukemia and cMPNs. Cis- and trans-regulation analysis of lncRNAs showed that ZNF141, DHX29, NOC2L, MAS1L, AFAP1L1, and CPN2 were significantly cis-regulated by lncRNA ENST00000356347, ENST00000456816, hsa-mir-449c, NR_026874, TCONS_00012136, uc003lqp.2, and ENST00000456816, respectively, and DELs were mostly correlated with transcription factors including CTBP2, SUZ12, REST, STAT2, and GATA4 to jointly regulate multiple target genes. In summary, expression profiles of lncRNAs and mRNAs were significantly altered in JAK2V617F-positive cMPNs, the relative signaling pathway, co-expression, cis- and trans-regulation were regulated by dysregulation of lncRNAs and several important genes, such as ITGB3, which may act as a promising carcinogenic factor, warrant further investigation.
... It is widely accepted that RNA can be stabilized at − 80 °C in TRIzol Reagent for a long time, providing a convenient solution for large sample collections
[8]
. However, in most cases, leukocytes cannot be isolated from blood immediately before TRIzol treatment, because unpredictable changes may occur in the transcriptome. ...
Impact of storage conditions on peripheral leukocytes transcriptome
Article
Full-text available
Feb 2021
MOL BIOL REP
Yanru Xing
Xi Yang
<here is a image e5961ed035fed28b-6ccd933234648a34> Haixiao Chen
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Wen-Jing Wang
Leukocytes reflect the physiological and pathological states of each individual, and transcriptomic data of leukocytes have been used to reflect health conditions. Since the overall impact of ex vivo conditions on the leukocyte transcriptome before RNA stabilization remains unclear, we evaluated the influence of temporary storage conditions on the leukocyte transcriptome through RNA sequencing. We collected peripheral blood with EDTA tubes, which were processed immediately or stored either at 4 °C or room temperature (RT, 18–22 °C) for 2 h, 6 h and 24 h. Total cellular RNA was extracted from 42 leukocyte samples after red blood cells lysis for subsequent RNA sequencing. We applied weighted gene co-expression network analysis to construct co-expression networks of mRNA and lncRNA among the samples, and then performed gene ontology (GO) term enrichment to explore possible biological processes affected by storage conditions. Storage conditions change the gene expression of peripheral leukocytes. Comparing with fresh leukocytes, storage for 24 h at 4 °C and RT affected 1515 (1.51%) and 10,823 (10.82%) genes, respectively. Pathway enrichment analysis identified nucleosome assembly enriched in up-regulated genes at both conditions. When blood was stored at RT for 24 h, genes involved in apoptotic signaling pathway, negative regulation of cell cycle and lymphocyte activation were upregulated, while the relative proportion of neutrophils was significantly decreased. Temporary storage conditions profoundly affect the gene expression profiles of leukocytes and might further change cell viability and state. Storage of blood samples at 4 °C within 6 h largely maintains their original transcriptome.
... This procedure relies on the differential solubility of cellular components in organic solvents. The first components of this protocol are commonly marketed as Trizol and will denature proteins, including RNases, allowing safe long-term storage
(67)
. After phase separation, which is often facilitated by adding guanidinium thiocyanate, RNA is recovered by precipitation with isopropyl alcohol. ...
Environmental and epigenetic factors involved in cardiac differentiation from human induced pluripotent stem cells
Thesis
Jan 2019
Solenne Paiva
The objective of this thesis was to evaluate some physical and epigenetic parameters involved during cardiac differentiation of human induced pluripotent stem cells. Environmentally, an often undervalued physical parameter remains, the stiffness defined by the Young’s modulus. Commonly stem cells are cultured and adapted to in vitro rigidities ranging between 1-10 GPa very far from physiological values, for instance 10-15 kPa for the heart. The impact of soft culture substrates with 3 kPa, 12 kPa and 25 kPa was studied on the initial stem cells. Globally, results indicated that rigidities lower than 25 kPa were not suited for total pluripotency maintenance after 6 passages. Also, cellular colonies started to grow in 3D suggesting that softness drove them to build their own microenvironment. Epigenetically, the exact role of one of the first discovered microRNAs, the let-7 family has not yet been fully elucidated. Throughout differentiation its expression was characterized by an early transient peak at the time of mesoderm formation, after which their expression extinguished to only gradually re-increase later in the course of cardiomyocytes maturation. Modulation experiments involving mimics or inhibitors of the let-7 family on different cellular contexts suggested that initially let-7 acted on future cardiac specification but later, this family had to be repressed in order for cardiac progenitors to emerge. Oppositely, the cardiac specific miR-1 always contributed to their progression into cardiomyocytes. Together these researches contribute to fundamental research on human heart development and to applied research on human engineered cardiac tissues.
... Reverse phrase protein array (RPPA) and gene expression profiling (GEP) BTX306-or vehicle-treated cell lysate samples were evaluated by RPPA as detailed in the Online Resource 1. For GEP analysis, 1-2 million BTX306-or vehicle-treated MM1.S cells were pelleted and processed for GEP as detailed previously
[21]
. In arrays, the probes expressed above background ≥ 25% were selected for normalization. ...
The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance
Aug 2020
J MOL MED-JMM
<here is a image 9a78eec758268a55-42b74f4e99645b87> Jianxuan Zou
<here is a image a4c3d5f488495263-5aa7d40b71167ace> Richard J Jones
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Hua Wang
Robert Z. Orlowski
Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9. While lenalidomide and pomalidomide induced greater degradation of Ikaros and Aiolos in myeloma cells, BTX306 more potently reduced levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC. Suppression of cereblon or overexpression of Aiolos or Ikaros induced relative resistance to BTX306, and this agent did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon. Interestingly, BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53. Finally, BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone, and was effective in an in vivo systemic model of multiple myeloma. Taken together, the data support further translational studies of BTX306 and its derivatives to the clinic for patients with relapsed and/or refractory myeloma.
Key messages
BTX306 has a unique thiophene-fused scaffold bearing phenylurea and glutarimide.
BTX306 is more potent against myeloma cells than lenalidomide or pomalidomide.
BTX306 overcomes myeloma cell resistance to lenalidomide or bortezomib in vitro.
BTX306 is active against primary myeloma cells, and shows efficacy in vivo.
Sample management: a primary critical starting point for successful omics studies
Jan 2022
MOL CELL TOXICOL
Eun Jung Koh
Seung Hwan Kim
Seung Yong Hwang
Biological samples collected from cohort studies are widely utilized in molecular genetic studies and are typically stored long term for future applications, such as omics analyses. The extent of sample availability is determined by proper sample handling, and it is of primary importance for successful omics studies. However, questions on whether samples in long-term storage are properly available for omics experiments has been raised, because the quality and availability of such samples remain unknown until their actual utilization. In that perspective, several guidelines for proper sample management have been suggested. In addition, several researchers assessed how improper management damages sample using mock sample and suggested a set of requirements for sample handling. In this review, we present several considerations for sample handling eligible for omics studies. Focusing on birth cohorts, we describe the types of samples collected from which omics data were generated. This review ultimately aims to provide proper guidelines for sample handling for successful human omics studies.
Good laboratory and experimental practices for microRNA analysis in cardiovascular research
Chapter
Jan 2021
<here is a image 2a68fdbfcab96297-619d0b141a77f944> Christos P Papaneophytou
<here is a image d942b177156864f4-5b19abf627be4832> Eleftheria Galatou
<here is a image 4b7ba3e70262d8f4-4791bfa83c8d8ca3> Kyriacos N Felekkis
Cardiovascular diseases (CVDs) are a major cause of death worldwide, especially in developed countries. Noncoding RNA molecules and particularly circulating microRNAs (miRNAs) have become potential diagnostic, prognostic, and therapeutic biomarkers for CVDs. In the cardiovascular system, miRNAs regulate numerous biological functions while they have been implicated in the pathogenesis of several CVDs. miRNAs exhibit several advantages over other biological molecules (proteins, cytokines, and peptides), especially due to their high stability in circulation and under extreme pH and temperature conditions. However, it is still challenging to accurately determine miRNA levels and several preanalytical and analytical issues need to be addressed. Methodological heterogeneity in sample storage and handling, extraction and quantification of miRNAs, and data normalization resulted in inconsistency among different studies. In this chapter, we highlight the factors that must be taken into account when studying circulating miRNAs and we propose laboratory and experimental practices to ensure valid scientific inference.
Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma
Article
Jan 2021
CELL METAB
Zongwei Li
Huan Liu
Jin He
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jing Yang
Obesity is often linked to malignancies including multiple myeloma, and the underlying mechanisms remain elusive. Here we showed that acetyl-CoA synthetase 2 (ACSS2) may be an important linker in obesity-related myeloma. ACSS2 is overexpressed in myeloma cells derived from obese patients and contributes to myeloma progression. We identified adipocyte-secreted angiotensin II as a direct cause of adiposity in increased ACSS2 expression. ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4), and enhances IRF4 stability and IRF4-mediated gene transcription through activation of acetylation. The importance of ACSS2 overexpression in myeloma is confirmed by the finding that an inhibitor of ACSS2 reduces myeloma growth both in vitro and in a diet-induced obese mouse model. Our findings demonstrate a key impact for obesity-induced ACSS2 on the progression of myeloma. Given the central role of ACSS2 in many tumors, this mechanism could be important to other obesity-related malignancies.
| https://www.researchgate.net/publication/46095267_Effect_of_Long-Term_Storage_in_TRIzol_on_Microarray-Based_Gene_Expression_Profiling |
B Lenkey's research works | University of Debrecen, Debrecen and other places
B Lenkey's 8 research works with 102 citations and 139 reads, including: [Study of the effects of alkali metals on some virulence characteristics of Candida albicans]
B Lenkey's research while affiliated with University of Debrecen and other places
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Publications (8)
[Study of the effects of alkali metals on some virulence characteristics of Candida albicans]
May 2003
Peter Hermann
Krisztina Márton
Katalin Forgács
[...]
Ferenc Rozgonyi
The effects of the alkali metals sodium, potassium and lithium on the growth and on certain virulence factors (adhesion, cell-surface hydrophobicity and the germinating ability) of Candida albicans were investigated. It can be concluded that high concentrations of alkali metals possessed an inhibitory effect on the growth of the Candida cells and p...
Effects of alkali metal ions on some virulence traits ofCandida albicans
Article
Feb 2003
Peter Hermann
K Forgács
E Gál
[...]
Ferenc Rozgonyi
The effects of the alkali metal ions (Li+, Na+ and K+) on the growth and on certain virulence factors (adhesion, cell-surface hydrophobicity and germinating ability) of Candida albicans were determined. High concentrations of these ions displayed an inhibitory effect on the growth of the Candida cells; preincubation in their presence showed a negat...
Comparative study of Glycyrrhiza glabra L. and Glycyrrhiza echinata L. of different origin. Medicinal plant polysaccharides III
Nov 2001
Gyöngyi Gyémánt
B Lenkey
Péter Nánási
Comparative study was carried out among the polysaccharides of Chinese, Lithuanian and Hungarian origin Glycyrrhiza glabra L. as well as the Hungarian origin Glycyrrhiza echinata L. Monosaccharide composition, measured as alditol acetates, of Chinese and Hungarian G. glabra was very similar, but the Lithuanian G. glabra and the G. echinata were qui...
Changes of virulence factors accompanying the phenomenon of induced fluconazole resistance in Candida albicans
Article
Sep 2000
K Fekete-Forgács
L Gyüre
B Lenkey
We investigated a fluconazole-sensitive (MICflu = 5 micrograms ml-1) clinical isolate and a fluconazole-resistant (MICflu > 80 micrograms ml-1) laboratory mutant Candida albicans strain developed from the sensitive one. We studied putative virulence factors including germination, adherence ability to either buccal epithelial cells or acrylate surfa...
Investigation of -glucosidase as a potential virulence factor of Candida albicans
May 2000
Katalin Fekete-Forgács
Apor Jeney
Gábor Varga
Béla Lenkey
In this study, the α-glucosidase of C. albicans as a potential virulence factor was investigated. We compared the intracellular and intact-cellular activities of two C. albicans strains: a clinical isolate (FS) and a laboratory mutant (FR) derived from the former. Although the FR strain was superior in all the virulence factors examined as well as...
Effect of fluconazole on the growth and adhesion ofCandida albicans in the presence of antineoplastic agents
Dec 1999
Katalin Fekete-Forgács
Bernadett Kis
Gábor Nagy
Béla Lenkey
The effect of fluconazole and the antineoplastic agents etoposide and methotrexate on the growth and adhesion of Candida albicans were studied. All the tested chemicals inhibited the growth and the adhesion of the yeast to buccal epithelial cells, while fluconazole and etoposide inhibited the adhesion to acrylate surface as well. Our experiments al...
Effect of fluconazole on the growth and adhesion of Candida albicans in the presence of antineoplastic agents
Feb 1999
K Fekete-Forgács
B Kis
G Nagy
B Lenkey
The effect of fluconazole and the antineoplastic agents etoposide and methotrexate on the growth and adhesion of Candida albicans were studied. All the tested chemicals inhibited the growth and the adhesion of the yeast to buccal epithelial cells, while fluconazole and etoposide inhibited the adhesion to acrylate surface as well. Our experiments al...
The formation of hyphae of Candida albicans induced by cyclodextrins
Jan 1998
Katalin Fekete-Forgács
Erika Szabó
B Lenkey
Hyphal growth of Candida albicans was observed when yeast was cultured at 27 d̀C in liquid media containing 1% Tripcasine® and 1.8% cyclodextrins (α, β, and γ respectively). Tripcasine as the sole nitrogen source did not induce the formation of hyphae of C. albicans, but cyclodextrins, especially CD-β, were able to induce yeast-mycelial transition....
Citations
... Forg acs et al
45
examined the possibility of a-glucosidase being a virulence factor. The enzyme activity was compared between a fluconazole-resistant C. albicans strain and a fluconazole-sensitive strain and they found that a-glucosidase plays an insignificant role in the virulence of C. albicans. ...
Reference: Exploration of the anticandidal mechanism of Cassia spectabilis in debilitating candidiasis
Investigation of -glucosidase as a potential virulence factor of Candida albicans
Katalin Fekete-Forgács
Apor Jeney
Gábor Varga
B Lenkey
... Common chlamydospore-inducing media are based on corn or rice and are therefore rich in starch, indicating that polysaccharides have an inducing or at least non-repressing effect on chlamydospore development. Complex carbohydrates are known to influence fungal morphology: In S. cerevisiae, starch degradation is associated with the ability to grow invasively and form pseudohyphae (Vivier et al., 1997) and polymeric cyclodextrines were described to induce hyphae by C. albicans
(Fekete-Forgács et al., 1997)
. The repressing effect of glucose on chlamydosporulation, in contrast, was described almost half a century ago for C. albicans (Jansons and Nickerson, 1970b). ...
Reference: Candida species Rewired Hyphae Developmental Programs for Chlamydospore Formation
The formation of hyphae of Candida albicans induced by cyclodextrins
Jan 1998
PubMed
Katalin Fekete-Forgács
Erika Szabó
B Lenkey
View
... In fact, C. albicans is a eukaryotic organism and expresses a TMP-insensitive DHFR that is closely similar to the mammalian enzyme. On the other hand, MTX, which is a potent inhibitor of C. albicans DHFR [10], shows no detectable anticandidal activity
[11]
. Recently, we have shown that a tea polyphenol, epigallocatechin-3gallate, inhibited ergosterol biosynthesis by disturbing folic acid metabolism in C. albicans [12]. ...
Reference: Antifolates as antimycotics? Connection between the folic acid cycle and the ergosterol biosynthesis pathway in Candida albicans
Effect of fluconazole on the growth and adhesion of Candida albicans in the presence of antineoplastic agents
PubMed
Katalin Fekete-Forgács
Bernadett Kis
G Nagy
B Lenkey
... As a result, mutations in SAP genes cause attenuated virulence of C. albicans in mouse models (Naglik et al. 2003). Interestingly, several studies recognized that subinhibitory concentrations of certain antifungals (azoles, amphotericin B) can promote the production and secretion of virulence factors, such as SAPs
(Fekete-Forgács et al. 2000
, Mores et al. 2011. These findings present an indirect connection between the short-term response to drug treatment and proteolytic activity of the fungal strains, further underlining the importance of understanding cellular processes to improve therapeutic choices during fungal infections (Silva et al. 2014). ...
Reference: The effect of antifungal resistance development on the virulence of Candida species
Changes of virulence factors accompanying the phenomenon of induced fluconazole resistance in Candida albicans
PubMed
Katalin Fekete-Forgács
László Gyüre
B Lenkey
... A few prenylated flavanone like pinocembrin and licoflavanone [127], minor isoflavanoid glabroisoflavanone A, B [121] along with pyrano-2-arylbenzofuran derivatives like glabrocoumarones A and B have also been isolated from the plant [128]. Polysaccharide in the plant is reported to be composed of glucuronic acid, galacturonic acid and uronic acid along with glucofuranose, D-mannopyranose, -D-glucopyranose, myoinositol, saccharose, -fructose, -D-fructose [129]
[130]
[131]. An alkaloid, licorine A had also reported from asl-us-soos [132]. ...
Reference: Joshanda: A Traditional Herbal Approach for Treatment of Respiratory Catarrh
Comparative study of Glycyrrhiza glabra L. and Glycyrrhiza echinata L. of different origin. Medicinal plant polysaccharides III
PubMed
Gyöngyi Gyémánt
B Lenkey
Péter P Nánási
... In yeast, one of such proteins is Cnh1, which is involved in the exchange of intracellular sodium for extracellular protons [35]; hence, it is also involved in the maintenance of intracellular pH. Furthermore, in yeast, including C. albicans alkali cations contributes towards the growth and virulence by regulating adhesion and cell-surface hydrophobicity, as well as cell morphology
[36,
37]. Hence, such systems can be potential drug targets. ...
Reference: Cation Transporters of Candida albicans-New Targets to Fight Candidiasis?
Effects of alkali metal ions on some virulence traits ofCandida albicans
PubMed
Péter Hermann
Katalin Forgács
Edina Gál
B Lenkey
Ferenc Rozgonyi
Top co-authors (14)
Ferenc Rozgonyi
Semmelweis University
Peter Hermann
Semmelweis University
Gyöngyi Gyémánt
University of Debrecen
Péter Nánási
Debreceni Egyetem, Orvos- és Egészségtudományi Centrum
Krisztina Márton
Semmelweis University
Katalin Fekete-Forgács
| https://www.researchgate.net/scientific-contributions/B-Lenkey-7563012 |
Volume 43 Issue 3 | The Annals of Mathematical Statistics
The Annals of Mathematical Statistics
The Annals of Mathematical Statistics
VOL. 43 · NO. 3 | June, 1972
Front Matter
Miscellaneous front pages, Ann. Math. Statist. , Volume 43, Number 3 (1972)
Ann. Math. Statist. 43 (3), (June, 1972)
No abstract available
Articles
The 1971 Rietz Lecture Sums of Independent Random Variables--Without Moment Conditions
Harry Kesten
Ann. Math. Statist. 43 (3), 701-732, (June, 1972) DOI: 10.1214/aoms/1177692541
Analogues of classical limit laws for sums of independent random variables (central limit theorem, laws of large numbers and law of the iterated logarithm) are discussed. We stress results which go through without moment or smoothness assumptions on the underlying distributions. These include (i) estimates for the spread of the distribution of S n = ∑ n 1 X i S n = ∑ 1 n X iin terms of concentration functions (Levy-Rogozin inequality), (ii) comparison of the distribution of S n S non different intervals (ratio limit theorems and Spitzer's theorem for the existence of the potential kernel for recurrent random walk), (iii) study of the set of accumulation points of S n / Υ ( n ) S n / Υ ( n )for suitable Υ ( n ) ↑ ∞ Υ ( n ) ↑ ∞. Only the following parallel to the law of the iterated logarithm is new: If X 1 , X 2 , ⋯ X 1 , X 2 , ⋯are independent random variables all with distribution F , S n = ∑ n 1 X 1 , m n = med ( S n ) F , S n = ∑ 1 n X 1 , m n = med ( S n ), then there exists a sequence { Υ ( n ) } { Υ ( n ) }such that Υ ( n ) → ∞ Υ ( n ) → ∞and − ∞ < lim inf ( S n − m n ) / Υ ( n ) < lim sup ( S n − m n ) / Υ ( n ) < ∞ − ∞ < lim inf ( S n − m n ) / Υ ( n ) < lim sup ( S n − m n ) / Υ ( n ) < ∞w.p. 1, if and only if F Fbelongs to the domain of partial attraction of the normal law.
Bounds for Stopped Partial Sums
Howard M. Taylor
Upper bounds are derived for the expected value of a stopped random sum under each of four sets of assumptions concerning the summands, plus under an additional set describing a related and similar problem. Too complex to abstract, these assumptions in part, typically limit the first two moments of the summands. The bounds have an interpretation in a stock market timing problem in which the random sum represents the sequence of daily prices of a stock and the positive part of the sum reflects a potential profit a holder of an option in the stock could realize were he to exercise. In only one case are the summands required to be independent and identically distributed, and thus we obtain bounds on the expected profit that do not require the controversial random walk model for stock prices. Of course, the bounds are of interest for other reasons as well. For example, as a related result we show that if ( S n ) ( S n )is a random walk for which the summands ( X n ) ( X n )have a negative mean, then E [ S + T ] < ∞ E [ S T + ] < ∞for all stopping times T Tif and only if E [ ( X + 1 ) 2 ] < ∞ E [ ( X 1 + ) 2 ] < ∞. For the most part, techniques familiar to readers of Dubins and Savage (How to Gamble if You Must, McGraw-Hill 1965) are used.
Asymptotic Theory for Successive Sampling with Varying Probabilities Without Replacement, II
Bengt Rosen
Ann. Math. Statist. 43 (3), 748-776, (June, 1972) DOI: 10.1214/aoms/1177692543
This paper is a direct continuation of the corresponding paper [7], in which our main results were formulated in Section 3. Some of these results were proved and we prepared ourselves for the proof of the asymptotic normality of the sample sum. Our main concern in this part is to carry through the remaining proofs.
Bayes, Likelihood, or Structural
D. A. S. Fraser
Ann. Math. Statist. 43 (3), 777-790, (June, 1972) DOI: 10.1214/aoms/1177692544
The traditional model of statistics is examined in Section 1. The model, as such, distinguishes response values only by their likelihood functions. Recognition of this restricted identification effectively precludes the need for any theory of sufficient statistics. A probability space that has an attached observer-processor-reporter (OPR) mechanism is examined in Section 2 as a means of assessing the nature of reported information; such information may or may not be observational in character depending on properties of the OPR mechanism. A variation-response model is a probability space and a class of random variables: the probability space describes the sources of variation in the system under investigation and the class of random variables describes the possible presentations of this variation in the response of the system. Section 3 examines how realized values on the probability space are distinguished or identified by the model; Section 4 considers how distributions on the probability space are identified by response variable data. In Sections 5, 6, 7 the essentials of three contemporary approaches to inference are presented and each is accompanied by criticisms that proponents of the other methods might make. The key to these criticisms lies primarily in whether hypothetical information is added to or substantiated information is omitted from the assembled information concerning the system under investigation. In certain contexts the bayesian approach makes an arbitrary but typically consistent choice of input to its analyses; it is not the input suggested by standard invariance analysis. In those cases where a variation-response model is appropriate, the use of this more embracing model presents theoretical support for the bayesian choice (Section 8); but of course with the more embracing model the bayesian premises are not needed to obtain the usual bayesian result. An example in Section 9 illustrates the theoretical simplicity of classical probabilities for certain unknowns other than realized values on a probability space.
An Analogue, for Signed Rank Statistics, of Jureckova's Asymptotic Linearity Theorem for Rank Statistics
Constance van Eeden
Ann. Math. Statist. 43 (3), 791-802, (June, 1972) DOI: 10.1214/aoms/1177692545
Sequential Estimation of a Poisson Integer Mean
George P. McCabe Jr.
Ann. Math. Statist. 43 (3), 803-813, (June, 1972) DOI: 10.1214/aoms/1177692546
Let X 1 , X 2 , ⋯ X 1 , X 2 , ⋯be a sequence of i.i.d. Poisson random variables with mean λ λ. It is assumed that true value of the parameter λ λlies in the set { 0 , 1 , 2 , ⋯ } { 0 , 1 , 2 , ⋯ }. From observations on the sequence it is desired to estimate the true value of the parameter with a uniformly (for all λ λ) small probability of error. There is no fixed sample size rule which can accomplish this. A sequential procedure based on a likelihood ratio criterion is investigated. The procedure, which depends on a parameter α > 1 α > 1, is such that (i) P λ P λ(error) < 2 / ( α − 1 ) < 2 / ( α − 1 )for all λ λ, and (ii) E λ E λsample size) ∼ k λ log α ∼ k λ log α, as α → ∞ α → ∞, where k λ = ( 1 − λ log ( 1 + 1 / λ ) ) − 1 k λ = ( 1 − λ log ( 1 + 1 / λ ) ) − 1. The procedure is asymptotically optimal as α → ∞ α → ∞.
On a Class of Subset Selection Procedures
Shanti S. Gupta , S. Panchapakesan
Ann. Math. Statist. 43 (3), 814-822, (June, 1972) DOI: 10.1214/aoms/1177692547
A class of procedures is considered for the subset selection problem when the populations are from a stochastically increasing family { F λ } { F λ }. A theorem concerning the monotonicity of an integral associated with { F λ } { F λ }which generalizes an earlier result of Lehmann is obtained. This leads to a sufficient condition for the monotonicity of the probability of a correct selection for the procedure considered. It is shown that this condition is relevant to another sufficient condition for the supremum of the expected subset size to occur when the distributions are identical. The main results are applied to the specific cases where (i) λ λis a location parameter (ii) λ λis a scale parameter and (iii) the case where the density f λ ( x ) f λ ( x )is a convex mixture of a sequence of known density functions. The earlier known results are shown to follow from the general theory.
Locally Most Powerful Rank Tests for the Two-sample Problem with Censored Data
Richard A. Johnson , K. G. Mehrotra
Ann. Math. Statist. 43 (3), 823-831, (June, 1972) DOI: 10.1214/aoms/1177692548
Weak Convergence of Weighted Empirical Cumulatives Based on Ranks
Hira Lal Koul , Robert G. Staudte Jr.
Ann. Math. Statist. 43 (3), 832-841, (June, 1972) DOI: 10.1214/aoms/1177692549
The weak convergence of weighted empirical cumulatives based on the ranks of independent, not necessarily identically distributed, observations to a continuous Gaussian process is proved. The results contain a shorter proof of a central limit theorem by Dupac and Hajek (1969) Ann. Math. Statist. Analogous results are proved for signed rank processes.
Some Asymptotic Results on Random Rank Statistics
Hira Lal Koul
Ann. Math. Statist. 43 (3), 842-859, (June, 1972) DOI: 10.1214/aoms/1177692550
This paper deals with two different problems. The first one deals with asymptotic normality of simple linear rank statistics based on random number of observations X i X i, henceforth called random rank statistics, under the alternative where each X i X ihas a different distribution F i F i. The second problem deals with showing that the random rank statistics as a function of the regression parameter in the simple linear regression model is asymptotically uniformly linear (hence continuous) in that parameter. Obviously the two problems are different and could be solved in separate papers but for certain lemmas which are common to the solution of both of these problems. It is suggested not to try to apply the result of Section 3 to Section 4, unless mentioned explicitly. The results of Section 2 are the results which are common, to some extent, to the solution of these two problems. Pyke and Schorack [11] proved asymptotic normality of a class of two sample random rank statistics under two sample alternatives. Our theorem 3.1 could be thought of as a generalization of the result of [11] to more than two samples situation. Our score function φ φis in smaller class than that of [11]. On the other hand our methods yield the asymptotic normality for random rank-sign statistics. This is also contained in Section 3. Section 2 proves a basic lemma about weak convergence of random weighted empirical cumulatives to a tied down continuous Gaussian process. In [5] and [7] asymptotic uniform linearity of rank statistics based on nonrandom number of observations was proved. In [5] conditions are very general on φ φand underlying distribution F Fwhereas conditions in [7] are quite stringent. But in [7] we do not need any artificial condition like (2.1) of [5] on underlying regression constants. However in both of these references, regression scores were assumed to be bounded. In Section 4 here we extend the results of [7] to random rank and random rank-sign statistics and to the case where regression scores need not be bounded. In Section 5 we show how the results of Section 4 can be used to construct a bounded length confidence interval for a regression parameter using rank sign statistics with asymptotic (as length → 0 → 0) coverage probability achieved. Apart from applying Theorem 3.1 to the i.i.d. case, as is mentioned in the remark at the end of Section 5, it is hoped that Theorem 3.1 can be found applicable in some other interesting situations.
Unbiased Coin Tossing with Discrete Random Variables
Meyer Dwass
Ann. Math. Statist. 43 (3), 860-864, (June, 1972) DOI: 10.1214/aoms/1177692551
Hoeffding and Simons (Ann. Math. Statist. (1970) 341-352) show how to convert a sequence of i.i.d. indicator random variables with parameter p pinto such a sequence with parameter p = 1 2 p = 1 2. In the present paper an extension is made to generating sequences of i.i.d. indicator random variables with parameter p = 1 2 p = 1 2from arbitrary sequences of i.i.d. discrete random variables. Also considered is the generating of sequences of i.i.d. r r-valued, equiprobable random variables. Some optimality criteria are established.
The Efficient Construction of an Unbiased Random Sequence
Peter Elias
Ann. Math. Statist. 43 (3), 865-870, (June, 1972) DOI: 10.1214/aoms/1177692552
We consider procedures for converting input sequences of symbols generated by a stationary random process into sequences of independent, equiprobable output symbols, measuring the efficiency of such a procedure when the input sequence is finite by the expected value of the ratio of output symbols to input symbols. For a large class of processes and a large class of procedures we give an obvious information-theoretic upper bound to efficiency. We also construct procedures which attain this bound in the limit of long input sequences without making use of the process parameters, for two classes of processes. In the independent case we generalize a 1951 result of von Neumann and 1970 results of Hoeffding and Simons for independent but biased binary input, gaining a factor of 3 or 4 in efficiency. In the finite-state case we generalize a 1968 result of Samuelson for two-state binary Markov input, gaining a larger factor in efficiency.
A Bernoulli Two-armed Bandit
Donald A. Berry
Ann. Math. Statist. 43 (3), 871-897, (June, 1972) DOI: 10.1214/aoms/1177692553
One of two independent Bernoulli processes (arms) with unknown expectations ρ ρand λ λis selected and observed at each of n nstages. The selection problem is sequential in that the process which is selected at a particular stage is a function of the results of previous selections as well as of prior information about ρ ρand λ λ. The variables ρ ρand λ λare assumed to be independent under the (prior) probability distribution. The objective is to maximize the expected number of successes from the n nselections. Sufficient conditions for the optimality of selecting one or the other of the arms are given and illustrated for example distributions. The stay-on-a-winner rule is proved.
The Determination of Likelihood and the Transformed Regression Model
D. A. S. Fraser
Ann. Math. Statist. 43 (3), 898-916, (June, 1972) DOI: 10.1214/aoms/1177692554
The traditional model of statistics is a class of probability measures for a response variable. Under reasonable continuity this can be given as a class C Cof probability density functions relative to an atom-free measure. With a realized value of the response variable, the model C Cgives the possible probabilities for that realized value--it gives the likelihood function. The likelihood function can be accepted alone or in conjunction with the distribution of possible likelihood functions. In a variety of applications, the variation in a response variable can be traced to a well-defined source having a known probability distribution. The model then is not a class of probability measures but is a single probability measure and a class of random variables. Under moderate conditions this can be given as a probability density function and a class C 2 C 2of transformations from the variation space to the response space. And if the distribution for variation is not completely known, the model becomes a class C 1 C 1of probability density functions and a class C 2 C 2of transformations from the variation space to the response space. With an observed response value, the component C 2 C 2identifies a set, the set of possible values for the realized variation. If C 2 C 2is a transformation group, then C 2 C 2identifies a set--in a partition on the variation space. Standard probability argument using C 1 C 1then gives the probability of what has been "observed," and the conditional distribution of what has not been "observed": it gives the likelihood function from the identified set, and the conditional density within the identified set. The likelihood function alone or with its distribution gives the information concerning the parameter of C 1 C 1; and for any assumed value of that parameter the conditional density gives the information concerning possible values for the realized variation, and accordingly gives the information concerning the parameter of C 2 C 2, it being what stands between the realized variation and the observed response. The probability of what is identified as having occurred--the likelihood function--is a fundamental output of a model involving density functions. The determination of this probability can however involve certain complexities as soon as the class C 2 C 2of random variables is no longer effectively a group. Certainly the class C 2 C 2identifies a set on the variation space. But in moderately general cases the range of alternatives can be a partition on the variation space depends on the element of C 2 C 2. Thus an e v e n t ' i s i d e n t if i e d b u t t h e r a n ≥ o f p o s s i b ≤ e v e n t ′ i s i d e n t if i e d b u t t h e r a n ≥ o f p o s s i b ≤events' depends on the parameter of C 2 C 2. For two kinds of generalized model ( C 1 , C 2 ) ( C 1 , C 2 )this paper explores the determination of the probability of what is identified as having occurred--it explores the determination of the likelihood function. In Section 1 the notation and results are summarized for the special model ( C 1 , C 2 ) ( C 1 , C 2 )with C 2 C 2a transformation group. Two generalizations are examined in Section 2: first, the class C 2 C 2is a group but its application as a transformation group has an additional parameter; second, the class C 2 C 2is a class of expression transformations L Lapplied to a group of transformations G G, i.e. C 2 = L G C 2 = L G. These two generalizations are not as distinct as they may at first appear but they are quite distinct in contexts. The transformed regression model is the central example. Several formulas for volume change in subspaces are recorded in Section 3 and used in Section 4 to make four determinations of likelihood for the generalized model ( C 1 , C 2 ) ( C 1 , C 2 ). These are applied to the transformed regression model in Section 5 and compared by means of examples in Section 6. The effects of initial variable on the likelihood functions is examined in Section 7 and two compensating routes for analysis are proposed. The class L Lof expression transformations is examined in Section 8 and shown to be a group under mild consistency conditions. A corresponding invariant likelihood is determined in Section 9, and a transit likelihood in Section 10; the power-transformed regression model is examined in Section 11. In Section 12 the transit likelihood is shown to be the natural likelihood when the semi-direct product L G L Gis itself a group.
Subjective Expected Utility with Mixture Sets and Boolean Algebras
Peter C. Fishburn
Ann. Math. Statist. 43 (3), 917-927, (June, 1972) DOI: 10.1214/aoms/1177692555
No abstract available
On Subjective Probability and Expected Utilities
Pedro E. Ferreira
Ann. Math. Statist. 43 (3), 928-933, (June, 1972) DOI: 10.1214/aoms/1177692556
The Anscombe and Aumann double relation approach for defining subjective probabilities and utilities in terms of a person's preferences is generalized for the case in which the set of states of the world is unrestricted (finite or not). A monotone continuity condition enables us to prove σ σ-additivity; the necessity of this condition is also proved if our other assumptions hold. Although the single relation approach used by Fishburn appears to be more elegant, the present approach has the advantage of showing how the subjective probabilities arise.
Convergence Rates for Empirical Bayes Two-Action Problems II. Continuous Case
M. V. Johns Jr. , J. Van Ryzin
Ann. Math. Statist. 43 (3), 934-947, (June, 1972) DOI: 10.1214/aoms/1177692557
For a general discussion of empirical Bayes problems and motivation of the present paper see Section 1 of the previous paper [1]. In that paper we studied the convergence to Bayes optimality and its rate properties for empirical Bayes two-action problems in certain discrete exponential families. This paper continues that investigation for the continuous case. Under appropriate conditions, Theorems 3 and 4 yield convergence rates to Bayes risk of O ( n − β ) O ( n − β )for 0 < β < 1 0 < β < 1, for the ( n + 1 ) s t ( n + 1 ) s tstage risk of the continuous case empirical Bayes procedures of Section 2. These theorems provide, for the continuous case, convergence rate results for the empirical Bayes procedures of the general type considered by Robbins [5] and Samuel [6] for two different parameterizations of a model. The rate results given here in the continuous case involve upper bounds and are weaker than the discrete case results in [1] wherein exact rates are reported. Specifically, in Section 2 we present the two cases to be considered and define the appropriate empirical Bayes procedures for each. Section 3 gives some technical lemmas and Section 4 establishes the asymptotic optimality (the asymptotic Bayes property) of the procedures introduced. The main results on rates, Theorems 3 and 4, are given in Section 5. Section 6 examines in detail two specific examples--the negative exponential and the normal distributions--and gives corollaries to Theorems 3 and 4 which state convergence rates depending on moment properties of the unknown prior distribution of the parameters. Section 7 gives an example with β βarbitrarily close to 1 in the rate O ( n − β ) O ( n − β ). The model we consider is the following. Let f λ ( x ) f λ ( x )be a family of Lebesgue densities indexed by a parameter λ λin an interval of the real line. As in [1], we wish to test the hypothesis H 1 : λ ≦ c v s . H 2 : λ > c H 1 : λ ≦ c v s . H 2 : λ > cwith the loss function being L 1 ( λ ) = 0 if λ ≦ c = b ( λ − c ) if λ > c L 2 ( λ ) = b ( c − λ ) if λ ≦ c = 0 if λ > c L 1 ( λ ) = 0 if λ ≦ c = b ( λ − c ) if λ > c L 2 ( λ ) = b ( c − λ ) if λ ≦ c = 0 if λ > cwhere L i ( λ ) L i ( λ )indicates the loss when action i i(deciding in favor of H i H i) is taken, i = 1 , 2 i = 1 , 2and b bis a positive constant. Let δ ( x ) = P r { accepting H 1 ∣ X = x } δ ( x ) = P r { accepting H 1 ∣ X = x }be a randomized decision rule for the above two-action problem. If G = G ( λ ) G = G ( λ )is a prior distribution on λ λ, then the risk of the (randomized) decision procedure δ δunder prior distribution G Gis given as in [1] by, r ( δ , G ) = ∫ ∫ { L 1 ( λ ) f λ ( x ) δ ( x ) + L 2 ( λ ) f λ ( x ) ( 1 − δ ( x ) ) } d x d G ( λ ) = b ∫ α ( x ) δ ( x ) d x + C G (1) (1) r ( δ , G ) = ∫ ∫ { L 1 ( λ ) f λ ( x ) δ ( x ) + L 2 ( λ ) f λ ( x ) ( 1 − δ ( x ) ) } d x d G ( λ ) = b ∫ α ( x ) δ ( x ) d x + C Gwhere C G = ∫ L 2 ( λ ) d G ( λ ) C G = ∫ L 2 ( λ ) d G ( λ )and α ( x ) = ∫ λ f λ ( x ) d G ( λ ) − c f ( x ) (2) (2) α ( x ) = ∫ λ f λ ( x ) d G ( λ ) − c f ( x )with f ( x ) = ∫ f λ ( x ) d G ( λ ) . (3) (3) f ( x ) = ∫ f λ ( x ) d G ( λ ) .From (1) it is clear that a Bayes rule (the minimizer of (1) given G G) is δ G ( x ) = 1 if α ( x ) ≦ 0 = 0 if α ( x ) > 0. (4) (4) δ G ( x ) = 1 if α ( x ) ≦ 0 = 0 if α ( x ) > 0.Hence, the minimal attainable risk knowing G G(the Bayes risk) is r ∗ ( G ) = inf δ r ( δ , G ) = r ( δ G , G ) . (5) (5) r ∗ ( G ) = inf δ r ( δ , G ) = r ( δ G , G ) .
On Mixture, Quasi-mixture and Nearly Normal Random Processes
R. D. Martin , S. C. Schwartz
Ann. Math. Statist. 43 (3), 948-967, (June, 1972) DOI: 10.1214/aoms/1177692558
The properties of both a mixture random process, specified by the multi-dimensional simple mixtures, ^ F ( x 1 , x 2 , ⋯ , x n ) = a 1 F 1 ( x 1 , x 2 , ⋯ , x n ) + a 2 F 2 ( x 1 , x 2 , ⋯ , x n ) , a 1 + a 2 = 1 F ^ ( x 1 , x 2 , ⋯ , x n ) = a 1 F 1 ( x 1 , x 2 , ⋯ , x n ) + a 2 F 2 ( x 1 , x 2 , ⋯ , x n ) , a 1 + a 2 = 1, and a related quasi-mixture process are investigated. It is shown that if the set of random variables of the component cdf's (cumulative distribution functions) are independent, then the random variables of the resulting mixture are independent if and only if the mixture cdf ^ F F ^is degenerate. The quasi-mixture process, on the other hand, does have the property that factorization of the component cdf's implies factorization of the resulting mixture cdf. Specializing to the case of Gaussian cdf's, it is further shown that the GMP (Gaussian Mixture Process) never satisfies the strong mixing condition, while with reasonable assumptions on the component correlation functions the GQMP (Gaussian Quasi-Mixture Process) does satisfy the strong mixing condition. These, and other properties of the resulting mixture cdf's are of importance when mixture processes are used as models in various estimation and hypothesis testing problems. Some examples are also given for generating GMP and GQMP processes.
Central Limit Theorems for Sums of Dependent Vector Variables
W. J. Cocke
Ann. Math. Statist. 43 (3), 968-976, (June, 1972) DOI: 10.1214/aoms/1177692559
We prove the following central limit theorems for sums of mutually dependent random vector variables: Given that a sequence of random vector variables satisfies a certain type of decoupling condition (and two milder restrictions), we present a Lindeberg-Feller condition which we show to be both necessary and sufficient for central limit behavior. The decoupling condition and one of the two milder conditions is then applied to a Markov process with stationary transition mechanism.
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On the Variance of the Number of Zeros of a Stationary Gaussian Process
Donald Geman
Ann. Math. Statist. 43 (3), 977-982, (June, 1972) DOI: 10.1214/aoms/1177692560
For a real, stationary Gaussian process X ( t ) X ( t ), it is well known that the mean number of zeros of X ( t ) X ( t )in a bounded interval is finite exactly when the covariance function r ( t ) r ( t )is twice differentiable. Cramer and Leadbetter have shown that the variance of the number of zeros of X ( t ) X ( t )in a bounded interval is finite if ( r " ( t ) − r " ( 0 ) ) / t ( r " ( t ) − r " ( 0 ) ) / tis integrable around the origin. We show that this condition is also necessary. Applying this result, we then answer the question raised by several authors regarding the connection, if any, between the existence of the variance and the existence of continuously differentiable sample paths. We exhibit counterexamples in both directions.
A Consistent Estimation of Kernel Functions in the Multiple Wiener Integrals
Won Joon Park
Ann. Math. Statist. 43 (3), 983-987, (June, 1972) DOI: 10.1214/aoms/1177692561
A Matrix Occupancy Problem
Patrick J. Eicker , M. M. Siddiqui , Paul W. Mielke Jr.
Ann. Math. Statist. 43 (3), 988-996, (June, 1972) DOI: 10.1214/aoms/1177692562
Stationary Measures for a Class of Storage Models Driven by a Markov Chain
R. V. Erickson
Ann. Math. Statist. 43 (3), 997-1007, (June, 1972) DOI: 10.1214/aoms/1177692563
A storage model in which the growth rate is proportional to the level of the dam plus a factor, both proportionality constant and factor depending on a finite Markov chain, is shown to be a Hunt process. Hitting distributions are shown to satisfy certain integral equations, communicating and recurrence classes are studied, and stationary measures are shown to exist when the dam is finite and the level has at least one recurrent linear growth phase, and in some other cases as well.
Short Communications
A Note on the Zero-one Law
Julius R. Blum , Pramod K. Pathak
Ann. Math. Statist. 43 (3), 1008-1009, (June, 1972) DOI: 10.1214/aoms/1177692564
Let M = { μ n : n ≧ 1 } M = { μ n : n ≧ 1 }be a sequence of probability measures defined on the measurable space ( R n , B n ) ( R n , B n )and suppose that the measures { μ n : n ≧ 1 } { μ n : n ≧ 1 }satisfy the following condition ( B ) : ∀ ε > 0 , k ≧ 1 ( B ) : ∀ ε > 0 , k ≧ 1and m ≧ 1 m ≧ 1, there exists an n ≧ m n ≧ msuch that ∥ μ k − μ n ∥ < ε ‖ μ k − μ n ‖ < ε. We show that if A ∈ × ∞ 1 B n A ∈ × 1 ∞ B nand if A Ais permutation invariant then μ ( A ) = 0 μ ( A ) = 0or 1. The zero-one laws of Hewitt and Savage [Trans. Amer. Math. Soc. 80 (1955) 470-501] and Horn and Schach [Ann. Math. Statist. 41 (1970) 2130-2131] follow as special cases of our result.
A Generalization of the Weak Version of the Glivenko-Cantelli Theorem
Jonathan Shuster
Ann. Math. Statist. 43 (3), 1010-1011, (June, 1972) DOI: 10.1214/aoms/1177692565
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Moments of Oscillations and Ruled Sums
Howard H. Stratton
Ann. Math. Statist. 43 (3), 1012-1016, (June, 1972) DOI: 10.1214/aoms/1177692566
A Note on Approachability in a Two-person Game
Harold Sackrowitz
Ann. Math. Statist. 43 (3), 1017-1019, (June, 1972) DOI: 10.1214/aoms/1177692567
Riesz Decomposition for Weak Banach-Valued Quasi-Martingales
Zoran R. Pop-Stojanovic
Ann. Math. Statist. 43 (3), 1020-1026, (June, 1972) DOI: 10.1214/aoms/1177692568
Irreducible Markov Shifts
R. L. Adler , P. Shields , M. Smorodinsky
Ann. Math. Statist. 43 (3), 1027-1029, (June, 1972) DOI: 10.1214/aoms/1177692569
A Remark on Quadratic Mean Differentiability
Bruce Lind , George Roussas
Ann. Math. Statist. 43 (3), 1030-1034, (June, 1972) DOI: 10.1214/aoms/1177692570
Back Matter
Ann. Math. Statist. 43 (3), (June, 1972)
| https://www.projecteuclid.org/journals/annals-of-mathematical-statistics/volume-43/issue-3 |
Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria | The BMJ
Papers
Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria
BMJ
1999
;
319
doi: https://doi.org/10.1136/bmj.319.7201.24
(Published 03 July 1999)
Cite this as: BMJ 1999;319:24
Article
Metrics
Elisabeth R Mathiesen , consultant ( [email protected] ) ,
Henrik P Hansen , research fellow ,
Ulla M Smidt , laboratory technician ,
Hans-Henrik Parving , professor
Author affiliations
Steno Diabetes Center, DK 2860 Gentofte, Copenhagen, Denmark
Correspondence to: Dr E R Mathiesen, Medical Endocrine Department, University Hospital of Copenhagen, Rigshospitalet, 2100 Copenhagen Ø, Denmark
Accepted 31 December 1998
In patients with insulin dependent diabetes, angiotensin converting enzyme inhibition delays the progression from microalbuminuria to diabetic nephropathy, but previous studies have been too short to show a preservation of kidney function.1 –3We assessed the effectiveness of angiotensin converting enzyme inhibition on preservation of kidney function in an 8 year prospective, randomised controlled trial.
Patients, methods, and results
Forty four normotensive patients with insulin dependent (type I) diabetes and persistent microalbuminuria (30-300 mg/24 h) were enrolled as previously described in detail.1The treatment group (n=21) was given captopril (100 mg/24 h) and bendrofluazide (2.5 mg/24 h). The 23 remaining patients were left untreated. Diabetic nephropathy was defined as albuminuria persistently >300 mg/24 h. Glomerular filtration rate was measured annually with Crom EDTA plasma clearance over 4 hours.1
After 4 years two patients in each group were excluded because they did not attend follow up sessions. Four of the patients in the control group started antihypertensive treatment with diuretics, βblockers, or a calcium channel blocker. Three patients in the treatment group were changed from bendrofluazide to frusemide because of oedema or diastolic blood pressure >95 mm Hg. After 8 years 16 of the 21 patients in the treatment group and two patients from the control group were subsequently investigated after a treatment pause of 2 months.
The proportion of patients who progressed to diabetic nephropathy was 40% (9/23) in the control group and 10% (2/21) in the captopril group (survival analysis P=0.019). In the captopril group there was a significant increase in urinary albumin excretion (P<0.001) during the treatment pause. In six (38%) of the 16 patients albuminuria exceeded 300 mg/24 h.
Glomerular filtration rate in the captopril group declined from 126 (24) at baseline to 114 (23) ml/min after 8 years but rose again to 126 (21) during the pause in treatment (table). Follow up values of glomerular filtration rate measured during the treatment pause were therefore used whenever available. The decline in mean glomerular filtration rate (ml/min) was 11.8 (95% confidence interval 1.2 to 22.0; t test P value 0.03) and 1.4 (−4.9 to 7.7; P=0.65) in the control and captopril group, respectively (P=0.09 between the groups). The fall in glomerular filtration rate during the 8 year study period in the eight control patients who developed nephropathy was 27.3 (3.7 to 51.0; P=0.03) while glomerular filtration rate increased by 3.8 (−3.5 to 11.0) in the six patients treated with captopril with urinary albumin excretion >300 mg/24 h during the treatment pause (P=0.02 between the groups). Haemoglobin A1c and blood pressure did not differ between the two groups at any time during the study.
Mean glomerular filtration rates (ml/min) in normotensive patients with insulin dependent diabetes at baseline, after 8 years' follow up, and during pause in treatment in captopril and control groups
Comment
Our study has shown that the beneficial effect of angiotensin converting enzyme inhibition in the prevention of diabetic nephropathy is long lasting and associated with preservation of normal glomerular filtration rate. To obtain a valid determination of the rate of decline in glomerular filtration rate the applied glomerular filtration rate method should have a good accuracy and precision and the observation period should exceed 2 years.4These requirements have been fulfilled in our study in contrast with previous studies.2 –3The second part of the study showed a return in glomerular filtration rate to the values before treatment after 2 months of withdrawal of antihypertensive treatment. The temporary fall in glomerular filtration rate in the intervention group was therefore regarded as a reversible haemodynamic phenomenon. Patients with persistent microalbuminuria at follow up had a stable normal glomerular filtration rate.5The clinically significant effect of angiotensin converting enzyme inhibition on preservation of normal glomerular filtration rate was related to prevention of progression from microalbuminuria to diabetic nephropathy in patients with insulin dependent diabetes.
Acknowledgments
Contributors: HHP had the original idea for the study. ERM and HHP were responsible for conducting the study and interpreting the results and are guarantors. ERM and EH conducted the clinical evaluation during the 8 years of study. HPH and ERM conducted the clinical evaluation during the treatment pause. UMS performed the assessments of glomerular filtration rate. All authors participated in the interpretation of the results and reporting.
Footnotes
FundingERM was funded by a senior research fellowship from the University of Copenhagen. Steno Diabetes Center supplied us with equipment for glomerular filtration analysis and laboratory tests. Squibb donated the tablets and a 1 month research fellowship for ERM.
Competing interestsNone declared.
Reference
1.
↵
Mathiesen ER ,
Hommel E ,
Giese J ,
Parving H-H
. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria . BMJ 1991 ; 303 : 210 – 216 .
2.
↵
Viberti G ,
Mogensen CE ,
Groop LC ,
Pauls JF
. Effect of captopril on progression to clinical proteinuria in patients with insulin dependent diabetes mellitus and microalbuminuria . JAMA 1994 ; 271 : 275 – 279 .
3.
↵
Laffel LMB ,
Gans DJ
. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria . Am J Med 1995 ; 99 : 497 – 504 .
4.
↵
Levey AS ,
Gassman J ,
Hall PM ,
Walker WG
. Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean . J Am Soc Nephrol 1991 ; 1 : 1087 – 1094 .
5.
↵
Mathiesen ER ,
Feldt-Rasmussen B ,
Hommel E ,
Deckert T ,
Parving H-H
. Stable glomerular filtration rate in normotensive IDDM patients with stable microalbuminuria: a 5 year prospective study . Diabetes Care 1997 ; 20 : 286 – 289 .
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Mechanics, Planning, and Control for Tapping | Request PDF
Request PDF | Mechanics, Planning, and Control for Tapping | We present analysis and experimental demonstration of manipulation by tapping. Our problem domain is positioning planar parts on a support surface... | Find, read and cite all the research you need on ResearchGate
October 2000 The International Journal of Robotics Research 19(10):883-894
DOI: 10.1177/02783640022067841
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Wesley H. Huang
Wesley H. Huang
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Carnegie Mellon University
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References (34)
Abstract
We present analysis and experimental demonstration of manipulation by tapping. Our problem domain is positioning planar parts on a support surface by a sequence of taps; each tap imparts some initial velocities to the object, which then slides until it comes to rest due to friction. We formulate the mechanics of tapping for circular axisymmetric objects, show how to plan a single tap and a sequence of taps to reach a goal configuration, and present feedback control methods to robustly accomplish positioning tasks. With these methods, we have experimentally demonstrated positioning tasks using tapping, including high-precision positioning tasks in which the object is positioned more precisely than the tapping actuator. We show stability and sensitivity analysis in support of these results.
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... Let us consider the manipulation system in Fig. 8, which is a simple example of impulsive manipulation
(Huang & Mason, 2000;
Spong, 2001;Zhu, Aiyama, Arai, & Kawamura, 2005) (the systems in Figs. 3(b) and 5 can also be used on that purpose). ...
... This shows the fundamental influence of the interaction force in the overall control problem. This problem is close to impulsive or release manipulation tasks
(Huang & Mason, 2000;
Zhu et al., 2005). ...
... Impulsive controllers design boils down to design as a Dirac measure, or an approximation of it (Francois & Samson, 1998) (thus it is not to be confused with impulsive manipulation which consists of striking objects to send them at a desired position/orientation
(Huang & Mason, 2000;
Spong, 2001;Zhu et al., 2005)). It shares with slidingmode control and dead-beat control some finite-time properties. ...
Modeling, analysis and control of robot-object nonsmooth underactuated Lagrangian systems: A tutorial overview and perspectives Article
Dec 2022 ANNU REV CONTROL
Bernard Brogliato
So-called robot–object Lagrangian systems consist of a class of nonsmooth underactuated complementarity Lagrangian systems, with a specific structure: an “object” and a “robot”. Only the robot is actuated. The object dynamics can thus be controlled only through the action of the contact Lagrange multipliers, which represent the interaction forces between the robot and the object. Juggling, walking, running, hopping machines, robotic systems that manipulate objects, tapping, pushing systems, kinematic chains with joint clearance, crawling, climbing robots, some cable-driven manipulators, and some circuits with set-valued nonsmooth components, belong this class. This article aims at presenting their main features, then many application examples which belong to the robot–object class, then reviewing the main tools and control strategies which have been proposed in the Automatic Control and in the Robotics literature. Some comments and open issues conclude the article.
View Show abstract
... Impulse-based manipulation is an area in robotics where very little work
[6,
14] is known. An impulsive force has very short execution time, and thus good potential for improving task efficiency. ...
... Instead of computing u and w, we keep track of √ 2k 0 u and √ 2k 0 w by updating D, without any knowledge about k 0 . The update of D is possible because v ⊥ is from the contact kinematics, and E n is by (6)
. The values of α and β in (10) are immediately known from the signs of D ·û and D ·ŵ. ...
... When the contact slips, equation (19) holds. We substitute the spring energies E u and E w from (6)
in and obtain, by the use of (4), ...
Energy-Based Modeling of Tangential Compliance in 3Dimensional Impact
Article Full-text available
Jan 2010
Yan-Bin Jia
This paper studies modeling of tangential compliance as two rigid bodies collide in the space. Stronge’s spring-based contact
structure [13, pp. 95-96] is extended to three dimensions. Slip or stick is indicated by the tangential motion of a massless
particle connected to the contact point (viewed as an infinitesimal region) on one body via three orthogonal springs. We show
that the effect of tangential compliance can be analyzed using normal impulse rather than time, contrary to a previous claim
by Stronge. This is primarily due to the ability of updating the elastic energies of the three springs without knowledge of
their stiffnesses or length changes. The change rates, nevertheless, are computable. So are sliding velocity and tangential
impulse. The latter is then integrated into impact equations and contact kinematics, making the whole system driven by normal
impulse alone. Examples include a ball and a pencil bouncing on a table, and a massé billiard shot. The theory has potential
impact on impulsive robotic manipulation in which the ability to deal with friction and compliance is vital for skillful maneuvers.
View Show abstract
... Our experimental implementation of the improved algorithm is described in Section 4. Our analysis builds upon our previous work in the mechanics , planning, and control for using tapping as a mode of manipulation, e.g. Huang [7] and Huang and Mason [9]
. In turn, the foundation of this earlier work is the study of sliding objects by Goyal et al. [5] and Voyenli and Erik- sen [12]. ...
... In this section, we briefly summarize relevant properties of the mechanics of tapping. The interested reader can consult Huang and Mason [9]
for further details. We consider the classical model of two-dimensional impact with friction; we use Routh's method as presented by Wang and Mason [13]. ...
... These stem from the fact that the net force and torque on the object are functions of the velocity ratio, ω v , rather than functions of the rotational and translational velocities themselves. Again, we simply state the following properties of the sliding mechanics; the interested reader can consult Huang and Mason [9]
@BULLET The ratio of rotation to translation w = r d , as a function of the ratio of initial velocities ω0 v0 is monotonic increasing. ...
Control strategies for fine positioning via tapping
Conference Paper
Aug 2003
W.H. Huang
There are many industrial tasks that require fine positioning, for example: parts feeding, subassembly alignment, and certain inspection tasks. In this paper, we describe an approach to positioning parts or subassemblies on a support surface by tapping them. We have built a "positioning cell" where an object placed in this cell is positioned and oriented by a number of "tapping actuators" placed about the perimeter. When fired, a tapping actuator strikes the object producing translational and rotational velocities. The object then slides and comes to rest due to friction. An overhead camera provides feedback on the part configuration. This paper presents a control strategy for this task, describes our hardware, and shows our experimental results.
View Show abstract
... He solved this manipulation as two problems; the inverse sliding problem which finds an initial kinematic condition to send the object to a desired position, and the impact problem to find a strike that achieves the condition. Huang et al. [4]
also researched a tapping mechanism which is one particular form of impulsive manipulation. This work suggests a planning method to position a rotationally symmetric object with multiple tapping. ...
... If the object shape is rotationally symmetrical, the search domain is monotonic, therefore relatively simple search methods can be applied. However if the object is of a nonsymmetrical shape, the search domain may be nonmonotonic and therefore advanced search methods are needed to find the global optimum
[4]
. In this manipulation method, the initial conditions consist of the force and torque that need to be applied on the object. ...
... In this manipulation method, the initial conditions consist of the force and torque that need to be applied on the object. The inverse sliding problem can be solved using the same method as in [3] [4]
. However the inverse sliding solutions may not be applicable for precision positioning because the equation of motion uses simplified friction model and object shape. ...
Micromanipulation using a friction force field
Conference Paper
Feb 2001
Jeongsik Sin T. Winther H. Stephanou
Most common requirements for micromanipulation are high precision, parallel manipulation, cost, etc. In this paper, we examine a manipulation method that may be useful for these requirements. The presented method uses an actively generated friction force field as a driving force of manipulation, and the method can have several actuation modes depending on the sliding condition of the friction force field. Planar dynamics regarding the proposed method were analyzed, and the design of the force field was investigated.
View Show abstract
... Relatively little work exists on impact planning, despite some noticeable efforts on impulsive manipulation [7], [14], [3], [5]
, and [13]. Impact-based modeling was also used to determine the orientation of an object after bring dropped on a surface [10]. ...
... At time 0, the polygon is located at (1.9, 0.9) T . Impact happens 5
Negative energy is obtained due to potential energy being relative to the zero value of J1 6 Its six vertices about the origin are (−0.07, 0.0), (−0.05, 0.06), (0.0, 0.08), (0.06, 0.02), (0.03, −0.04), and (−0.01, 0.0). ...
Batting flying objects to the target in 2D
Conference Paper Full-text available
Oct 2016
Matthew Gardner Yan-Bin Jia Huan Lin
View
... Parts with simple geometry floating on an air table can be sorted by hitting them with a rotating stick (Hirai et al. 1999). A part can be struck only once (Han and Park 2001) or tapped repetitively (Huang and Mason 2000)
to reach a desired configuration, by imparting initial velocities calculated through analyses of impacts and the part's post-impact sliding motions. For space robots, collisions are inevitable either with other free-floating objects (Yoshida and Nenchev 1995) or from landing on other planets, either inside spacecraft or by themselves. ...
... Such an amount could not be provided by contact friction alone or generated under Poisson's hypothesis.
26
10 Discussion and Future Work ...
Multiple impacts: A state transition diagram approach
Article Full-text available
Jan 2013
Michael A. Erdmann Yan-Bin Jia
Matthew T. Mason
Impact happens when two or more bodies collide, generating very large impulsive forces in a very short period of time during which kinetic energy is first absorbed and then released after some loss. This paper introduces a state transition diagram to model a frictionless multibody collision. Each state describes a different topology of the collision characterized by the set of instantaneously active contacts. A change of state happens when a contact disappears at the end of restitution, or when a disappeared contact reappears as the relative motion of two bodies goes from separation into penetration. Within a state, (normal) impulses are coupled differentially subject to relative stiffnesses at the active contact points and the strain energies stored there. Such coupling may cause restart of compression from restitution during a single impact. Impulses grow along a bounded curve with first-order continuity, and converge during the state transitions. To solve a multibody collision problem with friction and tangential compliance, the above impact model is integrated with a compliant impact model. The paper compares model predictions to a physical experiment for the massé shot, which is a difficult trick in billiards, with a good result.
View Show abstract
... This work builds upon our previous work on the mechanics , planning, and control for using tapping as a mode of manipulation (Huang and Mason [7,
6]). The foundation of this work lies in the study of friction and impact. ...
... The basis of this work is the mechanics of tapping which can be found in our previous work, e.g. Huang and Mason [7]
. Here, we adapt it to the situation where the tapping actuators have fixed position and orientation. ...
Tapping micropositioning cell
Conference Paper
Feb 2000
Wesley H. Huang
Describes the use of tapping actuators in a
“micropositioning cell.” Tapping actuators are fixed (both
in position and orientation) about the perimeter of the cell. A part in
the cell can be precisely positioned by firing a sequence of tapping
actuators (sensing the position of the object after each tap for
feedback control). Such a system could be used for micropositioning
tasks or in parts feeding applications. We show the controllability of
this system for circular parts, describe an algorithm to position these
objects, and present the results of simulated experiments. We conclude
with some future directions and address the issues in extending this
work to more efficient algorithms that work on a broader class of parts
View Show abstract
... This includes rolling (Bicchi and Sorrentino, 1995;Cherif and Gupta, 1999;Doulgeri and Droukas, 2013;Han et al., 1997;Han and Trinkle, 1998), sliding (Cherif and Gupta, 1999;Shi et al., 2017), finger gaiting (Han and Trinkle, 1998), finger tracking (Rus, 1992), pushing (Dafle and Rodriguez, 2017), and re-grasping (Dafle et al., 2014;Tournassoud et al., 1987). For some hand types, strategies such as pivoting (Aiyama et al., 1993), tilting (Erdmann and Mason, 1988), tumbling (Sawasaki and Inoue, 1991), tapping
(Huang and Mason, 2000)
, two-point manipulation (Abell and Erdmann, 1995), and two-palm manipulation (Erdmann, 1998) are also options. These approaches use planning and therefore require exact models of both the hand and object. ...
Learning dexterous in-hand manipulation
Article Full-text available
Nov 2019
Bowen Baker Maciek Chociej Wojciech Zaremba Marcin Andrychowicz
We use reinforcement learning (RL) to learn dexterous in-hand manipulation policies that can perform vision-based object reorientation on a physical Shadow Dexterous Hand. The training is performed in a simulated environment in which we randomize many of the physical properties of the system such as friction coefficients and an object’s appearance. Our policies transfer to the physical robot despite being trained entirely in simulation. Our method does not rely on any human demonstrations, but many behaviors found in human manipulation emerge naturally, including finger gaiting, multi-finger coordination, and the controlled use of gravity. Our results were obtained using the same distributed RL system that was used to train OpenAI Five. We also include a video of our results: https://youtu.be/jwSbzNHGflM .
View Show abstract
... This includes rolling [10,41,42,15,26], sliding [15,100], finger gaiting [42], finger tracking [90], pushing [24], and re-grasping [109,25]. For some hand types, strategies like pivoting [2], tilting [30], tumbling [96], tapping [46]
, two-point manipulation [1], and two-palm manipulation [29] are also options. These approaches use planning and therefore require exact models of both the hand and object. ...
Solving Rubik's Cube with a Robot Hand
Preprint Full-text available
Oct 2019
Ilge Akkaya Marcin Andrychowicz Lei Zhang OpenAI
We demonstrate that models trained only in simulation can be used to solve a manipulation problem of unprecedented complexity on a real robot. This is made possible by two key components: a novel algorithm, which we call automatic domain randomization (ADR) and a robot platform built for machine learning. ADR automatically generates a distribution over randomized environments of ever-increasing difficulty. Control policies and vision state estimators trained with ADR exhibit vastly improved sim2real transfer. For control policies, memory-augmented models trained on an ADR-generated distribution of environments show clear signs of emergent meta-learning at test time. The combination of ADR with our custom robot platform allows us to solve a Rubik's cube with a humanoid robot hand, which involves both control and state estimation problems. Videos summarizing our results are available: https://openai.com/blog/solving-rubiks-cube/
View Show abstract
... By controlling impacts, the robotic paddle designed by Rizzi and Koditschek (1992) was able to bat a ping-pong ball into a steady periodic motion. A single strike (Han and Park, 2001) or repeated taps
(Huang and Mason, 2000)
at a part could impart velocities to change its resting configuration to a desired one, as supported by impact analysis and planning of the part's post-impact sliding motion. ...
Batting an in-flight object to the target
Article Full-text available
Apr 2019
Xiaoqian Mu Yan-Bin Jia Matthew Gardner
Striking a flying object such as a ball to some target location is a highly skillful maneuver that a human being has to learn through a great deal of practice. In robotic manipulation, precision batting remains one of the most challenging tasks in which computer vision, modeling, planning, control, and action must be tightly coordinated in a split second. This paper investigates the problem of a two-degree-of-freedom robotic arm intercepting an object in free flight and redirecting it to some target with a single strike, assuming all the movements take place in one vertical plane. Two-dimensional impact is solved under Coulomb friction and energy-based restitution with a proof of termination. Planning combines impact dynamics and projectile flight mechanics with manipulator kinematics and image-based motion estimation. As the object is on the incoming flight, the post-impact task constraint of reaching the target is propagated backward in time, while the arm’s kinematic constraints are propagated forward (via joint trajectory interpolation), all to the pre-impact instant when they will meet constraints that allow batting to happen. All the constraints (16 in total) are then exerted on the arm’s pre-impact joint angles and velocities, which are repeatedly planned based on updated estimates of the object’s motion captured by a high-speed camera. The arm keeps adjusting its motion in sync with planning until batting takes place. Experiments have demonstrated a better batting performance by a Barrett Technology WAM Arm than by a human being without training.
View Show abstract
... This includes rolling [8,22,23,9,13], sliding [9,59], finger gaiting [23], finger tracking [51], pushing [11], and re-grasping [65,12]. For some hand types, strategies like pivoting [3], tilting [15], tumbling [55], tapping [26]
, two-point manipulation [2], and two-palm manipulation [14] are also options. These approaches use planning and therefore require exact models of both the hand and object. ...
Learning Dexterous In-Hand Manipulation
Preprint
Aug 2018
OpenAI
We use reinforcement learning (RL) to learn dexterous in-hand manipulation policies which can perform vision-based object reorientation on a physical Shadow Dexterous Hand. The training is performed in a simulated environment in which we randomize many of the physical properties of the system like friction coefficients and an object's appearance. Our policies transfer to the physical robot despite being trained entirely in simulation. Our method does not rely on any human demonstrations, but many behaviors found in human manipulation emerge naturally, including finger gaiting, multi-finger coordination, and the controlled use of gravity. Our results were obtained using the same distributed RL system that was used to train OpenAI Five. We also include a video of our results: https://youtu.be/jwSbzNHGflM.
View Show abstract
... In the past, little work has been done on impulsive manipulation. Noticeable results include [4]
, [13], [3] and [14]. Recent work by the third author [7] modeled contacts during a multi-body collision as virtual springs, with a focus on three-body impact, and described the entire process as a diagram showing different periods that transition into one and another. ...
Computational modeling of N-body collisions
Conference Paper Full-text available
Sep 2015
Feifei Wang Huan Lin Yan-Bin Jia
View
... Yamagata [1995] addressed actuation by impact in micropositioning using piezoelectric elements.
Huang and Mason [2000]
applied the theory of balancing impact energy with frictional dissipation to positioning. ...
Application of a linear center identification scheme to deterministic polar positioning Article
Jan 2006
Laine Mears T. Kurfess
In a number of manufacturing applications, parts of circular cross-section must be centered for optimal processing or measurement. However, part form is never perfect, making accurate determination of the "centered" state of a part difficult. Imperfect inputs to the manufacturing process such as rough-processed parts, deformation due to heat treatment, or raw formed materials present difficulty in centering by the traditional manual method. This paper presents a filtering and quantification technique for identifying the true center of an imperfect round part through isolation of the lowest polar frequency component. A low-cost device is presented that centers parts based on this frequency domain identification of center.
View Show abstract
... This type of problem has been analyzed by many researchers. Impulsive manipulation [21,22], releasing manipulation [19], tapping manipulation [23,
24], multi-agent dynamic cooperative manipulation [17,25], pushing manipulation [26] are some examples. ...
Ball Positioning in Robotic Billiards: A Nonprehensile Manipulation-Based Solution Article Full-text available
Jul 2015 IEEE-ASME T MECH
Senthan Mathavan Michael R. Jackson
Robert Parkin
The last two decades have seen a number of developments in creating robots to play billiards. The designed robotic systems have successfully incorporated the kinematics required and have had appropriate machine vision elements for a decent gameplay. Independently, computer scientists have also developed the artificial intelligence programs needed for the strategy to play billiards. Despite these developments, the accurate ball manipulation aspect of the game, needed for good performance, has not been addressed enough; two important parameters are the potting accuracy and advantageous cue ball positioning for next shot. In this regard, robotic ball manipulation by predicting the ball trajectories under the action of various dynamic phenomena, such as ball spin, impacts and friction, is the key consideration of this research. By establishing a connection to the methods used in nonprehensile robotic manipulation, a forward model is developed for the rolling, sliding and two distinct types of frictional impacts of billiards balls are developed. High-speed camera based tracking is performed to determine the physical parameters required for the developed dynamic models. To solve the inverse manipulation problem, i.e. the decision on shot parameters, for accurate ball positioning, an optimization based solution is proposed. A simplistic ball manipulator is designed and used to test the theoretical developments. Experimental results show that a 90% potting accuracy and a 100–200 mm post-shot cue ball positioning accuracy has been achieved by the autonomous system within a table area of 6 × 5 ft 2 .
View Show abstract
... Here, we propose an impulsive feedback control strategy which guarantees the robust stability of the set-point in the face of frictional uncertainties, where we consider a large class of position-dependent, velocity-dependent, and time-varying friction models. The practical feasibility of impulsive force manipulation for the positioning of motion control systems has been illustrated in [13], [14]
, [16], [17]. Moreover, different impulsive feedback control strategies have been proposed in [15], [17]- [19]. ...
Impulsive control of mechanical motion systems with uncertain friction
Article Full-text available
Dec 2011
Nathan van de Wouw Remco Leine
In this paper, we consider the robust set-point stabilisation problem for motion systems subject to friction. Robustness aspects are particularly relevant in practice, where uncertainties in the friction model are unavoidable. We propose an impulsive feedback control design that robustly stabilises the set-point for a class of position-, velocity- and time-dependent friction laws with uncertainty. Moreover, it is shown that this control strategy guarantees the finite-time convergence to the set-point which is a favourable characteristic of the resulting closed loop from a transient performance perspective. The results are illustrated by means of an example.
View Show abstract
... The basic idea behind impulsive control strategies is the introduction of controlled impulsive forces when the system gets stuck at a nonzero steady-state error (due the stiction effect of friction), see e.g. [3,4,10,1213 14
18,19,24,28,323334. One of the key practical problems faced in any of those 'friction-beating' strategies is the fact that friction is a phenomenon which is particularly hard to model accurately, especially due to e.g. ...
Robust impulsive control of motion systems with uncertain friction
Article
Mar 2012 INT J ROBUST NONLIN
Nathan van de Wouw Remco Leine
In this paper, we consider the robust set-point stabilization problem for motion systems subject to friction. Robustness aspects are particularly relevant in practice, where uncertainties in the friction model are unavoidable. We propose an impulsive feedback control design that robustly stabilizes the set-point for a class of position-, velocity-and time-dependent friction laws with uncertainty. Moreover, it is shown that this control strategy guarantees the finite-time convergence to the set-point which is a favorable characteristic of the resulting closed loop from a transient performance perspective. The results are illustrated by means of a representative motion control example. Copyright © 2011 John Wiley & Sons, Ltd.
View Show abstract
... Manipulating objects by pushing and hitting (also called nonprehensile manipulation) is an important robotic task, see [1,16, 12,
24] and references therein. It is easily recast in the setting of so-called juggling systems [9,15,26,28] (a class that encompasses systems with dynamic backlash [18], manipulators with dynamic passive environments, controlled structures, hopping machines, tethered sattelites [14], etc.). ...
A Controllability Criterion for Linear Juggling Mechanical Systems
Conference Paper Full-text available
Feb 2001
Arturo Zavala Rio Bernard Brogliato
Mongi Mabrouk
This paper deals with the controllability of a class of nonsmooth complementarity mechanical systems. Due to their particular structure they can be decomposed into an “object” and a “robot”, consequently they are named juggling systems. It is shown that the controllability properties of the ”object” can be characterized by nonlinear constrained equations, or generalized equations. Examples are presented, including a simple model of backlash, whose accessibility is shown. The main focus of the work is about linear jugglers.
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... RISC implies a shift of the complexity of system design to computer science, as the fundamental question becomes algorithmic in nature: configure, or plan, a sequence of simple physical actions that accomplishes a higher level manipulation task on a given part or collection of parts. Over the past years researchers have explored the suitability of sequences of actions such as pushing [1], [2], [4], [5], [7], [10], [16], [23], [25], [27], [30], [31], [45] squeezing [11], [15], [19], [34], [32], [33], [35], toppling [24], [46], pulling [6], tapping [21]
, dropping [20], [22], [29] wobbling [17], rolling [26], and vibrating [8], [9], [37] by simple hardware elements to accomplish a common task like feeding (or orienting) parts. Considerable attention has also been given to the design of modular fixtures [12], [38], [39], [40], [43], [41], [42], [47] which hold parts using simple reuable elements whose placements are constrained to a grid of holes. ...
A Polynomial-time Algorithm to Design Push Plans for Sensorless Parts Sorting.
Conference Paper Full-text available
Jun 2005
Mark de Berg Xavier Goaoc A. Frank van der Stappen
We consider the efficient computation of sequences of push actions that simultaneously orient two different polygons. Our motivation for studying this problem comes from the observation that appropriately oriented parts admit simple sensorless sorting. We study the sorting of two polygonal parts by first putting them in properly selected orientations. We give an O(n^2 log n)-time algorithm to enumerate all pairs of orientations for the two parts that can be realized by a sequence of push actions and admit sensorless sorting. We then propose an O(n^4 log2 n)-time algorithm for finding the shortest sequence of push actions establishing a given realizable pair of orientations for the two parts. These results generalize to the sorting of k polygonal parts.
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... Impulse-based manipulation is an area in robotics where very little work
[6,
14] is known. An impulsive force has very short execution time, and thus good potential for improving task efficiency. ...
Energy-Based Modeling of Tangential Compliance in 3-Dimensional Impact.
Conference Paper Full-text available
Jan 2010
Yan-Bin Jia
Impact is indispensable in robotic manipulation tasks in which objects and/or manipulators move at high speeds. Applied research using impact has been hindered by underdeveloped computational foundations for rigid-body collision. This paper studies the computation of tangential impulse as two rigid bodies in the space collide at a point with both tangential compliance and friction. It extends Stronge’s spring-based planar contact structure to three dimensions by modeling the contact point as a massless particle able to move tangentially on one body while connected to an infinitesimal region on the other body via three orthogonal springs. Slip or stick is indicated by whether the particle is still or moving. Impact analysis is carried out using normal impulse rather than time as the only independent variable, unlike in previous work on tangential compliance. This is due to the ability to update the energies stored in the three springs. Collision is governed by a system of differential equations that are solvable numerically. Modularity of the impact model makes it easy to be integrated into a multibody system, with one copy at each contact, in combination with a model for multiple impacts that governs normal impulses at different contacts.
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... Actuation by Tapping Huang and Mason (2000)
have studied manipulation of sliding objects by imparting a momentum through impulsive actuation, then allowing the object to come to rest. Analysis of such actuation requires separate analysis of energy transfer during impact, then analysis of the free sliding motion with friction. ...
Design of a flexible centring tooling system
Article
Jan 2007
Laine Mears Francis Mark Kolarits
Michael Thompson T. Kurfess
Precise machining of bearing rings is integral to finished bearing assembly quality. The output accuracy of centre-based machining systems relates directly to the precision of part centring before machining. Traditional tooling is subject to wear, dimensional inaccuracy and human error. A flexible tooling system for initial part centring is proposed based on a single measurement system and actuator. In this system, the part is rotated and measured to identify centre of geometry offset from centre of rotation, then moved by a series of pushes to align the centres. The actuation algorithm is self-modifying based on residual error. This tooling control architecture is based on a real-time version of LabVIEW and employs only a single fixed pusher tip. This enables the system to be readily adaptable to a range of part sizes with only internal variable changes. Such a flexible tooling system can be readily integrated into existing manufacturing equipment.
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Learning to Transfer In‐Hand Manipulations Using a Greedy Shape Curriculum Article
May 2023
Sehoon Ha Yunbo Zhang Alexander Clegg Yuting Ye
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Progressive Transfer Learning for Dexterous In-Hand Manipulation with Multi-Fingered Anthropomorphic Hand Preprint
Apr 2023
Yongkang Luo Wanyi Li Peng Wang Jia Sun
Dexterous in-hand manipulation for a multi-fingered anthropomorphic hand is extremely difficult because of the high-dimensional state and action spaces, rich contact patterns between the fingers and objects. Even though deep reinforcement learning has made moderate progress and demonstrated its strong potential for manipulation, it is still faced with certain challenges, such as large-scale data collection and high sample complexity. Especially, for some slight change scenes, it always needs to re-collect vast amounts of data and carry out numerous iterations of fine-tuning. Remarkably, humans can quickly transfer learned manipulation skills to different scenarios with little supervision. Inspired by human flexible transfer learning capability, we propose a novel dexterous in-hand manipulation progressive transfer learning framework (PTL) based on efficiently utilizing the collected trajectories and the source-trained dynamics model. This framework adopts progressive neural networks for dynamics model transfer learning on samples selected by a new samples selection method based on dynamics properties, rewards and scores of the trajectories. Experimental results on contact-rich anthropomorphic hand manipulation tasks show that our method can efficiently and effectively learn in-hand manipulation skills with a few online attempts and adjustment learning under the new scene. Compared to learning from scratch, our method can reduce training time costs by 95%.
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Learning to Transfer In-Hand Manipulations Using a Greedy Shape Curriculum Preprint Full-text available
Mar 2023
Yunbo Zhang Alexander Clegg Sehoon Ha
Yuting Ye
In-hand object manipulation is challenging to simulate due to complex contact dynamics, non-repetitive finger gaits, and the need to indirectly control unactuated objects. Further adapting a successful manipulation skill to new objects with different shapes and physical properties is a similarly challenging problem. In this work, we show that natural and robust in-hand manipulation of simple objects in a dynamic simulation can be learned from a high quality motion capture example via deep reinforcement learning with careful designs of the imitation learning problem. We apply our approach on both single-handed and two-handed dexterous manipulations of diverse object shapes and motions. We then demonstrate further adaptation of the example motion to a more complex shape through curriculum learning on intermediate shapes morphed between the source and target object. While a naive curriculum of progressive morphs often falls short, we propose a simple greedy curriculum search algorithm that can successfully apply to a range of objects such as a teapot, bunny, bottle, train, and elephant.
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Real-time grasp planning based on motion field graph for human-robot cooperation Conference Paper
Oct 2016
Jaepyung Hwang Myungsik Yang Il Hong Suh Taesoo Kwon
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Handling uncertainty due to the delay between complex sensing and manipulation in an industrial workcell Article
Jan 2006
Y. Liu Adam Hoover Ian D. Walker
Allowing dynamic motions for payloads within a workcell is a fundamentally novel idea for practical industrial robots. The ability to handle payloads moving in semi-structured ways would significantly increase the potential markets for industrial robotics. However, due to the inherent time delay between complex sensing and manipulation, the manipulation fails in some circumstances. Therefore, in this paper, we propose a generic method to model the dynamic intercept and manipulation capability of vision based industrial robot systems. In order to verify the method, we present experiments using our industrial workcell prototype to dynamically intercept and manipulate semi-randomly moving objects. We conduct experiments over 1000 runs with two different kinds of dynamic tasks, "scoop" and "trap." The experimental results validate our theory.
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Impulsive-actuation part positioning through constrained energy balance planning Article
Jan 2007
Laine Mears T. Kurfess
Impulsive actuation has been researched in the past two decades as an inexpensive alternative to multi-degree-of-freedom precision positioning systems. The position of a sliding workpiece can be controlled by a 2-degree-of-freedom actuation system through simple pushing path planning. However, the final part position as a result of the last touch of the actuator is subject to uncertainty in the friction model used for actuation planning, particularly the free-sliding distance undergone by the workpiece after losing contact with the actuator. This paper first reviews an impact planning method, then augments it using a restitution-based model that results in an explicit actuator velocity function. Results are given for positioning of a continually rotating workpiece that show improvement over constant-velocity pushing actuation. Such a positioning system is applicable to dynamic positioning for precision metrology or positioning prior to manufacturing operations (e.g., magnetic chuck grinding with part being moved while the table is rotating).
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Dexterous manipulation using both palm and fingers
Conference Paper
May 2014
Yunfei Bai Karen Liu
This paper focuses on the problem of manipulating the orientation of a polygonal object in hand. We propose a control technique which integrates the use of palm and fingers to pick up a given object on the table, to drop it on a specific spot on the palm, and to let it roll continuously and controllably on the palm, subject to the gravitational and contact forces. We formulate a simple and fast algorithm to control the tilting angle of the palm based on the conservation of mechanical energy and an empirical model of energy dissipation due to collisions. We also develop a multifingers controller for stable grasp and for correcting the rolling motion. The proposed technique is demonstrated on a simulated robotic hand manipulating a wide range of objects with different geometry and physical properties.
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Intermittent tapping control
Article
Sep 2012 P I MECH ENG I-J SYS
Henrik Gollee P.J. Gawthrop
Control using a sequence of 'taps', in contrast to the usual smooth control, is shown to fit within the established intermittent control framework. In particular, a specially designed generalised hold gives rise to tapping behaviour optimised according to the underlying linear-quadratic design. Both fixed-interval and event-driven tapping are included in this approach and some basic stability analysis is given. Illustrative examples are presented and the advantages of tapping in the context of electromechanical servo systems with friction are explored using a laboratory experiment.
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A distributed manipulation concept using selective braking
Conference Paper
Jun 2014
Mark Bedillion Randy C. Hoover
Jeff Mcgough
This paper introduces a new distributed manipulation concept whereby objects operating under the action of a uniform force field are positioned perpendicular to the force field and oriented by selectively applying braking forces at various locations on the object. We assume that the braking locations do not slip, which gives the object dynamics the familiar form of the pendulum equation, but with the pendulum hinge location changing as a function of time. Such a system may find applications in parts handling or in the control of robots descending on inclines. This paper discusses the dynamics of such a robotic system and the sequential control of lateral object position and orientation. Simulation results show the effectiveness of the developed control laws.
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Progress in Nonprehensile Manipulation
Article
Nov 1999
Matthew T. Mason
This paper reviews my recent research in robotic manipulation and speculates on potentially fruitful directions for future work. My recent work is focused on nonprehensile manipulation: manipulating objects without grasping them. In particular, the paper surveys work on a single joint robot that orients parts on a conveyor belt; a robot that uses dynamics to snatch, roll, or throw objects; hitting things to position them; manipulating things whose shapes are not completely known; and integration of manipulation with locomotion. In the future, a broad view of robotics will allow us to focus on fundamental principles and at the same time address a variety of new applications.
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The system-matched hold and the intermittent control separation principle Article
Dec 2011
P.J. Gawthrop Liuping Wang
An intermittent controller is a form of hybrid controller which adds a generalised sample and hold mechanism to an underlying continuous-time feedback control system. The sampling may be non-uniform or event driven. One particular form of the hold, termed the system-matched hold (SMH) mimics the behaviour of the closed-loop feedback control signal during the intermittent intervals. It is shown in this article that this choice of hold leads to an intermittent separation principle. In particular, this simple analytical result ensures that when using the SMH, the separation properties of the underlying state-estimate feedback control system carry over to the intermittent control system. This separation principle for the SMH has the important consequence that, unlike the zero-order hold case, the stability of the closed-loop system in the fixed sampling case is not dependent on sample interval. It is therefore suggested that the SMH should replace the conventional zero-order hold in circumstances where the sample interval is unknown, time-varying or determined by events.
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Automated Part Centering With Impulse Actuation
Article
Feb 2010 J MANUF SCI E-T ASME
Stephen Furst Thomas Dow Kenneth P. Garrard Alex Sohn
Centering a part on a spindle for precision machining is a tedious, time-consuming task. Currently, a skilled operator must measure the run-out of a part using a displacement gauge, then tap the part into place using a plastic or rubber hammer. This paper describes a method to automatically center a part on a vacuum chuck with initial run-out as large as 2.5 mm. The method involves measuring the magnitude and direction of the radial run-out and then actuating the part until the part and spindle centerlines are within 5 mu m of each other. The run-out can be measured with either a touch probe mounted to a machine axis or an electronic gauge. The part is tapped into place with a linear actuator driven by a voice coil motor. This paper includes an analysis of run-out measurement uncertainty as well as the design, performance modeling, and testing of the alignment actuator. This actuator was employed for part realignment and successfully positioned a hemispherical part with an initial run-out of 1-2.5 mm to within 5 mu m of the spindle centerline. This capability shows that the run-out of a part manually placed on flat vacuum chuck can be automatically corrected.
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Frictional sliding motion in releasing manipulation
Article
Jan 2005
Chi Zhu Yasumichi Aiyama Tamio Arai
Atsuo Kawamura
The characteristics of frictional sliding motion in releasing manipulation are discussed in this paper. Releasing manipulation is such a manipulation in which an object obtains its initial translational and rotational velocities by the striking of a manipulator and slides on a surface, and comes to stop at the destination with the desired orientation under the action of friction. First, based on our previous work, the properties of releasing manipulation are described. Second, the conclusion that trajectories of arbitrary shaped objects in sliding motion are nearly rectilinear is presented. Third, a phenomenon of simultaneous stopping of translational and rotational motion for arbitrary shaped objects is clarified. Fourth, motion monotonicity for two extreme cases, i.e. initially translation-dominated motion and initially rotation-dominated motion are discussed; several important original results are obtained. With the above obtained results, two simple approaches of determining the necessary initial velocities for releasing manipulation are naturally developed and their accuracies are confirmed.
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Planning Velocities of Free Sliding Objects as a Free Boundary Value Problem Article
Jan 2004
Qingguo Li Shahram Payandeh
In this paper, a novel planning method is proposed to solve initial velocities of the free sliding object for given initial and final configurations. Finding the desired initial velocities for free sliding objects is a key step for implementing impulse manipulation and multi-agent dynamic cooperative manipulation. The motion of free sliding objects on a plane is governed by friction forces and the initial state of the object; this motion can be modeled by a set of six first-order differential equations. In this paper, the planning problem is formulated as a free boundary value problem (FBVP). In order to solve the problem, the FBVP is first reduced to a standard two-point boundary value problem, then quasi-Newton based optimization procedures are utilized to solve the planning problem. The proposed method does not require qualitative motion characteristics; thus, it can be used for objects with general shape and arbitrary pressure distribution. Numerical and experimental results on objects with different geometries and pressure distributions are used to demonstrate the performance of the proposed planner.
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Impulsive Motion Planning for Positioning and Orienting a Polygonal Part Article
Mar 2001
Inhwan Han Sang-Uk Park
In this paper, the authors analyze the dynamic behavior of a rigid polygonal part struck on a horizontal surface under the action of friction and present how to propel the part to a desired configuration through the impulsive operation. In the dynamic analysis of the impulsive operation, the part motion is typically analyzed in two phases, impact motion and sliding motion. These are usually analyzed in reverse order of occurrence. The authors characterize the impact and sliding dynamics with friction for polygonal parts and develop an approach to compute the inverse dynamic solution for motion planning of the impulsive operation. Finally, the authors verify the effectiveness of the simulation results and the developed motion plans through comparison with experimental results using a high-speed video camera.
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Positioning in Releasing Manipulation by Iterative Learning Control
Article
Aug 2006
Chi Zhu Yasumichi Aiyama Tamio Arai
Atsuo Kawamura
In order to improve the positioning precision of the stop posture (position and orientation) of an object and decrease the trial numbers in our proposed releasing manipulation, two iterative learning control (ILC) schemes, learning control based on convergent condition (LCBCC), and learning control based on optimal principle (LCBOP) are designed in experimental-oriented way. These two methods are all based on a linearized system model. The experimental results show that these methods are effective. Having discussed the characteristics of these control methods, we conclude that in the case there is no enough system knowledge, LCBCC is the only choice to be used to learn the system knowledge; after the enough experience has been acquired, LCBOP is better than LCBCC, in the view of both of the convergent rate and the precision.
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On the controllability of linear juggling mechanical systems
Article
Apr 2006 SYST CONTROL LETT
Bernard Brogliato Mongi Mabrouk
Arturo Zavala
This paper deals with the controllability of a class of nonsmooth complementa- rity mechanical systems. Due to their particular structure they can be decomposed into an "object" and a "robot", consequently they are named juggling systems. It is shown that the accessibility of the "object" can be characterized by nonlinear constrained equations, or generalized equations. Examples are presented, including a simple model of backlash. The main focus of the work is about linear jugglers, but extensions towards more complicated models are considered.
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Unconstrained dynamic planar manipulation with one joint manipulator
Conference Paper
Sep 2005
S. Payendeh Qingguo Li
This paper explores the unconstrained dynamic manipulation for parts on a plane using a one joint manipulator. The goal of dynamic manipulation is to pose an object from an initial to a desired goal configuration on a frictional supporting surface. The overall manipulation process is decomposed into two conjunct phases, namely, acceleration of the object and free sliding of the object. We study the acceleration of an object with a one joint manipulator, and develop a planning method by solving a free boundary value problem in this paper. Experimental results are presented to demonstrate the proposed manipulation approach.
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Planning velocities of free sliding objects for dynamic manipulation
Conference Paper
Oct 2003
Qingguo Li Shahram Payandeh
In this paper, a novel numerical approach is proposed to solve the initial velocities of the free sliding object for given initial and final configurations. To find the desired initial velocities for free sliding objects is a key step for implementing dynamic manipulation. In order to plan the initial velocities, the motion of free sliding objects is modeled as a set of 6 first order differential equations, and the planning problem is formulated as a free boundary value problem (FBVP). Through a simple transformation, the FBVP is reduced to a standard Two-point boundary value (TPBV) problem. Quasi-Newton based optimization procedures are utilized to solve the planning problem. Unlike existing approaches, the proposed method does not require qualitative motion characteristics, thus it can be used for objects with general shape and arbitrary pressure distribution. Simulation results on polygonal objects with three to five vertices are used to demonstrate the planning method.
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Modeling and analysis of dynamic multi-agent planar manipulation
Conference Paper
Feb 2001
Qingguo Li Shahram Payandeh
A dynamic model for multi-agent manipulation is investigated under a nonlinear control framework. The motion of the rigid body on a plane under two-finger pushing is modeled as a nonlinear system. The local controllability is derived for different cooperation patterns. The motion of the rigid body under pushing is composed of two stages: during the first stage, the fingers maintain contact with the object, and through adjusting the pushing position, orientation and force on the object, the configuration of the object can reach some subsets in configuration space. Due to local contact constraints, the fingers may lose contact with the object where the second stage of motion starts. Here, the motion of the object is governed by the friction force only. Thus manipulation planning consists of two parts. First, an initial state response problem needs to be solved to find the subset of configuration space which can reach the final configuration under the friction-governed sliding. The remaining problem can be categorized as optimal control problem, which solves the cooperation between agents which force the object moving into the subset found by the initial state response problem. The possibility of cooperation is illustrated through an example.
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Bounds on the Friction-Dominated Motion of a Pushed Object Article Full-text available Jun 1993 James Alexander John H. Maddocks We consider the friction-dominated, or quasistatic, motion of a rigid body being pushed over a horizontal plane in situations where the precise frictional interaction cannot be determined. Consequently, the complete set of motions corresponding to all possible friction distributions must be found. We demonstrate that if the contact region between the body and the support ing plane has one or two components, the set of all possible motions coincides with the set of motions arising for friction distributions restricted to two-point contact in the boundary of the contact region. These two-point problems are solved analytically. In previous formulations of the problem, general friction support had only been reduced to the case of tripods, which does not have an analytic solution. Various examples are presented, and an effective numerical scheme based on a dissipation function is implemented. View Show abstract On the motion of an ice hockey puck Article Full-text available Dec 1985 AM J PHYS Kjell Vøyenli E. Eriksen Some easily observed, but surprising properties, of a homogeneous, circular ring or disk sliding on a smooth horizontal surface under the action of friction are pointed out and discussed. View Show abstract Rigid Body Collisions with Friction Article Full-text available Oct 1990 Proc Math Phys Eng Sci W.J. Stronge An energetically consistent theory is presented for dynamics of partly elastic collisions between somewhat rough rigid bodies with friction that opposes slip. This theory is based on separately accounting for frictional and non-frictional sources of dissipation. Alternative theories derived from Newton's impact law or Poisson's impact hypothesis are shown to be valid only for central (collinear) or non-frictional collisions; generally the latter theories yield erroneous energy dissipation if small initial slip stops during collision between eccentric bodies. Collision processes are complex when small slip is stopped by friction; then either the direction of slip reverses or contact points roll without slip. An inconsistent theory based on Newton's impact law can yield erroneous energy increases when slip stops during collision; the consistent theory always dissipates energy. The impact law that specifies a simple proportionality between normal components of contact velocity for incidence and rebound is not applicable in any range of incident velocities with small slip if the collision is non-collinear with friction. View Show abstract A New Algebraic Rigid-Body Collision Law Based on Impulse Space Considerations Article Full-text available Dec 1998 J APPL MECH-T ASME Anindya Chatterjee Andy Ruina We present a geometric representation of the set of 3D rigid body collisional impulses that are rea-sonably permissible by the combination of non-negative post-collision separation rate, non-negative collisional compression impulse, non-negative energy dissipation and the Coulomb friction inequality. The construction is presented for a variety of special collisional situations involving special symmetry or extremes in the mass distribution, the friction coefficient, or the initial conditions. We review a variety of known friction laws and show how they do and do not fit in the permissible region in impulse space as well as comment on other attributes of these laws. We present a few parameterizations of the full permissible region of impulse space. We present a simple generalization to arbitrary 3D point contact collisions of a simple law previously only applicable to objects with contact-inertia eigenvectors aligned with the surface normal and initial relative tangent velocity component (e.g. spheres and disks). This new algebraic collision law has two restitution parameters for general 3D frictional single-point rigid-body collisions. The new law generates a collisional impulse that is a weighted sum of the impulses from a frictionless but non-rebounding collision and from a perfectly sticking, non-rebounding collision. We describe useful properties of our law; show geometrically the set of impulses it can predict for several collisional situations; and compare it with existing laws. For simultaneous collisions we propose that the new algebraic law be used by recursively breaking these collisions into a sequence ordered by the normal approach velocities of potential contact pairs. View Show abstract From stable to chaotic juggling: theory, simulation, and experiments Conference Paper Full-text available Jun 1990 Martin Buehler Daniel Koditschek Recent results of dynamical systems theory are used to derive
strong predictions concerning the global properties of a simplified
model of a planar juggling robot. In particular, it is found that
certain lower-order local (linearized) stability properties determine
the essential global (nonlinear) stability properties, and that
successive increments in the controller gain settings give rise to a
cascade of stable period-doubling bifurcations that comprise a universal
route to chaos. The theoretical predictions are verified by simulation
and corroborated by experimental data from the juggling robot View Show abstract “RISC” industrial robotics: recent results and open problems Conference Paper Full-text available Jun 1994 John Francis Canny Kenneth Yigael Goldberg At the intersection of robotics, computational geometry, and
manufacturing engineering, we have identified collection of research
problems with near-term industrial applications. The common thread is
robot systems with reduced intricacy in sensing and control (RISC), such
as light beam sensors and parallel-jaw grippers. We conjecture that such
systems, coupled with appropriate algorithms, are capable of recognizing
and orienting a broad class of industrial parts. When compared with
general-purpose robots, the resulting systems could be: (1) lower in
cost, (2) more reliable, and (3) easier to reconfigure. The proposed
hardware bears a close resemblance to existing “hard”
automation; what is new is the application of computational methods for
robust design and control of these systems, and more extensive use of
simple sensors. By focusing on a small vocabulary of simple hardware,
planning become computationally tractable and we can in some cases make
guarantees about the existence of solutions. We borrowed the RISC
acronym from computer architecture to acknowledge a common theme:
identifying a minimal set of hardware primitives and matching these
primitives with highly efficient software. In this paper, we review
recent algorithms for locating, feeding, inserting and fixturing
industrial parts. We discuss related work and propose a set of open
problems for future research View Show abstract Automatic planning of robot pushing operations Conference Paper Full-text available Jun 1993 Zdravko Balorda A method for automatic planning of robot pushing operations is
described. The operation is performed by a two-point pusher. It has been
shown that such an operation can entirely constrain polygonal workpiece
in a plane and can deal with objects in the presence of initial
uncertainty. The operation is discussed with regard to bounds on initial
error in position and orientation. The success of an attempt to push the
object depends on correct pushing direction and starting point of the
pusher. The goal is to catch the object between the fingers and to
eventually bring it to known position and orientation. The starting
point and the pushing direction define an operation space of all
possible tasks. A bounded region in this space is constructed, such that
any point inside this region guarantees the object will not be pushed
away. The planner also accounts for the uncertainty in positioning,
suggesting the pushing operation that will succeed even if worst case
error occurs View Show abstract Progress in spatial robot juggling Conference Paper Full-text available Jun 1992 Alfred A. Rizzi Daniel Koditschek The authors review their progress to date in eliciting dynamically
dexterous behaviors from a 3-d.o.f. direct drive robot manipulator whose
real-time stereo cameras provide 60 Hz sampled images of multiple freely
falling bodies in highly structured lighting conditions. At present, the
robot is capable of forcing a single ping-pong ball into a specified
steady-state (near) periodic vertical motion by repeated controlled
impacts with a rigid paddle. The robot sustains the steady-state
behavior over long periods (typically many thousands of impacts) and is
capable of recovering from significant unexpected adversarial
perturbations of the ball's flight phase. Gain tuning experiments
corroborate the authors' contention that the stability mechanism
underlying the robot's reliability can be attributed to the same
nonlinear dynamics responsible for analogous behavior in a previous
1-d.o.f. robot View Show abstract Planar Sliding With Dry Friction 1: Limit Surface and Moment Function Article Full-text available Mar 1991 WEAR Suresh Goyal A. Ruina Jim Papadopoulos We present two geometric descriptions of the net frictional force and moment between a rigid body and a planar surface on which it slides. The limit surface, from classical plasticity theory, is the surface in load space which bounds the set of all possible frictional forces and moments that can be sustained by the frictional interface. Zhukovskii's moment function (N.E. Zhukovskii, Collected Works, Vol. 1, Gostekhizdat, Moscow, 1948, pp. 339–354) is the net frictional moment about the body's instantaneous center of rotation as a function of its location. Both of these descriptions implicitly contain the full relation between slip motion and frictional load. While Zhukovskii's moment function applies only to ordinary isotropic Coulomb friction, the limit surface applies to a wider class of friction laws that includes, for example, contact mediated by massless rigid wheels. Both the limit surface and the moment function can be used to deduce results concerning the motion of sliding rigid bodies. View Show abstract Dexterous manipulation planning and execution of an enveloped slippery workpiece Conference Paper Full-text available Jun 1993 J.C. (Jeff) Trinkle R.C. Ram A.O. Farahat Peter F. Stiller When robotic hands or arms are capable of enveloping the
workpieces that they manipulate, envelopment of the workpiece ensures
grasp maintenance even if the object experiences significant external
forces in directions unknown prior to grasp synthesis. The enveloping
mechanism is useful in low-friction and microgravity environments.
First-order stability cells are defined. They are used to plan a planar,
whole-arm, manipulation task of a slippery workpiece. For most, but not
all, of the plan, the workpiece is enveloped. Experimental results are
presented View Show abstract A RISC approach to robotics Article Full-text available Apr 1994 John Francis Canny Kenneth Yigael Goldberg This article describes a framework that combines simple hardware traditionally used in manufacturing with sensor-based planning and design algorithms from robotics. For repetitive assembly, the authors argue that this combination can reduce start-up and maintenance costs, increase throughput, and greatly reduce the set-up and changeover times for new products. The proposed hardware bears a close resemblance to existing "hard" automation; what is new is the application of computational methods for robust design and control of these systems, and more extensive use of (simple) sensors. Clearly this enhances the capabilities of the hardware. A less-obvious benefit is that software capability is also enhanced--algorithms for fine-motion, grasp planning and some sensing algorithms which would be intractable on a general-purpose robot work in real-time when applied to simple hardware. To describe this approach the authors chose the acronym RISC--Reduced Intricacy in Sensing and Control-by analogy with computer architecture. Analogously, the authors propose to use simple hardware elements that are coordinated by software to perform complex tasks.< > View Show abstract First-Order Stability Cells of Active Multi-Rigid-Body Systems Article Full-text available Sep 1995 IEEE Trans Robot Autom J.C. (Jeff) Trinkle A.O. Farahat Peter F. Stiller A stability cell is a subset of the configuration space (C-space)
of a set of actively controlled rigid bodies (e.g., a manipulator) in
contact with a passive body in which the contact state is guaranteed to
be stable under Coulomb friction and external forces. A first-order
stability cell is a subset of a stability cell with the following two
properties: the state of contact uniquely determines the rate of change
of the object's configuration given the rate of change of the
manipulator's configuration; and the contact state cannot be altered by
any infinitesimal variation in the generalized applied force.
First-order stability cells can be used in planning whole-arm
manipulation tasks in a manner analogous to the use of free-space cells
in planning collision-free paths: a connectivity graph is constructed
and searched for a path connecting the initial and goal configurations.
A path through a free-space connectivity graph represents a motion plan
that can be executed without fear of collisions, while a path through a
stability-cell connectivity graph represents a whole-arm manipulation
plan that can be executed without fear of “dropping” the
object. The paper gives a conceptual and analytical development of
first-order stability cells of 3D rigid-body systems as conjunctions of
equations and inequalities in the C-space variables. Additionally, our
derivation leads to a new quasi-static jamming condition that takes into
account the planned motion and kinematic structure of the active bodies View Show abstract The Motion of a Pushed, Sliding Workpiece Article Full-text available Jan 1989 IEEE J Robot Autom Michael Peshkin Arthur C. Sanderson It occurs frequently in robotic applications that a robot
manipulates a workpiece which is free to slide on a work surface.
Because the pressure distribution supporting the workpiece on the work
surface cannot in general be known, the motion of the workpiece cannot
be calculated uniquely. The authors find the locus of centers of
rotation of a workpiece for all possible pressure distributions. The
results allow a quantitative understanding of open-loop robot motions
which guarantee the alignment of a workpiece. Several sample problems
are solved using the results, including the distance that a flat fence,
or robot finger, must push a polygonal workpiece to assure that a facet
of the workpiece comes into alignment with the fence View Show abstract Stable Pushing: Mechanics, Controllability, and Planning Article Full-text available Nov 1999 Kevin M. Lynch Matthew T. Mason We would like to give robots the ability to position and orient Erratum: Figures 13 and 15 are transposed. parts in the plane by pushing, particularly when the parts are too large or heavy to be grasped and lifted. Unfortunately, the motion of a pushed object is generally unpredictable due to unknown support friction forces. With multiple pushing contact points, however, it is possible to find pushing directions that cause the object to remain fixed to the manipulator. These are called stable pushing directions. In this article we consider the problem of planning pushing paths using stable pushes. Pushing imposes a set of nonholonomic velocity constraints on the motion of the object, and we study the issues of local and global controllability during pushing with point contact or stable line contact. We describe a planner for finding stable pushing paths among obstacles, and the planner is demonstrated on several manipulation tasks. 1. Introduction One of the most basic tasks for a rob... View Show abstract An Exploration of Nonprehensile Two-Palm Manipulation: Planning and Execution Chapter Jan 1996 Michael Erdmann This paper describes our current research into nonprehensile palm manipulation. The term “palm” refers to the use of the entire device surface during manipulation, as opposed to use of the fingertips alone. The term “nonprehensile” means that the palms hold the object without wrapping themselves around it, as distinguished from a force/from closure grasp often employed by a fingered hand. Indeed, nonprehensile Operations such as purposeful sliding and constrained dropping constitute important palm primitives. We have implemented a system for orienting parts using two palms. The system consists of a planner and an executive. As input, the system expects a geometric description of a part, its center of mass, the coefficients of friction between the part and each of the palms, and a start and goal configuration of the part in stable contact with one of the palms. As Output, the system computes and executes a sequence of palm motions designed to reorient the part from the specified start to the specified goal configuration. View Show abstract Robot Hands and The Mechanics of Manipulation Article Mar 1989 J DYN SYST-T ASME Matthew T. Mason John Kenneth Salisbury Jr Joey K. Parker The abridged contents include: Kinematic and force analysis of articulated hands: contact - freedom and constraint; contacts in groups; force application and velocity analysis; force error analysis. Manipulator grasping and pushing operations: theory of pushing; application; conclusion. Index. This book, based on the doctoral dissertations of the two authors, examines several aspects of manipulating objects. At present, the authors believe that industrial robots are not used effectively. Tasks performed by robot manipulators are now limited to simple packing and stacking operations. By understanding the principles discussed in this book, better industrial robots are presented. View Show abstract The Friction and Lubrication of Solids Article Oct 1951 AM J PHYS F. P. Bowden Scitation is the online home of leading journals and conference proceedings from AIP Publishing and AIP Member Societies View Show abstract Mechanical Impact Dynamics: Rigid Body Collisions Article May 1991 J Eng Ind Trans ASME Raymond M. Brach Werner Goldsmith Principles, Assumptions, and Definitions Point-Mass Collisions in a Plane Restitution, Friction, and Energy Loss Three-Dimensional Particle Collisions Planar Rigid Body Collisions Planar Barrier Collisions Three-Dimensional Impact of Rigid Bodies Planar Impact of Linkages and Articulated Rigid Bodies Vibratory Impact Application to Vehicle Collisions Index. View Show abstract Planar sliding with dry friction Part 2. Dynamics of motion Article Mar 1991 WEAR Suresh Goyal A. Ruina Jim Papadopoulos Some problems in the dynamics of sliding of planar rigid bodies are treated by geometric methods based on the limit surface description of friction (S. Goyal, A. Ruina and J. Papadopoulos, Wear, 143 (1991) 307–330). The problems we consider, where the normal force is known a priori, have unique solutions although the friction force (and torque) may be a discontinuous function of the direction of motion. When a freely sliding object comes to rest it always does so with one of several definite ratios of translation to rotation. These special generalized velocity directions, termed eigen-directions, depend on the friction law used, the contact pressure distribution and the mass distribution. The eigen-directions correspond to local extrema of the generalized frictional load ¦P¦ on the limit surface, i.e. to directions in load space where P is parallel to the generalized direction of motion q. For most objects, if the contact region is sufficiently smaller than the radius of gyration, final motion is always pure rotation about the center of mass; if the contact region is sufficiently spread out final motion is a pure translation. A simple model of a car with locked rear wheels shows the effect of speed and orientation on skid stability at finite speeds. Sliders have a propensity to rotate about points of support. View Show abstract The Advanced Part of a Treatise on the Dynamics of a System of Rigid Bodies Article Mar 2013 E. J. Routh Preface; 1. Moving axes and relative motion; 2. Oscillations about
equilibrium; 3. Oscillations about a state of motion; 4. Motion of a
body under no forces; 5. Motion of a body under any forces; 6. Nature of
the motion given by linear equations and the conditions of stability; 7.
Free and forced oscillations; 8. Determination of the constants of
integration in terms of the initial conditions; 9. Calculus of finite
differences; 10. Calculus of variations; 11. Precession and nutation;
12. Motion of the moon about its centre; 13. Motion of a string or
chain; 14. Motion of a membrane; Notes. View Show abstract Application of Electromagnetic Impulsive Force to Precise Positioning Article Jan 1985 Higuchi Toshiro In this paper a new method for precise positioning is introduced. The principle of positioning method is based on the following well known kinematic phenomenon. When a small impulsive force is applied on one end of a solid body placed on a plane surface, the body will move in the direction of the force with a very small displacement. This phenomenon has scarcely been applied in factory automation since an apparatus that can supply an appropriately controlled impact has not been obtained. In this method, electromagnetic force which is produced between a coil and a conductive plate is used as the source of the impact. The waveform of this electromagnetic impulsive force can be controlled by an electric circuit. Experiments show that a rigid mass of 1 kg can be moved from 20 nm to 300 µm by one shot of the electric discharge according to the charged energy. As an application of this method, a precise Х,Ү,Θ stage is also developed by attaching eight impact generator units around a square solid block. View Show abstract Two-Dimensional Rigid-Body Collisions With Friction Article Sep 1992 J APPL MECH-T ASME Yu Wang Matthew T. Mason This paper presents an analysis of a two-dimensional rigid-body collision with dry friction. We use Routh's graphical method to describe an impact process and to determine the frictional impulse. We classify the possible modes of impact, and derive analytical expressions for impulse, using both Poisson's and Newton's models of restitution. We also address a new class of impacts, tangential impact, with zero initial approach velocity. Some methods for rigid-body impact violate energy conservation principles, yielding solutions that increase system energy during an impact. To avoid such anomalies, we show that Poisson's hypothesis should be used, rather than Newton's law of restitution. In addition, correct identification of the contact mode of impact is essential. View Show abstract Ultrahigh vacuum precise positioning device utilizing rapid deformations of piezo-electric element Article Dec 1990 J VAC SCI TECHNOL A Yutaka Yamagata Higuchi Toshiro Hiroshi Saeki Hajime Ishimaru Recently precise positioning devices with low outgassing rates have been required for production systems of very large scale integrated circuits, surface analysis systems, and scanning tunneling microscopes in ultrahigh vacuum. A bakable XYθ three‐axis positioning table using a unique positioning mechanism utilizing friction and inertial forces caused by rapid deformations of piezoelectric elements was developed. The table has a hexagonal shape of 120 mm in diameter and is mainly made of aluminum alloys with an EX‐process. The table has three feet with an Si 3 N 4 ball on each bottom side and set on a plate made of Pyrex glass. The table was able to operate in an ultrahigh vacuum environment of the order of 10 to the -12 Torr. View Show abstract Open Loop Stable Control Strategies for Robot Juggling. Conference Paper Jan 1993 Stefan Schaal Christopher G. Atkeson Open-loop stable control strategies for a variety of juggling
tasks are explored. The specific tasks studied are paddle juggling,
ball-in-a-wedge juggling, five ball juggling, and devil sticking. All
dynamic tasks introduced are solved by special purpose systems. The
results of these investigations may provide insight into how open loop
control can serve as a useful foundation for closed loop control and,
particularly, what to focus on in learning control View Show abstract The Friction and Lubrication of Solids / F.P. Bowden, D. Tabor. Article Frank Philip Bowden David Tabor View Releasing manipulation Conference Paper Dec 1996 Chi Zhu Yasumichi Aiyama T. Chawanya Toshiro Arai In this paper, first we propose a new kind of
manipulation-releasing manipulation, that is, by some means, the
manipulator gives the object initial translational and rotational
velocities to make the object slide on a surface by its inertia under
the action of friction. Second, we give the basic equations and analyze
the motion of the object. Third, based on numerical calculation, we
summarize the motion characteristics, especially for a rectangle.
Finally, we perform experiments to verify the validity of this
manipulation View Show abstract Micropositioning device for precision automatic assembly using impact force of piezoelectric elements Conference Paper Jun 1995 Yutaka Yamagata Higuchi Toshiro A micropositioning system for automatic precision assembly is
introduced. The proposed precision assembly system is aimed at
automation of precision assembly of precision optical or magnetic
components, which was previously performed by specially trained
technicians. The positioning system is based on the motion mechanism
driven by impact force made by piezoelectric actuator; it utilizes dry
friction and impulsive inertial force. The motion mechanism consists of
the main body, a piezoelectric actuator, and a weight. The motion
mechanism can make minute motion of several nanometer and has an
unlimited movable range at the same time. The proposed assembly system
uses the motion mechanism as a source of impact force. The motion
mechanism is proved to have the advantage of positioning resolution,
range, and flexibility. An industrial application of this device is also
presented View Show abstract Vision-based control of an air hockey playing robot Article Jul 1999 IEEE CONTR SYST MAG Bradley Bishop M.W. Spong We demonstrate an integrated sensing and control design for
high-speed ballistic manipulation in two dimensions. We show the
effectiveness of a vision-based switched control scheme for precision
impulsive manipulation. Vision-based hybrid control is a promising
avenue of research for fully autonomous interaction between robots and
complicated environments. Much work remains to be done in both computer
vision and hybrid systems. In the context of robot air hockey, important
future areas to investigate include the problems of modeling and
identification of the environment dynamics, in particular, the table
friction and puck spin. We show how the puck spin significantly
influences its trajectory and subsequently our ability to perform
accurate trajectory estimation and prediction View Show abstract Impulsive Manipulation Article Nov 1999 Wesley H. Huang Eric P. Krotkov Matthew T. Mason In this paper, we examine a little-studied method of manipulation --- manipulation by striking an object and letting it slide. There are two parts to this problem: The Inverse Sliding Problem, determining the velocities required to send an object to a desired configuration, and The Impact Problem, determining how to strike the object in order to achieve those velocities. We will present a solution to these two problems for the class of rotationally symmetric objects and conclude with some observations about this method of manipulation. 1 Introduction Most robots today manipulate an object by grasping it, moving, and then releasing the object. A few robots make use of pushing strategies to manipulate objects. However, there has been very little explorationof another method of manipulation, striking an object and letting it slide until it comes to rest---a method of manipulation which is not uncommon in our daily lives. Imagine a two dimensional world in which a robot manipulates obj... View Show abstract A Nonprehensile Method for Reliable Parts Orienting Article Nov 1999 Nina B. Zumel Prehension may be defined as "The act of taking hold, seizing or grasping, as with the hand" (Webster's 3rd International Dictionary). Nonprehensile manipulation, then, can be defined as the manipulation of objects without grasping them. Manipulation without prehension is a natural way of handling objects for both humans and machines. The ability to manipulate objects which may not be graspable increases the flexibility of a robot interacting with its environment, without adding complexity to the mechanical design. This research analyses the mechanics of nonprehensile contact between a simple, two degree of freedom manipulator and a part. The intent is to develop reliable but sensorless manipulation routines for use in an automated assembly environment. While nonprehensile, sensorless devices are in common use in such environments, existing parts orienting devices, such as bowl feeders or the SONY Automatic Parts Orienting System, must be custom designed for each specific task. To decr... View Show abstract Control of Planar Rigid Body Sliding with Impacts and Friction Article Jun 1999 Chad B. Partridge M.W. Spong In this paper we continue our investigations into robotic air hockey by studying the problem of controlling the trajectory of a puck subject to intermittent impacts. Impacts are modeled using the Routh two-dimensional impact model which incorporates spin and friction. Using this model, we derive an explicit mapping between pre-impact and post-impact velocities of the puck. We will see that this mapping is discontinuous and separates the velocity space of the puck into regions determined by whether or not relative sliding ends during impact. This discontinuity depends in a fundamental way on the relative velocity of the objects at impact and the coefficients of restitution and friction. We then present results on planning of puck trajectories and control of the puck through impacts with a mallet or striker, which is essentially the problem of inverting the mapping between pre-impact and post-impact velocities. Our results confirm the intuitive notion that a large coefficient of friction... View Show abstract A New Algebraic Rigid Body Collision Model With Some Useful Properties Article Dec 1997 Anindya Chatterjee Andy Ruina We present a simple new algebraic model with two restitution parameters for general 3D frictional single-point rigid-body collisions. The model is motivated by, and guaranteed to satisfy, basic restrictions on the collisional impulse. For disks and spheres, it becomes a bilinear model successfully used elsewhere. For general collisions, the predicted impulse is somewhat physically motivated -- a weighted sum of impulses corresponding to two special kinds of plastic collisions -- and lies in a plane proposed independently by Rubin [20]. We describe useful properties of our model, show geometrically the behavior ranges it captures for several types of collisions, and compare with some well known models. We suggest constructing combined collision models from this and other well-understood models, for fitting data better. View Show abstract
Robot Hands and the Mechanics of Manipulation Control of planar rigid body sliding with impacts and friction Jan 1985 336-348 M T Mason Salisbury Jr J K C B Spong
Mason, M. T., and Salisbury Jr., J. K. 1985. Robot Hands and the Mechanics of Manipulation. Cambridge, MA: MIT Press. Partridge, C. B., and Spong, M. W. 1999. Control of planar rigid body sliding with impacts and friction. International Journal of Robotics Research 19(4):336–348.
Impulsive Manipulation Available as Carnegie Mellon Robotics Institute technical report Jan 1997 97-29 W H Huang
Huang, W. H. 1997. Impulsive Manipulation. Ph.D. thesis, Carnegie Mellon University, Pittsburgh, PA. Available as Carnegie Mellon Robotics Institute technical report CMU– RI–TR–97–29.
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Discover more about:
Feedback Control
Conference Paper
Experiments in impulsive manipulation
June 1998
W.H. Huang M.T. Mason
In this paper, we present the results of our experimental effort
in one form of impulsive manipulation: tapping. Our previous work
studied the mechanics of tapping a planar object which then slides on a
support surface, coming to rest due to friction. This work addresses the
practical issues in creating a system which uses this mode of
manipulation. We begin with the design of tapping devices-end ... [Show full abstract]
effecters
designed to deliver an impulse to an object, and report some of the
issues we have found to be important in their design. Our next step was
to perform single-tap experiments in order to fit and evaluate the
models of impact and sliding. These experiments have shown that objects
rotate less than predicted; we have found that the addition of a scaling
factor for the torque due to friction enables the models to predict
object motion reasonably well. In order to do positioning experiments,
we developed a number of planning methods (or feedback control
strategies) to compensate for errors in modeling, parameters, and
actuation. These planning methods were successfully used to demonstrate
a positioning task. We also have experimentally demonstrated that
tapping can be used to position an object more precisely than the
manipulator can position the tapping device. We offer some sensitivity
analysis in support of this result
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Use and overuse of diagnostic neck ultrasound in Ontario | The College of Family Physicians of Canada
Use and overuse of diagnostic neck ultrasound in Ontario
Retrospective population-based cohort study
Stephen F. Hall and Rebecca Griffiths
Canadian Family Physician February 2020, 66 (2) e62-e68;
Article
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Abstract
ObjectiveTo provide an overview of the use and possible overuse of diagnostic neck ultrasound (DNUS) by describing and comparing both the ordering rates and the downstream results of DNUS by regions across Ontario.
DesignRetrospective population-based cohort study based on electronic health care data.
SettingOntario.
ParticipantsOntario residents (adults aged > 18 years) who had a diagnosis of thyroid cancer between October 1, 1999, and June 30, 2014, and residents who had a DNUS in 2012.
Main outcome measuresProportion of Ontario residents in each sub–Local Health Integration Network (LHIN) group who had their first DNUS in 2012 and went on to other relevant tests, diagnoses, and surgery. The sub-LHIN groups were based on increasing age- and sex-adjusted rates of first DNUS.
ResultsThere were 77 238 DNUS tests in 2012 and there was a 7.4-fold variation in the rate of test ordering across the sub-LHIN populations leading to variable rates of actual disease, suggesting screening or uncertain indications for tests.
ConclusionAcross Ontario, the indications for ordering DNUS are variable, and screening or testing without indication might be a common practice. Establishing effective guidelines for the ordering of DNUS would potentially reduce costs and ultimately reduce the rates of thyroid cancer.
The overuse of medical testsis the ordering of tests that are unnecessary or inappropriate, and represents poor use of resources. Berwick and Hackbarth 1estimated that 6% to 8% of annual health care expenses in the Unites States (the equivalent at least $270 billion) could have been defined as overusein 2013. Research on the overuse of medical tests in inpatient and outpatient medical practice 2 – 5has led to the development of campaigns and coalitions such as Choosing Wisely, 6 , 7the Right Care Alliance, 8 , 9and Wiser Healthcare. 10Owing to many factors, including the over-reporting of poor evidence by various media, many physicians and members of the public believe that more tests are better, as they might uncover treatable disease, 11 , 12and in clinical practice, physicians order routine tests for a variety of reasons. 13
The diagnosis of thyroid cancer is increasing at epidemic rates throughout Canada, 14 – 16the United States, 17and the world. 18 , 19It is now agreed that the increasing “incidence” is actually the increasing detection 19 – 22of smaller cancers owing to the increasing use and sophistication of diagnostic neck ultrasound (DNUS), as there is no evidence of increased incidence of thyroid cancer or changes in causation. 19Although there are indications for DNUS, rates of use vary widely. 15 , 21
The objective of this study was to provide an overview of the use and possible overuse of DNUS by describing and comparing both the ordering rates of DNUS and the downstream results of DNUS by regions across Ontario. The universal health care and electronic data holdings at ICES, which include all health care encounters for the population of Ontario, provided the opportunity to perform this audit and feedback study.
METHODS
Data set creation
The electronic data holdings of ICES include all health care–related events for the complete population of insured Ontario residents linked using anonymous unique identifiers. Linkages include all hospital encounters and all physician billing data for treatments, investigations, and procedures thus creating the clinical story for each anonymized patient.
Setting
The population of the province of Ontario is approximately 14 million. For the funding and provision of health care, Ontario is divided into 14 regions (Local Health Integration Networks [LHINs]); however, as the LHINs vary in size, geography, rurality, and ethnicity of the population, they are subdivided into 97 sub-LHINs to improve homogeneity for analysis.
Data sources
We used several data sources for this study:
The Ontario Cancer Registry (OCR) is a population-based cancer registry that includes all incident cases of cancer, patient demographic characteristics, and dates of diagnoses.
The Ontario Health Insurance Plan (OHIP) database contains data on all fee-for-service claims submitted by and paid to physicians, including office visits, consultations, laboratory tests, imaging tests, and biopsies. The data include the dates of all encounters, the referring physician, and the physician type or specialty.
The Registered Person’s Database provides demographic information on all residents of Ontario who are eligible for OHIP.
The Canadian Institute for Health Information includes the Discharge Abstract Database, with information on all hospital discharges, and the National Ambulatory Care Reporting System data set of outpatient hospital visits.
We used version 9 of the sub-LHIN boundaries (Ontario Ministry of Health and Long-Term Care, 2010) for this project.
Overview and study populations
Based on diagnostic codes in the OHIP fee schedule for DNUS (J105, J405), we identified all patients in Ontario older than 18 years of age who had their first DNUS in 2012. We excluded patients who had had a previous DNUS (within 2 years) or a previous diagnosis (within 10 years) of thyroid cancer, head and neck cancer, or leukemia or lymphoma. We were interested in the use of DNUS as a screening test, so we included only tests ordered by family doctors, emergency department physicians, and geriatricians.
The yearly incidence of thyroid cancer was based on all patients older than age 18 with a diagnosis of thyroid cancer (ICD code 193) in the OCR between October 1, 1999, and June 30, 2014, who had initial therapeutic thyroid surgery (hemithyroidectomy, subtotal thyroidectomy, or total thyroidectomy) based on Canadian Institute for Health Information codes between January 1, 2000, and December 31, 2013 (N = 26 311). All patients were included regardless of histology findings.
Outcomes
The outcomes were the downstream tests and diagnoses after the first DNUS in 2012 and included 1 or more events within 1 year (a second DNUS, another imaging test [computed tomography of neck, magnetic resonance imaging of neck, barium swallow, computed tomography of chest], any neck surgery for common benign [eg, branchial cleft cyst] or malignant neck disease [eg, neck dissection]) or the diagnosis of other cancers that present as neck masses, including head and neck cancers, lymphoma, and lung cancer within 2 years. A diagnosis of thyroid cancer was based on the ICD code 193 in the OCR and included only those who had initial therapeutic thyroid surgery (hemithyroidectomy, subtotal thyroidectomy, or total thyroidectomy) (CCP codes 19.1, 19.2, 19.21, 19.29; CCI codes 1FU87, 1FU89). Rates of downstream events are reported as the proportion of those who had the initial DNUS in each sub-LHIN group and are not adjusted for age or sex.
Analysis
The 97 sub-LHINs of Ontario were divided into 5 evenly spaced groups (fixed bins) based on the range of the increasing age- and sex-standardized rates (age > 18 years) of DNUS in 2012, with the denominator of the population of each sub-LHIN in 2012 according to the Registered Persons Database. The Cochran-Armitage trend test was used to assess linear trend in outcome proportions across increasing exposure categories.
Ethics
Ethics approval was granted by the ethics review boards of Queen’s University in Kingston, Ont, and Sunnybrook Hospital in Toronto, Ont.
RESULTS
There were 115 660 DNUS tests in 2012; 37 443 residents who had had a previous DNUS and 979 who had a previous diagnosis of thyroid, head and neck cancer, or hematologic cancer were excluded—leaving a total of 77 238 DNUS tests.
The overall rate of DNUS across the province was 1900.70 per 100 000 people. The rates of DNUS for the 5 sub-LHIN groups in increasing order were 1049.44, 1394.07, 2189.12, 2776.82, and 3512.84 per 100 000 people. The rates across all 97 sub-LHINs ranged from 505.90 to 3715.47 per 100 000 people, representing a 7.4-fold difference across Ontario (Figure 1).
Figure 1.
The proportion of a first DNUS in 2012, by sub-LHIN groups
DNUS—diagnostic neck ultrasound, LHIN—Local Health Integration Network.
The downstream events (second ultrasound, fine-needle aspiration, other imaging test, neck surgery within 1 year, and new cancer diagnosis within 2 years) overall and the proportion of those who had had the initial DNUS in 2012 (sub-LHIN groups) are presented inTable 1. The rates of subsequent tests (that might suggest a reported abnormality on the initial DNUS) such as needle biopsy or other relevant imaging declined with increasing use of the initial DNUS. The rates of thyroid or neck surgery declined with increasing use of DNUS. Overall, 24.36% of patients had a second DNUS, but paradoxically the rates of a second DNUS increased with increasing rates of the initial DNUS. The true incidence of thyroid cancer in the general population is not known, and interestingly the rates of thyroid cancer initially rose with increasing tests and then declined, suggesting a threshold or saturation effect. The rates of other malignancy declined with increasing use of DNUS.
View inline
Table 1.
Downstream events: The proportion of the Ontario patients in each sub-LHIN group who had their first DNUS in 2012 who went on to other relevant tests, diagnoses, and surgery. The sub-LHIN groups are based on increasing age- and sex-adjusted rates of first neck ultrasound in adults.
Figure 2presents the 180% increase in thyroid cancer diagnosis by year across Ontario.
Figure 2.
Increasing incidence of thyroid cancer diagnosis in Ontario, by year
DISCUSSION
The objective of this study was to provide an overview of the use and possible overuse of DNUS against the backdrop of the increasing rate of thyroid cancer detection and the variation in the rates of thyroid cancer across Ontario. 15We found a 7.4-fold difference in the rates of ordering DNUS across the sub-LHIN regions, consistent with previous Ontario reports on both DNUS and the geographic differences in rates of thyroid cancer diagnosis. 15 , 23When we examined the outcomes of 77 238 tests, we found both low yield and that the frequency of important events declined with increasing use of initial tests, suggesting that DNUS might be being used for screening or for testing without indication. The increasing rates of a second DNUS within 1 year suggest that repeat imaging also might have variable indications.
Overdiagnosisoccurs “when a condition is diagnosed that would otherwise not go on to cause symptoms or death,” 24and typically refers to the detection of subclinical diseases or conditions by tests that were not indicated. 15 , 19The importance of these results is the waste of resources—not only the imaging test but also the subsequent cascade of tests, consultations, surgery, and follow-up when it is clear that most patients were not going to need treatment, as they would never have been diagnosed. There is no evidence that the actual prevalence of thyroid cancer has increased and there is no new pathogenesis or cause. 19The increased rates of new cases are the result of detection by DNUS of what were previously undetected cases. There is ample evidence from sources such as autopsy studies, 25incidence versus mortality curves, 24 , 26population-based studies, 27 , 28and observational trials 29 – 31that a large proportion of thyroid cancer cases behave in a benign way, would never have appeared, and would never have needed treatment. Differentiated thyroid cancer has a 98% 15-year survival 28 – 32even after treatment delay. 27 , 31
The American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi have suggested guidelines for the investigation of thyroid disease: “ultrasound evaluation is recommended for patients who are at risk for thyroid malignancy … have palpable thyroid nodules or goiter, or have neck lymphadenopathy suggestive of a malignant lesion.” 33Choosing Wisely Canada, and more specifically the second of 5 recommendations from the Canadian Society of Endocrinology and Metabolism, states, “Don’t routinely order a thyroid ultrasound in patients with abnormal thyroid function tests unless there is a palpable abnormality of the thyroid gland.” 34For the investigation of a patient with other suspect benign, malignant, or infectious diseases with no previous neck disease, there are at least 6 clinical indications for DNUS (a palpable neck mass, a visible neck mass or asymmetry, the sensation of swelling in the neck, unexplained pain in the anterior or lateral neck, abnormal parathyroid hormone levels, and further investigation of an incidental thyroid abnormality on other imaging). It is unlikely that rates of these indications would vary 7 times across the sub-LHINs of Ontario, suggesting indistinct indications for DNUS, screening, testing without indications, and test overuse.
The definition of overuseby Chassin et al 35is “the provision of medical services for which the potential for harm exceeds the potential for benefit,” and overuse is particularly relevant in thyroid cancer, in which the rates of complications of treatment exceed the rates of disease-specific mortality. 20 , 27 , 32 , 36 , 37Our data suggest that the use of DNUS without clinical indication or as a screening test might be at least partially responsible for the 180% increase in the rate of diagnosis of thyroid cancer from 2000 to 2012 in Ontario.
In our recently published study on medical test variations, we used an entirely different methodology. 38We divided 6849 Ontario physicians based on their OHIP billing codes for 23 routine laboratory and imaging tests for their 4.9 million patients over 5 years into higher testers (26%), typical testers (41%), and lower testers (33%). We found that the higher testers ordered 80% more imaging tests than typical testers did and, not surprisingly, diagnosed more thyroid (and prostate) cancers than the typical and lower testers did. The lower testers diagnosed fewer thyroid cancers. We also found wide variation in the rates of ordering the 23 common tests.
“A cautionary tale for the rest of the world” about screening has been presented by Ahn et al 18based on the experience of South Korea. In 1999 South Korea introduced optional routine DNUS screening for thyroid cancer. After 1999, the very slow gradual increase in thyroid cancer cases abruptly changed; the incidence of thyroid cancer increased 15 times between 1993 and 2011, and thyroid cancer became the most commonly diagnosed cancer in South Korea (in Canada, thyroid cancer is the fifth leading cancer in women behind breast, lung, colon, and uterine cancer 39). Park et al of the Korean National Cancer Control Institute recommends that “concerted efforts are needed at [a] national level to reduce unnecessary ultrasound examination of the thyroid in the asymptomatic general population, unless clinically indicated.” 40
Strengths and limitations
The study design and the complete data set are the strengths of this study. There are 3 potential limitations. In the ideal study, the indications for the test would be included in the analysis but this is not available in the OHIP data set. The second limitation is that we cannot differentiate between thyroid and general neck ultrasound requests, as the OHIP fee code is the same for both. The third limitation is that we cannot assess the effect of access, as we had no data on the density of ultrasound equipment or clinics in Ontario.
There are 2 studies on the appropriateness of thyroid ultrasound and 1 on the appropriateness of general DNUS. Liel and Fraenkel 41reported that 93% of thyroid ultrasounds were inappropriately ordered based on 208 new patient referrals in an endocrinology clinic. Landry et al 42reported in a Canadian study that 18.8% of thyroid ultrasounds were inappropriately ordered based on a review of 620 ultrasound requests by GPs. Russell and Madani 43reviewed 68 neck ultrasound requests at a single diagnostic facility; they found 16% were inappropriate based on the iRefer guidelines and suggested reducing access to DNUS as a potential solution.
Falchook et al 44provided a useful example of the inappropriate use of bone scans in prostate cancer patients. They reported that 21% of patients at low risk and 48% of patients at moderate risk of bone metastases underwent at least 1 scan despite recommendations against screening in these groups. They calculated the estimated cost of the overuse to be more than $11 million (US) per year. In Ontario, if one-third of the DNUS examinations in 2012 were not performed, the savings would have been almost $2 million for those 25 746 tests alone, 45not including the subsequent tests, investigations, treatments, follow-up, and complications of potentially unnecessary treatments.
Conclusion
Across Ontario, the indications for ordering DNUS are variable and screening or testing without indication might be a common practice. Establishing effective guidelines for the ordering of DNUS would potentially reduce costs and ultimately reduce the rates of thyroid cancer.
Acknowledgments
This project was funded by the Applied Health Research Question program of the Ontario Ministry of Health and Long-Term Care (OMHLT). This project was approved by the Cancer Program at ICES, which is an independent, non-profit research organization that is funded with an annual grant from OMHLT. The opinions, results, and conclusions reported in this paper are those of the authors. No endorsement by ICES or OMHLT is intended or should be inferred. The data set creation and data analysis were performed at ICES Queen’s byMs Rebecca Griffiths. The sub–Local Health Integration Networks map was created byDr Paul Nguyenof ICES Queen’s. Parts of this work are based on data and information provided by Cancer Care Ontario (CCO). The opinions, results, views, and conclusions reported in the paper are those of the authors and do not necessarily reflect those of CCO. No endorsement by CCO is intended or should be inferred. Parts of this work are based on data and information compiled and provided by the Canadian Institute for Health Information. The analyses, conclusions, opinions, and statements expressed herein are those of the authors and not necessarily those of the Canadian Institute for Health Information. This research was presented at conferences including Preventing OverDiagnosis in Barcelona, Spain, in September 2016, and the Annual Meeting of the Canadian Society of Otolaryngology—Head and Neck Surgery in Saskatoon, Sask, in June 2017.
Notes
Editor’s key points
▸ The objective of this study was to provide an overview of the use and possible overuse of diagnostic neck ultrasound (DNUS) against the backdrop of the increasing rate of thyroid cancer detection and the variation in the rates of thyroid cancer across Ontario. This study found a 7.4-fold difference in the rates of ordering DNUS across the sub–Local Health Integration Network regions of Ontario.
▸ When the authors examined the outcomes of 77 238 DNUS tests, they found both low yield and that the frequency of important events declined with increasing use of initial tests, suggesting that DNUS might be being used for screening or for testing without indication. The increasing rates of a second DNUS within 1 year suggest that repeat imaging also might have variable indications.
Points de repère du rédacteur
▸ Cette étude avait pour but de donner un aperçu de l’utilisation et de la possible surutilisation de l’échographie diagnostique du cou (EDC) dans le contexte de la hausse du taux de dépistage du cancer de la thyroïde et de la variation des taux de cancers thyroïdiens dans les différentes régions de l’Ontario. L’étude a fait valoir une disparité de l’ordre de 7,4 dans les taux de prescription de l’EDC dans les divers sous-groupes des Réseaux locaux d’intégration des services de santé de l’Ontario.
▸ Lorsque les auteurs ont examiné les issues des 77 238 examens par EDC, ils ont trouvé à la fois un faible rendement, de même que le déclin de la fréquence des événements importants avec le recours accru de l’utilisation des tests initiaux, ce qui porte à croire que les EDC pourraient être utilisés pour un dépistage ou des examens en l’absence d’indications. Les taux accrus d’une deuxième EDC durant la même année suggèrent aussi que l’imagerie répétée pourrait aussi avoir des indications variables.
Footnotes
Contributors
Dr Halldesigned the study, is responsible for all aspects of data analysis and interpretation, and wrote the manuscript.Ms Griffithsperformed the data acquisition, performed the analysis, provided critical revisions to the manuscript, and approved the final manuscript.
Competing interests
None declared
This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
Copyright© the College of Family Physicians of Canada
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Improving Outcomes of Severe Adult Asthma
In this episode, Dr Rizzo interviews Sally E. Wenzel, MD, to discuss her review titled “Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics,” examining comorbidities (including those that could mimic severe asthma) pulmonary function testing, and biomarker assessments. Podcasts
Improving Outcomes of Severe Adult Asthma
This podcast series aims to highlight clinical advancements in pulmonology, sleep medicine, and critical care medicine. Moderator, Albert Rizzo, MD, interviews prominent health professionals to help our community gain insight on leadership lessons learned.
Podcasts360 · Improving Outcomes of Severe Adult Asthma: Critical Observations in Pulmonary Medicine, Ep. 5
In this episode, Dr Rizzo interviews Sally E. Wenzel, MD, to discuss her review titled “Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics,” examining comorbidities (including those that could mimic severe asthma) pulmonary function testing, and biomarker assessments.
Additional Resources:
Wenzel SE. Severe adult asthmas: integrating clinical features, biology, and therapeutics to improve outcomes. Am J Respir Crit Care Med . 2021;203(7):809-821. doi:10.1164/rccm.202009-3631CI
Nagasaki T, Schuyler AJ, Zhao J, et al. 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation. J Clin Invest. 2022;132(1):e151685. doi:10.1172/JCI151685
Zhao J, Dar HH, Deng Y, et al. PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells. Proc Natl Acad Sci U S A. 2020 Jun;117(25):14376-14385. doi:10.1073/pnas.1921618117
Sally E. Wenzel, MD, is a professor of medicine and immunology and acting director of the University of Pittsburgh Asthma and Environmental Lung Health Institute@UPMC.
Albert A. Rizzo, MD, is the chief medical officer of the American Lung Association and a member of ChristianaCare Pulmonary Associates in Newark, Delaware.
TRANSCRIPTION:
Moderator: Hello, and welcome to Critical Observations in Pulmonary Medicine, led by Chief Medical Officer of the American Lung Association, Dr Albert Rizzo, the views of the speakers are their own and do not reflect the views of their respective institutions.
Dr Albert Rizzo: Thank you for listening today, and welcome to this next episode of Critical Observations in Pulmonary Medicine. I am fortunate today to speak with Dr Sally Wenzel, who practices pulmonary allergy and critical care medicine. She is a professor of medicine in immunology and the Rachel Carson Chair in Environmental Health, as well as the chair in the Department of Environmental and Occupational Health. And she is also the acting director at the University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC.
So thank you for taking the time today to speak about an important topic, severe asthma, that by many estimates could include up to 5 to 10% of the patients with asthma. You have published extensively on this topic, and I would refer our listeners to your concise clinical review of this topic that was published in the American Journal of Respiratory and Critical Care Medicine back in April of 2021. To start off, would you please define what severe asthma should mean to a clinician?
Dr Sally Wenzel: Well, severe asthma is something that actually should probably concern a clinician. The first time they see a patient, these remain difficult to manage patients and very complex patients. And I think it's very important to go through multiple different steps to try to understand these folks who come in with an ostensible diagnosis of severe asthma. And so the first step is that you have to make sure that the patient has asthma. That sounds like such a simple thing, but it's really not. Patients can develop asthma anytime in their life. The concept that all asthma is a pediatric disease and just migrates into childhood, of course, is, is not correct. And there are people that can develop asthma after a respiratory infection. There are people that can develop asthma after a job change that they're exposed to various occupational threats. And, and of course, just for no reason at all, at least that we can identify.
And, and these are patients who, when you see them, it's really critical to do very well performed spirometry both before and after a bronchodilator. Asthma is still defined as reversible airflow limitation. Now that doesn't mean reversing back to normal. That's a common misperception, but they really need to have some element of reversibility of at least 12% or 200 MLS, or they cannot have a diagnosis of asthma. Now you can do it several times, but you still need to need to confirm at some point that they have a reversible component to the airway. And why is that important? That's really important because it helps to identify which treatments are appropriate for given patients. If a patient has truly has COPD, non-reversible, generally nonreversible airflow limitation, the responses to treatment are going to be very different than what might one might see in, in an asthmatic condition.
And then of course there are other things like bronchitis, even bronchiectasis that often masquerades as asthma, but really are not. And then of course, you've got vocal cord dysfunction on the other end, where you really have almost completely normal spirometry for the most part, but evidence of upper airway obstruction. So, all of those things can sometimes be labeled as severe asthma, but they're really not even asthma. So, let's get that first step out of the way and make sure that they have asthma. And then I think once you have determined that they have asthma, one has to identify whether this is really asthma, that if you, you address a few of the comorbid conditions that I know, we'll probably talk about later if you address things like current smoking if you address things like reflux disease if you address things like nasal congestion and postnasal drip that their asthma will in fact be manageable.
And certainly, I think that's the first piece of this. So to address those and then to if you've addressed those and the patient is still having symptoms, make sure that you're optimizing their asthma prescription medications. So again, are they on the the gold standard for the treatment of asthma, which is of course, high-dose inhaled corticosteroids in combination with a long-acting beta-agonist that is still the gold standard for the treatment of asthma and specifically severe asthma. And when you have a patient who you've addressed all those comorbid conditions, as best you can, you're convinced that they really have asthma, and when they are either still symptomatic on high dose, what we define is high-dose inhaled corticosteroids with a long-acting beta-agonist, or who really require that dose to maintain their asthma, then you have a patient who truly has severe asthma.
And that was the definition that was provided by the European Respiratory Society and the American Thoracic Society, now close to 10 years ago, actually, but I think is still pretty much the gold standard today. And, and again, it really does require a rather extensive evaluation to assess all of those things. And as part of that, we would even recommend that in these complex patients that they spend at least three months under the care of an asthma specialist, an allergist, a pulmonologist who can address all these things in, in detail before you actually give the person a diagnosis of severe asthma.
Dr Albert Rizzo: This is assuming that they're adherent to the regimen you want them to be on.
Dr Sally Wenzel: Absolutely.
Dr Albert Rizzo: And, and is that 5 to 10% of the asthmatics? Is that a good number to think?
Dr Sally Wenzel: I think it is a good number. I absolutely do think it's, it's a good number. You know, there have been some very rigorous studies that have been done in Europe that got to about 4%, but I think they actually probably eliminated some folks that they maybe should not have eliminated. So, I would say 5 to 10% is, is pretty close.
Dr Albert Rizzo: OK. Yeah. And you touched quite a bit on some of the, the comorbidities that I know many of these patients can have, and as you kind of mentioned, these comorbidities sometimes mimic asthma and you need to make sure you're not missing actually the underlying asthma when they have something else going on. I think you touched on that very nicely, and we know that the primary care physicians or the pediatricians are the ones who are frontline at this point and they have to be the ones then decide to move the patients on other than the spirometry that you mentioned, I think there are a number of other terms that are used looking at biomarkers, whether it's high-T2, low-T2, early-onset, late-onset, can you kind of break that down somewhat and tell us what biomarkers or other testing may be helpful to make some distinction among these patients?
Dr Sally Wenzel: Yeah, I think it's a very exciting time for asthma because we can start to think about asthma in the realm of precision medicine that we have directed treatments that will help certain people, and even non-specific treatments seem to help certain people better. And so, I think in 2022, any patient with asthma should be assessed at a minimum for whether they have a disease that is type 2 high, th2 high, or not. And the current gold standard for that is something that everyone, almost everyone, can measure in their clinical labs, whatever that supports them is just a complete blood count with a differential. It's one of the cheapest tests that you could even order today as a clinician. And so you want to look at the eosinophils, and for years, eosinophils have been completely ignored on a differential. It was like, well, you know, is there neutrophilia or not?
No, we're, we are really talking about are the eosinophils present? And in fact, are they elevated? And the threshold for what's high eosinophils has somewhat varied from study to study and, and the guidelines to guidelines, but in someone who's not on any inhaled corticosteroids, not on any systemic steroids like prednisone, then I think you would want to see the eosinophils be about 300 or above. Anything 300 or above is considered abnormally high eosinophils in an asthma population and qualifies them for a type 2 high asthma patient. And we say type 2 high, as opposed to th2 high, because other cells besides th2 cells can make these cytokines or these biochemicals that actually drive this type of inflammation that produces eosinophils, IL-4, 5, and 13. And those are important cytokines to actually remember because there are therapies targeted to them, but we now refer to it as type 2 high, as opposed to th2 high, because other cells can make them, besides th2 cells.
So in people that are on high doses of inhaled corticosteroids already, or even certainly people that are on prednisone on a daily basis, you cut that threshold a little bit lower, and it really goes more to around 150, but I think you still want to have at least 150 before you would call a person a truly a type 2 high asthmatic. There's a lot of overlap between eosinophilic asthma and type 2 high asthma. They're not completely the same thing. I think eosinophilic is a subset of type 2 high asthma that you can have people, because of their inhaled corticosteroids or their systemic corticosteroids, where you can't measure eosinophils in their blood. So you say, okay, they are eosinophil low, but if you look for other biomarkers of type-2 inflammation, you find that they're elevated. So eosinophilic high is a subset of type 2 high asthma.
And so that's the first thing that I think any clinician after you've seen a patient probably twice for asthma, I don't think you have to do it the first time you see an asthma patient, but once you've seen a patient because of follow up and maybe they're not doing quite as well as, as you would like a low dose inhaled corticosteroids, then I think it's time to get a CBC and just start phenotyping them, or assigning them to type 2 high or type-2 low asthma. And I think that we know that inhaled corticosteroids are again, gold standard for the treatment of all asthma patients for that matter, seem to work better in people that have evidence of type-2 inflammation. So, if you have elevated eosinophils in your blood, you're likely to respond to inhaled corticosteroids. If you have no eosinophils in your blood, and you've never been treated with corticosteroids before, chances are, you won't respond as well as if you had some measurable eosinophils in your blood. And that's, I think at the primary care level, that's really all you need to do to start characterizing the patients. I think once you get to the specialist level, then I think there are more things that should be done.
Dr Albert Rizzo: And where would the term allergic asthma come into play at this level?
Dr Sally Wenzel: Yeah, so again, that's a very excellent question. And it's another subset or umbrella under the big umbrella of type 2 high asthma for the most part. So allergic asthma is typically asthma that develops in childhood. It's typically associated with other allergic conditions like allergic rhinitis, hay fever, those sorts of things, sometimes with eczema. And it is typically associated with evidence for type-2 inflammation, so elevated blood eosinophils, but not always. There are people that have allergic asthma that you rarely see an eosinophil in the blood. And again, I think that's been a point of confusion for many people. It's, well, they're allergic, they must be type 2, but that doesn't always happen to be the case. And in fact, the drugs that we use to treat patients with this type 2 high asthma actually seem to work a little bit better in people with a disease that isn't necessarily characterized by allergic symptoms, and the less allergic asthma patients seem to do as well, if not better, than the allergic patients.
Dr Albert Rizzo: Before we talk about some of the other biomarkers, you mentioned spirometry being very important, obviously. What role at this point is the methacholine of the bronchoprovocation studies? Is that something that primary care physicians should be thinking about or is that really in the realm of the specialist?
Dr Sally Wenzel: Yeah, I would say that the methacholine challenges are generally going to be things that the specialist is going to use. I think a primary care physician can do repeated spirometry that I think is very easy. And one of the little tricks that I like to do is actually if a patient comes to me and they said “oh, you know, last week I was feeling terrible, and I got some prednisone from my brother or whatever, and now, you know, now I'm feeling good.” So, they come in with normal spirometry. I like to say, just, you know, let me know if you're having any increase in your symptoms. Give me a call, and then I'm going to order spirometry for you when you're having symptoms because spirometry is much more likely to be abnormal when someone's having symptoms and when they're not.
And you're much more likely to demonstrate that reversibility if a patient is having symptoms than when they're not, and most primary care offices can still call, you know, their local lab or whatever, and get a patient in within a window. And I don't know, everyone's very, every setting is different, obviously. And if it takes two weeks to get somebody spirometry, well, that may be too late, but certainly, I think that's a really nice way to demonstrate both obstruction and reversibility if you didn't demonstrate it when they first came into the office.
Dr Albert Rizzo: Very good. Talk about some of the other biologics. I know we have an older one that really dealt with the IgE antibody. And then as you mentioned, we have the, IL-4, IL-5 receptors. And now more recently, the thymic stromal lymphopoietin. Can you just kind of talk a little bit about the inflammatory cascade, where these biologics, where these cytokines and antibodies play a role and then how we get the targeted medications that help individuals?
Dr Sally Wenzel: Yeah. So again, all of this falls under the big umbrella as we've been talking about of type 2 high asthma. And type 2 high asthma seems to be associated with th2 cells, T-helper type-2 cells, and or some other cells, including maybe macrophages and monocytes that also seem to make these cytokines, as well as innate lymphoid cells, and maybe even mass cells. So, there's a range of different cell types that, under certain circumstances, may be related to allergies, may be related to viruses, may be related to family history, and environmental exposures that we don't even fully understand that causes cells to start making these cytokines, IL-4 and IL-13. And really, IL-4 is probably the first critical cytokine here, in that it's the one that actually develops th2 cells. And without IL-4, you can't have a th2cell.
So that starts the development of the th2cell. The th2 cells then make the cytokines, IL-4, IL-5, IL-13, these cytokines then can activate B cells. And by activating B cells, they make IgE, which is part of this cascade. IgE then combines to mass cells. Once it’s bound to mass cells, it serves as a receptor for various IgEs that are made to allergens– cats, dust, mites, cockroaches, etc., all those things– which the antibody binds to, and then binds to the mass cells on through the IgE receptor and activates the mass cell and that sort of the mass cell allergic cascade part of the paradigm. But then in addition, it's very complicated, these IL-4, certainly IL-5, and IL-13, we know can be made by these innate lymphoid cells.
So innate lymphoid cells are not th2 cells. They are a different type, what they call lineage negative lymphocytes, that make IL-5 and IL-13, maybe a little bit of IL-4, and they seem to be activated by viral-related pathways, maybe bacterial-related pathways, but they don't require T-helper cells to function. But once they start making IL-5 and IL-13, then you can start activating the same processes that you would if it was coming from a th2cell. It's just that it starts at a different level. And it, and at least there's some suggestion that it may start later in life and may be associated with people that have nasal polyposis as part of their asthma characteristics. They have nasal polyps as part of that. And the ILC-2 cells are also stimulated, of course, then by this new cytokine, this TSLP, thymic stromal lymphopoietin.
Dr Albert Rizzo: I had the same problem.
Dr Sally Wenzel: It’s a hard thing to say all at once but anyway, thymic stromal lymphopoietin, TSLP, that is felt to be generated primarily by epithelial cells and epithelial cells in response to virus. And so it may be that at some point in your life, you were exposed to a virus that caused your epithelium to produce this TSLP that then stimulated these innate lymphoid cells. And these innate lymphoid cells started making these cytokines that then drive an asthma reaction, with increases in mucus, with increases in these blood eosinophils, and another biomarker that we haven't talked about, which is of course, exhaled nitric oxide.
Dr Albert Rizzo: So, when you're presented with, or we have a patient with severe asthma who you now are starting to decide that a biologic may be for them, how do you start sorting out which the biologic is right for that particular patient?
Dr Sally Wenzel: Yeah. Again, this a is really an important question and one that there is not a black and white, yes and no answer on. And I think this is where it is important to have a specialist see a patient, because it's not an easy decision to make. I think the data would suggest that the anti-IL-5s and anti-IL-5 receptor antibodies, and there are three of them that are available in the US that those work better in people that don't have an allergic type of asthma. So, if you have someone who got their disease later in life, after the age of 18, maybe even 12 but later in life, specifically if they have nasal polyps, specifically if they have severe disease that requires corticosteroids, oral corticosteroids, prednisone a lot, those are the patients who seem to do pretty well with anti-IL-5, if you've had your disease your whole life.
And you're very allergic to, you know, the neighbor's cat, then anti-IL-5 is not likely the best treatment for you. And even the data in children is very limited with the anti-IL-5 and, of course, allergic asthma is typically the type of asthma that begins in childhood. So, if anti-IL-5 are only marginally effective in patients who are above the age of 12, and it’s Nucala, sorry, mepolizumab is approved for children, I believe above the age of 5 to 12, but it really was based, not on efficacy studies, it was based on safety studies. And so, it's really hard to know whether the anti-IL-5 in the younger allergic asthma population has any efficacy. So, if you get a whiff of allergies in the patients, I would consider another drug. And that's probably the first sort of cut point that I use.
If there are allergies, then I would consider an anti-IL-4 receptor antibody, especially if there's evidence of type-2 inflammation, especially if there's an elevated blood eosinophil count or an elevated exhaled nitric oxide, I would positively consider that before I would consider omalizumab. And the reason for that is even when you cut the data by the high type-2 biomarkers with omalizumab, the data on reduction in exacerbations and improvement in lung function is not as good as what you see with dupilumab with the IL-4 receptor antibody. So again, just based on published data, I would start with the IL-4 receptor antibody. Now, if you have somebody who has had asthma since their childhood, and they are allergic, but you can't find a type-2 biomarker anywhere, then I would probably start with omalizumab. I think that that's not an unreasonable choice at all.
And then finally, you know, the newest kid on the block is the anti-TSLP Tezepelumab, and I don't think we know really where that fits yet, to be quite honest with you. You know, the data in their oral corticosteroid sparing study was not as good as the data was for the anti-IL-5 or the anti-IL-5 receptor antibody or the anti-IL-4 receptor antibodies. And that would make me think that at least it's possible that if you have a very severe asthma patient, who's on a lot of oral steroids, anti-TSLP Tezepelumab may not be the first choice that you probably should go with an anti-IL-4 receptor antibody or an anti-IL-5. On the other hand, the data with the Tezepelumab would suggest that maybe it's also efficacious in people with very low levels of type-2 biomarkers. So maybe you can extend the biologics down a little bit lower with Tezepelumab than you can with the dupilumab or mepolizumab and benralizumab, and I think that's sort of the little niche where that might be the first drug that you would try in a patient with very difficult type of asthma. But again, with the caveat that being on prednisone right now, doesn't seem to make you have a better response. Unlike the IL-4 receptor antibodies and the anti-IL-5.
Dr Albert Rizzo: You mentioned the exhaled nitric oxide, and I don't think you specifically mentioned the IgE antibody level. Are those levels of those two biomarkers? Do they play a role in helping you decide which drug to use or not?
Dr Sally Wenzel: Certainly, exhaled nitric oxide does. I am a pretty strong proponent of exhaled nitric oxide. IgE doesn't seem to predict much of anything, although the companies that started to develop omalizumab thought that would be a good biomarker for them. It ended up not being a good biomarker for them. Now, I think it's helpful, can be helpful in more complicated patients to help me as an asthma specialist understand them. But I think routinely an IgE level by itself, doesn't do very much specific IgE testing. So again, IG-specific IgE to dust mites, to dogs, cats, etc., ragweed, that can be helpful, even from an avoidance perspective. If somebody finds out that indeed they're allergic to dogs and, you know, they're sleeping with their dog, well, that might be something to consider, maybe not sleeping with your dog. But beyond that, I don't think that it really predicts responses to biologics very well.
Exhale, nitric oxide is something that requires specific testing equipment for, but it's very simple equipment. And the cost probably to actually do the test is somewhere between $20 and $30. Now, obviously there are all sorts of other layers on hospitals and clinics, etc., that have to be paid for. But the actual price of doing the test is still quite reasonable. And it is a very nice biomarker measured in people's breath of enzyme that generates this nitric oxide that's produced by the airway epithelial cells. It's produced by the airway epithelial cells, primarily under the influence of IL-4 and IL-13, not IL-5. Only IL-4 and IL-13. And so, if you see elevated levels of this, you can pretty safely determine that there is IL-4 and IL-13 active in this person.
And, and it responds very nicely to treatment with dupilumab. So, it, if it's high, you treat with dupilumab, there's typically at least a 50% reduction in the exhaled nitric oxide. So again, you know you've hit your target when you're treating somebody with dupilumab. And the degree of drop actually correlates with the degree of improvement in lung function, the degree of improvement in FEV1. So, for those reasons, I actually think it's a pretty good biomarker. Some people would also suggest that it's a biomarker of adherence and that if you have somebody and you say you put them on inhaled corticosteroids… inhaled corticosteroids typically make the exhaled nitric oxide levels go down. In more severe patients, that's not always the case. But in your average asthma patient, when you put somebody on inhaled corticosteroids, that exhale nitric oxide should be reduced. And so, if you have that situation and you don't… and again, the patient is still symptomatic, and their exhale nitric oxide hasn't changed after you put them on inhaled corticosteroids, it’s worth of having a conversation with the patient regarding their adherence to therapy.
Dr Albert Rizzo: Aside from the science behind which drug should be used, I know in the real world we have to deal with a couple things, like making sure that coverage by insurance is available. And those biomarkers, you mentioned, certainly have to be ticked off to the right levels for that to happen. And then I also wonder, do you see much difference that the dosing schedules for these medications in-office vs at-home administration, does that help some of your patients decide which one they want to use or do you direct them more?
Dr Sally Wenzel: Yeah, they can certainly, if you're concerned that someone is going to have difficulty administering their medications, the home situation isn't ideal or whatever, then certainly the less frequent at-home dosing is probably the best way to go. I think most medications are now available as at-home dosing, including omalizumab, which for years you could not dose at home but now has become available. And so, there is a difference between having a medication that you dose every two weeks vs every two months there. There's no doubt about that, but to be quite honest with you, at least in the severe asthma patients that I take care of, their main concern is that they feel better. And if they feel better, they are willing to inject themselves every two weeks. And I almost never had anybody say “You know, that's too often.” If I could only be on an every two months drug, I would do this.
Dr Albert Rizzo: Just switching gears a little bit. You mentioned T2-low earlier. Do you see a role for bronchial thermoplasty in this population of T2-low? What been your experience with thermoplasty?
Dr Sally Wenzel: Yeah, that's a really good question. And I am certainly of the belief that if thermoplasty has any true indication, it would be in somebody who has type-2 low inflammation. And we haven't as a scientific community really sorted that out yet. I mean, there are some studies, none of which are placebo-controlled that really have suggested that “oh, maybe it's your T2 high people that actually respond better to thermoplasty.” And then, you know, even though it was set up initially as a way to ablate the smooth muscle in the airways, the data to actually support that is still pretty modest. And there are other data to suggest maybe it's a change in the epithelium. Well, if there's a change in the epithelium and the epithelium secretes all these things to drive mucus production and so on, then maybe it's a broader treatment than that.
I will say that the few people that I've had under my care are that have had bronchial thermoplasty, when it's successful… and it's successful a portion of the time, and I don't want to say because my sample size is too limited to actually speak to that, but people would say 50, 60% probably of people respond… is that it's not a long-term effect that after three to five years, there's evidence that the whatever effect was there in the first place has actually gone away. And I actually don't know of anyone who's doing repeat thermoplasty, not in my practice. I'm sure there are some somewhere that have done repeat thermoplasty, but I have not. And it would scare me a little bit because you are structurally changing the airways when you do this and to do this repeatedly over time, good safety data to support that, would certainly make me concerned. I think thermoplasty came on the market really before the, IL-4, IL-5, and IL-13 drugs came on. And, you know, at one point it was the only other option that we had besides omalizumab and oral corticosteroids. And I think now there are so many other options on the market that seem to work really, pretty well in many people that I think thermoplasty is used less now than it was in the past.
Dr Albert Rizzo: Where do you see the future development of drugs, for least severe asthmatics heading? Are we going to see more biologics or what do you think at this point in time based on your experience?
Dr Sally Wenzel: Yeah, again, really good question. I think the biologics, the combinations of IL-4 receptor antibodies in the anti-IL-5s have probably done a good to a great job of treating somewhere between 50 and 70% of the severe asthma population. And, you know, I think that these have been transformative drugs. There's no doubt about that, but there still remains again, 25 to 50%, depending on where you cut the improvement, who are still having some degree of symptoms and some many people who haven't responded at all. So, I think… and then those people who have very little evidence of type-2 inflammation… so, I think trying to understand what are the pathways that are driving the other 25%, that don't have any evidence of type-2 inflammation. And then those people that actually don't respond as well to the type-2 biologics, even though they make the biomarker criteria for a type-2 biologic.
| https://www.consultant360.com/podcasts/improving-outcomes-severe-adult-asthma?page=2%3Fpage=6%3Fpage=7%3Fpage=6%3Fpage=7 |
UNIPROT:Q9BYE7 - FACTA Search
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Target Concepts:
Query: UNIPROT:Q9BYE7 (
PCGF6
)
15
The ring finger protein PCGF6 ( polycomb group ring finger 6 ) interacts with RING1A/B and E2F6 associated factors to form a non-canonical PRC1 (polycomb repressive complex 1) known as PCGF6 -PRC1. Here, we demonstrate that PCGF6 -PRC1 plays a role in repressing a subset of PRC1 target genes by recruiting RING1B and mediating downstream mono-ubiquitination of histone H2A. PCGF6 -PRC1 bound loci are highly enriched for promoters of germ cell-related genes in mouse embryonic stem cells (ESCs). Conditional ablation of Pcgf6 in ESCs leads to robust de-repression of such germ cell-related genes, in turn affecting cell growth and viability. We also find a role for PCGF6 in pre- and peri-implantation mouse embryonic development. We further show that a heterodimer of the transcription factors MAX and MGA recruits PCGF6 to target loci. PCGF6 thus links sequence specific target recognition by the MAX /MGA complex to PRC1-dependent transcriptional silencing of germ cell-specific genes in pluripotent stem cells.
...
PMID:PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes. 2844 Jul 49
In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6 -polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6 -PRC1 regulates the expression of only a subset of genes repressed by MAX . Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX -DNMT and MAX -SETDB1 pathways are independent of the PCGF6 -PRC1 pathway. Our findings provide insights into our understanding of MAX -based repressive mechanisms of germ cell-related genes in ESCs.
...
PMID:DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells. 3040 91
Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) control cell identity by establishing facultative heterochromatin repressive domains at common sets of target genes. PRC1, which deposits H2Aub1 through the E3 ligases RING1A/B, forms six biochemically distinct subcomplexes depending on the assembled PCGF protein (PCGF1- PCGF6 ); however, it is yet unclear whether these subcomplexes have also specific activities. Here we show that PCGF1 and PCGF2 largely compensate for each other, while other PCGF proteins have high levels of specificity for distinct target genes. PCGF2 associates with transcription repression, whereas PCGF3 and PCGF6 associate with actively transcribed genes. Notably, PCGF3 and PCGF6 complexes can assemble and be recruited to several active sites independently of RING1A/B activity (therefore, of PRC1). For chromatin recruitment, the PCGF6 complex requires the combinatorial activities of its MGA- MAX and E2F6-DP1 subunits, while PCGF3 requires an interaction with the USF1 DNA binding transcription factor.
...
PMID:Functional Landscape of PCGF Proteins Reveals Both RING1A/B-Dependent-and RING1A/B-Independent-Specific Activities. 3102 42
Genomic analysis of lung adenocarcinomas has revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX , is significantly mutated or deleted in lung adenocarcinomas. Most of the mutations are loss of function for MGA, suggesting that MGA may act as a tumor suppressor. Here, we characterize both the molecular and cellular role of MGA in lung adenocarcinomas and illustrate its functional relevance in the MYC pathway. Although MGA and MYC interact with the same binding partner, MAX , and recognize the same E-box DNA motif, we show that the molecular function of MGA appears to be antagonistic to that of MYC. Using mass spectrometry-based affinity proteomics, we demonstrate that MGA interacts with a noncanonical PCGF6 -PRC1 complex containing MAX and E2F6 that is involved in gene repression, while MYC is not part of this MGA complex, in agreement with previous studies describing the interactomes of E2F6 and PCGF6 . Chromatin immunoprecipitation-sequencing and RNA sequencing assays show that MGA binds to and represses genes that are bound and activated by MYC. In addition, we show that, as opposed to the MYC oncoprotein, MGA acts as a negative regulator for cancer cell proliferation. Our study defines a novel MYC/ MAX /MGA pathway, in which MYC and MGA play opposite roles in protein interaction, transcriptional regulation, and cellular proliferation. IMPLICATIONS: This study expands the range of key cancer-associated genes whose dysregulation is functionally equivalent to MYC activation and places MYC within a linear pathway analogous to cell-cycle or receptor tyrosine kinase/RAS/RAF pathways in lung adenocarcinomas.
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PMID:Multi-Omics Analysis Identifies MGA as a Negative Regulator of the MYC Pathway in Lung Adenocarcinoma. 3186 96
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=UNIPROT%3AQ9BYE7%7C111111%7C0%7C0%7C8929%7C0%7C10 |
Study on the Surface Crack Propagation Mechanism of Coal and Sandstone Subjected to Cryogenic Cooling with Liquid Nitrogen | Request PDF
Request PDF | Study on the Surface Crack Propagation Mechanism of Coal and Sandstone Subjected to Cryogenic Cooling with Liquid Nitrogen | Conventional hydraulic fracturing often causes problems such as reservoir damage, water consumption, and pollution. Recently, liquid nitrogen... | Find, read and cite all the research you need on ResearchGate
Study on the Surface Crack Propagation Mechanism of Coal and Sandstone Subjected to Cryogenic Cooling with Liquid Nitrogen
June 2020
Journal of Natural Gas Science and Engineering 81(12):103436
DOI: 10.1016/j.jngse.2020.103436
Abstract
Conventional hydraulic fracturing often causes problems such as reservoir damage, water consumption, and pollution. Recently, liquid nitrogen (LN2) fracturing, an environmentally friendly fracturing technology, has attracted more attention. In this paper, the mechanism of surface crack propagation in coal and sandstone induced by LN2 is explored through laboratory tests and numerical simulations. An ultrasound detection analyser is employed to investigate the longitudinal wave velocity (Vp) changes in specimens before and after LN2 cooling. The micromorphology of specimens is observed through scanning electron microscopy (SEM). Furthermore, the heat transfer characteristics and damage zone of specimens induced by LN2 are determined. The experimental results indicate that LN2 cooling is more effective for improving coal permeability than it is for improving sandstone permeability. After LN2 cooling, a complex fracture network is observed from the coal surface. However, limited damage to the sandstone surface is observed. Vp decreases by 24.7%∼38.1% for coal specimens after cooling but by less than 0.06% for sandstone. The simulation results indicate that the low-temperature region and the tensile area gradually expand into the interior of the specimens with time. However, the temperature of sandstone drops faster than coal when specimens contact LN2. The maximum tensile stress induced by the instantaneous contact between the specimens and LN2 can be generated at the outer surface of the specimens. Moreover, the maximum damage area of coal extends 3.3 mm from the outer surface, while the damage zone of the sandstone is almost zero.
... New cracks created close to the initial ones can form a crack network by linking them to each other [24].
Du et al. (2020)
[31] compared coal samples from the Yulin coal mine in Shanxi, China, and sandstone samples from Sichuan, China. The samples were dried for 12 h at 60 • C, weighted, and evaluated for P-wave velocity (V p ). ...
... This outcome showed that thermal stress compromised the integrity of the coal specimens by creating fractures. Hence, LN 2 is more effective in coal fracturing than sandstone fracturing
[31]
, which was confirmed by Cai et al. (2014) in their NMR analysis [25]. Du et al. (2020) [31] also used an ultrasonic technique to compare coal and sandstone samples after the use of LN 2 . ...
... Hence, LN 2 is more effective in coal fracturing than sandstone fracturing [31], which was confirmed by Cai et al. (2014) in their NMR analysis [25].
Du et al. (2020)
[31] also used an ultrasonic technique to compare coal and sandstone samples after the use of LN 2 . Differentiation in wave velocities relates to the creation of new crevices or extending pre-existing crevices in rock specimens [32]. ...
Advances in Cryogenic Fracturing of Coalbed Methane Reservoirs with LN2
... New cracks created close to the initial ones can form a crack network by linking them to each other [24].
Du et al. (2020)
[31] compared coal samples from the Yulin coal mine in Shanxi, China, and sandstone samples from Sichuan, China. The samples were dried for 12 h at 60 • C, weighted, and evaluated for P-wave velocity (V p ). ...
, which was confirmed by Cai et al. (2014) in their NMR analysis [25]. Du et al. (2020) [31] also used an ultrasonic technique to compare coal and sandstone samples after the use of LN 2 . ...
... Hence, LN 2 is more effective in coal fracturing than sandstone fracturing [31], which was confirmed by Cai et al. (2014) in their NMR analysis [25].
Du et al. (2020)
[31] also used an ultrasonic technique to compare coal and sandstone samples after the use of LN 2 . Differentiation in wave velocities relates to the creation of new crevices or extending pre-existing crevices in rock specimens [32]. ...
sotirios longinos energies-15-09464
Coalbed methane (CBM) is a significant unconventional natural gas resource existing in matrix pores and fractures of coal seams and is a cleaner energy resource compared to coal and crude oil. To produce CBM, stimulation operations are required, given that the coal permeability is generally too low. Hydraulic fracturing is the most widely used technology for reservoir stimulation; however, there are a few challenging issues associated with it, e.g., huge water consumption. In the past decade, the use of liquid nitrogen (LN2) as a fracturing fluid has been intensively studied for stimulating CBM reservoirs, achieving considerable progress in understanding fracturing mechanisms and optimizing fracturing techniques. This paper presents a thorough review of experimental design and observations, modeling procedures and results, field applications, and published patents. Existing studies are divided into five different groups for discussion and comparison, including immersion tests, injection tests, jet drilling tests, numerical modeling, and field applications. Based on the comprehensive evaluation of the outcomes, it is obvious that cryogenic fracturing using LN2 is a promising eco-friendly fracturing technique that can effectively enhance coal rock permeability to increase the production of CBM.
... Through the LN 2 soaking tests of the coal, the temperature changes of coal can be divided into three stages: accelerated cooling, decelerated cooling, and low-temperature maintenance (Liu et al. 2021). Based on the isotropy assumption and thermo-mechanical coupling model,
Du et al. (2020b)
found that the surface and central parts of the coal sample are subjected to tensile stress and compressive stress, respectively. The maximum thermal stress induced by LN 2 cryotherapy occurred at the surface of the specimens. ...
... The first one is that the obvious structural damage including the generated microcracks and pore damage is induced by LN 2 freeze-thaw. The second one is that the damage of the coal surface structure is more serious than that of the coal internal structure, because the thermal stress induced by LN 2 is maximum at the initial contact surface between LN 2 and coal
(Du et al. 2020b
). ...
Influence of Liquid Nitrogen Cooling State on Mechanical Properties and Fracture Characteristics of Coal
Jul 2022
ROCK MECH ROCK ENG
Peng Hou
su Shanjie
Feng Gao
Chengzheng Cai
To determine the role of LN2-cooling in the fracturing process of the coal, the LN2-cooling process of the coal samples is divided into three states: initial state, frozen state, and freeze–thaw state. Changes in the mechanical properties and fracture behaviors of the coal samples under three states are systematically evaluated by a series of laboratory experiments. The thermal cracking behavior of the coal during LN2 freeze–thaw is revealed through a crack phase-field model. The results indicate that the compressive strength, elastic modulus, and fracture toughness of the frozen coal significantly increase, while they decrease for the freeze–thaw coal. The tensile strength of the coal under the freeze and freeze–thaw states has an obvious reduction, where a greater decrease for the freeze–thaw coal is induced. The fracture propagation process and induced fracture morphology of the coal under both the freeze and freeze–thaw states become complex, in which a greater change for the freeze–thaw coal is presented. The micro-fracture in the coal during LN2-cooling mainly comes from the temperature gradient and mismatch of thermal stress between adjacent mineral particles. Both fracture growth rate and fracture area in the LN2 thaw process are larger than that in the LN2 freeze process. The variations in the fracturing behaviors of the coal with different LN2 treatment states in the mechanical experiments are well explained by the numerical simulation results.
... Thus, finding the optimal combination of cyclic/pulsating liquid nitrogen injection parameters that are safe, efficient, and economical is necessary. At the same time, the crack scale produced by using lowtemperature liquid nitrogen is small, and the penetration has some limitations
[17,
18]. The CBM blasting method has certain safety problems in fracturing the coalbed, which may cause mine vibration, workforce collapse, and pose a hidden risk to the safety of workers. ...
Research on Deep Coalbed Methane Localized Spotting and Efficient Permeability Enhancement Technology
Article
Full-text available
Nov 2022
Jiayong Zhang
Yongzhen Niu
Jian Chen
Liwen Guo
To solve the bottleneck problem of low deep coal seam permeability and difficult coalbed methane (CBM) mining. Combining hydraulic splitting technology and directional drilling technology, a directional hydraulic splitting enhancement method of deep CBM mining was proposed. The selection equation for the directional hydraulic splitting of deep coalbed was constructed. The numerical simulation reveals the variation in coal fractures around different split angles. The split angle under the maximum coal damage effect was obtained. It was found that the combined effect of the double crack damage disturbance region led to reciprocal stress fluctuations during crack development and, eventually, the formation of a zigzag fracture. The larger the splitting angle, the larger the fissure development length and the larger the coal-damaged area. A double crack takes 25% less time to complete propagation than a single crack. When the splitting angle is 90°, the disturbed area occupies 2/3 of the area around the borehole, and the overall fracturing effect is the best. In the application process, the new directional hydraulic splitting technology can increase CBM mining by 5.08%, greatly improve CBM mining efficiency, and reduce the coal mining risk, which is of great significance to the project.
View
Show abstract
... There are vast global reserves of coal bed methane (CBM), a non-conventional energy source [1][2][3]; however, unconventional natural gas is frequently confined in low-permeability media with complex geological conditions and poor physical characteristics
[4]
. Exploitation and utilization of CBM can not only generate energy, but also reduce greenhouse gas emissions [1,2,5]. ...
Laboratory Investigation on Cryogenic Fracturing of Coal Rocks: An Experimental Study in Kazakhstan
Conference Paper
Full-text available
Nov 2022
Sotirios Nik. Longinos
Mirlan Tuleugaliyev
Alina Serik
Randy Hazlett
Cryogenic fracturing with liquid nitrogen (LN2) has been identified as a feasible and promising waterless fracturing method for coalbed methane extraction for its environmental safety and effectiveness. Though it performed well in certain field tests in the late twentieth century, the use of LN2 as the fracturing fluid is still largely unexplored. This research work examines the thermo-mechanical properties of coal specimens from the Karaganda basin in Kazakhstan. Coal specimens were subjected to LN2 treatment under varied lab-controlled conditions, such as the freezing time (FT) length and number of freezing-thawing cycles (FTC), both in dried and water-saturated conditions. SEM investigation for FTC and FT experiments for dried coal samples indicated that the LN2 freezing-thawing process can enhance the cryogenic fracture extent and the fracture interconnectivity. Moreover, uniaxial compressive tests indicated that compressive strength decreases beneficially with an increase in both the number of freezing-thawing cycles, while water-saturated experiments indicated substantial change after liquid nitrogen treatment compared to dried ones.
... It was found that liquid nitrogen affects the pore structure at the microscale.
37,
38 When the lowtemperature liquid nitrogen reaches the coal and rock, the water in the pores of the coal and rock rapidly condenses into ice due to the ultralow temperature. This phase change of the pore water can result in a 9% volumetric expansion inside the coal pores. ...
Experimental Study of the Influence of Moisture Content on the Pore Structure and Permeability of Anthracite Treated by Liquid Nitrogen Freeze–Thaw
Article
Full-text available
Feb 2022
Changxing Li
Baisheng Nie
Zhiwei Feng
Chunlian Cheng
The liquid nitrogen freeze-thaw (LN2-FT) method has been widely used to improve the coal permeability in the coalbed methane (CBM) production. However, the influence of moisture content on the permeability of coal treated by LN2-FT remains unclear, limiting the broad application of this technique. A novel seepage system was proposed to analyze the permeability evolution of anthracite coal samples treated by LN2-FT. Moreover, variations of the pore structure were analyzed using scanning electron microscopy (SEM), mercury intrusion porosimetry (MIP), and low-field NMR. The results showed that pores and fractures appeared on the coal surface after the LN2-FT treatment. As the moisture content of the coal increased, more pores and fractures tended to be formed during the LN2-FT treatment. The total pore volume, porosity, and average pore diameter of the anthracite coal after the treatment were 1.77, 2.44, and 5.58 times higher, respectively, than that of the raw coal. The change in the specific surface area exhibited three trends as the moisture content of the coal samples increased: a slow descent, a steady increase, and a rapid descent. Moreover, it was found that the LN2-FT treatment increased the connections between pores and fractures, improving gas migration in the coal. Furthermore, the LN2-FT treatment significantly increased the permeability of the anthracite coal samples. The higher the coal moisture, the higher the permeability of the coal samples after the LN2-FT treatment. Hence, the LN2-FT technique can substantially improve the permeability of coal reservoirs, providing essential information for the efficient utilization of CBM.
... They held the view that the damage in water-saturated sandstone was generated by the expansion of the water-ice phase transition.
Du et al. (2020)
explored the fracture propagation mechanism induced by LN 2 in sandstone with laboratory tests and numerical simulations. They confirmed that the rapid cooling induced by LN 2 can generate new micro-fractures and weaken the cohesion between mineral particles in sandstone. ...
Fracture Initiation and Morphology of Tight Sandstone by Liquid Nitrogen Fracturing
Article
Full-text available
Mar 2022
ROCK MECH ROCK ENG
Chunyang Hong
Ruiyue Yang
Zhongwei Huang
Jianxiang Chen
Hydraulic fracturing is a commonly used stimulation method in developing tight sandstone reservoirs. Creation of complex fracture networks to enlarge stimulated reservoir volume plays an increasingly significant role. However, planar fracture patterns are generally generated by water-based fluid fracturing. Besides, the water consumption and environmental burden of water-based fluid fracturing cannot be ignored. To solve the above issues, we investigated the liquid nitrogen (LN2) fracturing performance on tight sandstone with respect to breakdown pressures and fracture network patterns, and also compared the results with water fracturing in this paper. A comprehensive quantitative analysis was made for the fracture network induced by LN2 fracturing so as to enhance understandings of the fracturing mechanisms. Based on laboratory fracturing experiments and computed tomography (CT) scanning, we find that the breakdown pressure of LN2 fracturing can be reduced by 12.4–51.5% compared with water fracturing. Besides, LN2 fracturing can lead to volumetric fracturing patterns rather than planar fractures compared with water fracturing. The average tortuosity of LN2 fracturing was increased by 5.9% compared with water fracturing. Furthermore, the major fracture tends to traverse the bedding plane with an angle of around 45–80 degrees under lower horizontal stress difference. This study, for the first time, shows potential benefits of high-pressure LN2 fracturing in tight sandstone under triaxial in situ stress. It is expected to provide a viable alternative for the efficient development of tight sandstone reservoirs in a clean and waterless way.
Coupled TMD modeling of cryogenic treatment of borehole in coal under confinement
Article
Apr 2023
Lei Wang
Xinchuang Yan
Zhaoying Zhu
Bowen Yao
Numerical Study on Heat Transfer within a Rock-air-water-ice System under Cryogenic Conditions
Article
Jan 2023
HEAT TRANSF RES
Chengyu Huang
Bo Dong
Weizhong Li
Wenhua Wang
A numerical heat transfer model which couples heat conduction, natural convection, and the freezing process is built with ANSYS FLUENT. Then, 2D simulations of heat transfer in a rock-air-water-ice system under cryogenic conditions are conducted by using the model for studying the heat transfer mechanism in the reservoir stratum during cryogenic fracturing. The effects of air and water on the local temperature evolution are analyzed from the aspect of thermophysical properties, natural convection, and the water freezing process. For thermophysical properties, it is found that the influence of volumetric heat capacity is significant in the early stage of heat transfer, while in a long-term heat transfer process the effect of thermal conductivity is dominant. Natural convection alters the cold energy distribution and exerts different influences on the local temperature variation, and these effects could be weakened due to the presence of water. The release of latent heat due to water freezing delays the decrease of local temperature, while the newly formed ice phase accelerates the decrease of local temperature due to its relatively high thermal conductivity compared with that of water. Besides, the effect of water distribution on heat transfer is analyzed. Variation in water distribution alters the range and intensity of the impact brought by natural convection and water freezing, affecting temperature evolution. The combined effect of natural convection and water freezing affects the local temperature variation differently, depending on the time and position concerned.
Experimental study on fracture characteristics of coal due to liquid nitrogen fracturing
Article
Jan 2023
Shengcheng Wang
Dengke Wang
Xianghe Gao
su Shanjie
Chengzheng Cai
Liquid nitrogen (LN2) fracturing is a novel waterless fracturing technology that has significant potential for application in the development of geothermal resources. In this study, we performed physical and mechanical experiments on marble samples to determine the influence of LN2 cooling on the damage behavior of hot dry rock (HDR). Specifically, we evaluated the changes in the internal structure, mechanical properties, and fracture behavior of the marble samples after subjecting them to thermal shock. The results revealed that the porosity of the heated marble increased significantly after LN2 cooling, whereas the P-wave velocity, compression strength, and elastic modulus decreased. The complexity of the fracture propagation process and the induced fracture morphology of the marble samples subjected to thermal shock increased under uniaxial compression. Furthermore, the changes in these properties increased with the increase in the marble temperature. Compared to air cooling, LN2 cooling significantly changes the physical and mechanical properties and fracture behavior of marble. Based on the coupled thermal-mechanical simulations from macroscopic and microscopic perspectives, the thermal damage that occurs in heated marble subjected to rapid cooling is primarily due to the temperature gradient inside the rock and the difference in the thermal expansion of adjacent mineral particles.
Influence of Various Control Factors on Fracture Toughness and Fracture Energy of Sandstone Subjected to Liquid Nitrogen Cooling
Article
Dec 2021
Peng Hou
Guoqing Chen
su Shanjie
Feng Gao
Differences in Petrophysical and Mechanical Properties Between Low- and Middle-Rank Coal Subjected to Liquid Nitrogen Cooling in Coalbed Methane Mining
Sep 2021
Menglin Du
Feng Gao
Chengzheng Cai
Zekai Wang
Exploring the damage differences between different coal rank coal reservoirs subjected to liquid nitrogen (LN2) cooling is of great significance to the rational development and efficient utilization of coalbed methane. For this purpose, the mechanical properties, acoustic emission (AE) characteristics and energy evolution law of lignite and bituminous coal subjected to LN2 cooling were investigated based on the Brazilian splitting tests. Then, pore structure changes were analyzed to reveal the difference in the microscopic damage between lignite and bituminous coal after LN2 cooling. The results showed that compared with bituminous coal, the pore structure of lignite coal changed more obviously, which was manifested as follows: significant increases in porosity, pore diameters, and pore area; a larger transformation from micropores and transition pores to mesopores and macropores. After LN2 cooling, the thermal damage inside lignite and bituminous coal was 0.412 and 0.069, respectively. The thermal damage reduced the cohesive force between mineral particles, leading to the deterioration of the macroscopic physical and mechanical properties. Simultaneously, denser AE ringing counts and larger accumulated ringing counts were observed after LN2 cooling. Moreover, the random distribution of thermal damage enhanced the randomness of the macrocrack propagation direction, resulting in an increase in the crack path tortuosity. With more initial defects inside coal, a more obvious thermal damage degree and wider damage distribution will be induced by LN2 cooling, leading to more complicated crack formation paths and a higher fragmentation degree, such as that of lignite coal.
Propagation of Cryogenic Thermal Fractures from Unconfined PMMA Boreholes
Article
Full-text available
Sep 2021
Minsu Cha
Naif Alqahtani
Xiaolong Yin
Yu-Shu Wu
In cryogenic fracturing, a rock surface exposed to cryogenic fluids undergoes a large thermal gradient, and the resultant local tensile stress overcomes rock strength and initiates fractures. This study investigates the development of cracks generated from the cryogenic treatment of a borehole under no external confining stress on specimens. The experiments were performed on transparent PMMA specimens to observe fracture proliferation around boreholes. Liquid nitrogen was flowed through the boreholes to cool the borehole surface. The results show that initial fracture growth is characterized by abrupt starts and stops, and as the fracture propagates outward, the growth appears more continuous. In an early stage, horizontal/radial fractures and vertical fractures are the defining patterns. Horizontal fractures tend to be separated by a specific exclusion distance (i.e., spacing between cracks). While distinct horizontal/vertical fractures and exclusion distance manifest themselves at an early stage, fractures resulting from fracture interactions and curvatures can develop into complex shapes at later stages. Cryogenic thermal loading induces distinctively curved fractures. The tendency of curvature may prevent greater penetration. An increase in the borehole pressure during liquid nitrogen flow, however, can lessen fracture tortuosity and facilitate radial propagation. A high flow pressure and rate are also advantageous in that they accelerate cooling and fracture propagation.
Experimental Study on Changes in Pore Throat Systems Owing to Liquid CO 2 Cooling in Shale Oil Reservoirs
Article
Aug 2021
Mengqing He
Tiantai Li
Xing Huang
Ke Wu
Evolution of pore and fracture of coal under heating–freezing effects: An experimental study
Article
Dec 2021
FUEL
Ning Liu
Lulu Sun
Botao Qin
Wenzhou Du
To explore the evolution of pores and fractures of coal under heating–freezing effects, a tube furnace was used to heat samples. The coal sample was heated to 100 °C and 300 °C in air, and liquid nitrogen was used to freeze the heated coal sample. Low-temperature nitrogen adsorption experiments were used to analyse the damage degree of the coal pore structure quantitatively, and the surface characteristics of the coal sample were qualitatively analysed using a scanning electron microscope. Experimental studies have shown that liquid nitrogen injection increases the pore volume of coal. By injecting liquid nitrogen into the heat-treated coal sample, the pore volume of the macropores of the water-saturated coal sample increased by 19.61%. When the heat treatment temperature reached 300 °C, the macroporosity of the dry coal sample increased by 38.75%. In addition, the fractal dimension of the pores increased after liquid nitrogen treatment, indicating that the freezing of liquid nitrogen caused the surface of the coal sample to become rough. The development of pores and fractures caused by liquid nitrogen injection results from the low-temperature fracturing characteristics of liquid nitrogen and the volume expansion caused by the freezing of pore water.
Experimental Study on the Damage and Cracking Characteristics of Bedded Coal Subjected to Liquid Nitrogen Cooling
Nov 2021
ROCK MECH ROCK ENG
Menglin Du
Feng Gao
Chengzheng Cai
Zekai Wang
Liquid nitrogen (LN2) cooling can induce significant cracking damage in coalbed methane (CBM) reservoirs. To investigate the combined effects of LN2 cooling and bedding angles on the mechanical behaviors of bedded coal, coal specimens with different bedding angles (0°, 30°, 60° and 90°) were cooled. The variations in the surface features and P-wave velocity of the specimens were analyzed. The mechanical properties (tensile strength, peak strain and absorbed energy) were measured under Brazilian test conditions and compared. Furthermore, the crack propagation processes and the failure mechanisms were observed and compared. The results showed that LN2 cooling can induce considerable thermal damage inside the coal, resulting in the deterioration of the coal’s mechanical properties. This deterioration led to easier cracking and a higher fragmentation degree under splitting load. In addition, the reductions in tensile strength, peak strain and absorbed energy exhibited obvious anisotropic characteristics. The thermal cracks induced by LN2 cooling participated in the formation of macrocracks. After LN2 cooling, the failure mode remained unchanged from that before cooling at bedding angles of 0°, 30° and 90°. Notably, a transition from mixed-mode failure (primarily caused by tensile failure) to tensile failure occurred at the 60° bedding angle. This transition caused the specimen to fail at a relatively lower load, resulting in maximum reductions in tensile strength (34.8%), peak strain (27.6%) and absorbed energy (55.0%) at the 60° bedding angle. This paper provides new insights into the LN2 fracturing of bedded coal seams.
Methane adsorption thermodynamics of coal sample subjected to liquid nitrogen freezing–thawing process
Mar 2021
Hai-fei Lin
Hang Long
Min Yan
Yang Bai
A B S T R A C T
In order to explore the characteristics and thermodynamic parameters of methane (CH4) adsorption in coal sample subjected to liquid nitrogen (LN2) freezing–thawing. The adsorption experiments of coal sample unfrozen, 5 cycles frozen, and 10 cycles frozen were conducted with the temperature range of 313–353 K at 10 K intervals. The influence of freezing–thawing on the adsorption amounts and thermodynamic parameters of CH4 adsorbed by coal sample were quantitatively compared. Electron microscope scanning (SEM) were carried out to analyse the pores structure distribution on the coal sample surface. The changes of pore structure on the coal sample surface under different freezing–thawing cycles were counted. The results showed that, the adsorption amounts of CH4 were positively correlated with the cycles of freezing–thawing. The standard adsorption enthalpy Hθ, the standard adsorption Gibbs free energy Gθ, and the standard adsorption entropy Sθ, isosteric heat of adsorption, and mean isosteric heat of adsorption all increased with the cycles of freezing–thawing. The freezing–thawing of LN2 was observed to saliently enhance the spontaneity and heat-transfer effect of adsorption process. The freezing–thawing of LN2 can effectively change the pores structure of the coal sample surface, and pores size presented a normal distribution. The study of adsorption characteristics and pore changes can provide reference for the technology development with LN2 cracked coal sample for enhancing coal bed methane (CBM) drainage.
A heterogeneous model for simulating fluid flow in naturally fractured-vuggy carbonate reservoirs
Article
Jan 2019
Haixiang Zhang
Pengfei Hao
Weihong Peng
Menglin Du
In this paper, a heterogeneous model named matrix-fracture-vug (MFV), which considers the interactions of flow regimes in matrix, discrete natural fractures, large-scale fractures and vugs, is developed for simulating fluid flow in fractured-vuggy reservoirs. In the MFV model, coupling Darcy-Stokes equations are used to describe flow regime in matrix and vugs. Fluid flow follows the cubic law in each discrete natural fracture. An equivalent method is put forward in large-scale fractures. The flow mechanisms in fractured-vuggy reservoirs are analyzed, and the oil well productivity is demonstrated by investigating the influences of the matrix, fractures and vugs. The matrix permeability controls the production rate in the whole production process, and the conductivity of fracture network is another main influence factor. The cumulative production will increase due to the storage capacity of vugs in later period. This model can provide insights into the history matching and the production prediction for fractured-vuggy.
Experimental Investigation on the Deformability, Ultrasonic Wave Propagation, and Acoustic Emission of Rock Salt Under Triaxial Compression
Article
Feb 2019
Haoran Li
Dong Zhikai
Zuolin Ouyang
In context of this work, a new formation damage mechanism is proposed: the mechanically induced fracture face skin (FFS). This new mechanism results from mechanical interactions between the proppants and the reservoir rock, due to the increasing stress on the rock-proppant system during production. Proppant embedment into the fracture face and proppant crushing leads to fines production and may ... [Show full abstract] impair the fracture performance. In order to achieve sustainable, long-term productivity from a reservoir, it is indispensable to understand the hydraulic and mechanical interactions in rock-proppant systems. Permeability measurements on sandstones with propped fractures under stress using different flow cells were performed, allowing localizing and quantifying the mechanical damage at the fracture face. The laboratory experiments identified a permeability reduction at the fracture face up to 90 %. The mechanical damage at the rock-proppant interface begins immediately with loading the rock-proppant system and for fracture closure stresses below 35 MPa; the damage is localized at the fracture face. Microstructure analysis identified quartz grain crushing, fines production and pore space blocking at the fracture face causing the observed mechanically induced FFS. At higher stresses, damage and embedment of the ceramic proppants further reduces the fracture permeability. Numerical modeling of the rock-proppant system identified highly inhomogeneous stress distributions in the granular system of grains and proppants. High tensile stress concentrations beneath the area of contact between quartz grains and proppants are observed even at small differential stress applied to the rock-proppant system. These high stress concentrations are responsible for the early onset of damage at the fracture face. Therefore, even low differential stresses, which are expected under in-situ conditions, may affect the productivity of a hydraulically fractured well.
| https://www.researchgate.net/publication/342308549_Study_on_the_Surface_Crack_Propagation_Mechanism_of_Coal_and_Sandstone_Subjected_to_Cryogenic_Cooling_with_Liquid_Nitrogen |
Shelby, TN 1910 Federal Census
ftp://ftp.us-census.org/pub/usgenweb/census/tn/shelby/1910/
(File 1 of 4 for ED:224)
This Census was transcribed by Hugh Cloyes and is NOT YET proofread
for the USGenWeb Census Project http://www.us-census.org/
Copyright (c) 2002 by Hugh Cloyes
=========================================================================
USGENWEB NOTICE: These electronic pages may NOT be reproduced in any
format for profit or presentation by any other organization or persons.
Persons or organizations desiring to use this material must obtain the
written consent of the transcriber or the legal representative of the
transcriber and contact the USGenWeb Census Project File Manager via
the email address <[email protected]> with proof of this consent.
=========================================================================
Formatted by USGenWeb Census Project File Manager, Connie Burkett
All of the above information must remain when copied or downloaded.
=========================================================================
Census Year 1910
Microfilm Roll #T624-1521
State Tennessee
County Shelby
---------------------Begin Actual Transcription----------------------------------
TRANSCRIBER'S NOTE: Columns 30, 31, and 32 are not clear.
While the column headings call for survivors of the Civil War, Blind or Deaf and Dumb, the entries do not follow the enumerator's guidelines.
I entered exactly what the enumerator wrote down, but it seemed wrong.
In the beginning, I was placing a '-' in front of some of the numbers, because it looked that is what the enumerator had placed there.
Later on, I quit doing that, because it did not seem to mean anything and was not useful.
==============================================================================================================================================================================================================================================================================================================================================================================================
CENSUS YEAR: 1910 STATE: TN COUNTY: Shelby INCORP-PLACE: Memphis WARD-OF-CITY: 18 MICROFILM#: T624-1521 SUPV/DISTR: 10 ENUM/DISTR: 224 ENUMERATOR: Holloway Manning ENUM/DATE-RANGE: April 15 - 30, 1910
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Stamped AGE S-M #YRS # #CHILD BIRTH FATHER MOTHER YEAR NATUR- SPEAK TRADE OR GENERAL EMPL OUT OF #WKS CAN CAN ATTD OWN FREE FARM #FARM SURV DEAF ENUMERATION TRANSCRIBER'S
PG# LN# ED SH# STREET HS# DW# FM# LAST NAME FIRST NAME RELATION SEX RACE LAST W-D MAR CHILD LIVING PLACE BIRTHPL BIRTHPL IMMI ALIZED ENG? PROFESSION INDUSTRY ACCT WORK UNEMPL READ WRITE SCH RENT MORT HOME SCH WAR BLIND DUMB DATE REMARKS
(1) (2) (3) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32)
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1A 1 224 1A Union Avenue 801 1 1 Shipman Ed V. Head M W 60 S . . . New York Unknown New Jersy . . English Cook Restaurant W NO 0 Yes Yes . RENT . HOME 14 -0 -7 -X April 15, 1910 .
1A 2 224 1A Union Avenue 803 2 2 White Wilmin Head M W 29 S . . . Mississippi Mississippi Mississippi . . English Motorman Street Car W NO 0 Yes Yes . RENT . HOME 2 -1 1 4 April 15, 1910 .
1A 3 224 1A Union Avenue 803 2 2 Clayton Willie Aunt F W 40 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 4 224 1A Union Avenue 817 3 3 Page Samuel Head M W 53 M2 6 . . Indiana Unknown Unknown . . English Carpenter General Work W Yes 12 Yes Yes . RENT . Home 12 -2 -9 -8 April 15, 1910 .
1A 5 224 1A Union Avenue 817 3 3 Page Ida Wife F W 40 M2 6 4 4 Tennessee N.Carolina Arkansas . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 6 224 1A Union Avenue 817 3 3 Page Leon G. Son M W 16 S . . . Tennessee Indiana Tennessee . . English Plumber Helper W NO 0 Yes Yes No . . . 2 -8 -9 -8 April 15, 1910 .
1A 7 224 1A Union Avenue 817 3 3 Page Reuben D. Son M W 14 S . . . Tennessee Indiana Tennessee . . English Office Boy Express Office W NO 0 Yes Yes No . . . 14 -3 -X -6 April 15, 1910 .
1A 8 224 1A Union Avenue 817 3 3 Page Chas. H. Son M W 8 S . . . Tennessee Indiana Tennessee . . English None . . . . . . No . . . . . . . April 15, 1910 .
1A 9 224 1A Union Avenue 817 3 3 Page Samuel H. Son M W 4 S . . . Arkansas Indiana Tennessee . . . None . . . . . . No . . . . . . . April 15, 1910 .
1A 10 224 1A Union Avenue 817 3 4 Aycock Joe A. Head M W 28 M1 1 . . Tennessee Unknown Unknown . . English Plumber House W NO 0 Yes Yes . RENT . Home 13 -4 -9 -8 April 15, 1910 .
1A 11 224 1A Union Avenue 817 3 4 Aycock Myrtle Wife F W 27 M1 1 0 0 Missouri Missouri Illinois . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 12 224 1A Union Avenue 819 4 5 Carmen Frank Head M W 35 M1 14 . . Kentucky Kentucky Kentucky . . English Electrican Arc Light W NO 0 Yes Yes . RENT . Home 12 -7 -9 -0 April 15, 1910 .
1A 13 224 1A Union Avenue 819 4 5 Carmen Esther Wife F W 34 M1 14 1 1 Tennessee Mississippi Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 14 224 1A Union Avenue 819 4 5 Carmen Clarence Son M W 13 S . . . Mississippi Kentucky Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 15, 1910 .
1A 15 224 1A Union Avenue 819 4 5 Busby Mattie Sister-in-law F W 41 S . . . Tennessee Mississippi Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 16 224 1A Union Avenue 843 5 6 Glass Jacob V. Head M W 62 M1 32 . . Ger. Prussia Ger. Prussia Ger. Prussia 1856 AL English Merchant Grocery EMPL . . Yes Yes . RENT . Home 3 -2 -3 -X April 15, 1910 .
1A 17 224 1A Union Avenue 843 5 6 Glass Bessie E. Wife F W 53 M1 32 6 6 New York Ireland Ireland . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 18 224 1A Union Avenue 843 5 6 Glass Vincent Son M W 33 S . . . Tennessee Ger. Prussia New York . . English Fireman City W NO 0 Yes Yes . . . . 4 -3 -5 -X April 15, 1910 .
1A 19 224 1A Union Avenue 843 5 6 Glass Gustave Son M W 30 S . . . Tennessee Ger. Prussia New York . . English Clerk Grocery W NO 0 Yes Yes . . . . 10 -7 -3 -X April 15, 1910 .
1A 20 224 1A Union Avenue 843 5 6 Glass Harry Son M W 25 S . . . Tennessee Ger. Prussia New York . . English Printer Newspaper W NO 0 Yes Yes . . . . 3 -0 -7 -1 April 15, 1910 .
1A 21 224 1A Union Avenue 843 5 6 Glass Sallie Daughter F W 20 S . . . Tennessee Ger. Prussia New York . . English None . . . . Yes Yes Yes . . . . . . . April 15, 1910 .
1A 22 224 1A Union Avenue 843 5 6 Shannon Charles R, Boarder M W 33 S . . . Kentucky Ireland Ireland . . English Accountant Public W NO 0 Yes Yes . . . . 10 -4 -4 -X April 15, 1910 .
1A 23 224 1A Union Avenue 843 5 6 Persons Lucy Servant F B 62 S . . . Mississippi Mississippi Mississippi . . English Servant Private Family W NO 0 Yes Yes . . . . 0 -3 -7 -X April 15, 1910 .
1A 24 224 1A Union Avenue 843 5 7 Malion John H. Head M W 49 M1 12 . . Illinois Ireland Ireland . . English Doctor General Practice OA . . Yes Yes . RENT . Home 0 -6 -6 -X April 15, 1910 .
1A 25 224 1A Union Avenue 843 5 7 Malion Josephine Wife F W 31 M1 12 0 0 Tennessee Ger. Prussia New York . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 26 224 1A S. Dunlap St. 157 6 8 Bizot Emil Head M W 30 M1 5 . . Indiana France Indiana . . English Inspector City Milk W NO 0 Yes Yes . Rent . Home 5 -2 -5 -X April 15, 1910 .
1A 27 224 1A S. Dunlap St. 157 6 8 Bizot Maud Wife F W 27 M1 5 1 1 Tennessee Ger. Prussia New York . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 28 224 1A S. Dunlap St. 157 6 8 Bizot Emil Jr. Son M W 2 S . . . Tennessee Indiana Tennessee . . . None . . . . . . . . . . . . . . April 15, 1910 .
1A 29 224 1A S. Dunlap St. 159 7 9 Jones Franklin A. Head M W 53 M2 23 . . Georgia Georgia Georgia . . English Blacksmith Car Shop W NO 0 Yes Yes . Rent . Home 12 -0 -3 -8 April 15, 1910 .
1A 30 224 1A S. Dunlap St. 159 7 9 Jones Mary K. Wife F W 45 M1 23 1 1 Tennessee Alabama Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 31 224 1A S. Dunlap St. 159 7 9 Jones Fred Son M W 19 S . . . Tennessee Georgia Tennessee . . English Blacksmith Car Shop W NO 0 Yes Yes . . . . 12 -0 -3 -8 April 15, 1910 .
1A 32 224 1A S. Dunlap St. 167 8 10 Gilchrist Henry Y. Head M W 35 M1 8 . . Tennessee Unknown Unknown . . English Driver Brewery Wagon W NO 0 Yes Yes . Rent . Home 15 -4 -4 -9 April 15, 1910 .
1A 33 224 1A S. Dunlap St. 167 8 10 Gilchrist Marian Wife F W 32 M1 8 0 0 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 34 224 1A S. Dunlap St. 171 9 11 Estes Jospeh F. Head M W 38 M1 6 . . Georgia Georgia Georgia . . English Clerk Railroad W NO 0 Yes Yes . Rent . Home 10 -7 -X -5 April 15, 1910 .
1A 35 224 1A S. Dunlap St. 171 9 11 Estes Ella Wife F W 34 M1 6 2 2 Tennessee Virginia Mississippi . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 36 224 1A S. Dunlap St. 171 9 11 Estes Evlyn Daughter F W 4 S . . . Tennessee Georgia Tennessee . . . None . . . . . . . . . . . . . . April 15, 1910 .
1A 37 224 1A S. Dunlap St. 171 9 11 Estes Edward W. Son M W 2 S . . . Tennessee Georgia Tennessee . . . None . . . . . . . . . . . . . . April 15, 1910 .
1A 38 224 1A S. Dunlap St. 176 10 12 Spence Thos P. Head M W 32 M1 4 . . Tennessee Tennessee Tennessee . . English Custodian Mason's Lodge W NO 0 Yes Yes . Rent . Home 1 -0 -7 -X April 15, 1910 .
1A 39 224 1A S. Dunlap St. 176 10 12 Spence Nancy K. Wife F W 30 M1 4 2 2 Tennessee N.Carolina Missouri . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 40 224 1A S. Dunlap St. 176 10 12 Spence Thos P. Jr. Son M W 5 S . . . Tennessee Tennessee Tennessee . . . none . . . . . . . . . . . . . . April 15, 1910 .
1A 41 224 1A S. Dunlap St. 176 10 12 Spence Margurite Daughter F W 1 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 15, 1910 .
1A 42 224 1A Walnut Street 172 11 13 Clay Henry J. Head M W 32 M1 8 . . Tennessee Virginia Alabama . . English Manager Restaurant EMPL . . Yes Yes . Rent . Home 1 -5 -7 -X April 15, 1910 .
1A 43 224 1A Walnut Street 172 11 13 Clay Pearl O. Wife F W 25 M1 8 1 1 Tennessee Tennessee Unknown . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 44 224 1A Walnut Street 172 11 13 Clay Mary L. Daughter F W 6 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 15, 1910 .
1A 45 224 1A Walnut Street 182 12 14 Pierce Thos. E. Head M W 30 M2 1 . . Tennessee Tennessee Tennessee . . English Motorman Street Car W NO 8 Yes Yes . Rent . Home 2 -1 -X -4 April 15, 1910 .
1A 46 224 1A Walnut Street 182 12 14 Pierce Mary B. Wife F W 30 M2 1 1 1 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 47 224 1A Walnut Street 182 12 14 Pierce William J. Son M W 13 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 15, 1910 .
1A 48 224 1A Walnut Street 201 13 15 Price Claude Head M W 34 M2 6 . . Tennessee Tennessee Tennessee . . English Motorman Street Car W NO 0 Yes Yes . Rent . Home 2 -1 -X -4 April 15, 1910 .
1A 49 224 1A Walnut Street 201 13 15 Price Cora Wife F W 25 M1 6 0 0 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 15, 1910 .
1A 50 224 1A Walnut Street 201 13 15 Price Addie Daughter F W 15 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 15, 1910 .
==============================================================================================================================================================================================================================================================================================================================================================================================
CENSUS YEAR: 1910 STATE: TN COUNTY: Shelby INCORP-PLACE: Memphis WARD-OF-CITY: 18 MICROFILM#: T624-1521 SUPV/DISTR: 10 ENUM/DISTR: 224 ENUMERATOR: Holloway Manning ENUM/DATE-RANGE: April 15 - 30, 1910
==============================================================================================================================================================================================================================================================================================================================================================================================
Stamped AGE S-M #YRS # #CHILD BIRTH FATHER MOTHER YEAR NATUR- SPEAK TRADE OR GENERAL EMPL OUT OF #WKS CAN CAN ATTD OWN FREE FARM #FARM SURV DEAF ENUMERATION TRANSCRIBER'S
PG# LN# ED SH# STREET HS# DW# FM# LAST NAME FIRST NAME RELATION SEX RACE LAST W-D MAR CHILD LIVING PLACE BIRTHPL BIRTHPL IMMI ALIZED ENG? PROFESSION INDUSTRY ACCT WORK UNEMPL READ WRITE SCH RENT MORT HOME SCH WAR BLIND DUMB DATE REMARKS
(1) (2) (3) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32)
==============================================================================================================================================================================================================================================================================================================================================================================================
1B 51 224 1B Walnut Street 201 13 15 Toril Vic Servant F B 35 M1 15 1 1 Mississippi Mississippi Mississippi . . English Servant Private Family W NO 0 Yes Yes . . . . 2 -3 -7 -x April 15, 1910 .
1B 52 224 1B Union Avenue 859 14 16 Moon Emily L. Head F W 41 Wd . 4 4 Tennessee Germany Germany . . English Superintant Shirt Factory W . . Yes Yes . Rent . Home 10 -6 -2 -7 April 16, 1910 .
1B 53 224 1B Union Avenue 859 14 16 Noon Samuel Son M W 15 S . . . Tennessee Germany Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 54 224 1B Union Avenue 859 14 16 Moon Jerry Son M W 14 S . . . Tennessee Germany Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 55 224 1B Union Avenue 859 14 16 Moon Marjorie
Daughter F W 13 S . . . Tennessee Germany Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 56 224 1B Union Avenue 859 14 16 Moon Elizabeth Daughter F W 10 S . . . Tennessee Germany Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 57 224 1B Union Avenue 859 14 16 Dorne Ella Ma Boarder F W 45 Wd . 0 0 Mississippi N.Carolina Tennessee . . English None some income . . . Yes Yes . . . . 19 -9 -X -X April 16, 1910 .
1B 58 224 1B Union Avenue 859 14 16 Grey Walter Servant M B 31 S . . . Arkansas Unknown Unknown . . English Servant Private Family W NO 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
1B 59 224 1B Union Avenue 859 14 16 Moore Christine Servant F B 25 S . . . Mississippi Mississippi Mississippi . . English Servant Private Family W NO 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
1B 60 224 1B Union Avenue 871 15 17 Bruce Henry F. Head M W 54 M1 19 . . Maryland Maryland So. Carolina . . English Manager Laundry W NO 0 Yes Yes . Own Free Home 10 -2 -8 -X April 16, 1910 .
1B 61 224 1B Union Avenue 871 15 17 Bruce Veronica H. Wife F W 35 M1 19 11 3 Missouri Missouri Missouri . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 62 224 1B Union Avenue 871 15 17 Bruce John Son M W 18 S . . . Tennessee Maryland Missouri . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 63 224 1B Union Avenue 871 15 17 Bruce Genevieve Daughter F W 14 S . . . Tennessee Maryland Missouri . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 64 224 1B Union Avenue 871 15 17 Bruce Valerie Daughter F W 6 S . . . Tennessee Maryland Missouri . . . None . . . . . . No . . . . . . . April 16, 1910 .
1B 65 224 1B Union Avenue 871 15 17 Norris Ben Servant M B 58 M1 6 . . Alabama Alabama Alabama . . English Servant Private Family W NO 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
1B 66 224 1B Union Avenue 871 15 17 Norris Laurie E. Servant F B 24 M2 5 1 0 Alabama Alabama Alabama . . English Servant Private Family W NO 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
1B 67 224 1B Union Avenue 883 16 18 Phillips James S. H. Head M W 45 M2 5 . . Tennessee Tennessee Tennessee . . English Motorman Street Car W NO 0 Yes Yes . Rent . Home 2 -1 -X -4 April 16, 1910 .
1B 68 224 1B Union Avenue 883 16 18 Phillips Laurie E. Wife F W 33 M1 5 0 0 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 69 224 1B Union Avenue 885 17 19 Owen Andrew W. Head M W 38 M1 10 . . Mississippi Mississippi Mississippi . . English Inspector Street Car W NO 0 Yes Yes . Rent . Home 1 -3 -X -4 April 16, 1910 .
1B 70 224 1B Union Avenue 885 17 19 Owen Fannie Wife F W 38 M2 10 6 4 Mississippi Alabama Alabama . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 71 224 1B Union Avenue 885 17 19 Owen Bell Daughter F W 8 S . . . Mississippi Mississippi Mississippi . . . None . . . . . . Yes . . . . . . . April 16, 1910 .
1B 72 224 1B Union Avenue 885 17 19 Owen Clara Daughter F W 7 S . . . Mississippi Mississippi Mississippi . . . None . . . . . . Yes . . . . . . . April 16, 1910 .
1B 73 224 1B Union Avenue 885 17 19 Owen Harry Son M W 2 S . . . Tennessee Mississippi Mississippi . . . . . . . . . . . . . . . . . . April 16, 1910 .
1B 74 224 1B Union Avenue 885 17 19 Ross Bertha Daughter-In-Law F W 15 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 75 224 1B Union Avenue 887 18 20 Crocker James Head M W 25 m1 8 . . Tennessee Unknown Alabama . . English Machinist Automobile W No 0 Yes Yes . Rent . Home 13 -7 -X -3 April 16, 1910 .
1B 76 224 1B Union Avenue 887 18 20 Crocker Ella Wife F W 22 M1 8 3 3 Tennessee Georgia Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 77 224 1B Union Avenue 887 18 20 Crocker Calo Son M W 4 S . . . Texas Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
1B 78 224 1B Union Avenue 887 18 20 Crocker Roslie Daughter F W 3 S . . . Alabama Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
1B 79 224 1B Union Avenue 887 18 20 Crocker not named Son M W 2/12 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
1B 80 224 1B Union Avenue 889 19 21 Chamberlain Ben L. Head M W 26 M1 3 . . Tennessee Unknown Unknown . . English Clerk Express Office W No 0 Yes Yes . Rent . Home 10 -7 -X -6 April 16, 1910 .
1B 81 224 1B Union Avenue 889 19 21 Chamberlain Sallie Wife F W 26 M1 3 0 0 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 82 224 1B Union Avenue 899 20 22 Miller Erwin M. Head M W 29 M1 11 . . Tennessee Tennessee Unknown . . English Foreman Car Stables W No 0 Yes Yes . Rent . Home 10 -3 -X -4 April 16, 1910 .
1B 83 224 1B Union Avenue 899 20 22 Miller Prudence Wife F W 30 M1 11 1 1 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 84 224 1B Union Avenue 899 20 22 Miller Annie Daughter F W 10 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
1B 85 224 1B Union Avenue 899 20 23 Everitt Arthur Head M W 30 M1 3 . . Georgia Georgia Georgia . . English Steam Fitter Boiler Shop W No 0 Yes Yes . Rent . Home 13 -4 -3 -9 April 16, 1910 .
1B 86 224 1B Union Avenue 899 20 23 Everitt Annie Wife F W 22 M1 3 0 0 Georgia Unknown Unknown . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 87 224 1B Union Avenue 901 21 24 Bonderant John W. Head M W 43 M1 15 . . Kentucky Kentucky Kentucky . . English Salesman Real Estate W No 0 Yes Yes . Rent . Home 11 -0 -2 -X April 16, 1910 .
1B 88 224 1B Union Avenue 901 21 24 Bonderant Nellie Wife F W 30 M1 15 1 1 Tennessee Ireland Ireland . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 89 224 1B Union Avenue 901 21 24 Bonderant John W. Jr. Son M W 6 S . . . Tennessee Kentucky Tennessee . . . None . . . . . . No . . . . . . . April 16, 1910 .
1B 90 224 1B Union Avenue 901 21 24 Breen Ellen Mother-in-law F W 64 Wd . 4 3 Ireland Ireland Ireland . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 91 224 1B Union Avenue 901 21 24 Breen John J. Brother-in-law M W 40 S . . . Tennessee Ireland Ireland . . English Clerk Warehouse W No 0 Yes Yes . . . . 9 -0 -2 -X April 16, 1910 .
1B 92 224 1B Union Avenue 901 21 24 Breen James Brother-in-law M W 45 S . . . Tennessee Ireland Ireland . . English Painter House W No 0 Yes Yes . . . . 13 -3 -9 -8 April 16, 1910 .
1B 93 224 1B Union Avenue 903 22 24 Tennyson Harry L. Head M W 42 M1 2 . . Tennessee Unknown Unknown . . English Shipping Clerk Whole sale house W No 0 Yes Yes . Rent . Home 11 -4 -3 -X April 16, 1910 .
1B 94 224 1B Union Avenue 903 22 24 Tennyson Lillian Wife F W 26 M1 2 1 1 Tennessee Virginia Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
1B 95 224 1B Union Avenue 903 22 24 Tennyson Harry L. Jr. Son M W 1 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
1B 96 224 1B Union Avenue 905 23 25 Barbrains James D. Head M W 43 S . . . Louisiana Louisiana Louisiana . . English Cleaner Pressing Club W No 0 Yes Yes . Rent . Home 3 -2 -7 -X April 16, 1910 The surname spelling is my best guess.
1B 97 224 1B Union Avenue 905 23 25 Barbrains George Brother M W 36 S . . . Louisiana Louisiana Louisiana . . English Cleaner Pressing Club W No 0 Yes Yes . . . . 3 -2 -7 -X April 16, 1910 The surname spelling is my best guess.
1B 98 224 1B Union Avenue 907 24 26 Gish Edward L. Head M W 27 M1 7 . . Texas Virginia Virginia . . English Conductor Street Car W No 0 Yes Yes . Rent . Home 2 -0 -X -4 April 16, 1910 The surname spelling is my best guess.
1B 99 224 1B Union Avenue 907 24 26 Gish Ada Wife F W 28 M1 7 1 1 Tennessee Tennessee Tennessee . . English Dressmaker at home AO . . Yes Yes . . . . 9 -0 -0 -X April 16, 1910 The surname spelling is my best guess.
1B 100 224 1B Union Avenue 907 24 26 Gish Claude S. Son M W 6 S . . . Kentucky Texas Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 The surname spelling is my best guess.
==============================================================================================================================================================================================================================================================================================================================================================================================
CENSUS YEAR: 1910 STATE: TN COUNTY: Shelby INCORP-PLACE: Memphis WARD-OF-CITY: 18 MICROFILM#: T624-1521 SUPV/DISTR: 10 ENUM/DISTR: 224 ENUMERATOR: Holloway Manning ENUM/DATE-RANGE: April 15 - 30, 1910
==============================================================================================================================================================================================================================================================================================================================================================================================
Stamped AGE S-M #YRS # #CHILD BIRTH FATHER MOTHER YEAR NATUR- SPEAK TRADE OR GENERAL EMPL OUT OF #WKS CAN CAN ATTD OWN FREE FARM #FARM SURV DEAF ENUMERATION TRANSCRIBER'S
PG# LN# ED SH# STREET HS# DW# FM# LAST NAME FIRST NAME RELATION SEX RACE LAST W-D MAR CHILD LIVING PLACE BIRTHPL BIRTHPL IMMI ALIZED ENG? PROFESSION INDUSTRY ACCT WORK UNEMPL READ WRITE SCH RENT MORT HOME SCH WAR BLIND DUMB DATE REMARKS
(1) (2) (3) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32)
==============================================================================================================================================================================================================================================================================================================================================================================================
2A 1 224 2A Union Avenue 911 25 28 Neuberger Louise Head F W 34 Wd . 7 2 Germany Germany Germany 1881 . English Merchant Grocery EMPL . . Yes Yes . Rent . Home 3 2 3 -X April 16, 1910 Family number is correct, a number was skipped.
2A 2 224 2A Union Avenue 911 25 28 Neuberger Leinhart Son M W 14 S . . . Tennessee Germany Germany . . English None . . . . Yes Yes No . . . . . . . April 16, 1910 .
2A 3 224 2A Union Avenue 911 25 28 Neuberger Herman Son M W 12 S . . . Tennessee Germany Germany . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 4 224 2A Union Avenue 911 25 28 Griswold John G. Boarder M W 34 S . . . N.Carolina N.Carolina N.Carolina . . English Clerk Grocery W . . Yes Yes . . . . 10 7 3 -X April 16, 1910 .
2A 5 224 2A Union Avenue 911 25 28 Cook Edward Boarder M B 16 S . . . Texas Texas Missouri . . English Porter Grocery W . . Yes Yes . . . . 14 -4 -3 -X April 16, 1910 .
2A 6 224 2A East Street 167 26 29 Kirt Louise Head F W 32 Wd . 2 2 Tennessee Indiana Georgia . . English Dressmaker at home OA . . Yes Yes . Rent . Home 9 -0 -9 -8 April 16, 1910 .
2A 7 224 2A East Street 167 26 29 Kirt Lawrence P. Son M W 15 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 8 224 2A East Street 167 26 29 Kirt Howard Son M W 5 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 9 224 2A East Street 173 27 30 Harty Jessie D. Head M W 28 M1 6 . . Alabama Alabama Mississippi . . English Conductor Street Car W No 0 Yes Yes . Rent . Home 2 0 -X 4 April 16, 1910 .
2A 10 224 2A East Street 173 27 30 Harty Lula Mae Wife F W 25 M1 6 1 1 Mississippi Virginia Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 11 224 2A East Street 173 27 30 Harty Jessie V. Son M W 4 S . . . Tennessee Alabama Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 12 224 2A East Street 175 28 31 McMahon Thomas M. Head M W 38 M1 16 . . Louisiana Ireland Ireland . . English Fireman City Department W No 0 Yes Yes . Own Free Home 4 3 -5 -X April 16, 1910 .
2A 13 224 2A East Street 175 28 31 McMahon Ruby F. Wife F W 36 M1 16 0 0 Mississippi Mississippi Alabama . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 14 224 2A East Street 177 29 32 Watson William S. Head M W 52 M1 30 . . Tennessee Virginia N.Carolina . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 -1 -X 4 April 16, 1910 .
2A 15 224 2A East Street 177 29 32 Watson Laura Wife F W 52 M1 30 . . Tennessee Maryland Maryland . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 16 224 2A East Street 177 29 32 Watson Ada G. Niece F W 27 S . . . Tennessee Tennessee Tennessee . . English Dressmaker at home OA . . Yes Yes . . . . 9 -0 -9 -8 April 16, 1910 .
2A 17 224 2A Beale Street 849 30 33 Carruthers Chas. W. Head M W 47 M1 26 . . Tennessee S.Carolina Tennessee . . English Motorman Street Car W No 3 Yes Yes . Rent . Home 2 -1 -X 4 April 16, 1910 .
2A 18 224 2A Beale Street 849 30 33 Carruthers Lenore Wife F W 46 M1 26 6 5 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 19 224 2A Beale Street 849 30 33 Carruthers Willie Son M W 14 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 20 224 2A Beale Street 849 30 33 Carruthers Mary Daughter F W 12 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 21 224 2A Beale Street 849 30 33 Carruthers Minnie Daughter F W 9 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . Yes . . . . . . . April 16, 1910 .
2A 22 224 2A Beale Street 853 31 34 Mathis James Head M W 34 M1 15 . . Alabama Illinois Alabama . . English Conductor . W No 0 Yes Yes . Rent . Home 2 0 X 4 April 16, 1910 .
2A 23 224 2A Beale Street 853 31 34 Mathis Lillie Wife F W 35 M1 15 2 0 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 24 224 2A Beale Street 853 31 34 Mathis Ethel Daughter F W 8 S . . . Alabama Alabama Tennessee . . . None . . . . . Yes . . . . . . . . April 16, 1910 .
2A 25 224 2A Beale Street 853 31 34 Mathis Annie Daughter F W 5 S . . . Alabama Alabama Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 26 224 2A Beale Street 857 32 35 Farrell John Head M W 28 M1 4 . . Tennessee Tennessee Virginia . . English Conductor Street Car W No 0 Yes Yes . Rent . Home 2 0 -X 4 April 16, 1910 .
2A 27 224 2A Beale Street 857 32 35 Farrell Bettie Wife F W 21 M1 4 1 1 Arkansas Arkansas Alabama . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 28 224 2A Beale Street 857 32 35 Farrell Hilda Daughter F W 1 S . . . Tennessee Tennessee Arkansas . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 29 224 2A Beale Street 859 33 36 Miller George T. Head M W 39 M1 13 . . Tennessee New York Tennessee . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 -1 X -4 April 16, 1910 .
2A 30 224 2A Beale Street 859 33 36 Miller Claudia Wife F W 36 M1 13 4 4 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 31 224 2A Beale Street 859 33 36 Miller Sadie Daughter F W 12 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 32 224 2A Beale Street 859 33 36 Miller Cecil Son M W 9 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . Yes . . . . . . . April 16, 1910 .
2A 33 224 2A Beale Street 859 33 36 Miller Leonard Son M W 7 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . No . . . . . . . April 16, 1910 .
2A 34 224 2A Beale Street 859 33 36 Miller Charles B. Son M W 4 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 35 224 2A Beale Street 863 34 37 Carruthers John Head M W 32 M1 4 . . Tennessee Tennessee Tennessee . . English Foreman Rail Road Shop W No 0 Yes Yes . Rent . Home 10 3 -X 5 April 16, 1910 .
2A 36 224 2A Beale Street 863 34 37 Carruthers Sallie Wife F W 23 M1 4 1 1 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 37 224 2A Beale Street 863 34 37 Carruthers J. C. Son M W 2 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 16, 1910 .
2A 38 224 2A Beale Street 867 35 38 Montgomery William H. Head M W 50 M1 15 . . Mississippi Mississippi Mississippi . . English Watchman Night W No 0 Yes Yes . Rent . Home 14 9 -5 -X April 16, 1910 .
2A 39 224 2A Beale Street 867 35 38 Montgomery Emma Wife F W 39 M1 15 1 1 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 40 224 2A Beale Street 867 35 38 Montgomery Faye Daughter F W 14 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 41 224 2A Beale Street 867 35 38 Montgomery Carrie Niece F W 26 S . . . Mississippi Mississippi Mississippi . . English Seamtress Tailor Shop W No 0 Yes Yes . . . . 9 -2 -2 -2 April 16, 1910 .
2A 42 224 2A Beale Street 869 36 39 Raymond James S. Head M W 50 M2 8 . . Mississippi Georgia Unknown . . English Carpenter General Work W No 0 Yes Yes . Rent . Home 12 -2 9 8 April 16, 1910 .
2A 43 224 2A Beale Street 869 36 39 Raymond Ellie Wife F W 48 M1 8 0 0 Tennessee Alabama Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 44 224 2A Beale Street 869 36 39 Raymond Jimmie Son M W 21 S . . . Mississippi Mississippi Unknown . . English Electrician Car Shops W No 0 Yes Yes . . . . 12 -7 -3 -8 April 16, 1910 .
2A 45 224 2A Beale Street 869 36 39 Raymond Mary Daughter F W 20 S . . . Mississippi Mississippi Unknown . . English Clerk Dry Goods Store W No 0 Yes Yes . . . . 10 -7 -3 -X April 16, 1910 .
2A 46 224 2A Beale Street 869 36 39 Raymond Edna Daughter F W 18 S . . . Mississippi Mississippi Unknown . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 47 224 2A Beale Street 869 36 39 Raymond Roberta Daughter F W 16 S . . . Mississippi Mississippi Unknown . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2A 48 224 2A East Street 895 37 40 Moore Harry G. Head M W 32 M1 6 . . Arkansas Arkansas Arkansas . . English Lawyer General Practice OA . . Yes Yes . Rent . Home 1 -0 -6 -X April 16, 1910 .
2A 49 224 2A East Street 895 37 40 Moore Florence Wife F W 28 M1 6 1 1 Canada Canada Canada . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2A 50 224 2A East Street 895 37 40 Moore Louis Son M W 5 S . . . Michigan Arkansas Canada . . . None . . . . . . . . . . . . . . April 16, 1910 .
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CENSUS YEAR: 1910 STATE: TN COUNTY: Shelby INCORP-PLACE: Memphis WARD-OF-CITY: 18 MICROFILM#: T624-1521 SUPV/DISTR: 10 ENUM/DISTR: 224 ENUMERATOR: Holloway Manning ENUM/DATE-RANGE: April 15 - 30, 1910
==============================================================================================================================================================================================================================================================================================================================================================================================
Stamped AGE S-M #YRS # #CHILD BIRTH FATHER MOTHER YEAR NATUR- SPEAK TRADE OR GENERAL EMPL OUT OF #WKS CAN CAN ATTD OWN FREE FARM #FARM SURV DEAF ENUMERATION TRANSCRIBER'S
PG# LN# ED SH# STREET HS# DW# FM# LAST NAME FIRST NAME RELATION SEX RACE LAST W-D MAR CHILD LIVING PLACE BIRTHPL BIRTHPL IMMI ALIZED ENG? PROFESSION INDUSTRY ACCT WORK UNEMPL READ WRITE SCH RENT MORT HOME SCH WAR BLIND DUMB DATE REMARKS
(1) (2) (3) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32)
==============================================================================================================================================================================================================================================================================================================================================================================================
2B 51 224 2B East Street 197 38 41 White William W. Head M W 31 M1 8 . . Tennessee Kentucky Virginia . . English Drug Clerk Retail House W No 0 Yes Yes . Rent . Home 10 -7 -3 -X April 16, 1910 .
2B 52 224 2B East Street 197 38 41 White Pearl C. Wife F W 29 M1 8 . . Tennessee Missouri Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 53 224 2B East Street 197 38 41 White Lillie M. Daughter F W 6 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . No . . . . . . . April 16, 1910 .
2B 54 224 2B East Street 197 38 41 Geiger Carolina Servant F W 63 Wd . 2 2 Australia Unknown Unknown 1872 . English Servant Private Family W No 0 No No . . . . 0 -3 -7 -X April 16, 1910 .
2B 55 224 2B East Street 201 39 42 Dalebrimer Elsie Head F W 67 Wd . 2 2 Germany Germany Germany 1861 . English None . . . . Yes Yes . Rent . Home . . . . April 16, 1910 .
2B 56 224 2B East Street 201 39 42 Dalebrimer George Son M W 41 S . . . Tennessee Germany Germany . . English Salesman City W No 0 Yes Yes . . . . 6 -2 -3 -X April 16, 1910 .
2B 57 224 2B East Street 201 39 42 Rosenthal Harry Son-in-Law M W 41 M1 12 . . Arkansas Germany Germany . . English Salesman City W No 0 Yes Yes . . . . 6 -2 -3 -X April 16, 1910 .
2B 58 224 2B East Street 201 39 42 Rosenthal Julia Daughter F W 35 M1 12 . . Tennessee Germany Germany . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 59 224 2B East Street 201 39 42 Rosenthal Louis Son M W 9 S . . . Tennessee Arkansas Tennessee . . . None . . . . . . Yes . . . . . . . April 16, 1910 .
2B 60 224 2B East Street 201 39 42 Rosenfind William Boarder M W 66 M1 44 . . Germany Germany Germany 1849 Ga English Merchant Dry Goods EMPL . . Yes Yes . . . . 2 -1 -3 -X April 16, 1910 .
2B 61 224 2B East Street 201 39 42 Rosenfind Bertha Boarder F W 62 M1 44 . . New York Germany Germany . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 62 224 2B East Street 201 39 42 Smith Lizzie Servant F MU 45 Wd . 2 2 Arkansas Unknown Unknown . . English Servant Private Family W No 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
2B 63 224 2B East Street 209 40 43 Rozier Frank G. Head M W 47 M2 5 . . Missouri Unknown Unknown . . English Manager Laundry W No 0 Yes Yes . Rent . Home 10 -2 -8 -X April 16, 1910 .
2B 64 224 2B East Street 209 40 43 Rozier Dorn Wife F W 27 M1 5 1 1 Missouri Germany Unknown . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 65 224 2B East Street 209 40 43 Rozier Byron F. Son M W 3 S . . . Tennessee Missouri Missouri . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 66 224 2B East Street 209 40 43 Wells Gertrude Servant F W 18 S . . . Missouri Unknown Unknown . . English Servant Private Family W No 0 Yes Yes . . . . 0 -3 -7 -X April 16, 1910 .
2B 67 224 2B East Street 215 41 44 Pritchard Fred J. Head M W 35 M1 9 . . Illinois Wales Wales . . English Merchant Plummer Supplies EMPL . . Yes Yes . Own Free Home 5 -8 -3 -X April 16, 1910 .
2B 68 224 2B East Street 215 41 44 Pritchard Mabel Wife F W 38 M1 9 2 2 Illinois Illinois Illinois . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 69 224 2B East Street 215 41 44 Pritchard Fred J. Jr. Son M W 7 S . . . Tennessee Illinois Illinois . . . None . . . . . Yes . . . . . . . . April 16, 1910 .
2B 70 224 2B East Street 215 41 44 Pritchard Howard W. Son M W 5 S . . . Tennessee Illinois Illinois . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 71 224 2B East Street 215 41 44 Brice Henry Servant M B 40 3 1 0 0 Mississippi Mississippi Mississippi . . English Servant Private Family W No 0 No No . . . . 0 -3 -7 -X April 16, 1910 .
2B 72 224 2B East Street 215 41 44 Brice Bettie Servant F B 45 1 1 . . Tennessee Tennessee Mississippi . . English Servant Private Family W No 0 Yes No . . . . 0 -3 -7 -X April 16, 1910 .
2B 73 224 2B Eastmoreland Ave 868 42 45 Dixon Harry N Head M W 30 M1 11 . . Mississippi Mississippi Mississippi . . English Driver Ice Wagon W No 0 Yes Yes . Rent . Home 15 -4 -3 -X April 16, 1910 .
2B 74 224 2B Eastmoreland Ave 868 42 45 Dixon Ida Wife F W 31 M1 11 4 4 Mississippi Mississippi Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 75 224 2B Eastmoreland Ave 868 42 45 Dixon Ivan Son M W 10 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2B 76 224 2B Eastmoreland Ave 868 42 45 Dixon Ross Son M W 4 S . . . Mississippi Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 77 224 2B Eastmoreland Ave 868 42 45 Dixon Earnest Son M W 6/12 S . . . Tennessee Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 78 224 2B Eastmoreland Ave 868 42 45 Dixon Grace Daughter F W 6/12 S . . . Tennessee Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 79 224 2B Eastmoreland Ave 866 43 46 Weirmyer James M. Head M W 33 M1 9 . . Mississippi Unknown Unknown . . English Policeman City W No 0 Yes Yes . Rent . Home 4 5 5 -X April 16, 1910 .
2B 80 224 2B Eastmoreland Ave 866 43 46 Weirmyer Mary Wife F W 31 M1 9
3 3 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 81 224 2B Eastmoreland Ave 866 43 46 Weirmyer Alice Daughter F W 6 S . . . Mississippi Mississippi Mississippi . . . None . . . . . . No . . . . . . . April 16, 1910 .
2B 82 224 2B Eastmoreland Ave 866 43 46 Weirmyer Mamie Daughter F W 5 S . . . Mississippi Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 83 224 2B Eastmoreland Ave 866 43 46 Weirmyer Lucinda Daughter F W 1 S . . . Tennessee Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 84 224 2B Eastmoreland Ave 864 44 47 Mc Mulle Mrs. John E. Head F W 50 Wd . 2 2 Tennessee Unknown Unknown . . English None own income . . . Yes Yes . Rent . Home 19 -9 X X April 16, 1910 .
2B 85 224 2B Eastmoreland Ave 864 44 47 Mc Mulle William Son M W 22 S . . . Tennessee Tennessee Tennessee . . English Timer Car Barn W No 0 Yes Yes . . . . 13 -5 -X -4 April 16, 1910 .
2B 86 224 2B Eastmoreland Ave 864 44 47 Mc Mulle Mary Daughter F W 19 S . . . Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 87 224 2B Eastmoreland Ave 864 44 47 Clapp Sam W. Nephew M W 26 S . . . Tennessee Unknown Tennessee . . English Conductor Street Car W No 0 Yes Yes . . . . 2 -0 X 4 April 16, 1910 .
2B 88 224 2B South Dunlap 222 45 48 Luici Will C. Head M W 36 M1 5 . . Arkansas Arkansas Arkansas . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 -1 -X -4 April 16, 1910 .
2B 89 224 2B South Dunlap 222 45 48 Luici Lucy Wife F W 25 M1 5 3 2 Arkansas North Carolina North Carolina . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 90 224 2B South Dunlap 222 45 48 Luici Cleo Daughter F W 4 S . . . Arkansas Arkansas Arkansas . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 91 224 2B South Dunlap 222 45 48 Luici William H. Son M W 1 S . . . Tennessee Arkansas Arkansas . . . None . . . . . . . . . . . . . . April 16, 1910 .
2B 92 224 2B South Dunlap 220 46 49 Purly David J. Head M W 40 M1 21 . . Tennessee Tennessee Tennessee . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 1 X -4 April 16, 1910 .
2B 93 224 2B South Dunlap 220 46 49 Purly Lucy Wife F W 36 M1 21 4 2 Kentucky North Carolina Kentucky . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 94 224 2B South Dunlap 220 46 49 Purly Mamie Daughter F W 19 S . . . Tennessee Tennessee Kentucky . . English Clerk Dry Goods Store W No 0 Yes Yes . . . . 10 7 -3 -X April 16, 1910 .
2B 95 224 2B South Dunlap 220 46 49 Purly Raymond Son M W 11 S . . . Tennessee Tennessee Kentucky . . English . . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2B 96 224 2B South Dunlap 208 47 50 Pickle James C. Head M W 35 M1 10 . . Mississippi Mississippi Mississippi . . English Policeman City W No 0 Yes Yes . rent . Home 4 -5 -5 -X April 16, 1910 .
2B 97 224 2B South Dunlap 208 47 50 Pickle Stella Wife F W 30 M1 10 4 4 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
2B 98 224 2B South Dunlap 208 47 50 Pickle Mayfred Daughter F W 10 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
2B 99 224 2B South Dunlap 208 47 50 Pickle Harris Son M W 6 S . . . Tennessee Mississippi Mississippi . . . None . . . . . . No . . . . . . . April 16, 1910 .
2B 100 224 2B South Dunlap 208 47 50 Pickle Warren Son M W 4 S . . . Tennessee Mississippi Mississippi . . . None . . . . . . . . . . . . . . April 16, 1910 .
==============================================================================================================================================================================================================================================================================================================================================================================================
CENSUS YEAR: 1910 STATE: TN COUNTY: Shelby INCORP-PLACE: Memphis WARD-OF-CITY: 18 MICROFILM#: T624-1521 SUPV/DISTR: 10 ENUM/DISTR: 224 ENUMERATOR: Holloway Manning ENUM/DATE-RANGE: April 15 - 30, 1910
==============================================================================================================================================================================================================================================================================================================================================================================================
Stamped AGE S-M #YRS # #CHILD BIRTH FATHER MOTHER YEAR NATUR- SPEAK TRADE OR GENERAL EMPL OUT OF #WKS CAN CAN ATTD OWN FREE FARM #FARM SURV DEAF ENUMERATION TRANSCRIBER'S
PG# LN# ED SH# STREET HS# DW# FM# LAST NAME FIRST NAME RELATION SEX RACE LAST W-D MAR CHILD LIVING PLACE BIRTHPL BIRTHPL IMMI ALIZED ENG? PROFESSION INDUSTRY ACCT WORK UNEMPL READ WRITE SCH RENT MORT HOME SCH WAR BLIND DUMB DATE REMARKS
(1) (2) (3) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32)
==============================================================================================================================================================================================================================================================================================================================================================================================
3A 1 224 3A South Dunlap 208 47 50 Pickle Fred Son M W 4/12 S . . . Tennessee Mississippi Mississippi . . . none . . . . . . . . . . . . . . April 16, 1910 .
3A 2 224 3A South Dunlap 232 48 51 Cunningham Frank O. Head M W 35 M1 5 . . Illinois Ohio Ohio . . English Inspector Street Car W No 0 Yes Yes . Rent . Home 11 -3 -X 4 April 16, 1910 .
3A 3 224 3A South Dunlap 232 48 51 Cunningham Willie May Wife F W 25 M1 5 0 0 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
3A 4 224 3A South Dunlap 232 48 51 Cunningham Benjamin Father M W 71 Wd . . . Ohio Ohio Ohio . . English None . . . . Yes Yes . . . . . No . . April 16, 1910 .
3A 5 224 3A South Dunlap 202 49 52 Bryant John Head M W 46 M2 10 . . Mississippi Mississippi Mississippi . . English Driver Express Wagon W No 0 Yes Yes . Rent . Home 15 4 X -3 April 16, 1910 .
3A 6 224 3A South Dunlap 202 49 52 Bryant Ida Wife F W 39 M2 10 5 0 Mississippi Mississippi Mississippi . . English None . . . . Yes Yes . . . . . . . . April 16, 1910 .
3A 7 224 3A South Dunlap 202 49 52 Bryant Walter Son M W 23 S . . . Mississippi Mississippi Mississippi . . English Motorman Street Car W No 0 Yes Yes . . . . 2 -1 X -4 April 16, 1910 .
3A 8 224 3A South Dunlap 202 49 52 Bryant Henry Son M W 21 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
3A 9 224 3A South Dunlap 202 49 52 Bryant Mary Daughter F W 19 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
3A 10 224 3A South Dunlap 202 49 52 Bryant Jessie Son M W 16 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
3A 11 224 3A South Dunlap 202 49 52 Bryant Annie Daughter F W 13 S . . . Mississippi Mississippi Mississippi . . English None . . . . Yes Yes Yes . . . . . . . April 16, 1910 .
3A 12 224 3A Linden Street 813 50 53 Bell Gig H. Head M W 31 M1 7 . . Tennessee Tennessee Tennessee . . English Patrolman City W No 0 Yes Yes . Rent . Home 4 5 5 -X April 17, 1910 .
3A 13 224 3A Linden Street 813 50 53 Bell Ellen Wife F W 30 M1 7 0 0 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 14 224 3A Linden Street 817 51 54 Atkins Jerome A. Head M W 31 M2 6 . . Tennessee Virginia Virginia . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 1 X -4 April 17, 1910 .
3A 15 224 3A Linden Street 817 51 54 Atkins Grace Wife F W 29 M1 6 2 1 Tennessee Missouri Mississippi . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 16 224 3A Linden Street 817 51 54 Atkins Maggie Daughter F W 2 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 17 224 3A Linden Street 821 52 55 Park Sam W. Head M W 36 M1 13 . . Tennessee Mississippi Mississippi . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 1 X 4 April 17, 1910 .
3A 18 224 3A Linden Street 821 52 55 Park Edna Wife F W 31 M1 13 6 6 Texas Alabama Mississippi . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 19 224 3A Linden Street 821 52 55 Park Garvin Son M W 12 S . . . Texas Tennessee Texas . . English None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 20 224 3A Linden Street 821 52 55 Park Ruby Daughter F W 11 S . . . Texas Tennessee Texas . . English None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 21 224 3A Linden Street 821 52 55 Park Nellie Daughter F W 9 S . . . Tennessee Tennessee Texas . . . None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 22 224 3A Linden Street 821 52 55 Park Edward Son M W 6 S . . . Tennessee Tennessee Texas . . . None . . . . . . Yes . . . . . . . April 17, 1910 .
3A 23 224 3A Linden Street 821 52 55 Park Gus Son M W 4 S . . . Tennessee Tennessee Texas . . . None . . . . . . No . . . . . . . April 17, 1910 .
3A 24 224 3A Linden Street 821 52 55 Park Mary Daughter F W 2 S . . . Tennessee Tennessee Texas . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 25 224 3A Linden Street 823 53 56 Moore Chambers J. Head M W 24 M1 4 . . Tennessee Unknown Unknown . . English Conductor Street Car W No 0 Yes Yes . Rent . Home 2 0 X 4 April 17, 1910 .
3A 26 224 3A Linden Street 823 53 56 Moore Birdie Wife F W 23 M1 4 1 1 Virginia Tennessee N.Carolina . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 27 224 3A Linden Street 823 53 56 Moore Gladys Daughter F W 1 S . . . Tennessee Tennessee Virginia . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 28 224 3A Linden Street 823 53 56 Halbert Nancy Mother-in-law F W 46 Wd . 2 2 North Carolina North Carolina North Carolina . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 29 224 3A Linden Street 823 54 57 Garner Robt Head M W 35 M1 9 . . Tennessee Tennessee Tennessee . . English Carpenter Rail Road Shop W No 0 Yes Yes . Rent . Home 2 2 X -5 April 17, 1910 .
3A 30 224 3A Linden Street 823 54 57 Garner Eva Wife F W 37 M1 9 4 4 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 31 224 3A Linden Street 823 54 57 Garner Clara Daughter F W 9 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . Yes . . . . . . . April 17, 1910 .
3A 32 224 3A Linden Street 823 54 57 Garner Thelma Daughter F W 7 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . Yes . . . . . . . April 17, 1910 .
3A 33 224 3A Linden Street 823 54 57 Garner Ray Son M W 5 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 34 224 3A Linden Street 823 54 57 Garner Herman Son M W 4 S . . . Tennessee Tennessee Tennessee . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 35 224 3A Linden Street 833 55 58 Fraser William S. Head M W 54 M1 32 . . Tennessee Tennessee Tennessee . . English Landlord Boarding House OA No 0 Yes Yes . Rent . Home 1 2 7 X April 17, 1910 .
3A 36 224 3A Linden Street 833 55 58 Fraser Mary N. Wife F W 44 M1 32 6 4 Tennessee Tennessee Tennessee . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 37 224 3A Linden Street 833 55 58 Fraser Raymond Son M W 22 S . . . Tennessee Tennessee Tennessee . . English Carpenter Car Barn W No 0 Yes Yes . . . . 12 2 X 4 April 17, 1910 .
3A 38 224 3A Linden Street 833 55 58 Fraser Alma Daughter F W 16 S . . . Tennessee Tennessee Tennessee . . English Clerk Novelty Store W No 0 Yes Yes . . . . 10 7 3 X April 17, 1910 .
3A 39 224 3A Linden Street 833 55 58 Fraser Aubrey Son M W 7 S . . . Tennessee Tennessee Tennessee . . . None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 40 224 3A Linden Street 835 56 59 Bailey William E. Head M W 32 M2 8 . . Mississippi Mississippi Mississippi . . English Motorman . W No 0 Yes Yes . Rent . Home 2 1 X 4 April 17, 1910 .
3A 41 224 3A Linden Street 835 56 59 Bailey Della Wife F W 28 M1 8 0 0 Georgia Georgia Georgia . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 42 224 3A Linden Street 835 57 60 Spencer James H. Head M W 41 M2 4 . . Kentucky Kentucky Kentucky . . English Motorman Street Car W No 0 Yes Yes . Rent . Home 2 1 X 4 April 17, 1910 .
3A 43 224 3A Linden Street 835 57 60 Spencer Maggie Wife F W 27 M1 4 1 1 Arkansas Kentucky Tennessee . . English None . . . . Yes Yes . . . . . . . . April 17, 1910 .
3A 44 224 3A Linden Street 835 57 60 Spencer Herman Son M W 11 S . . . Tennessee Kentucky Unknown . . English None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 45 224 3A Linden Street 835 57 60 Spencer Elmo Son M W 10 S . . . Tennessee Kentucky Unknown . . English None . . . . Yes Yes Yes . . . . . . . April 17, 1910 .
3A 46 224 3A Linden Street 835 57 60 Spencer Annie M. Daughter F W 1 S . . . Tennessee Kentucky Arkansas . . . None . . . . . . . . . . . . . . April 17, 1910 .
3A 47 224 3A Vance Street 828 58 61 Morrison William H. Head M W 39 M1 15 . . Georgia South Carolina South Carolina . . English Conductor Street Car W No 0 Yes Yes . Rent . Home 2 0 X 4 April 18, 1910 .
3A 48 224 3A Vance Street 828 58 61 Morrison Sahara Wife F W 42 M2 15 12 8 Georgia North Carolina South Carolina . . English None . . . . Yes Yes . . . . . . . . April 18, 1910 .
3A 49 224 3A Vance Street 828 58 61 Morrison James Son M W 14 S . . . Georgia Georgia Georgia . . English None . . . . Yes Yes Yes . . . . . . . April 18, 1910 .
3A 50 224 3A Vance Street 828 58 61 Morrison Doctor Cocker Son M W 12 S . . . Georgia Georgia Georgia . . English None . . . . Yes Yes Yes . . . . . . . April 18, 1910 The given name seemed strange, but this is what it looked like. | http://us-census.org/pub/usgenweb/census/tn/shelby/1910/ed224-pg001a.txt |
A Study of DCC-2618 vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib - Full Text View - ClinicalTrials.gov
A Study of DCC-2618 vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib (intrigue)
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: NCT03673501 Recruitment Status : Unknown Verified January 2021 by Deciphera Pharmaceuticals LLC. Recruitment status was: Active, not recruiting First Posted : September 17, 2018 Last Update Posted : January 6, 2021
Sponsor:
Deciphera Pharmaceuticals LLC
Information provided by (Responsible Party):
Deciphera Pharmaceuticals LLC
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:
This is a 2-arm, randomized, open-label, international, multicenter study comparing the efficacy of DCC-2618 to sunitinib in GIST patients who progressed on or were intolerant to first-line anticancer treatment with imatinib. Approximately 426 patients will be randomized in a 1:1 ratio to DCC-2618 150 mg once daily (QD) (continuous dosing for 6 week cycles) or sunitinib 50 mg QD (6 week cycles, 4 weeks on, 2 weeks off).
Condition or disease Intervention/treatment Phase Gastrointestinal Stromal Tumors Drug: DCC-2618 Drug: Sunitinib Phase 3
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 : 426 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Phase 3, Interventional, Randomized, Multicenter, Open-Label Study of DCC-2618 vs Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumors After Treatment With Imatinib Actual Study Start Date : February 11, 2019 Estimated Primary Completion Date : June 2021 Estimated Study Completion Date : March 2022
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics: Gastrointestinal stromal tumor
Drug Information available for: Sunitinib malate Sunitinib
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 Experimental: DCC-2618 150 mg QD DCC-2618 Drug: DCC-2618 Oral KIT/PDGFRA kinase inhibitor Other Name: ripretinib Active Comparator: sunitinib 50 mg QD sunitinib Drug: Sunitinib Oral receptor tyrosine kinase (RTK) inhibitor Other Name: Sutent
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Progression free survival (PFS) [ Time Frame: 30 months ]
PFS Based on independent radiologic review using modified RECIST
Secondary Outcome Measures
:
Objective response rate (ORR) [ Time Frame: 30 months ]
Objective response rate as determined by confirmed CR + confirmed PR by independent radiologic review
Overall Survival (OS) [ Time Frame: 30 months ]
Measure of overall survival
Eligibility Criteria
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.
Criteria
Inclusion Criteria:
Patients ≥ 18 years of age at the time of informed consent.
Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample, otherwise, a fresh biopsy is required.
Molecular pathology report must be available. If molecular pathology report is not available or insufficient, an archival tumor tissue sample or fresh biopsy is required for mutation status confirmation by the central laboratory prior to randomization.
Patients must have progressed on imatinib or have documented intolerance to imatinib.
Eastern Cooperative Oncology Group (ECOG) PS of ≤ 2 at screening.
Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug.
Patients of reproductive potential must agree to follow the contraception requirements outlined in the study protocol.
Patients must have at least 1 measurable lesion according to mRECIST Version 1.1 (non nodal lesions must be ≥ 1.0 cm in the long axis or ≥ double the slice thickness in the long axis) within 21 days prior to the first dose of study drug.
Adequate organ function and bone marrow reserve as indicated by the central laboratory assessments performed at screening.
Resolution of all toxicities from prior therapy to ≤ Grade 1 (or patient baseline) within 1 week prior to the first dose of study drug (excluding alopecia and ≤ Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase [CPK] laboratory abnormalities).
The patient is capable of understanding and complying with the protocol and the patient has signed the informed consent document. Signed informed consent form (ICF) must be obtained before any study-specific procedures are performed and the patient must agree to not participate in any other interventional clinical trial while on treatment in this clinical trial. Participation in a noninterventional study (including observational studies) is permitted.
Exclusion Criteria:
Treatment with any other line of therapy in addition to imatinib for advanced GIST. Imatinib-containing combination therapy in the first-line setting is not allowed.
Patients with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible.
Patient has known active central nervous system metastases.
Left ventricular ejection fraction (LVEF) < 50% at screening.
Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months before the first dose of study drug.
Venous thrombotic events (e.g. deep vein thrombosis) or pulmonary arterial events (e.g. pulmonary embolism) within 1 month before the first dose of study drug. Patients on stable anticoagulation therapy for at least one month are eligible.
12-lead ECG demonstrating QT interval corrected (QTc) by Fridericia's formula > 450 ms in males or > 470 ms in females at screening or history of long QTc syndrome
Use of known substrates or inhibitors of BCRP transporters within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug.
Major surgeries (e.g. abdominal laparotomy) within 4 weeks of the first dose of study drug. All major surgical wounds must be healed and free of infection or dehiscence before the first dose of study drug.
Any other clinically significant comorbidities.
Known human immunodeficiency virus or hepatitis C infection only if the patient is taking medications that are excluded per protocol, active hepatitis B, or active hepatitis C infection.
If female, the patient is pregnant or lactating.
Known allergy or hypersensitivity to any component of the study drug.
Gastrointestinal abnormalities including but not limited to:
inability to take oral medication
malabsorption syndromes
requirement for intravenous (IV) alimentation
Any active bleeding excluding hemorrhoidal or gum bleeding.
| https://clinicaltrials.gov/ct2/show/NCT03673501 |
Rheumatoid Arthritis | Consultant360
Clinical Updates
Ongoing updates of key clinical trial advances and new study data for common conditions.
Introduction Etiology Screening and Diagnosis Treatment and Management Conclusion References
Introduction
Rheumatoid arthritis is a type of chronic autoimmune arthritis that primarily causes joint pain, stiffness, swelling, and decreased movement of the joints. It affects more than 1.3 million Americans, and approximately 75% of patients with rheumatoid arthritis are women. Around 1% to 3% of women may develop rheumatoid arthritis in their lifetime, which most often begins between the ages of 30 and 50 years. 1 Uncontrolled rheumatoid arthritis leads to inflammation that can damage cartilage leading to bone erosion and joint fusion. 2 Therefore, early treatment and well-controlled disease is necessary to avoid inflammation in joints that could lead to permanent damage. 3
Etiology
The exact cause of rheumatoid arthritis is unknown, but genetic, environmental, hormonal, immunologic, and infectious factors play large roles in its development. Indeed, genetic factors account for up to approximately 50% of rheumatoid arthritis cases, with strongest risks seen in first-degree relatives. 4
The risk of developing rheumatoid arthritis has been associated with several alleles. One gene family, the HLA-DRB1 alleles found within the human major histocompatibility complex on chromosome 6, is consistently highlighted when seeking to identify the disease. The HLA-DRB1 alleles constitute the strongest genetic association and may contribute to 30% or greater of the total genetic component of rheumatoid arthritis. 5 These HLA-DRB1 alleles contain a stretch of a conserved sequence of five amino acids and include HLA-DRB1*04 , HLA-DRB1*01 , and HLA-DRB1*10 . 5,6 Genome-wide association studies have identified polymorphisms in other genes, such as PAD14 , PTPN22 , CTLA4 , IL2RA , STAT4 , TRAF1 , CCR6 , and IRF5, as being associated with rheumatoid arthritis. 6 Further genome-wide association studies have identified even more loci that are consistently associated across ethnicities, such as PADI2 and NFKBIE . 5
Many environmental factors are associated with rheumatoid arthritis development. The strongest environmental risk is exposure to tobacco. Indeed, exposure to smoking accounts for approximately 20% to 30% of the environmental risk. 4 Other risks include female sex, exposure to silica, air pollution, a diet high in sodium, red meat, and iron, obesity, and low vitamin D intake. Factors associated with a decreased risk include fish and omega-3 fatty acid consumption, moderate alcohol intake, healthy diet, statin use, and oral contraceptive or hormone replacement use. 4
Finally, a possible immunologic and infectious risk component exists for developing rheumatoid arthritis. Several specific organisms have been identified as possibly being associated with the pathogenesis of rheumatoid arthritis, including Porphyromonas gingivalis ( P ging ), Anaeroglobus and Prevotella species, and Aggregatibacter actinomycetemcomitans. 4 These pathogens cause mucosal inflammation and may influence the early immunologic changes that lead to rheumatoid arthritis. This is an early area of investigation that requires more knowledge regarding the relationship between mucosal processes and the initiation of autoimmunity. In addition, it will be important to combine these factors to understand how mucosal processes relate to other risk factors for rheumatoid arthritis. 4
Screening and Diagnosis
The diagnosis of rheumatoid arthritis involves an examination of blood test results, joint and organ examinations, as well as a review of x-ray or ultrasound images. There is no single test available for its diagnosis. Blood tests are conducted to identify the presence of antibodies in the blood that may indicate the disease. 1 However, these antibodies can also be present in healthy individuals and can lead to a false positive outcome. Abnormal blood tests can show anemia, rheumatoid factor, antibodies to cyclic citrullinated peptides, and/or an elevated erythrocyte sedimentation rate. Although X-rays can be useful for detecting rheumatoid arthritis, the autoimmune disease may be within normal limits in its early stages. As such, imaging tests are typically more beneficial for measuring disease progress and severity. 1
In 2010, the American College of Rheumatology and European League Against Rheumatism published classification criteria for rheumatoid arthritis. 7 In the new criteria set, classification as definite rheumatoid arthritis is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis which better explains the synovitis, and achievement of a total score of 6 or greater from the individual scores in the following four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1), and symptom duration (two levels; range 0–1). 7
Dutch researchers developed a clinical prediction tool to help identify patients with undifferentiated arthritis who are at risk of progressing to rheumatoid arthritis. The clinical rule includes assigning points to various patient characteristics, including age, sex, distribution of involved joints, and more. The sum of the total points gives a score in which a score of 0 represents the lowest risk of rheumatoid arthritis and a score of 14 represents the highest risk. 8
Treatment and Management
In 2021, the American College of Rheumatology (ACR) published a guideline update for the treatment of rheumatoid arthritis, which was intended to serve as a tool to support clinical and patient decision making. 9 New topics included in this update are recommendations for administering methotrexate, using methotrexate in patients with subcutaneous nodules, pulmonary disease and nonalcoholic fatty liver disease, using rituximab in patients with hypogammaglobulinemia, and treating rheumatoid arthritis in patients with nontuberculous mycobacteria lung disease. The guidelines provide a general guidance for commonly encountered clinical scenarios, but individual treatment decisions should be made through a shared decision-making process based on the patients’ disease activity, values, goals, preferences, and comorbidities. 9
According to the guidelines, disease-modifying antirheumatic drugs (DMARDs) are the most effective treatment options for treating rheumatoid arthritis. Their timely initiation can prevent joint damage. The conventional synthetic disease-modifying antirheumatic drug (csDMARD) hydroxychloroquine is recommended for initial treatment in patients with rheumatoid arthritis with low disease activity. However, the csDMARD methotrexate is recommended as the initial treatment of patients with rheumatoid arthritis and moderate or high disease activity. If patients do not achieve low disease activity with methotrexate, triple therapy with the addition of sulfasalazine and hydroxychloroquine is as effective as adding a biologic or targeted synthetic medication, but with a slower response. 9
The newest therapeutic approach to rheumatoid arthritis approved by the FDA involves using Janus kinase (JAK) inhibitors. The ACR guideline updated its recommendations on using JAK inhibitors when csDMARDs are ineffective. Currently approved JAK inhibitors include tofacitinib, baricitinib, and upadacitinib. Other JAK inhibitors that have been investigated include peficitinib, filgotinib, decernotinib, ruxolitinib, and itacitinib. 10,11 Phase 4 studies investigating JAK inhibitors include the RA-BRANCH, RA-BRIDGE, CLOSEUP, and RINVOQ trials. 12–15
The goal of rheumatoid arthritis management is to begin an aggressive drug treatment plan to prevent joint damage. The 2016 update of the European League Against Rheumatism recommends that patients who present with arthritis and are at risk of persistent arthritis should be started on DMARDs as early as possible, even if they do not fulfill classification criteria for an inflammatory rheumatologic disease. 16 Of the DMARDs available, methotrexate should be the first treatment strategy. Rheumatologists should be the primary point of care for patients with early arthritis. 16
Conclusion
Rheumatoid arthritis management has made great progress over the last decades, but the mechanisms underlying the inflammatory process and the pharmacological effects of therapeutic molecules are still not completely understood. A more thorough understanding of why some patients become less responsive over time, how different therapies have comparable efficacies, detecting pre-rheumatoid arthritis and establishing an early treatment, and improving the efficacy and safety of treatments are necessary to fulfill unmet needs in the field.
References
Rheumatoid Arthritis. American College of Rheumatology. Updated December 2021. Accessed April 6, 2023. https://rheumatology.org/patients/rheumatoid-arthritis
Rheumatoid Arthritis. Cleveland Clinic. Updated February 18, 2022. Accessed April 6, 2023. https://my.clevelandclinic.org/health/diseases/4924-rheumatoid-arthritis
Rheumatoid arthritis - Complications. National Health Service. Updated March 8, 2023. Accessed April 6, 2023. https://www.nhs.uk/conditions/rheumatoid-arthritis/complications/
Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol . 2017;31(1):3-18. doi:10.1016/j.berh.2017.08.003
Dedmon LE. The genetics of rheumatoid arthritis. Rheumatology . 2020;59(10):2661-2670. doi:10.1093/rheumatology/keaa232
Chauhan K, Jandu JS, Brent LH, Al-Dhahir MA. Rheumatoid Arthritis . StatPearls Publishing; 2023. Accessed April 6, 2023. https://www.ncbi.nlm.nih.gov/books/NBK441999/
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis . 2010;69(9):1580-1588. doi:10.1136/ard.2010.138461
Mochan E, Ebell MH. Predicting rheumatoidarthritis risk in adults with undifferentiated arthritis. Am Fam Physician . 2008;77(10):1451-1453. https://www.aafp.org/pubs/afp/issues/2008/0515/p1451.html
Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol . 2021;73(7):1108-1123. doi:10.1002/art.41752
Radu AF, Bungau SG. Management of Rheumatoid Arthritis: an overview. Cells . 2021;10(11):2857. doi:10.3390/cells10112857
You H, Xu D, Zhao J, et al. JAK inhibitors: prospects in connective tissue disease. Clin Rev Allergy Immunol. 2020;59(3):334-351. doi:10.10007/s12016-020-08786-6.
A randomized, controlled pragmatic phase 3b/4 study of baricitinib in patients with rheumatoid arthritis. ClinicalTrials.gov. Published September 12, 2019. Updated March 7, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04086745. https://clinicaltrials.gov/ct2/show/NCT04086745
A randomized, active-controlled, parallel-group, phase 3b/4 sstudy of baricitinib in patients with rheumatoid arthritis. ClinicalTrials.gov. Published April 16, 2019. Updated March 24, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT03915964. https://clinicaltrials.gov/ct2/show/NCT03915964
Canadian real-life post-marketing observational study assessing the effectiveness of upadacitinib for treating rheumatoid arthritis (CLOSEUP). ClinicalTrials.gov. Published October 5, 2020. Updated January 18, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04574492. https://clinicaltrials.gov/ct2/show/NCT04574492
Post-marketing surveillance to evaluate the safety and effectiveness of upadacitinib in Korean patients. ClinicalTrials.gov. Published September 9, 2020. Updated March 29, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04541810. https://clinicaltrials.gov/ct2/show/NCT04541810
Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis . 2017;76(6):948-959. doi:10.1136/annrheumdis-2016-210602
| https://www.consultant360.com/clinical-updates/rheumatoid-arthritis?page=1%3Fpage=2%3Fpage=2%3Fpage=2%3Fpage=2%3Fpage=1%3FID=8pat |
Rapid diagnostic test for common type of pneumonia developed -- ScienceDaily
Researchers have developed a technique that can diagnose a common type of pneumonia within minutes, potentially replacing existing tests that can take several days for results. The researchers detected Mycoplasma pneumoniae, which causes atypical or " walking pneumonia," in true clinical samples with over 97 percent accuracy using a recently-developed nanotechnology-based platform.
Rapid diagnostic test for common type of pneumonia developed
University of Georgia
Summary:
Researchers have developed a technique that can diagnose a common type of pneumonia within minutes, potentially replacing existing tests that can take several days for results. The researchers detected Mycoplasma pneumoniae, which causes atypical or "walking pneumonia," in true clinical samples with over 97 percent accuracy using a recently-developed nanotechnology-based platform.
University of Georgia researchers have developed a technique that can diagnose a common type of pneumonia within minutes, potentially replacing existing tests that can take several days for results.
The researchers, whose findings are detailed online in the journal PLoS ONE, detected Mycoplasma pneumoniae,which causes atypical or "walking pneumonia," in true clinical samples with over 97 percent accuracy using a recently-developed nanotechnology-based platform.
"If you can make a positive identification from a 10-minute test, then appropriate antibiotics can be prescribed, limiting both the consequences in that patient and the likelihood that it will spread to others," said lead-author Duncan Krause, a professor in the department of microbiology in the UGA Franklin College of Arts and Sciences.
Krause and his colleagues built upon an existing technology called surface-enhanced Raman spectroscopy, which works by detecting spectral signatures of a near-infrared laser as it scatters off a biological specimen. They were able to enhance the Raman signal by using silver nanorod arrays to detect the tiny bacteria in throat swab specimens.
Krause, who also directs the interdisciplinary UGA Faculty of Infectious Diseases, compared the nanorod array developed by collaborator Yiping Zhao, director of the UGA Nanoscale Science and Engineering Center, to a brush with densely packed bristles, where each of the tiny silver rods extends out at a specific angle. The sample, such as bacteria from a throat swab, penetrates among the bristles, where the spectral signature produced by the laser is amplified and then analyzed by a computer program.
Krause noted that infections due to M. pneumoniaeare very common yet difficult to diagnose. The bacterium is a major cause of respiratory disease in humans and the leading cause of pneumonia in older children and young adults.
"Walking pneumonia feels like a bad chest cold that will not go away," he explained. "It can persist for weeks and even months and can cause permanent damage to the lungs if not diagnosed promptly. A delay in diagnosis extends the likelihood for complications as well as continued transmission of the infection to others."
Krause said the device can be reduced to a size that could fit in a briefcase, although their testing is currently done only in a laboratory setting. "Our hope is that when we begin to explore the capabilities of this technology, it can be applied in point-of-care testing," he added. "Then the impact becomes truly significant."
Krause hopes the combined efforts of the research specialists in nanotechnology and infectious disease will eventually be able to determine if the technique is effective in detecting other pathogens in clinical samples. "We need to do a thorough job with mycoplasmas first," said Krause. "Then we can go to other clinical samples and ask the same questions with other infectious agents."
Funding for the research was provided by the U.S. Army Research Laboratory, the National Science Foundation and the Georgia Research Alliance.
Story Source:
Materialsprovided byUniversity of Georgia. Original written by Kirk McAlpin. Note: Content may be edited for style and length.
Journal Reference:
Suzanne L. Hennigan, Jeremy D. Driskell, Richard A. Dluhy, Yiping Zhao, Ralph A. Tripp, Ken B. Waites, Duncan C. Krause. Detection of Mycoplasma pneumoniae in Simulated and True Clinical Throat Swab Specimens by Nanorod Array-Surface-Enhanced Raman Spectroscopy. PLoS ONE, 2010; 5 (10): e13633 DOI: 10.1371/journal.pone.0013633
Cite This Page:
MLA
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University of Georgia. "Rapid diagnostic test for common type of pneumonia developed." ScienceDaily. ScienceDaily, 16 December 2010. <www.sciencedaily.com/releases/2010/12/101215113251.htm>.
University of Georgia. (2010, December 16). Rapid diagnostic test for common type of pneumonia developed. ScienceDaily. Retrieved July 9, 2023 from www.sciencedaily.com/releases/2010/12/101215113251.htm
University of Georgia. "Rapid diagnostic test for common type of pneumonia developed." ScienceDaily. www.sciencedaily.com/releases/2010/12/101215113251.htm (accessed July 9, 2023).
| https://www.sciencedaily.com/releases/2010/12/101215113251.htm |
GtR
The Gateway to Research: UKRI portal onto publically funded research
Citizens' Expectations on Brexit Outcomes: 'Fact' Transmission and Persuasive Power in a Digital World
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Social and Political Science
Overview
Organisations
People
Publications
Outcomes
Abstract
This collaborative project between the Neuropolitics Research Lab (NRlabs), at the University of Edinburgh and Full Fact, the UK's independent fact-checking organization, employs neuroscientific, psychological and behavioural insights to help us to understand what makes Brexit-related claims spread on digital platforms. Using cutting edge scientific techniques in big data analysis this project offers new insights into how citizens' expectations on Brexit and its consequences are shaped in an increasingly digital world. It will inform organisations on how to communicate what is often dry and complex information related to Brexit in a credible, trustworthy and memorable way using digital communications. These insights will be essential for the strategic management, implementation and public communication of the Article 50 process for the UK's withdrawal from the EU.
The question of what constitutes a fact (or an alternative fact) has perhaps never been more salient in public debate. The thirst for 'facts' during the Brexit referendum campaign was a key feature of public debate as was the question of whose facts count. The role of experts in the delivery of factual information came under close scrutiny and became a substantive feature of campaign dialogues. The question of trust and authority in information transmission has been under serious challenge. Citizens' expectations of Brexit and its consequences are, at least in part, shaped by their evaluation of the facts - but how do they decide what is a trustworthy fact? What factors lead them to imbue some sources of information with greater authority than others and under what circumstances do they choose to engage with, share or champion certain 'facts'? How does the context in which 'facts' are disseminated shape the expectations of the citizens on Brexit?
Digital technology and online communication platforms such as Twitter and Facebook, play an increasingly important role in the public communication of both information and misinformation. To date, however, we have little information on how 'facts' transmitted in these digital platforms are internalized by recipients and on how this information impacts on citizens' expectations. We investigate how membership of a specific social media bubble impacts on the evaluation of the information received; how the status of the sender or even the content of the communication (whether it contains an image or a web link) matters; and how the nature of the information received, confirmatory or challenging of previous knowledge, impacts on fact transmission to different publics.
This project builds on the extensive engagement of two research teams on Brexit-related research and with the UK in a Changing Europe team. Both teams are engaged at the highest level in stakeholder engagement and the project is built on a co-production model, ensuring that the issues addressed are of direct interest to those most likely to utilise the insights developed directly in their daily work. The project is designed in close collaboration with stakeholders to ensure that it can adapt swiftly to maintain relevance in the fast-moving Brexit environment. The project has access to a unique social media data-base of over 40 million tweets that NRlabs has collected on the Brexit debate since August 2015; the cutting edge skills and facilities for conducting experimental research at NRlabs; and ensures daily policy relevance through Full Fact's engagement, nationally and internationally, in the fact checking environment. The contribution of this project addresses the very heart of the mission of the UK in a Changing Europe programme - to be the authoritative source for independent research on UK-EU relations, underpinned by scientific excellence and generating and communicating innovative research with real world impact.
Planned Impact
Fact-checkers and Public Engagement Organisations:
This research will feed directly into Full Fact's work and has direct application to the UK in a Changing Europe programme's work, guaranteeing direct research impact. Understanding how a piece of information comes to be perceived as a fact, how this varies between groups and according to the characteristics of the communication, the status of the communicator and the context in which communication takes place is essential for the effective communication of factual information on Article 50 and the Brexit process more generally.
Policy-makers dealing with Brexit:
Harnessing insights from political science and public policy experts and working with psychologists, information scientists and cognitive neuroscientists, NRlabs has developed close links with government officials, as well as public and private users interested in gaining new insights into the psychology behind decision processes. In addition to the expected impact of our Brexit-related research findings (such as citations in the international press and the House of Lords report on Brexit; contributions to House of Common's inquiries on Brexit; Brexit MOOC; European Futures web platform; Laura Cram's role as the Scottish Housing Federation's 'Brexpert' and regular monthly contributions to their in-house publication; regular expert panel appearances; school events; public exhibitions; and providing overnight EU referendum analysis for STV), one of NRlabs major impacts has been our role in encouraging innovative patterns of joint working between government officials, policy practitioners and academics at a fundamental level thus helping to develop the very practice of making policies. This innovative and intensive model of co-production was noted as an important outcome of a major impact event on Brexit, that we organized 12-13 Dec, just prior to the release of the Scottish Government's Brexit plan. A second Scottish Government workshop to run in April 2017, will employ this same co-production model, examining citizens' expectations of Brexit outcomes.
Influencers of public debate on Brexit and beyond:
Full Fact has worked with many of the major influencers of public debate, from the ESRC, the Institute for Fiscal Studies, the Office for National Statistics, the UK Statistics Authority, Wikimedia UK, the House of Commons Library and Parliamentary Office for Science and Technology at the information-providers end of the scale, through to national media such as the BBC, ITV News, Sky News and LBC, and membership organisations including 38 Degrees and the Federation of Small Businesses. Full Fact also has well developed relationships with the International Fact-Checking Network, and strong links with fact-checkers in Argentina, South Africa and the USA, where there is huge demand for this work. The unique nature of this collaboration brings significant added value to existing work on big data and the digital environment in the Brexit policy space and has potential for extension to other policy debates and electoral campaigns. Full Fact is working to predict and preempt information gaps before the 2020 election so that the public debate can happen on a solid footing. Our regular sand-pits are designed to ensure involvement of these stakeholders in the digital data analysis and in the conception, design and execution of the pilot experiments throughout the project.
Polling Agencies:
NRlabs tackles political and policy-relevant issues in a transdisciplinary environment using a neuropolitical perspective. The unique insights generated into citizen expectations, through the combination of psycho-social, behavioural and big data analysis, provide a powerful compliment to existing opinion poll data. Polling experts, including current UK and EU fellow, John Curtice, IPSOS Mori and Yougov will be invited to participate in our regular sand-pits to help develop and pilot our experimental interventions.
Funded Value:
£284,757
Funded Period:
Mar 17
-
Sep 19
Funder:
ESRC
Project Status:
Closed
Project Category:
Research Grant
Project Reference:
ES/R001901/1
Principal Investigator:
Laura Cram
Research Subject:
Pol. sci. & internat. studies
Psychology
Research Topic:
Cognitive Psychology
Politics
If populated the following is a graphic depicting where in the UK the given postcode is located.
Organisations
University of Edinburgh, United Kingdom (Lead Research Organisation)
Full Fact (Collaboration, Project Partner)
<table><tbody><tr><td> People</td><td> ORCID iD</td></tr><tr><td> Laura Cram
(Principal Investigator)</td></tr><tr><td> Adam Moore (Co-Investigator)</td></tr><tr><td> Clare Llewellyn (Researcher)</td></tr></tbody></table>
Llewellyn C
(2018) Russian Troll Hunting in a Brexit Twitter Archive
Llewellyn C
(2018) Answering Social Science Questions with Social media dat
Moore A
(2021) Trust in information, political identity and the brain: an interdisciplinary fMRI study.in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Key
Findings
Impact
Summary
Collaboration
Engagement Activities
<table><tbody><tr><td> Description</td><td> Our aim in this project was to get 'under the hood' of citizens' expectations in relation to ongoing Brexit developments and to shed light on: (i) how expectations about the Brexit issue and its outcomes are influenced by the presentation of 'facts' and 'counterfacts' on digital platforms; and (ii) how the most effective and accurate digital communication to citizens of accurate information in relation to the Brexit process and its potential outcomes can be achieved. We achieved this through a combination of big data Twitter analysis, online experiments, lab-based behavioural and physiological studies and fMRI brain imaging. Our Twitter analysis revealed the power of images and source (including celebrity and verified status) in ensuring the resonance of a message in the digital sphere. We demonstrated a clear lack of overlap between and within Leave and Remain communication networks in the Twittersphere underlining the heavy reliance on selected sources within the Brexit camps. The ongoing resonance of the £350 million promise for the NHS, in Twitter dialogue, despite its immediate statistical invalidation demonstrated the power of repetition over the power of correction. At the experimental level, we explored the issue of trust and the role of different information sources at increasingly granular levels. Our work was novel in that we attempted to combine research strategies/findings from work on (a) fake news, misinformation, and motivated cognition/reasoning with (b) the psychology of explanation (i.e. what makes a good explanation). From the former we leveraged the (mis)match between claims, rebuttals, and pre-existing political beliefs/ideologies to examine the impact on the likelihood of belief change as a result of conflicting information, and from the latter we employed differing types of explanations for why claims were upheld/rebutted in corrections. We also explored the impact of information regarding the source of information provided in corrections. Overall, it was difficult to change beliefs (to cohere with rebuttals) when measured over very short time intervals. In fact, there was some evidence for backfire effects - participants increasing belief in (a) rebutted/disproved claims when confronted with a correction that clashed with their political/ideological preference and (b) decreasing belief in claims, supported by corrective evidence, where both clashed with participants' political/ideological preferences. These findings are limited by the aforementioned short time scales - beliefs are resilient to challenge, typically, and so change may not be reliably measurable on timescales used here. Similarly, we could not address the asymmetry between offering evidence-based corrections on a single occasion versus having rebutted/debunked claims repeated large numbers of times in the media by politicians/authority figures before and during the course of an experiment. Examining the mechanism underpinning trust in information sources, we find that information source matters. Our physiological, behavioural and fMRI's study confirmed that exposure to the logo of selected information sources affected responses to the Tweet messages at a behavioural, emotional, physiological and neural level. Emotional self-report and physiological measures did not, however, directly align - this is an emerging discussion in the emotion and cognition literature and is worth pursuing further.</td></tr><tr><td> Exploitation Route</td><td> The project will feed into and stimulate further theoretical and methodological innovation in the relation to the mis/disinformation ecology as well as the wider literatures on emotion, cognition and trust. The team has worked throughout with government at both Scottish and UK-levels, and with EU officials, developing better understanding, and measures of digital influence, and of how our political nature impacts on public and policy-maker behaviour and political communication. Our collaborative stakeholder event on political persuasion was hosted in the offices of Twitter and attended by Twitter's senior public policy manager for the UK. We have published extensively on political influence on political social media activity and our work has been referenced in public inquiries in the US Senate and UK government select committee reports. We are currently collaborating with major corporate actors on developing an extension of this project, exploring the use of data and digital influence for the public good. This will feed into future collaborative research and impact agendas as well as informing programmes of executive education.</td></tr><tr><td> Sectors</td><td> Digital/Communication/Information Technologies (including Software),Government, Democracy and Justice,Security and Diplomacy</td></tr></tbody></table>
<table><tbody><tr><td> Description</td><td> We have been consulted by both the FCO to the presence of Russian IRA troll activity in our Twitter data set and by the Home Office in relation the process of disinformation in digital media. In November 2017 it became clear that our Brexit-related Twitter data set contained evidence of activity from accounts identified by Twitter to US congress as fake Russian 'troll' accounts, set up to disrupt the US election. This issue involved: (I) complex legal issues (in terms of our user agreement with Twitter); (2) ethical issues, in terms of our commitment to data privacy and our commitment to preserve evidence of public interest; (3) diplomacy as this was an issue of international concern that attracted the attention of the Russian and French embassies as well as the Foreign and Commonwealth Office, who all contacted us about these findings; and, (4) public and media relations - our findings were in almost all national papers and were published on the front page of the Guardian, in the New York Times, Wall Street Journal, Washington Post, the Economist, the Times, the Independent, the Huffington Post, VICE, Buzzfeed and featured on ITV, BBC and Channel 4. We have met with Stewart McDonald, SNP spokesman for defence, have been asked to brief the FCO on data methods and will be running a cross-party briefing on cyber-defence in early 2018.</td></tr><tr><td> First Year Of Impact</td><td> 2017</td></tr><tr><td> Sector</td><td> Government, Democracy and Justice</td></tr><tr><td> Impact Types</td><td> Policy & public services</td></tr></tbody></table>
<table><tbody><tr><td> Description</td><td> Full Fact Partnership</td></tr><tr><td> Organisation</td><td> Full Fact</td></tr><tr><td> Country</td><td> United Kingdom</td></tr><tr><td> Sector</td><td> Charity/Non Profit</td></tr><tr><td> PI Contribution</td><td> Partners on Brexit Priority grant</td></tr><tr><td> Collaborator Contribution</td><td> Application stage, experiment design consultation , co-production of presentation, impact</td></tr><tr><td> Impact</td><td> Twitter-hosted presentation; Home Office consultation; First Draft disinformation conference; Social Research Network presentation</td></tr><tr><td> Start Year</td><td> 2017</td></tr></tbody></table>
| https://gtr.ukri.org/projects?fetchSize=25&pn=0&ref=ES%2FR001901%2F1&selectedSortOrder=ASC&selectedSortableField=firstAuthorName |
WALSH v. COLUMBUS & c. RA | 176 U.S. 469 (1900) | 76us4691610 | Leagle.com
MR. JUSTICE BROWN after stating the case delivered the opinion of the court. 1. Motion was made to dismiss the writ of error in...76us4691610
WALSH v. COLUMBUS & c. RAILROAD CO.
No. 90.
View Case
Cited Cases
Citing Case
176 U.S. 469 (1900)
WALSH
v.
COLUMBUS, HOCKING VALLEY AND ATHENS RAILROAD COMPANY.
Supreme Court of United States. https://leagle.com/images/logo.png
Submitted December 13, 1899.
Decided February 26, 1900.
Attorney(s) appearing for the Case
Mr. J.B. Foraker, Mr. T.E. Powell and Mr. D.J. Ryan for plaintiffs in error.
Mr. D.L. Sleeper, Mr. C.H. Grosvenor and Mr. John J. Stoddart for defendant in error.
Supreme Court of United States.
MR. JUSTICE BROWN, after stating the case, delivered the opinion of the court.
[176 U.S. 475]
1. Motion was made to dismiss the writ of error in this case for want of a Federal question. The decision of this motion was postponed to the merits, and we are now of opinion that it must be denied.
The position of the plaintiff is that, the act of Congress of May 24, 1828, granting to the State of Ohio 500,000 acres of land for the construction of canals, and providing that such canals, "when completed or used, shall be, and forever remain, public highways, for the use of the Government of the United States," and the acceptance thereof, by the General Assembly, constitute a contract by the State for the perpetual maintenance of such canals as public highways, at least until they were given up by consent of the United States, and that the subsequent act of the General Assembly of May 18, 1894, providing for the abandonment of such canals, without such consent being given, was obnoxious to that provision of the Federal Constitution declaring that no State shall pass a law impairing the obligation of contracts.
The main question then is, whether the acceptance of this act of Congress of 1828 by the General Assembly of Ohio should be interpreted as raising a contract by the State for the perpetual maintenance of these canals as public highways. We have repeatedly held that, where the plaintiff relies for his recovery upon the impairment of a contract by subsequent legislation, it is for this court to determine whether such contract existed, as well as the question whether the subsequent legislation has impaired it. State Bank of Ohiov. Knoop,16 How. 369; Bridge Proprietorsv. Hoboken Co.,1 Wall. 116. This rule also applies to a contract alleged to be raised by a state statute, although the general principle is undoubted that the construction put by state courts upon their own statutes will be followed here. Jefferson Branch Bankv. Skelly,1 Black, 436; McGaheyv. Virginia,135 U.S. 662; Douglasv. Kentucky,168 U.S. 488; McCulloughv. Virginia,172 U.S. 102.
We cannot say that it is so clear that the statute in question is not open to the construction claimed that we ought to dismiss the writ as frivolous, within the meaning of the cases
[176 U.S. 476]
which hold that, where the question is not of the validity but of the existence of an authority, and we are satisfied that there was and could have been no decision by the state court against any authority of the United States, the writ of error will be dismissed. Millingar v. Hartupee, 6 Wall. 258; New Orleans v. N.O. Waterworks Co., 142 U.S. 79 , 87; Hamblin v. Western Land Co., 147 U.S. 531 . If the statute were given the construction claimed by the plaintiff, it would be difficult to avoid the conclusion that the abandonment of the canal under the act of 1894, and its lease to the defendant railroad company, was a repudiation of the duty of the State to maintain it as a public highway; though the question would still remain whether the plaintiff would be in a position to take advantage of such default.
2. In disposing of this case the Supreme Court of the State of Ohio held (1) that the defendant railroad corporation had the power to build a railroad between the termini named, and to acquire by purchase or condemnation a right of way for its road, and other property necessary for its operation; (2) that the act of Congress of 1828, donating land to the State for the construction of canals, and the act of the General Assembly of the State accepting the same, did not constitute a contract for the perpetual maintenance of such canals; (3) that if such a contract existed, the plaintiffs in these suits were not parties to it; (4) that the Lancaster Lateral Canal Company did not acquire a fee simple in the lands, but a title for the uses and purposes of the canal, and the company could not, when the use ended, sell them to others, but the lands reverted to the owners of the freehold; (5) that by leasing the lands for the purposes of a railroad, the original easement in the lands was not extinguished, but passed to the purchaser, who took it subject to the duty of making compensation to the owner of the freehold for the additional burden imposed on the land, and such damages as might result to him from the new use.
We are concerned only with the second and third of these conclusions, which turn upon the construction to be given to the act of Congress of 1828. If, by the acceptance of this act by the General Assembly of the State of Ohio, the State
[176 U.S. 477]
[176 U.S. 478]
became irrevocably bound to keep up the canals for all time, for the use, not only of the Government, but of every one who incidentally profited by their preservation, it is impossible to escape the conclusion that their subsequent abandonment impaired the obligation of such contract. But we think the Supreme Court of Ohio was clearly right in its interpretation of the statute. The principal object of the act was a donation of lands to aid the State in works of internal improvement, which were then being extensively contemplated in the newer States of the West. Canals, at that time, embodied the most advanced theories upon the subject of internal transportation. Congress annexed as a condition to the grant that the canals built by its aid should "when completed or used, be and forever remain, public highways, for the use of the Government." Counsel for the defendant insists that, under the terms of the proviso, the obligation to maintain these canals as public highways existed only so long as they were
"used"
as such, and this was evidently the opinion of the Supreme Court of Ohio. Counsel for plaintiff insists, upon the other hand, with much reason, that the proviso, that "the said canals,
when completed or used,
shall be and ever remain public highways," marks the beginning of the time when the obligation was intended to operate — that is, if the canals were completed, or without being completed, were so far completed as to be capable of use, and were
used,
the obligation to maintain them in perpetuity attached. Whatever be the proper interpretation of these words, and they are by no means free from ambiguity, the dominant idea of the proviso was evidently to compel the State to maintain the canals as
public
highways, and to allow the Government free use of them "for any property of the United States, or persons in their service passing along the same." Whether the canals should be maintained forever as such, or should give place to more modern methods of transportation, was a matter of much less moment to the United States than to the State. The General Government was only interested in securing their use for the public, and the free transportation of its own servants and property. The object of the act was to facilitate and encourage public improvements,
but not to stand in the way of the adoption of more perfect methods of transportation which might thereafter be discovered. Had the question of internal improvements arisen ten or fifteen years later, when railways began to be constructed, it is quite improbable that the State would have embarked upon this system of canals, or that Congress would have aided it in the enterprise. Waiving the question whether the State could have abandoned the lands upon which these canals were built as public highways, we think it entirely clear that Congress could not have intended to tie the State down to a particular method of using them, when subsequent experience has pointed out a much more practicable method, which has supplanted nearly all the canals then in use. There was no undertaking to keep up the canals for all time, and we think the proper construction of the proviso is that the Government should be entitled to the free use of the canals so long as, and no longer than, they were maintained as public highways, and that the act of 1894, leasing these lands to the defendant for an analogous purpose, does no violence to the contract clause of the Constitution.
Were the question one of doubt, we should hesitate long before refusing to defer to the many opinions of the Supreme Court of Ohio, through several changes in its personnel, holding it to be within the power of the State to abandon the canal for other public purposes, and that such abandonment gave no right of action to private parties incidentally affected or damnified by it, Hubbardv. City of Toledo,21 Ohio St. 379; Little Miami Elevator Co.v. Cincinnati,30 Ohio St. 629; Foxv. Cincinnati,33 Ohio St. 492, affirmed by this court, 104 U.S. 783; Hatchv. Railroad Co.,18 Ohio St. 92; Malonev. City of Toledo,28 Ohio St. 643; Statev. Board of Public Works,42 Ohio St. 607; Pennsylvania & Ohio Canal Co.v. Commissioners,27 Ohio St. 14; McCombv. Stewart,40 Ohio State, 647; Statev. Snook,53 Ohio State, 531; but the State of Ohio does not stand alone in affirming this principle. Peoplev. Kerr,27 N.Y. 188; Lexington &c. Railroadv. Applegate,8 Dana, 289; Westv. Bancroft,32 Vermont, 367; Haldemanv. Pennsylvania Central Railroad,50 Penn. St. 425; Chasev. Sutton Mfg. Co.,4 Cush. 152.
[176 U.S. 479]
In addition to this, however, the plaintiff stands in no position to take advantage of a default of the State in this particular. He was not a party to the contract between the state and the Federal Government; his rights were entirely subsidiary to those of the Government; and if the latter chose to acquiesce in the abandonment of the canals, as it seems to have done, he has no right to complain. He can only sustain this bill upon the theory that his rights are equal to those of the Government, and that he can call upon the State to maintain the canal for his benefit.
The case of
Grinnell
v.
Railroad Company,
103 U.S. 739
, is pertinent in this connection. That was an action in ejectment brought by a railroad company to recover certain parcels of its land grant, upon which the defendants had settled and asserted rights under the homestead and preemption laws of the United States. Their defence was that the company had no title, because it had lost whatever right it had to the lands by a change in the location of the road, and because locating the road as it was completed did not bring these lands within the limits of the land grant act. The court held that the lands, being within the limits of the first location, the construction of the road on the new line did not annul or defeat, without further action on the part of the United States, the title thus vested; that Congress had consented to the change without any declaration affecting the title already vested in the company by the first location, and that defendants were bound thereby. In delivering the opinion of the court, Mr. Justice Miller observed: "Another point equally fatal to the plaintiffs in error is, that the assertion of a right by the United States to the lands in controversy was wholly a matter between the Government and the railroad company, or its grantors. The legal title remains where it was placed before the act of 1864. If the Government desires to be reinvested with it, it must be done by some judicial proceeding, or by some act of the Government asserting its right. It does not lie in the mouth of every one who chooses to settle on these lands to set up a title which the Government itself can only assert by some direct proceeding. These plaintiffs had no right to stir
[176 U.S. 480]
up a litigation which the parties interested did not desire to be started. It might be otherwise if the legal title was in the Government. Then the land would be subject to homestead or preemption rights."
A similar case is that of Van Wyckv. Knevals,106 U.S. 360. In that case the railroad company had filed a map of definite location, and the land department had withdrawn the odd-numbered sections appropriate thereto; but in constructing the road the company departed from the line indicated. The lands in dispute were within ten miles of the road as built and of the line delineated on the map. They were entered by Van Wyck, who received a patent for them, and Knevals, who had acquired his rights from the railroad company, filed a bill against Van Wyck seeking to charge him as trustee for the lands, and the court decreed a conveyance accordingly. The defendant attacked the right of the company to the grant, alleging that it never completed the construction of the entire road for which the grant was made; that after filing its map with the Secretary of the Interior it changed the route of the road for a part of the distance. The court held, however, that the company had constructed a portion of the proposed road, and that portion was accepted as completed in the manner required by the act of Congress; that if the whole of the proposed road had not been completed any forfeiture consequent thereon could only be asserted by the United States through judicial proceedings or through the action of Congress. "A third party cannot take upon himself to enforce conditions attached to the grant when the Government does not complain of their breach. The holder of an invalid title does not strengthen his position by showing how badly the Government has been treated with respect to the property."
The only contract in this case was between the State of Ohio and the United States. Plaintiff was neither party nor privy to such contract. It was within the power of the Government to prosecute the State for a breach of it, or to condone such breach, if it saw fit. As it adopted the latter course and has deemed it proper to acquiesce in the abandonment of the canals and in the State turning them over to the railroad
[176 U.S. 481]
company, it does not lie in the mouth of the plaintiff to complain. This disposes of every question called to our attention in the briefs of counsel.
The plaintiff is amply protected by the decree of the Supreme Court enjoining the railroad company from entering upon his lands until payment has been made, after proper proceedings, for the increased burden caused by the use of the lands for the railroad. If any taking of the lands consequent upon the remanding of the cause for the purpose stated should suggest ulterior questions they do not arise there, and would not be concluded by an affirmance of the decree now before us for review.
The decree appealed from is therefore
Affirmed.
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(PDF) Analyzing spatial and temporal variability in short-term rates of post-fire vegetation return from Landsat time series
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Analyzing spatial and temporal variability in short-term rates of post-fire vegetation return from Landsat time series
February 2018
Remote Sensing of Environment205
DOI: 10.1016/j.rse.2017.11.007
License
CC BY-NC-ND 4.0
Authors:
<here is a image b317ecd023a63be6-6f00fb8f9d8307b5>
Ryan Frazier
Weber State University
<here is a image 64b7b9a37495e3eb-d12fd72fb78164ee>
Nicholas Coops
University of British Columbia - Vancouver
<here is a image 3b3f8d176549db70-115f380ff44c877e>
Michael Wulder
Natural Resources Canada
<here is a image b12c083aca88cb63-f25b408a96a1d9e3>
Txomin Hermosilla
Natural Resources Canada
Abstract and Figures
The disturbance and recovery cycles of Canadian boreal forests result in highly dynamic landscapes, requiring continued monitoring to observe and characterize environmental change over time. Well-established remote sensing methods capture change over forested ecosystems, however the return of forest vegetation in disturbed locations is infrequently documented and not well understood. Landsat time-series data allows for both the capture of the initial disturbance and the ability to monitor the subsequent vegetation regeneration with spectral vegetation indices. In this research, we used three spectral recovery metrics derived from an annual Landsat-based per-pixel Normalized Burn Ratio time series to determine trends in the short-term rates of spectral recovery for areas disturbed by wildfire (1986-2006), as assessed using a series of 5-year post-disturbance windows to observe forest recovery trends. Our results indicated that rates of spectral forest recovery vary over time and space in the Taiga and Boreal Shield ecozones. We found evidence that post-fire spectral forest recovery rates have accelerated over time in both the East and West Taiga Shield ecozones, with a consistent, positive, and significant trend measured using a Mann-Kendall test for monotonicity and Theil-Sen slope estimation. Over the analysis period (1986-2011), relative rates of spectral forest recovery increased by 18% in the Taiga Shield East and 9% in the Taiga Shield West. In contrast, spectral forest recovery rates in the Boreal Shield varied temporally , and were not consistently positive or negative. These results demonstrate that post-fire spectral recovery rates are not fixed over time and that spectral trends are dependent upon spatial location in the Canadian boreal. This retrospective baseline information on trends in spectral recovery rates highlights the value of, and continued need for detailed monitoring of vegetation regeneration in boreal forest ecosystems, particularly in the context of a changing climate.
<here is a image 821f2e32ac2790c1-d0c2b990fb11d838>
The study area is displayed with a false colour Landsat composite (R; Band 5, G: Band 4, B: Band 3). The four ecozones under study are displayed: the East and West sections of the Boreal and Taiga Shield. The featured ecozone areas are also restricted to the Boreal ecosystem as defined by Brandt (2009). …
Figures - uploaded by
Michael Wulder
Contents lists available at ScienceDirect
Remote Sensing of Environment
journal homepage: www.elsevier.com/locate/rse
Analyzing spatial and temporal variability in short-term rates of post- fire
vegetation return from Landsat time series
Ryan J. Frazier
a , ⁎
, Nicholas C. Coops
a
, Michael A. Wulder
b
, Txomin Hermosilla
a
,
Joanne C. White
b
a
Integrated Remote Sensing Studio, Department of Forest Resources Management, University of British Columbia, 2424 Main Mall, Vancouver, British Columbia V6T 1Z4,
Canada
b
Canadian Forest Service (Paci fi c Forestry Centre), Natural Resources Canada, 506 West Burnside Road, Victoria, British Columbia V8Z1M5, Canada
ARTICLE INFO
Keywords:
Boreal
Forest
Recovery
Regeneration
Disturbance
Landsat: Time series
Ecozone
Taiga
Shield
ABSTRACT
The disturbance and recovery cycles of Canadian boreal forests result in highly dynamic landscapes, requiring
continued monitoring to observe and characterize environmental change over time. Well-established remote
sensing methods capture change over forested ecosystems, however the return of forestvegetation in disturbed
locations is infrequently documented and not well understood. Landsat time-series data allows for both the
capture of the initial disturbance and the ability to monitor the subsequent vegetation regeneration with spectral
vegetation indices. In this research, we used three spectral recovery metrics derived from an annual Landsat-
based per-pixel Normalized Burn Ratio time series to determine trends in the short-term rates of spectral re-
covery for areas disturbed by wild fi re (1986 – 2006), as assessed using a series of 5-year post-disturbancewin-
dows to observe forest recovery trends. Our results indicated that rates of spectral forest recovery vary over time
and space in the Taiga and Boreal Shield ecozones. We found evidence thatpost- fi re spectral forest recovery
rates have accelerated over time in both the East and West Taiga Shield ecozones, with a consistent, positive, and
signi fi cant trend measured using a Mann-Kendall test for monotonicity and Theil-Sen slope estimation. Over the
analysis period (1986 – 2011), relative rates of spectral forest recovery increased by 18% in the Taiga Shield East
and 9% in the Taiga Shield West. In contrast, spectral forest recovery rates in the Boreal Shield varied tempo-
rally, and were not consistently positive or negative. These results demonstrate that post- fi re spectral recovery
rates are not fi xed over time and that spectral trends are dependent upon spatial location in the Canadianboreal.
This retrospective baseline information on trends in spectral recovery rates highlights the value of, and con-
tinued need for detailed monitoring of vegetation regeneration in boreal forestecosystems, particularly in the
context of a changing climate.
1. Introduction
Climate and disturbance are the two most important factors that
shape the Canadian boreal landscape ( Brandt et al., 2013 ). First, cli-
mate primarily controls where and which tree species grow and adapt
in forested areas, with annual tree growth limited by short growing
seasons and severe winters ( Gauthier et al., 2015 ). Second, disturbances
drive change in the boreal, particularly fi res, which occur frequently
over large areas, and are critical for many ecosystem functions ( Stocks
et al., 2002 ). As a result of the interplay between climate and dis-
turbance, Canadian boreal forest ecosystems are a mosaic of patches
with varying age, structure, biodiversity, productivity, and species
composition ( Weber and Flannigan, 1997 ). Thus, boreal tree species
have adapted to frequent disturbance by utilizing multiple post-
disturbance recovery methods, which occur over relatively long periods
of time. This post-disturbance recovery period is 1) a critical time to
monitor the reestablishment and health of boreal forests ( Gauthier
et al., 2015 ), and 2) highly susceptible to changes in climate. Any
disruption of the recovery process can in turn impact the essential
ecosystem goods and services provided by boreal forests ( Brandt et al.,
2013; Gauthier et al., 2014; Gauthier et al., 2015 ).
Boreal forests are expected to be altered extensively by a changing
climate ( Brandt et al., 2013; Price et al., 2013; Gauthier et al., 2014;
Gamache and Payette, 2004 ). Currently, boreal ecosystems are under-
going alterations in phenology ( Lemprière et al., 2008; Colombo, 1998),
productivity ( Nemani et al., 2003; Jarvis and Linder, 2000 ), and dis-
turbance ( Stocks et al., 1998; Flannigan et al., 2000; Flannigan et al.,
2005; Johnstone et al., 2010 ), all attributed to changes in climate. With
https://doi.org/10.1016/j.rse.2017.11.007
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T
respect to altered disturbance characteristics, a changing climate has
had mixed e ff ects on forest recovery as well. For example, three key tree
species within the Canadian boreal forest have shown divergent re-
sponses to a changing climate. Black spruce ( Picea mariana ) dominated
systems showed an increase in growth under cooler and wetter condi-
tions ( Girardin et al., 2016; Brooks et al., 1998 ), while jack pine ( Pinus
banksiana ) ecosystems displayed increased growth with warmer tem-
peratures and increased spring precipitation ( Brooks et al., 1998 ). Ad-
ditionally, white spruce ( Picea glauca ) trees have reacted positively to
warmer spring temperatures with increased annual growth, but also
negatively to much warmer summers with decreased annual growth
( Wilmking et al., 2004 ) that is likely caused by a lack of available
moisture ( Barber et al., 2000; D'Orangeville et al., 2016).
Spatially extensive temporal trends describing increasing or con-
versely decreasing vegetation quantity and vigor have been found oc-
curring across the Canadian boreal using coarse (100 – 1000 m) grained
remotely sensed data. Both increasing and decreasing spectral trends
have been detected occurring over Canadian boreal forests over time
( Pouliot et al., 2009 ) dependent on location, and those trends are well
correlated with trends found at coincident smaller spatial resolution
(30 m) data ( Olthof et al., 2008 ). However, some of the spectral trends
found at coarse scales have also been shown to be in fl uenced by the
inter-instrument calibration, sensor drift, and preprocessing steps
( Alcaraz-Segura et al., 2010 ). Moreover, coarse spatial resolution stu-
dies can fail to capture the fi ne scale mosaicked nature of the boreal
forest landscape and are often in disagreement with research done at
fi ner spatial scales ( Alcaraz-Segura et al., 2010; Fraser et al., 2011;
Wulder et al., 2010 ). In contrast to known issues with inter-instrument
calibration of broad-scale sensors ( Alcaraz-Segura et al., 2010 ), finer
spatial resolution Landsat data (30 m) has fewer inter-sensor calibration
issues ( Markham and Helder, 2012; Vogelmann et al., 2016 ), although
issues regarding inter-sensor calibration of certain spectral wavelengths
are noted to exist ( Sulla-Menashe et al., 2016; Ju and Masek, 2016).
Finer grained medium spatial resolution (30 – 100 m)remotely
sensed data have also shown some broad spectral trends derived from
time series of spectral indices, and importantly have been previously
tied to physical properties of forests ( Pouliot et al., 2009, McManus
et al., 2012, Chu and Guo, 2013, Fraser et al., 2014a, 2014b ). For ex-
ample, the Normalized Di ff erence Vegetation Index (NDVI) is a spectral
index that has often been used to examine active photosynthetic ve-
getation quantity and is linked to forest condition changes over time at
broad spatial scales ( Cuevas-González et al., 2009; McManus et al.,
2012; Turubanova et al., 2015 ). While some have found a widespread
NDVI derived trend of increasing vegetation over time that is associated
with a thickening canopy ( Myneni et al., 1997, Slayback et al., 2003,
Olthof and Latifovic, 2007 ), Goetz et al. (2005) found that Canadian
boreal forests experienced a negative trend between 1981 and 2003
related to reductions in vegetation abundance ( Beck and Goetz, 2011;
Bi et al., 2013 ). Often applied more commonly in fi re severity studies,
the Normalized Burn Ratio (NBR) spectral index and its change over
time have been linked to forest structural properties ( Wulder, 1998,
Epting et al., 2005, Schroeder et al., 2011 ), and may be more suitable
than NDVI for forest recovery tracking ( Pickell et al., 2016; Buma,
2012 ).
Detailed and annual forest recovery information over large areas
can be derived from fi ne spatial resolution wall-to-wall remotely sensed
datasets, principally due to free and open data access, data storage, and
processing capacity ( Kennedy et al., 2014 ). The United States Geolo-
gical Survey maintains the Landsat data archive and provides an ideal
data set for boreal-wide research that o ff ers a well-calibrated data re-
cord initiated in 1972 with complete spatial coverage in fi ne detail
( Wulder et al., 2012; White and Wulder, 2014 ). Larger areas and longer
time periods of spectral data can now be used to inform on the finely
detailed process of forest recovery, especially after the wild fire-caused
stand replacing disturbances that are typical of the Canadian boreal. For
example, Pickell et al. (2016) used Landsat time series analysis across a
range of forested boreal bioclimatic zones and observed di ffering
spectral forest recovery rates for each zone. Likewise, Frazier et al.
(2015) examined spectral forest recovery using Landsat time series data
and found a relationship between spectral recovery di ff erences related
to distinct forest recovery processes across two ecozones.
In summary, while research has indicated that boreal forest re-
covery rates vary spatially ( Schroeder et al., 2007; Frazier et al., 2015)
and temporally ( Chu and Guo, 2013 ), changes in the post-disturbance
forest recovery rates over time has been less well examined ( Ju and
Masek, 2016; Goetz et al., 2006 ). In this study, we examine boreal
forest recovery rates following wild fi re during a period of changing
climate to determine how recovery rates have changed over a 26-year
long period, both temporally and spatially. We focus on the Boreal and
Taiga Shield ecozones as representing nearly half of the Canadian
boreal zone, ensuring a wide array of boreal forest conditions and fire
severitiesareconsidered.The3,013,995 km
2
study area and wall-to-
wall mapping o ff er the ability to compare all observed forest fi re dis-
turbances and their subsequent recovery. To do so we: 1) use multiple
spectral forest recovery metrics derived from Landsat time series data to
inform on di ff erent aspects of post- fi re spectral recovery; 2) detect
trends in post- fi re spectral forest recovery rates fi rstata100 kmcell
spatial unit to visualize detailed trend patterns; 3) understand broad
environmental change by using ecozone analysis units to detect spectral
recovery rate trends; and, (4) determine if statistically signi fi cant trends
in spectral recovery rates exist over time. Signi fi cant results are then
discussed in relation to the disturbance and recovery regimes of Ca-
nadian boreal forests, as well as the bene fi ts and limitations of spectral
forest recovery metric approaches used in this study.
2.Materials and methods
2.1.Study area
Our study area covers the forested boreal areas with the Canadian
Boreal Shield and Taiga Shield ecozones ( Fig. 1 ; Ecological
Strati fi cation Working Group, 1996, Brandt, 2009 ). For scienti fi c ana-
lyses and due to di ff erences in climate and disturbance regimes, the
Boreal Shield and Taiga Shield ecozones are often divided into eastern
and western sections ( Andrew et al., 2012; Bolton et al., 2015 ). Eastern
sections generally experience a less harsh winter and more annual
precipitation when compared to the western counterparts ( Kurz et al.,
1992; Kull et al., 2006; Frazier et al., 2015 ). Both western ecozone
sections experience more forest fi res ( Stocks et al., 2002 ); forest har-
vesting occurs in all ecozones, and insect infestations play a larger role
in eastern than western disturbance regimes ( Brandt et al., 2013).
Forest fi res have a ff ected 25,039,523 haor9.9%ofthestudy areabe-
tween 1985 and 2010 ( White et al., 2017 ). When combined together,
these two ecozones account for 49% of the Canadian Boreal zone
( Brandt, 2009 ).
The West and East Boreal Shield ecozones are dominated by forests
and characterized by many small lakes and streams interspersed be-
tween rocky outcrops with rolling and hilly topography. A precipitation
gradient exists varying from higher (1000 mm per year)amounts in the
coastal east, and lesser (400mm per year) in the continental west.
January mean temperatures are − 20 °C and − 1 °C in the west and east
showing a pronounced colder west to warmer east temperature gradient
( Urquizo, 2000 ), and the mean annual temperature is approximately
3 °C.BorealShieldforestsaredominatedbyblackandwhitespruce
stands, with southerly portions having a wider mix of broadleaf and
coniferous species, i.e. white birch ( Betula papyrifera ), trembling aspen
( Populus tremuloides ), white ( Pinus strobus ), red ( Pinus resinosa ) and jack
pine ( Ecological Strati fi cation Working Group, 1996).
Located north of the Boreal Shield Ecozones, the Taiga Shield
Ecozones are physically divided by Hudson Bay. The topography is
marked by rolling uplands punctuated by rocky outcrops, and glacial
moraines and eskers. Di ff erences in temperature and precipitation
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
33
re fl ect the coastal eastern and continental western sections; the eastern
portion receives 500 – 800 mm per year of precipitationand experiences
a milder winter with mean January temperatures near − 11 °C. Annual
precipitation in the Taiga Shield West range is (300 – 600 mm)lower
than the eastern section, and average January temperatures are
− 25°C. The northern edge of the Taiga Shield delineates the edge of
where tree growth is possible; however, common throughout the eco-
zone are forest stands dominated by short black spruce and jack pine,
with white spruce dominated mixed wood stands including balsam fir
( Abies balsamea ), trembling aspen, balsam poplar ( Populus balsamifera),
and white birch ( Ecological Strati fi cation Working Group, 1996).
2.2.Spectral data
Annual, cloud-free, and spatially seamless surface re fl ectance image
composites and change products derived from Landsat Thematic
Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+) data were
utilized for this analysis, representing the period 1984 –2012
( Hermosilla et al., 2016; Hermosilla et al., 2015a; Hermosilla et al.,
2015b ). The Composites-to-Change (C2C) algorithm was applied to
produce these data and is brie fl y described here. First, annual best-
available-pixel (BAP) spectral composites were produced using all peak
growing season imagery ( White et al., 2014 ) and then the NBR spectral
index was calculated ( Key and Benson, 1999 ). A temporal segmentation
algorithm was then applied to the NBR time series to determine and
quantify change over time and to in fi ll data gaps with proxy spectral
values ( Hermosilla et al., 2015a ). Importantly, the NBR spectral index
ranges between 1 and − 1, with low values indicating low or no ve-
getation present, while high values are known to represent dense
healthy vegetation. NBR has been successfully used to: 1) assess burn
severity of fi res ( French et al., 2008 ); 2) detect and classify forest dis-
turbances ( Wulder et al., 2009 ), and; 3) inform on forest attributes
( P fl ugmacher et al., 2012; Frazier et al., 2014 ). Lastly, regions that
underwent change were geometrically, temporally and spectrally
characterized, and then classi fi ed by change type. Hermosilla et al.
(2015b) found their C2C methods to be accurate over the forested area
of Saskatchewan and reported user's and producer's accuracy for
wild fi re of 97.8% and 96.7%, respectively.
2.3. Methods
2.3.1.Data strati fi cation and filtering
Analysis of spectral forest recovery rate trends was fi rst undertaken
at a 100 km grid cell scale to ascertain if there were any spatial patterns
in spectral forest recovery trends within the ecozones themselves. The
use of the 100km grid cells allowed for the collection of spectral re-
covery rate data over a long periods and discrete areas, and allow the
results to be more e ffi ciently reported and shared. After the 100 km grid
cells were analyzed, then each ecozone analysis unit was analyzed as a
whole to determine if spectral forest recovery rates showed a consistent
trend over time. In order to better capture the initial signs that can
indicate forest recovery is possible, the Landsat time series data were
fi ltered such that only spectral recovery trajectories from moderate and
high severity fi res (typically stand replacing fi res) were considered
( Fig. 2 ). Fires were selected using a threshold value of NBR change
(dNBR) that represented a level of severity high enough to initiate the
growth of a new stand. Hall et al. (2008) examined dNBR values for fire
disturbances in the Boreal Shield West determining that moderate and
severe fi rescorrespondedtodNBRvalues >0.284.
2.3.2.Spectral forest recovery metrics
A fi ve-year post-disturbance period was used to examine spectral
forest recovery in this study with the knowledge that the initial fi rst few
years of tree species reestablishment after disturbance is critical for
monitoring forest recovery ( Fig. 3 )( Goetz et al., 2006; Kennedy et al.,
2012 ). Although the temporal window used to observe recovery in our
research was relatively short, it allowed for partitioning of the available
Landsat time series into multiple informative epochs. Kennedy et al.
(2012) proposed a fi ve-year window stating that it was critical to
monitor the initiation of recovery, and this was supported by Pickell
Fig. 1. The study area is displayed with a false colour Landsatcomposite (R; Band 5, G: Band 4, B: Band 3). The four ecozones under studyare displayed: the East and West sections of the
Boreal and Taiga Shield. The featured ecozone areas are also restricted to the Boreal ecosystem as de fi ned by Brandt (2009).
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
34
et al. (2016) who showed spectral signals tend to saturate and match
that of pre-disturbance values rapidly following disturbance. Likewise
Schroeder et al. (2011) found post-disturbance recovery of NDVI & TCA
returning back toan undisturbed range around5 years and NBRwithin
7 yearsafter fi re. Lastly, the work of Gauthier et al. (2015)provides
supporting insights, as they state that observing the initial period of
forest recovery (while not noting how long or exactly when) is in-
formative upon the ultimate return of forests.
The fi rst metric calculated was the Relative Recovery Indicator
(RRI) which is a modi fi ed version of the Recovery Indicator (RI) that
was used by Kennedy et al. (2012) to compare the spectral disturbance
magnitude to the recovery magnitude fi ve years post disturbance. We
modi fi ed it to work with our un fi tted spectral trajectory data ( Fig. 4)
and is calculated as:
R
RI ARI
NBR
disturbance
= ∆
where ΔNBR
disturbance
is the change in NBR due to disturbance. We
modi fi ed the RI to utilize the maximum NBR value from year four or
fi ve, calculated as:
Absolute Recovery IndicatorARIMaxNBRNBRNBR
Y5 Y4Y0
=−
++
()(,)
where Max(NBR
y+5,
NBR
y+4
) is the maximum of either NBR value
four or fi ve years after disturbance, and NBR
y0
is the NBR value the year
disturbance occurred. The maximum value from four or fi ve years after
disturbance was used in order to better accommodate our un fi tted post
disturbance spectral data.
The RI was originally de fi ned using the results of the temporal
segmentation, which are most often named fi tted values. To capture
typical pre-disturbance conditions in our un fi tted spectral data, we
modi fi ed ΔNBR
disturbance
to use the average of NBR values from two
years before disturbance and is calculated as:
NBRNBR NBR
disturbancepre Y
0
∆=−
where NBR
pre
is the average NBR value from two year pre-disturbance
Fig. 2. Example of spectral data used for three sites in the Taiga Shield West. The first
column is associated with Site 1, the second column Site 2 and the third column Site 3;
this pattern is repeated in Figs. 3 & 7 , and each site represents an area a ff ected by a fire
that occurred in the early, middle or later periods of the time series respectively. The top
row shows the pre-disturbance NBR values, while second row shows which year fire
occurred. The bottom row shows the dNBR values for each fi re year.
Fig. 3. For the same three sitesshown in Fig. 2 (Site 1, Site 2, and Site 3), NBR time series
from the year of disturbance to fi ve years after are shown, with time since disturbance
increasing from the top row to the bottom of the rows. Generally, NBR increases with time
since disturbance.
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
35
and is calculated as:
N
BR NBR NBR
2
pre Y2 Y1
= +
−−
()
where NBR
y − 2
and NBR
y − 1
are the NBR values from two years each
before disturbance. Unique to the RI and our RRI metric is the scaling
that occurs as spectral recovery is based on the amount (magnitude) of
disturbance, which can be related to fi re severity ( Hall et al., 2008 ) The
resultant scaling e ff ect can be helpful in areas like the boreal that have
diverse and heterogeneous signals before and after disturbance. For
instance, the RI metric has been used to detect di ff erences in spectral
forest recovery across forest ownership, climate, and substrates
( Kennedy et al., 2012 ). A value of zero indicates that no spectral forest
recovery has taken place, while one indicates that an equal amount of
spectral forest recovery and disturbance has occurred. Values greater
than one indicate that more spectral forest recovery has occurred than
spectral forest disturbance, and RI and RRI values practically range
between zero and two.
Ratio of Eighty Percent (R80P), adapted from Pickell et al. (2016)
was the second metric calculated, and represented the number of years
required for a disturbed pixel to return to 80% of the pre-disturbance
NBR value ( Fig. 5 ). For this study, the metric was modi fi ed to be a ratio
of the spectral value five years post-disturbance compared to 80% of the
pre-disturbance average of the NBR values from the two preceding
years, and represents the amount of spectral recovery relative to the
pre-disturbance condition and is calculated as:
R
80P Max NBRNBR
NBR 8
Y5 Y4
pre
= ++
∗
(, )
.
where the maximum NBR value from four or fi ve year post-disturbance
is used. This recovery rate metric is di ff erent from the RRI in that it
gauges the amount of spectral recovery by the spectral signal that ex-
isted before disturbance. This scaling can contextualize the spectral
recovery by relating the post-disturbance conditions to pre-disturbance
conditions. The R80P metric as used by Pickell et al. (2016) was able to
distinguish spectral recovery di ff erences between biogeoclimatic zones,
suggesting either di ff ering pre-disturbance conditions or forest recovery
processes occurring during their time series. Interpretation of R80 P
values is similar to the RRI, with a value of zero indicating thatspectral
forest recovery did not occur, while a value of one indicates that NBR
values have recovered to be equivalent to 80% of the pre-disturbance
values. Values greater than one indicate that spectral forest recovery
has exceeded that of the 80% of pre-disturbance threshold.
The fi nal metric was Year on Year Average (YrYr) which is an
average rate of spectral change from the year of disturbance to the fifth
post-disturbances years ( Fig. 6 ) and is calculated as
Y
rYr NBR NBR
5
Y5 Y0
= −
+
where NBR
y0
, and NBR
y+5
are NBR values from the year disturbance
occurred and fi ve years post-disturbance as denoted by their subscript.
This metric is important because it only considers spectral recovery and
is neither referenced to the disturbance magnitude, nor the pre-dis-
turbance values unlike the RRI and R80P metrics. Critical to this metric,
greater NBR values are generally related to increasing forest structure
and canopy cover ( Wulder et al., 2009 ). This metric provides an insight
on the average annual change after disturbance and can help capture
annual post-disturbance growth. A YrYr value of zero indicates that for
the fi ve year average, zero spectral forest recovery had occurred, while
positive values indicate the average gain in NBR in fi ve years that oc-
curred.
Three spectral forest recovery rate metrics were calculated on a
yearly basis (per-pixel) using a fi ve year recovery window. The three
metrics used in this research were selected due to their ability to gauge
di ff erent aspects of spectral recovery as to provide di ff erent possible
methods to spectrally measure forest recovery. For instance, the RRI
compares the spectral recovery magnitude to the spectral disturbance
magnitude, e.g. the metric is anchored by disturbance amounts, with
the disturbance magnitude quanti fi ed in terms of dNBR, which can be
related to fi re severity ( Hall et al., 2008 ). Likewise, recovery magnitude
has been shown to be related to forest structure throughout the re-
covery period ( P fl ugmacher et al., 2012 ). In contrast to the RRI, re-
covery using the R80P metric is related to pre-disturbance values. Be-
cause NBR values have been used to predict canopy cover ( Kennedy
et al., 2012 ) and forest structure ( Frazier et al., 2014 ), those pre-dis-
turbance NBR values are then a critical measure of spectral forest re-
covery. As opposed to evaluating recovery based on pre-disturbance
conditions, the YrYr metric is calculated as the average year-to-year
NBR change for fi ve years after disturbance. These three metrics
Fig. 4. The Relative Recovery Indicator (RRI), adapted from the Recovery Indicator (RI)
( Kennedy et al., 2012 ), utilized the average of two years pre-disturbance NBR values to
determine a pre-disturbance condition. The predisturbance condition is reduced by the
NBR value of the year of disturbance to create a magnitude of change as shown by the
term ΔNBR
disturbance
. The Absolute Recovery Indicator (ARI) is calculated as the max-
imum NBR value from four or fi ve years post-disturbance reduced by NBR value from the
year of disturbance.
Fig. 5. The Ratio 80% of Pre-disturbance (R80P) values were adapted from Pickell et al.
(2016) . Additionally, the NBR
pre
term in the denominator was calculated as the NBR
average of two years prior to disturbance; that term is then multiplied by 0.8. The nu-
merator (Max (NBR
(Y + 5)
, NBR
(Y + 4)
) is determined by obtaining the maximum NBR
value from four or fi ve years after disturbance.
Fig. 6. The Year on Year Average (YrYr) created for this study, and is the average annual
post-disturbance change in a spectral index for after fi ve years. The terms Y
+5
and Y
0
are
the NBR from the fi ve years after and the year of disturbance.
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
36
contextualize the measured spectral forest recovery di ff erently, possibly
providing separate insights into post-disturbance boreal forest recovery.
Areas that experienced a disturbance before 1986 or after 2006
were removed; either an insu ffi cient amount of spectral data existed
before disturbance to establish a spectral trend or not enough spectral
data existed after disturbance to assess spectral recovery in our fi ve year
window ( Fig. 7 ). The annual pre-disturbance values, dNBR values, and
the spectral forest recovery rates were then averaged to create a time
series for each metric for each ecozone analysis unit as well as each
100 kmcell,whichweretheneachsubjectedtostatisticaltestingfor
trend detection.
2.3.3.Trend detection
A Theil-Sen slope estimator was used to determine the average
yearly change of the pre-disturbance values, dNBR fi re severity, and
spectral forest recovery rates over time. A Mann-Kendall test was then
used to determine whether a time series exhibited a signi fi cant mono-
tonic increasing or decreasing trend ( p <0.05). Non-signi fi cant trends
were considered unimportant and discarded from further analysis, al-
though their Theil-Sen slopes are still displayed in the results for
completeness. Only Mann-Kendall signi fi cant Theil-Sen slope results are
reportedonintheresultssection.Additionally,100 kmcellandeco-
zone analysis unit time series with fi ve or less fi re disturbances were
determined to have an insu ffi cient quantity of data to test for recovery
rate trends.
Non-signi fi cant results for any of the spectral forest recovery metric
time series only indicate that the rate at which forests are spectrally
recovering in that cell have not changed consistently over time. Static
spectral forest recovery rates or a failure of a post disturbance forest to
recover cannot be indicated by a non-signi fi cant result. However, a non-
signi fi cant result does indicate that either the rates of spectral forest
recovery do not change greatly over time or that those rates have
changed erratically and do not show a consistent trend.
Time series of annual average pre-disturbance NBR and dNBR were
tested to determine if spectral recovery rates might be increasing as a
result of a general NBR gain over time or increased disturbance mag-
nitudes, which could a ff ect the spectral recovery rates. Spectral forest
recovery rate metric time series were then tested for signi fi cant trends.
A signi fi cant trend in spectral forest recovery rates indicates that the
rate at which vegetation is recovering within the cell is consistently
changing over time, with direct impacts for productivity and sustained
health. Results from both statistical tests were fi rst assessed at the
100 km gridscaleandthen byeachecozoneanalysisunit.
Fig. 7. Sample of spectral forest recovery metrics calculated for the same areas (Site 1,
Site 2, Site 3) shown in Figs. 2 and 3 , arranged in columns. Note that the YrYr values are
lower than the other metrics, and class divisions are adjusted accordingly.
60°W
70°W80°W 90°W100°W
110°W
60°N
50°N
None Pre-Disturbance
Values
Both
Ecozone Bounds
Insufficient Data
Disturbance
Severity
Fig. 8. Presence of signi ficant trends over time in either pre-disturbance values or disturbance severity in the 100 km grid cells. A trend in pre-disturbance values indicates that NBR
values before disturbance either increase or decrease consistently, while a trend in disturbance severity indicates that dNBR values have either increased or decreased over time.
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
37
3. Results
3.1.Non-recovery trends, fi re frequency and extent
Average pre-disturbance NBR values and NBR disturbance severity
time series trend detection results are shown in Fig. 8 . Approximately
85% of cells had no signi fi cant trend in NBR pre-disturbance values and
no signi fi cant trend in disturbance severity over time. The remaining
cells either exhibited a trend in pre-disturbance values (8.1%) or a trend
in disturbance severity (5.7%) or very rarely both (0.1%). Interestingly,
the cells that reported a disturbance severity trend average a very small
Theil-Sen slope of − 0.000399 per year, indicating that NBR assessed
severity has slightly declined over time, but not to a large degree.
Conversely, the cells that produced a trend in pre-disturbance average
values contain a very small positive Theil-Sen slope of 0.000191,
suggesting that a very small increase in NBR values over time has oc-
curred in those cells. These results should not alter the recovery rate
metrics time series as they both represent a very small change over
time. When compared to the possible range of NBR, the dNBR fi re se-
verity and pre-disturbance value, the estimated Theil-Sen slopes re-
present0.05%and <0.01%averageyearlychange,respectively.
The number of fi re-a ff ected years and percent area disturbed by fire
throughoutthetimeseriesforeach100 kmgridcellispresentedin
Figs. 9 and10 . As expected there are more moderate and severe fires
and more area burnt in western than eastern ecozone analysis units.
Eighty percent of grid cells exhibited 10 or more years of fi re, and
overall 35%ofall cellsexperiencedbetween10and 15 yearsof fi re in
their time series. Although 97% of all grid cells experienced fi re, 78% of
thegridcellshad <10%oftheirareaburnt,andonly1%ofallcells
recorded >30%burntarea.
60°W70°W80°W 90°W100°W110°W
60°N50°N
Fire Disturbance Years
015 15 10 21
Ecozone Bounds
Fig. 9. The total number of years that a cell experienced a moderate or high severity fi re disturbancewithin the time series.
60°W70°W80°W 90°W100°W110°W
60°N50°N
% C e l l D i s t r u b e d b y Fi
20 0 5 15 10 3040
Ecozone Bounds
r e
Fig. 10. The area of each grid cell that was a ff ected by a moderate or high severity fi re within the time series, shown as apercent of total area.
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
38
3.2.100 kmgridspectralforestrecoveryratetrend
The cell-based Theil-Sen regression slopes and signi fi cant Mann-
Kendall test results for the RRI metric time series are shown in Fig. 11.
Overall 13% of cells with su ffi cient data (more than fi ve years of fire
disturbances occurring between 1986 and 2006) report a signi ficant
trend, and 69% of all signi fi cant cells contain a positive Theil-Sen slope.
The largest proportion of signi fi cant trending cells (60%) contain a
slope between 0.0 and 0.025 (RRI/Yr), with an average slope among
them of 0.0178. This indicates that RRI values, which measure the rate
of spectral recovery, were larger at the end of the time series then the
beginning. Since RRI can only practically range between 0 and 2, the
average RRI rate is increasing by 0.89% yearly for those positive and
signi fi cant trending cells. Interestingly, 20% of all the cells in the Taiga
Shield East are signi fi cant and positively trending, which is the highest
proportion of any ecozone. Signi fi cant negative trends also exist,
although the majority of those RRI based Theil-Sen slopes are between
0 and −0.025.
For the R80P time series ( Fig. 12 ), only 9% of cells with su fficient
data reported a signi fi cant recovery rate trend and 70% of those sig-
ni fi cant cells contain positive Theil-Sen slopes. The majority (55%) of
signi fi cant slopes range between 0.0 and 0.025, with an average yearly
increase of 0.01565. This shows that R80P values among those cells
increase by 0.01565 NBR units annually throughout the time series,
indicating that the rate of spectral forest recovery is increasing with
time for those positive and signi fi cant cells. Similar to the spatial pat-
tern shown for the RRI results, the Taiga Shield East contains the
highest proportion of signi fi cant trending cells.
YrYr grid cell time series results show signi fi cant trends ( Fig. 13 )in
13% of all cells, with 64% of signi fi cant grid cells having a positive
slope. All positive signi fi cant slopes average 0.0021 NBR units an-
nually, indicating the di ff erence between NBR recovery rates are on
RRI Theil-Sen Slopes
Significant Theil-Sen Slopes
Non Significant Theil-Sen Slopes
Frequency
60°W70°W 90°W
100°W 80°W 110°W
60°N50°N
Ecozone Bounds
Insufficient Data
Significant Mann
Kendall Test
RRI Theil-Sen Slopes
-0.05
0.05
0.025
-0.025
0
a)
b)
Fig. 11. Signi fi cant trending grid cells and Theil-Sen Slopes for the Relative Recovery Indicator (RRI) metric time series. a) Cells with signi fi cant Mann-Kendall results are outlined in
thick gold borders, indicating a trend over time is present for that metric. Grey areas indicate that an insu ffi cient amount of data wasavailable to calculate a trend. b) A histogram of
signi fi cant and non-signi fi cant slopes is also displayed. (For interpretation of the references to colour in this figure legend, the reader is referred to the web versionof this article.)
R.J. Frazier et al. Remote Sensing of Environment 205 (2018) 32–45
39
average 0.0021 higher from year to year for those cells. Again, a con-
tiguous pattern of signi fi cant grid cells is located in the Taiga Shield
East, with that ecozone containing the majority (32%) signi fi cant cells,
and signi fi cant cells occupying 21% of all cells in the ecozone.
The combination of all signi fi cant trend results across the three
metrics shows two general areas where signi fi cant increasing trends
tend to spatially cluster ( Fig. 14 ). First, as previously shown in Figs. 11,
12 and 13 , a contiguous block of signi fi cant cells is located in the Taiga
Shield East near 70°W and 55°N. Grid cells reporting at least one sig-
ni fi cant trend occupy 26% of all cells in that ecozone. Interestingly,
25% of grid cells in the Taiga Shield West ecozone report at least one
signi fi cant trend; however, no cells report signi fi cant trends for all three
time series of spectral forest recovery rates. Moran's I spatial auto-
correlation results show that the signi fi cant metrics are clustered over
the study area ( Table 1 ). Both Eastern ecozone analysis units had a
signi fi cant clustered pattern, but the Western ecozones had non-sig-
ni fi cant and random patterns of signi fi cant recovery rate trends.
3.3.Ecozone-level analysis
The annual NBR pre-disturbance average and disturbance magni-
tude time series for each the ecozone analysis units showed no sig-
ni fi cant trend over time, except for the Boreal Shield West. The Boreal
Shield West pre-disturbance value time series had a signi fi cant trend
with a very small negative Theil-Sen slope ( − 0.00063 NBR units). That
small negative slope value is 0.03% of the whole range of NBR and
could a ff ect R80P or RRI time series, but not the YrYr recovery metric
time series.
Neither the Boreal Shield East nor West ecozone analysis units had a
signi fi cant trend for any of the three spectral recovery rate metrics
60°W70°W80°W 90°W100°W110°W
60°N50°N
Significant Mann
Kendall Test
Ecozone Bounds
Insufficient Data
-0.05
0.05
0.025
-0.025
0
051015 20 25 30
| https://www.researchgate.net/publication/321275896_Analyzing_spatial_and_temporal_variability_in_short-term_rates_of_post-fire_vegetation_return_from_Landsat_time_series |
Intervenciones psicológicas, sociales y de bienestar para la salud psicológica y el bienestar de los supervivientes de actos de tortura - Patel, N - 2014 | Cochrane Library
*Mental Health; Cognitive Behavioral Therapy [methods]; Human Rights [education]; Narrative Therapy [methods]; Psychotherapy [*methods]; Psychotherapy, Group; Quality of Life [*psychology]; Randomized Controlled Trials as Topic; Refugees [psychology]; Resilience, Psychological; Stress Disorders, Post‐Traumatic [psychology, therapy]; Stress, Psychological [psychology, therapy]; Torture [*psychology]
Intervenciones psicológicas, sociales y de bienestar para la salud psicológica y el bienestar de los supervivientes de actos de tortura
Information
DOI:
https://doi.org/10.1002/14651858.CD009317.pub2 Copy DOI
Database:
Cochrane Database of Systematic Reviews
Version published:
11 November 2014 see what's new
Type:
Intervention
Stage:
Review
Cochrane Editorial Group:
Cochrane Common Mental Disorders Group
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Article metrics
Altmetric:
Authors
Nimisha Patel
School of Psychology, University of East London, London, UK
International Centre for Health and Human Rights, London, UK
Blerina Kellezi
School of Medicine, Division of Primary Care, University of Nottingham, Nottingham, UK
Centre for Criminology, Univeristy of Oxford, Oxford, UK
Amanda C de C Williams
Correspondence to:International Centre for Health and Human Rights, London, UK
[email protected]
[email protected]
Research Department of Clinical, Educational & Health Psychology, University College London, London, UK
Contributions of authors
BK managed the overall review process, conducted the searches, selected studies, authored sections of the manuscript, extracted data, undertook analysis and coded papers.
AW selected studies, authored sections of the manuscript, extracted data, undertook analysis and coded papers.
NP authored sections of the manuscript and resolved differences among selecting papers and coding.
Sources of support
Internal sources
NP and AW were employed by the Medical Foundation, and BK part of the time, while writing the protocol, UK.
External sources
NP and AW were funded by the Oak Foundation, UK.
Declarations of interest
NP and AW are clinical practitioners as well as academics; both have extensive clinical and research experience with torture survivors; AW has conducted a treatment trial in another field of mental health.
Acknowledgements
Thanks to Les Hearn, Amschel de Rothschild, Katrina Scior and Olivia Stocker for help with translation.
Version history
Published
Title
Stage
Authors
Version
2014 Nov 11
Psychological, social and welfare interventions for psychological health and well‐being of torture survivors
Review
Nimisha Patel, Blerina Kellezi, Amanda C de C Williams
https://doi.org/10.1002/14651858.CD009317.pub2
Revision date This is the date when the review was published Event Description
2011 Oct 05
Psychological, social and welfare interventions for psychological health and well‐being of torture survivors
Protocol
Nimisha Patel, Blerina Kellezi, Amanda C de C Williams
https://doi.org/10.1002/14651858.CD009317
Revision date This is the date when the review was published Event Description
Differences between protocol and review
Data were insufficient for planned sensitivity analyses.
Given the considerable overlap of scale content, the primary outcome, distress, included the PTSD symptom scales that were initially described as secondary outcomes.
Three risk of bias items were added that were appropriate to psychological interventions when neither people taking part nor those delivering the treatment can be blinded to treatment allocation.
Detail has been added to the review regarding subset data and co‐morbidities (underTypes of participants) that were not included in the protocol.
Types of comparators were broadened from those envisaged in the protocol; specifically, we added conditions that were not therapist delivered but might be expected to provide therapeutic benefit, such as education, or facilitated group support; this is further addressed in the discussion of potential biases of the review process.
The timing of outcomes measures and the hierarchy of outcomes have been clarified and main comparisons defined in the review compared with the protocol.
A 'Summary of findings' table and use of GRADE to assess the quality of evidence have been added to the review.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
*Mental Health;
Cognitive Behavioral Therapy [methods];
Human Rights [education];
Narrative Therapy [methods];
Psychotherapy [*methods];
Psychotherapy, Group;
Quality of Life [*psychology];
Randomized Controlled Trials as Topic;
Refugees [psychology];
Resilience, Psychological;
Stress Disorders, Post‐Traumatic [psychology, therapy];
Stress, Psychological [psychology, therapy];
Torture [*psychology];
Medical Subject Headings Check Words
Adult; Humans;
PICOs
PICOs
Population
Intervention
Comparison
Outcome
The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.
See more on using PICO in theCochrane Handbook.
Figures and Tables -
Figure 1
Study flow diagram.
Figures and Tables -
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Analysis 1.1
Comparison 1 Psychological intervention versus control, Outcome 1 Distress.
Figures and Tables -
Analysis 1.2
Comparison 1 Psychological intervention versus control, Outcome 2 Post‐traumatic stress symptoms.
Figures and Tables -
Analysis 1.3
Comparison 1 Psychological intervention versus control, Outcome 3 Post‐traumatic stress caseness.
Summary of findings for the main comparison. Psychological intervention versus control for psychological health and well‐being of torture survivors
Psychological intervention versus control for psychological health and well‐being of torture survivors
Patient or population:people of any age who have survived any type of torture Settings:treatment clinics (Europe) and refugee camps (Africa) Intervention:psychological intervention vs control
Outcomes
Illustrative comparative risks* (95% CI)
Relative effect (95% CI)
Number of participants (studies)
Quality of the evidence (GRADE)
Comments
Assumed risk
Corresponding risk
Control
Psychological intervention versus control
Reduction on a scale of psychological distress— follow‐up DSM‐based scales: Hamilton Depression Scale, Hopkins Symptom Checklist 25, Beck Depression InventoryFollow‐up: median 6 months
Across studies, mean reduction on a scale of psychological distress at follow‐up in the intervention groups was 0.63 standard deviations lower(1.07 to 0.19 lower)
‐1.07 to ‐0.19
86(4)
⊕⊝⊝⊝ very low a,b,c,d
Corresponds to a mean improvement of 6.4 on the Hamilton Depression Scale, but the score at follow‐up remains at the borderline of severe to very severe depression
Adverse events
No data available
No data available
Reduction in post‐traumatic stress symptoms— follow‐up DSM‐based PTSD symptom scales: Clinician Administered PTSD Scale (CAPS), Post‐traumatic Depression Scale, Composite International Diagnostic Interview (CIDI), PTSD scaleFollow‐up: median 6 months
Across studies, mean reduction in post‐traumatic stress symptoms at follow‐up in the intervention groups was 0.52 standard deviations lower(0.97 to 0.07 lower)
‐0.97 to ‐0.07
86(4)
⊕⊝⊝⊝ very low a,b,c,d
Mean change of 13.6 points on the CAPS corresponds to a clinically significant change (10‐20 points, depending on population), but follow‐up score still represents substantial symptomatology
Improvement in quality of life— follow‐up
No data available
Data available only immediately post treatment
Improvement in participation
No data available
No data available
Improvement in family or social relationships
No data available
No data available
Satisfaction with treatment
No data available
No data available
*The basis for the assumed risk(e.g. median control group risk across studies) is provided in footnotes. The corresponding risk(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effectof the intervention (and its 95% CI). CI:Confidence interval.
GRADE Working Group grades of evidence. High quality:Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality:Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality:Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality:We are very uncertain about the estimate.
aThree of the four studies used interpreters for assessment or translation and oral interview. bSubstantial unblinding; transparency of content of measures as focus of treatment; neither conceptual nor linguistic validation of measures. cSubstantial differences among populations. dVery small sample sizes.
Figures and Tables -
Summary of findings for the main comparison. Psychological intervention versus control for psychological health and well‐being of torture survivors
Navigate to table in Review
Comparison 1. Psychological intervention versus control
Outcome or subgroup title
No. of studies
No. of participants
Statistical method
Effect size
1 Distress Show forest plot
7
Std. Mean Difference (IV, Random, 95% CI)
Subtotals only
1.1 End of treatment
5
290
Std. Mean Difference (IV, Random, 95% CI)
‐0.15 [‐0.39, 0.09]
1.2 Follow‐up
4
86
Std. Mean Difference (IV, Random, 95% CI)
‐0.63 [‐1.07, ‐0.19]
2 Post‐traumatic stress symptoms Show forest plot
9
Std. Mean Difference (IV, Random, 95% CI)
Subtotals only
2.1 End of treatment
7
388
Std. Mean Difference (IV, Random, 95% CI)
‐0.30 [‐0.66, 0.06]
2.2 Follow‐up
4
86
Std. Mean Difference (IV, Random, 95% CI)
‐0.52 [‐0.97, ‐0.07]
3 Post‐traumatic stress caseness Show forest plot
3
Odds Ratio (M‐H, Random, 95% CI)
Subtotals only
3.1 End of treatment
3
52
Odds Ratio (M‐H, Random, 95% CI)
0.28 [0.06, 1.36]
Figures and Tables -
Comparison 1. Psychological intervention versus control
Navigate to table in Review
| https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009317.pub2/information/es |
Design of a 50 TW/20 J chirped-Pulse Amplification Laser for High-Energy-Density Plasma Physics Experiments at the Nevada Terawatt Facility of the University of Nevada | Request PDF
Request PDF | Design of a 50 TW/20 J chirped-Pulse Amplification Laser for High-Energy-Density Plasma Physics Experiments at the Nevada Terawatt Facility of the University of Nevada | We have developed a conceptual design for a 50 TW/20 J short-pulse laser for performing high-energy-density plasma physics experiments at the... | Find, read and cite all the research you need on ResearchGate
Design of a 50 TW/20 J chirped-Pulse Amplification Laser for High-Energy-Density Plasma Physics Experiments at the Nevada Terawatt Facility of the University of Nevada
Abstract
We have developed a conceptual design for a 50 TW/20 J short-pulse laser for performing high-energy-density plasma physics experiments at the Nevada Terawatt Facility of the University of Nevada, Reno. The purpose of the laser is to develop proton and x-ray radiography techniques, to use these techniques to study z-pinch plasmas, and to study deposition of intense laser energy into both magnetized and unmagnetized plasmas. Our design uses a commercial diode-pumped Nd:glass oscillator to generate 3-nJ. 200-fs mode-locked pulses at 1059 m. An all-reflective grating stretcher increases pulse duration to 1.1 ns. A two-stage chirped-pulse optical parametric amplifier (OPCPA) using BBO crystals boosts pulse energy to 12 mJ. A chain using mixed silicate-phosphate Nd:glass increases pulse energy to 85 J while narrowing bandwidth to 7.4 nm (FWHM). About 50 J is split off to the laser target chamber to generate plasma while the remaining energy is directed to a roof-mirror pulse compressor, where two 21 cm x 42 cm gold gratings recompress pulses to â350 fs. A 30-cm-focal-length off-axis parabolic reflector (OAP) focuses â20 J onto target, producing an irradiance of 10¹⹠W/cm² in a 10-μm-diameter spot. This paper describes planned plasma experiments, system performance requirements, the laser design, and the target area design.
Experimental astrophysics with high power lasers and Z pinches
D. D. Ryutov
With the advent of high-energy-density HED experimental facilities, such as high-energy lasers and fast Z-pinch, pulsed-power facilities, millimeter-scale quantities of matter can be placed in extreme states of density, temperature, and/or velocity. This has enabled the emergence of a new class of experimental science, HED laboratory astrophysics, wherein the properties of matter and the processes that occur under extreme astrophysical conditions can be examined in the laboratory. Areas particularly suitable to this class of experimental astrophysics include the study of opacities relevant to stellar interiors, equations of state relevant to planetary interiors, strong shock-driven nonlinear hydrodynamics and radiative dynamics relevant to supernova explosions and subsequent evolution, protostellar jets and high Mach number flows, radiatively driven molecular clouds and nonlinear photoevaporation front dynamics, and photoionized plasmas relevant to accretion disks around compact objects such as black holes and neutron stars.
Petawatt laser system and experiments
Aug 2000
D. M. Pennington
C.G. Brown
Thomas E Cowan
S. C. Wilks
We have developed a hybrid Ti:sapphire-Nd:glass laser system that produces more than 1.5 PW of peak power. The system has produced up to 680 J of energy on target at 1054 nm in a compressed 440±20-fs pulse by use of 94-cm diffraction gratings. A focused irradiance of up to 6×10<sup>20</sup> W/cm<sup>2</sup> was achieved using an on-axis parabolic mirror and adaptive optic wavefront control. Experiments with the petawatt laser system focused the beam on solid targets and produced a strongly relativistic interaction. Energy content, spectra, and angular pattern of the photon, electron, and ion radiations were diagnosed in a number of ways, including several nuclear activation techniques. Approximately 40-50% of the laser energy was converted to broadly beamed hot electrons, with an associated bremsstrahlung beam. High luminosity ion beams were observed normal to the rear surface of various targets with energies up to ≥55 MeV, representing ∼7% of the laser energy. These and other results are presented.
E. B. Kim
We have demonstrated the selection and the amplification of the components of an optical frequency comb using femto-second laser injection-locking technique. We used a mode-locked Ti:sapphire laser as a master laser and a single-mode diode laser as a slave laser. After passing through the interference filter with the center wavelength 794.7 nm and the transmittance bandwidth 1.5 nm, the optical ... [Show full abstract] frequency comb by mode-locked femto-second laser was injected into the slave laser. The injection-locked slave laser had 3{\sim}4 multi-mode with the mode spacing 100.5 MHz, whichcorrespond to the repetition rate of a mode-locked Ti:sapphire laser. The power of the modes selected by femto-second laser injection-locking technique was amplified to several thousands times
Third-generation femtosecond technology
Lenard Vamos
Hanieh Fattahi
Femtosecond pulse generation was pioneered four decades ago using mode-locked dye lasers, which dominated the field for the following 20 years. Dye lasers were then replaced with titanium-doped sapphire (Ti:Sa) lasers, which have had their own two-decade reign. Broadband optical parametric amplifiers (OPAs) appeared on the horizon more than 20 years ago but have been lacking powerful, ... [Show full abstract] cost-effective picosecond pump sources for a long time. Diode-pumped ytterbium-doped solid-state lasers are about to change this state of affairs profoundly. They are able to deliver 1 ps scale pulses at kilowatt-scale average power levels, which, in thin-disk lasers, may come in combination with terawatt-scale peak powers. Broadband OPAs pumped by these sources hold promise for surpassing the performance of current femtosecond systems so dramatically as to justify referring to them as the next generation. Third-generation femtosecond technology (3FST) offers the potential for femtosecond light tunable over several octaves, multi-terawatt few-cycle pulses, and synthesized multi-octave light transients. Unique tunability, temporal confinement, and waveform variety in combination with unprecedented average powers will extend nonlinear optics and laser spectroscopy to previously inaccessible wavelength domains, ranging from the far IR to the x-ray regime. Here we review the underlying concepts, technologies, and proof-of-principle experiments. A conceptual design study of a prototypical tunable and wideband source demonstrates the potential of 3FST for pushing the frontiers of femtosecond and attosecond science.
Conceptual design of a hybrid KrF laser system for ICF commercial applications
David B. Harris
KrF lasers appear to be the most efficient lasers operating near the optimal wavelength for laser fusion. Most high-efficiency, low-cost KrF laser designs use large electron-beam-driven amplifiers and use pure angular multiplexing for the required pulse compression. A recent study carried out by Los Alamos National Lab. and Spectra Technology has defied a high-efficiency hybrid KrF laser system ... [Show full abstract] architecture that uses both angular multiplexing and Raman beam combination. The high overall system efficiency of this hybrid design, approx. 12%, is achieved primarily through the use of electron-beam sustained discharge lasers (EBSDL), and by using the efficient forward rotational Raman process in hydrogen. The new system appears attractive as a commercial-applications driver because the calculated efficiency is higher than the usual large electron-beam-pumped (EBP) KrF laser/pure angular multiplexing approach. In this paper, the hybrid system architecture will be described, and the trade-offs with respect to the large EBP amplifier/angular multiplexed system will be discussed.
Time-domain aspect of carrier-envelope-phase control; Field stabilized optical pulse generation - ar...
| https://www.researchgate.net/publication/255199091_Design_of_a_50_TW20_J_chirped-Pulse_Amplification_Laser_for_High-Energy-Density_Plasma_Physics_Experiments_at_the_Nevada_Terawatt_Facility_of_the_University_of_Nevada |
Asbury v. Hugh L. Bates Lodge No. 686, F.& A.M. - Ohio - Case Law - VLEX 891706516
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]
Asbury v. Hugh L. Bates Lodge No. 686, F.&A.M.
<table><tbody><tr><td> Court</td><td> United States Court of Appeals (Ohio)</td></tr><tr><td> Writing for the Court</td><td> MATTHEWS</td></tr><tr><td> Citation</td><td> 24 N.E.2d 638,62 Ohio App. 430</td></tr><tr><td> Decision Date</td><td> 22 November 1939</td></tr><tr><td> Parties</td><td> ASBURY et al. v. HUGH L. BATES LODGE NO. 686, F. &amp; A. M.</td></tr></tbody></table>
62 Ohio App.430
24 N.E.2d 638
ASBURY et al.
v.
HUGH L. BATES LODGE NO. 686, F. & A. M.
Court of Appeals of Ohio, First District, Butler County.
Nov. 22, 1939.
Action by one Asbury and others against Hugh L. Bates Lodge No. 686, Free and Accepted Masons, to enforce specific performance of contract to purchase realty. From an adverse decree, plaintiffs appeal. -[Editorial Statement.]
Decree for defendant.
[24 N.E.2d 638]
Harry J. Koehler, Jr., R. J. Shank, and Walter S. Harlan, all of Hamilton, for appellants.
Harry S. Wonnell, of Hamilton, for appellees.
MATTHEWS, Judge.
We have reached the conclusion that judgment should be rendered for the defendant, appellee herein.
The action is to enforce specific performance of a contract alleged to have been entered into by five members of the defendant lodge (its name then being the Fort Hamilton Lodge which was afterwards changed to Hugh L. Bates Lodge), whereby they agreed to convey certain real estate to it, in consideration of the lodge's agreement to pay $15,000 therefor.
It is sufficient for showing the basis of our decision to point out that the plaintiffs rely upon a resolution of the lodge introduced at its meeting on June 9, 1925, and adopted by a vote of 34 to 14 at the meeting on July 14, 1925. The minutes of these two meetings are as follows:
‘June 9, 1925.
‘Resolution of Temple Com. to purchase S. Front street property carried Yes 32, No 15.
‘The following motion was made and laid on the table, that Fort Hamilton Lodge purchase the Front St. site in the event that the temple board turns it down and that a vote be taken on the motion at the stated meeting next, and that notice be given to all members of the lodge in regard to the same, at least fifteen days before that meeting.
‘A motion carried that the master appoint a committee of seven to look into the possibilities of the site and report at the next stated meeting, further, that they be given power to employ an architect to assist them in making this investigation.
[24 N.E.2d 639]
‘The committee consists of Bros. H. L. Bates, S. G. Wirtz and Ralph H. Asbury, Homer Latimer, Wm. B. Wick, Guy Compton, and Earl Muncey.
‘July 14, 1925.
‘The temple committee reported that they employed an architect to look into the possibilities of the Front St. site and has plans to submit on a proposed temple. The lodge was called from labor to refreshment to allow the brethren to look over the plans and get information.
‘After resuming work as Master Masons, a motion was passed that the lodge take a secret ballot on the motion presented at the last meeting referring to the purchase of the Front street site. Votes Yes 34, No 14.
‘A motion passed that the master and wardens be given power to purchase the property.
‘A motion passed that the master appoint a committee of three or more, known as the Way and Means committee, whose duty it will be to plan a method of raising funds to buy the property and to report at the next stated meeting.Bros. R. F. Schneider, Holle Schneider, Jno. F. Kyger, Jesse Gilley and F. E. Pepper were appointed.’
Now, do these minutes show an acceptance of the offer communicated to the offerors? The evidence shows that the offerors were present and participated as members in the action taken by the lodge. In that way they knew of the action taken. No other notice of what had been done was given by any member or officer of the lodge. The master and wardens did nothing toward purchasing this property following this meeting. They gave the offerors no notice of the acceptance of the offer.
Unlike a human being, acting solely in his individual capacity, an association of persons, such as a lodge, must arrive at a conclusion to accept an offer by outward demonstration. Without a...
9 practice notes
Estate of Bogley v. United States, No. 52-73. United States Court of Federal Claims April 16, 1975 ...* Emphasis in original. Footnote omitted. Id. at 541-42. A case very much in point is Asbury v. Hugh L. Bates Lodge No. 686, F. & A.M., 62 Ohio App. 430, 24 N.E.2d 638 (1939), where a masonic lodge passed a resolution to buy certain realty from certain of its members for $15,000 and authori......
Union Stock Yards Co. v. City of Hillsboro, No. 09CA17. United States United States Court of Appeals (Ohio) December 2, 2010 ...[947 N.E.2d 188] {¶ 16} We further find the instant case similar to the facts presented in Asbury v. Hugh L. Bates Lodge No. 686 (1939), 62 Ohio App. 430, 16 O.O. 134, 24 N.E.2d 638. In Asbury, lodge members adopted a resolution to purchase real estate. The resolution recited that the “mast......
Union Stockyards v. City of Hillsboro, Case No. 09CA17 United States United States Court of Appeals (Ohio) December 2, 2010 ...under Shampton. {¶16} We further find the instant case similar to the facts presented in Asbury v. Hugh L. Bates Lodge No. 686 (1939), 62 Ohio App. 430, 24 N.E.2d 638. In Asbury, lodge members adopted a resolution to purchase real estate. The resolution recited that the "master and wardens ......
General Motors Corp. v. Keener Motors, No. 11380. United States United States Courts of Appeals. United States Court of Appeals (6th Circuit) February 14, 1952 ...definite promise than the expressions of the various representatives of appellant in the instant case. In Asbury v. Hugh L. Bates Lodge, 62 Ohio App. 430, 435, 24 N.E.2d 638, 640, Court of Appeals for Butler County, it was held that the acceptance in the circumstances did not establish a bi......
9 cases
Estate of Bogley v. United States, No. 52-73. United States Court of Federal Claims April 16, 1975 ...* Emphasis in original. Footnote omitted. Id. at 541-42. A case very much in point is Asbury v. Hugh L. Bates Lodge No. 686, F. & A.M., 62 Ohio App. 430, 24 N.E.2d 638 (1939), where a masonic lodge passed a resolution to buy certain realty from certain of its members for $15,000 and authori......
Union Stock Yards Co. v. City of Hillsboro, No. 09CA17. United States United States Court of Appeals (Ohio) December 2, 2010 ...[947 N.E.2d 188] {¶ 16} We further find the instant case similar to the facts presented in Asbury v. Hugh L. Bates Lodge No. 686 (1939), 62 Ohio App. 430, 16 O.O. 134, 24 N.E.2d 638. In Asbury, lodge members adopted a resolution to purchase real estate. The resolution recited that the “mast......
Union Stockyards v. City of Hillsboro, Case No. 09CA17 United States United States Court of Appeals (Ohio) December 2, 2010 ...under Shampton. {¶16} We further find the instant case similar to the facts presented in Asbury v. Hugh L. Bates Lodge No. 686 (1939), 62 Ohio App. 430, 24 N.E.2d 638. In Asbury, lodge members adopted a resolution to purchase real estate. The resolution recited that the "master and wardens ......
General Motors Corp. v. Keener Motors, No. 11380. United States United States Courts of Appeals. United States Court of Appeals (6th Circuit) February 14, 1952 ...definite promise than the expressions of the various representatives of appellant in the instant case. In Asbury v. Hugh L. Bates Lodge, 62 Ohio App. 430, 435, 24 N.E.2d 638, 640, Court of Appeals for Butler County, it was held that the acceptance in the circumstances did not establish a bi......
| https://case-law.vlex.com/vid/asbury-v-hugh-l-891706516 |
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Approved Group Buy with Wet Thumb Frags! | Page 11
Reefs.com Discussion - Thank you to Tina and Karman, without them this wouldn't have happened. I got a sweet scolymia and a couple nice frags. Also got...
Approved Group Buy with Wet Thumb Frags!
Where do we want delivery.
Bay Ridge - 75th St. and 6th Ave. 2 blocks from 77st R train
Votes: 1
6.3%
LIC - A short walk from 1st 7 train stop in Queens
Votes: 7
43.8%
128 Mott Street - Near 6,n,r,w,j,m,b,d,q stops
Near South St. Seaport - 7 blocks from F train
Votes: 1
6.3%
Total voters
16
Poll closed
Dec 21, 2009
.
Thank you to Tina and Karman, without them this wouldn't have happened. I got a sweet scolymia and a couple nice frags. Also got an open brain but it is not doing well. All in all a fabulous experience. I hope everyone is as happy as I am. Thank you everybody for making it happen, we must do it again sometime. James
Thank you to Jeff, James, Karman and Tina for a great GB. I think I'm the only one unfortunately to have 2 DOAs. But to no one's fault due to schedule I was only able to pick up after work and had to take the train home after Jeff kindly met me for it. I guess the cold was too much for the SPS. Good GB nevertheless. Thanks again Jeff for going out of your way to meet me.
Finksmart, what did you lose? i will give you some credit for them.
Hey Tina thanks for being generous it's the Snow Berries Acro and the pink millie.
yeah, the Acroporas wont take too cold or hot really well, they are very sensitive. i will replace those acroporas for you.
hey love to see pic of what you guys got thanx and welcome wetthumbfrags
a pic of the chalices I got, they seem to be doing well.
Attachments
1.jpg
the other, color is a little blue, have to balance the WB on the camera.
Attachments
well i got my only dead corals my umi xenia melted
Noodleman! i will give you credit on that !!
Did someone get two attractive blue acro frags? Both of my frags are doing nicely, but I dont think they are what I ordered. I ordered: Teal blue Aussie Horrida and The Blue Lagoon Acro I received one frag that was green and a frag that is a "purplish blue" with light brown, large polyps. It is possible that the Horrida is correct, I can no longer view the image of what I ordered. But the green frag is most definitely not the "Blue Lagoon Acro". Alfred
By the way, Karman is an AWESOME guy. He did me a real solid and dropped the frags off to me on his way home. I had to watch the babies this week and the shipment for this coming Saturday was cancelled. Two thumbs up for Karman!!! Alfred
Alfredo De La Fe said:
By the way, Karman is an AWESOME guy. He did me a real solid and dropped the frags off to me on his way home. I had to watch the babies this week and the shipment for this coming Saturday was cancelled. Two thumbs up for Karman!!! Alfred
So did you buy these frags with your babysitting money?
lol:lol_large , sorry had to do that. you have no idea how many times I get that when I tell my co workers "I'm watching the kids.
My wife is cheap, she did not pay me. Alfred
thanks karman for taking care of my corals. he put my mushroom rock and zoa frag in his tank (even though they sorta melted) on tues. so i can pick up wed. night. awesome guy. now i hope the shrooms and the zoa make it.
I don't get paid either and when I mention payment I get the kids sent after me, Isn't that some sort of Labor intimidation ? let me know we'll start a union for "Fair Practice of Domestic Babysitters".:biggrin: lol
Alfredo De La Fe said:
My wife is cheap, she did not pay me. Alfred
Knugenx, Thank you very much for holding the corals for me! The ricordea looks amazing. I got a closer look at the lobo; about 3/4 of it has melted : / I saw it as a wysiwyg piece so I am going to nurse it back to health (hopefully it will make it). Your tank looks amazing.
Hi Jcolon there is a big chance that lobo will be healing. when we first got this piece about 4 months ago , it looks like its going die ( i guess they dont travel well like some of the soft corals and Acroporas ), but in a month, it start to heal and come back. We thought for sure it will die but no, came back nice so i think thats how they usually look when they transit .
Ok. It is a large piece. I am going to try and nurse it back to health. Is there anything extra you did to help it along? Also, the ricordea is beautiful!
jcolon just let time heals it , could take up several week but thats what i remember when i first got it. Strange how it repeats the same way through shipping. Just keep me updated if there is anything wrong with it. its a Beautiful piece! well, it was . you got the nice Ricordea! i love that one when i saw it.
| https://reefs.com/forum/group-buys/69617-approved-group-buy-wet-thumb-frags-11.html |
Chaining Including Concentration | Request PDF
Request PDF | Chaining Including Concentration | The chaining method is discussed, as well as the more general generic chaining method developed by Talagrand, see e.g. Talagrand (2005). This... | Find, read and cite all the research you need on ResearchGate
Chapter
Chaining Including Concentration
June 2016
DOI: 10.1007/978-3-319-32774-7_17
In book: Estimation and Testing Under Sparsity (pp.239-253)
Abstract
The chaining method is discussed, as well as the more general generic chaining method developed by Talagrand, see e.g. Talagrand (2005). This allows one to bound suprema of random processes. Concentration inequalities are refined probability inequalities, for instance for suprema of random processes,
see e.g. Ledoux (2005), Boucheron et al. (2013) and Sect. 16. 2 in this monograph. This chapter combines the two. A deviation inequality is obtained using (generic) chaining.
Discover the world's research
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The Generic Chaining
Article
Jan 2005
Michel Talagrand
The Appendix was not published in the book. Therefore, the Appendix is shown on the next pages.
Probability Inequalities for Sums of Bounded Random Variables
Article
Mar 1963
J AM STAT ASSOC
Wassily Hoeffding
Upper bounds are derived for the probability that the sum S of n independent random variables exceeds its mean ES by a positive number nt. It is assumed that the range of each summand of S is bounded or bounded above. The bounds for Pr {S – ES ≥ nt} depend only on the endpoints of the ranges of the summands and the mean, or the mean and the variance of S. These results are then used to obtain analogous inequalities for certain sums of dependent random variables such as U statistics and the sum of a random sample without replacement from a finite population.
The sizes of compact subsets of Hilbert space and continuity of Gaussian processes
J FUNCT ANAL
R Dudley
Bin Chen
Chen lu
Dongliang Lin
Xiaoqin Zeng
The shear strain and its directions were thought to play an important role in severe plastic deformation. Asymmetric rolling, however, has a shear deformation zone in the middle section of deformation zone. Accordingly, Asymmetric cross rolling, a new rolling method was developed by us. And its experiments have been conducted to investigate its effects on microstructure and mechanical properties ... [Show full abstract] of AZ31 magnesium alloy. The influencing factors such as velocity ratio of rolls, total pass number, rolling route, rolling temperature were investigated. It was found that the shear strain of asymmetric cross rolling contributes to refinement of grain size. Samples rolled by asymmetric cross rolling have finer grain size than that rolled by common rolling.
Christophe Destouches
Gilles Grégoire
D. Beretz
[...]
M. Chiron
One of the main objectives of reactor dosimetry is the determination of the physical parameters characterizing the neutron field in which test samples are irradiated. These characteristics, from neutron spectrum to reaction rates characterization are used in experimental reactors to carry out the follow-up of the irradiation and to qualify the neutron calculation used to model the experiment. In ... [Show full abstract] power reactors these characteristics are used for the follow-up of the predicted damages to vessel and interns. Neutron parameters are derived from the dosimeter's activities which have suitable reactions (response functions and radioactive emissions). Then, the activities are analyzed using nuclear data, neutron computation results and data characterizing the conditions of irradiation (temporal and technological data, changes of location, etc.). The current CEA interpretation process applied for industrial power reactor interpretation process presents limitations coming mainly from the calculational tools and the nuclear data knowledge available at the time this method was developed in the mid 90's. However nowadays due to, first the improvement of the neutron calculational tools, for example, a full 3D Monte Carlo reactor modeling providing reaction in a point wise format is now possible in a reasonable time, and second, recent releases of the updated international nuclear data libraries, JEFF3.1, ENDF/B-VII for transport calculation and IRDF2002 and EAF2007 for dosimetry libraries, we have been engaged in a deep renewal of the reactor dosimetry interpretation process. The mains goals of this works are to improve the modeling of the experiment and the neutron parameters calculation for each phase of interest. In addition, uncertainties associated to the derived metrics are quantified in a rigorous way using simulation methods designed to cope with the high non-linearity of the process. After a detailed presentation of the current interpretation process and its limitations, this paper lists the main improvements of the neutron calculation codes and of the international nuclear data libraries. The principle of the new interpretation process is then detailed and a derivation process for the associated uncertainties is exposed. The paper finally analyzes the improvements expected from the refined process.
Article
STOKASTİK GÖREV ZAMANLI TEK MODELLİ U TİPİ MONTAJ HATTI DENGELEME PROBLEMLERİ İÇİN BİR SEZGİSEL
Hadi Gökçen
N. Nergiz SARAY
Suna ÖZEL
In this paper, a new heuristic procedure for single model U-line balancing problem with stochastic task time is proposed. The proposed procedure is based on the COMSOAL method developed by Arcus (16) for traditional deterministic single model assembly lines. The aim of the procedure is to assign tasks to stations such that number of station will be minimized and probability confidence levels set ... [Show full abstract] by management will not exceeded for each station time.
Article
Geoacoustic inversion via local, global, and hybrid algorithms
June 1999 · The Journal of the Acoustical Society of America
Mark R. Fallat
Stan E. Dosso
In this paper, local, global, and hybrid inversion algorithms are developed and applied to the problem of determining geoacoustic properties by minimizing the mismatch between measured and modeled acoustic fields. Local inversion methods are sensitive to gradients in the mismatch and move effectively downhill, but generally become trapped in local minima and must be initiated from a large number ... [Show full abstract] of starting points. Global inversion methods use a directed random process to search the parameter space for the optimal solution. They include the ability to escape from local minima, but as no gradient information is used, the search can be relatively inefficient. Hybrid inversion methods combine local and global approaches to produce a more efficient and effective algorithm. Here, downhill simplex (local) and simulated annealing (global) methods are developed individually and combined to produce a hybrid simplex simulated annealing algorithm. The hybrid inversion is found to be faster by more than an order of magnitude for a benchmark testcase in which the form of the geoacoustic model is known. The hybrid inversion algorithm is also applied to a testcase consisting of an unknown number of layers representing a general geoacoustic profile. Since the form of the model is not known, an underparameterized approach is employed to determine a minimum-structure solution.
Article
Quantitative analysis of some pharmaceuticals by the HPLC method
August 2009 · Moscow University Chemistry Bulletin
G. B. Golubitskii
V. M. Ivanov
A procedure for the quantitative analysis of a new multicomponent medicinal preparation “Pentalgin with propyphenazone and
drotaverine” by the HPLC method is developed. Analysis of model mixtures containing all active and auxiliary substances of
the tablets confirms the reliability of the obtained results. The analysis results of sample tablets correspond to the requirements
of the ... [Show full abstract] normative-engineering specifications and technological loadings. The technique is suggested for use in the pharmacopoeia
monograph of the enterprise producing the given preparation.
| https://www.researchgate.net/publication/304620560_Chaining_Including_Concentration |
An efficient adaptive variational quantum solver of the Schrödinger equation based on reduced density matrices | Request PDF
Request PDF | An efficient adaptive variational quantum solver of the Schrödinger equation based on reduced density matrices | Recently, adaptive variational quantum algorithms, e.g., Adaptive Derivative-Assembled Pseudo-Trotter-Variational Quantum Eigensolver (ADAPT-VQE)... | Find, read and cite all the research you need on ResearchGate
Article
An efficient adaptive variational quantum solver of the Schrödinger equation based on reduced density matrices
June 2021
The Journal of Chemical Physics154(24):244112
DOI: 10.1063/5.0054822
Authors:
<here is a image 0dbe773d08aabca7-3cdc50b3a9f9d858>
Jie Liu
University of Science and Technology of China
<here is a image 35831df00c8d2e68-2714c6cb95584d37>
Zhenyu Li
University of Science and Technology of China
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Jinlong Yang
Jinlong Yang
Abstract
Recently, adaptive variational quantum algorithms, e.g., Adaptive Derivative-Assembled Pseudo-Trotter-Variational Quantum Eigensolver (ADAPT-VQE) and Iterative Qubit-Excitation Based-Variational Quantum Eigensolver (IQEB-VQE), have been proposed to optimize the circuit depth, while a huge number of additional measurements make these algorithms highly inefficient. In this work, we reformulate the ADAPT-VQE with reduced density matrices (RDMs) to avoid additional measurement overhead. With Valdemoro’s reconstruction of the three-electron RDM, we present a revised ADAPT-VQE algorithm, termed ADAPT-V, without any additional measurements but at the cost of increasing variational parameters compared to the ADAPT-VQE. Furthermore, we present an ADAPT-Vx algorithm by prescreening the anti-Hermitian operator pool with this RDM-based scheme. ADAPT-Vx requires almost the same variational parameters as ADAPT-VQE but a significantly reduced number of gradient evaluations. Numerical benchmark calculations for small molecules demonstrate that ADAPT-V and ADAPT-Vx provide an accurate description of the ground- and excited-state potential energy curves. In addition, to minimize the quantum resource demand, we generalize this RDM-based scheme to circuit-efficient IQEB-VQE algorithm and achieve significant measurement reduction.
... The ansatz is built according to the gradient criterion, which approximates the idea of accounting for the maximal amount of the correlation energy by adding the operator with the largest gradient. In the reported numerical results, ADAPT-VQE is able to find a pathway to the desired state [27][28][29]
[30]
[31] . ADAPT-VQE simulations of the H 6 molecule, a prototype of strongly correlated molecules, have been demonstrated by Grimsley et al. 27 . ...
... Liu et al.
30
added a fixed number of operators to improve fermionic ADAPT-VQE slow convergence caused by inaccurate identification of operators due to Valdemoro's reconstruction of 3-RDM. The size of the batch in their implementation should be carefully tuned as inappropriate size leads to significant increases in the circuit depth. ...
... As such strings are obtained by cutting each fermionic excitation and removing Z Pauli operators, the pool grows polynomially with the system size as Oðn 4 Þ. Theoretically, this produces an Oðn 8 Þ overhead in the number of measurements in the straightforward implementation 29,
30
. That is why the idea of restricting the pool size seems to be attractive. ...
Variational quantum eigensolver techniques for simulating carbon monoxide oxidation
Article
Full-text available
Aug 2022
Mariia D. Sapova
<here is a image d4a14758784f5a05-9613dfedde30a7d0> A. K. Fedorov
Variational Quantum Eigensolver (VQE) methods aim to maximize the resources of existing noisy devices. However, they encounter difficulties in simulating molecules of industrially-relevant sizes, such as constructing the efficient ansatz. Adaptive variational algorithms (ADAPT-VQE) can solve this problem but with a significant increase in the number of measurements. Here, we reduce the measurement overhead of ADAPT-VQE via adding operator batches to the ansatz while keeping it compact. We reformulate the previously proposed qubit pool completeness criteria for the tapered qubit space and propose an automated pool construction procedure. Our numerical results indicate that reducing the qubit pool size from polynomial to linear conversely increases the number of measurements. We simulate a set of molecules, participating in the carbon monoxide oxidation processes using the statevector simulator and compare the results with VQE-UCCSD and classical methods. Our results pave the way towards usage of variational approaches for solving practically relevant chemical problems. The variational quantum eigensolver is a quantum-classical algorithm used to solve optimisation problems in machine learning but demonstrates limitations when applied to simulations of large molecules. Here, the authors explore the use of adaptive variational algorithms and demonstrate how they can be used to improve performance when simulating molecules participating in carbon monoxide processes.
... In-terested readers can refer to refs. [75][76][77]
[78]
[79][80][81] for other variants or optimizations, and we will not introduce them one by one. ...
... MPS rewrites the rank-n coefficient tensor c σ 1 ,...,σ n in eq.
(78)
as the product of a chain of rank-3 tensors as: c σ 1 ,σ 2 ,...,σ n = ∑ a 0 ,...,a n B σ 1 a 0 ,a 1 B σ 2 a 1 ,a 2 . . . B σ n a n−1 ,a n , ...
Near-term quantum computing techniques: Variational quantum algorithms, error mitigation, circuit compilation, benchmarking and classical simulation
Article
Apr 2023
<here is a image 3ff5139b1356f658-f03357c0fee36553> He-Liang Huang
Xiao-Yue Xu
<here is a image 840c8663ccfa48d9-c774538f406cbb77> Guo Chu
<here is a image ac56b2eb572e54f2-bcd5c7e2f1f7cc58> Gui Lu Long
Quantum computing is a game-changing technology for global academia, research centers and industries including computational science, mathematics, finance, pharmaceutical, materials science, chemistry and cryptography. Although it has seen a major boost in the last decade, we are still a long way from reaching the maturity of a full-fledged quantum computer. That said, we will be in the noisy-intermediate scale quantum (NISQ) era for a long time, working on dozens or even thousands of qubits quantum computing systems. An outstanding challenge, then, is to come up with an application that can reliably carry out a nontrivial task of interest on the near-term quantum devices with non-negligible quantum noise. To address this challenge, several near-term quantum computing techniques, including variational quantum algorithms, error mitigation, quantum circuit compilation and benchmarking protocols, have been proposed to characterize and mitigate errors, and to implement algorithms with a certain resistance to noise, so as to enhance the capabilities of near-term quantum devices and explore the boundaries of their ability to realize useful applications. Besides, the development of near-term quantum devices is inseparable from the efficient classical simulation, which plays a vital role in quantum algorithm design and verification, error-tolerant verification and other applications. This review will provide a thorough introduction of these near-term quantum computing techniques, report on their progress, and finally discuss the future prospect of these techniques, which we hope will motivate researchers to undertake additional studies in this field.
... The coupled cluster is also the motivation of the use of the unitary coupled cluster ansatz of VQE [153], where a similar structure of exponentiated excitations based around a reference configuration is constructed [37,80,81,[210][211][212], with modifications to ensure efficient use on a unitary set of quantum circuits. Similar considerations of dynamic inclusion of additional excitations are also possible with the ADAPT-VQE ansatz [213]
[214]
[215]. Furthermore, the Efficient Symmetry Preserving ansatz [216] looks to ensure the ability to systematically improve its span of the FCI description of Eq. (2.5) ensuring the preservation of symmetries inherent in its form. ...
... This is understandable given the challenge of simulating a VQE for more than a dozen qubits, however this raises the question of whether the barren plateau problem has been solved. This claim has been made in several studies, and most notably in the literature surrounding adaptive ansätze [213,
214,
268], where it has been numerically shown that gradients do not vanish in the system size as long as the ansatz is built progressively [215]. ...
Methods for variational computation of molecular properties on near term quantum computers
Thesis
Dec 2022
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jules Tilly
In this thesis we explore the near term applications of quantum computing to Quantum Chemistry problems, with a focus on electronic structure calculations. We begin by discussing the core subroutine of near-term quantum computing methods: the variational quantum eigensolver (VQE). By drawing upon the literature, we discuss the relevance of the method in computing electronic structure properties, compare it to alternative conventional or quantum methods and outline best practices. We then discuss the key limitations of this method, namely: the exploding number of measurements required, showing that parallelisation will be relevant for VQE to compete with conventional methods; the barren plateau problem; and the management of errors through error mitigation - we present a light touch error mitigation technique which is used to improve the results of experiments presented later in the thesis. From this point, we propose three methods for near term applications of quantum computing, with a focus on limiting the requirements on quantum resources. The first two methods concern the computation of ground state energy. We adapt the conventional methods of complete active space self consistent field (CASSCF) and energy-weighted density matrix embedding theory (EwDMET) by integrating a VQE subroutine to compute the electronic wavefunctions from which reduced density matrices are sampled. These method allow recovering additional electron correlation energy for a given number of qubits and are tested on quantum devices. The last method is focused on computing excited electronic states and uses techniques inspired from the generative adversarial machine learning literature. It is a fully variational method, which is shown to work on current quantum devices.
... However, these advantages come at the cost of a greater number of energy and gradient evaluations for optimizing and selecting new unitary operators. Investigating more efficient ways to select important operators is an ongoing area of research [66,
67]
. ...
... BothĤ and the operator pool {κ μ } contain of the order N 4 elements (assuming a pool of general one-and two-body operators). It has recently been pointed out
[67]
however that if the quantity [Ĥ ,κ μ ] is decomposed in terms of the reduced density matrices then one can determine the pool gradients [Eq. (D6)] with the evaluation of a number of Pauli terms that scales as N 6 (again assuming a pool of general oneand two-body operators). ...
Simulating Many-Body Systems with a Projective Quantum Eigensolver
<here is a image 3c0c3038368484ef-25c0e30557273f79> Francesco Evangelista
We present a new hybrid quantum-classical algorithm for optimizing unitary coupled-cluster (UCC) wave functions deemed the projective quantum eigensolver (PQE), amenable to near-term noisy quantum hardware. Contrary to variational quantum algorithms, PQE optimizes a trial state using residuals (projections of the Schrödinger equation) rather than energy gradients. We show that the residuals may be evaluated by simply measuring two energy expectation values per element. We also introduce a selected variant of PQE (SPQE) that uses an adaptive ansatz built from arbitrary-order particle-hole operators, offering an alternative to gradient-based selection procedures. PQE and SPQE are tested on a set of molecular systems covering both the weak and strong correlation regimes, including hydrogen clusters with four to ten atoms and the BeH2 molecule. When employing a fixed ansatz, we find that PQE can converge disentangled (factorized) UCC wave functions to essentially identical energies as variational optimization while requiring fewer computational resources. A comparison of SPQE and adaptive variational quantum algorithms shows that—for ansätze containing the same number of parameters—the two methods yield results of comparable accuracy. Finally, we show that for a target energy accuracy, SPQE provides a parameterization of similar size or more concise than the one obtained via selected configuration interaction and the density matrix renormalization group on one- to three-dimensional strongly correlated H10 systems in terms of number of variational parameters.
... However, it presents an important disadvantage: identifying the best operator to be added at each step introduces a drastic measurement cost, since the gradients of all the possible new operators must be estimated. Several works address this measurement overhead [23,
32,
33], in some cases with significant cost reductions, although with the caveat that they result in deeper circuits. Even in those cases, the overhead remains significant. ...
... Restricting the operator pool size and adding the operators according to different batching strategies have been suggested as possible ways to reduce the number of measurements in ADAPT-VQE [19,23,
32,
33]. Such approaches allow up to a quadratic improvement in the number of measurements, but may result into deeper ansatz circuits if applied too greedily. ...
Mitigating the measurement overhead of ADAPT-VQE with optimised informationally complete generalised measurements
ADAPT-VQE stands out as a robust algorithm for constructing compact ans\"atze for molecular simulation. It enables to significantly reduce the circuit depth with respect to other methods, such as UCCSD, while achieving higher accuracy and not suffering from so-called barren plateaus that hinder the variational optimisation of many hardware-efficient ans\"atze. In its standard implementation, however, it introduces a considerable measurement overhead in the form of gradient evaluations trough estimations of many commutator operators. In this work, we mitigate this measurement overhead by exploiting a recently introduced method for energy evaluation relying on Adaptive Informationally complete generalised Measurements (AIM). Besides offering an efficient way to measure the energy itself, Informationally Complete (IC) measurement data can be reused to estimate all the commutators of the operators in the operator pool of ADAPT-VQE, using only classically efficient post-processing. We present the AIM-ADAPT-VQE scheme in detail, and investigate its performance with several H4 Hamiltonians and operator pools. Our numerical simulations indicate that the measurement data obtained to evaluate the energy can be reused to implement ADAPT-VQE with no additional measurement overhead for the systems considered here. In addition, we show that, if the energy is measured within chemical precision, the CNOT count in the resulting circuits is close to the ideal one. With scarce measurement data, AIM-ADAPT-VQE still converges to the ground state with high probability, albeit with an increased circuit depth in some cases.
... The ADAPT-V and ADAPT-Vx algorithms introduced in
[54]
improve the scaling of the number of measurements using a different approach, based on RDMs. In ADAPT-V the measurement cost scales like O(N 4 ), the drawbacks being a larger number of variational parameters and deeper circuits. ...
... The measurements per iteration in ADAPT-VQE thus scale like O(N 8 ) (instead of O(N 4 ) like in VQE with static ansätze). It should be noted that, as mentioned previously, modified variants such as ADAPT-V and ADAPT-Vx manage to decrease this measurement overhead at the expense of an acceptable increase in the number of variational parameters and circuit depth
[54]
. ...
Ans\"atze for Noisy Variational Quantum Eigensolvers
<here is a image 771b48166fcf71c1-449be0797d7c5d2c> Mafalda Ramôa
The hardware requirements of useful quantum algorithms remain unmet by the quantum computers available today. Because it was designed to soften these requirements, the Variational Quantum Eigensolver (VQE) has gained popularity as a contender for a chance at quantum advantage with near-term quantum computers. The ansatz, a parameterized circuit that prepares trial states, can dictate the success (or lack thereof) of a VQE. Too deep ans\"atze can hinder near-term viability, or lead to trainability issues that render the algorithm inefficient. The purpose of this thesis was to analyse different ans\"atze proposed for quantum chemistry, examining their noise-resilience and viability in state-of-the-art quantum computers. In particular, dynamic ans\"atze (ADAPT-VQEs) were explored, and the impact of the choice of pool and selection criterion on their performance was analysed.
... Restarting the VQE optimization, which has been done in some ADAPT work, can lead to a suboptimal solution of the ACSE, or for the VQE subroutine to fail. Recent work by Liu et al.
48
used a reconstructed 3-RDM in the ACSE to showing that the ADAPT does produce a more compact representation of the ansatz. The lower-right shows the number of parameter evaluations (a lower bound on the number of gradients evaluated at each optimizer step), which is linear scaling with the ACSE procedure but for ADAPT becomes quadratic, with respect to the number of iterations. ...
... However, unlike Liu et al.,
48
it is important not to use ACSE residuals from reconstructed 3-RDMs in the CQE, because these will likely lead to convergence issues. The 3-RDM can still be directly obtained on a quantum computer through a variety of techniques. ...
Accelerated Convergence of Contracted Quantum Eigensolvers through a Quasi-Second-Order, Locally Parameterized Optimization
A contracted quantum eigensolver (CQE) finds a solution to the many-electron Schrödinger equation by solving its integration (or contraction) to the two-electron space─a contracted Schrödinger equation (CSE)─on a quantum computer. When applied to the anti-Hermitian part of the CSE (ACSE), the CQE iterations optimize the wave function, with respect to a general product ansatz of two-body exponential unitary transformations that can exactly solve the Schrödinger equation. In this work, we accelerate the convergence of the CQE and its wave function ansatz via tools from classical optimization theory. By treating the CQE algorithm as an optimization in a local parameter space, we can apply quasi-second-order optimization techniques, such as quasi-Newton approaches or nonlinear conjugate gradient approaches. Practically, these algorithms result in superlinear convergence of the wave function to a solution of the ACSE. Convergence acceleration is important because it can both minimize the accumulation of noise on near-term intermediate-scale quantum (NISQ) computers and achieve highly accurate solutions on future fault-tolerant quantum devices. We demonstrate the algorithm, as well as some heuristic implementations relevant for cost-reduction considerations, comparisons with other common methods such as variational quantum eigensolvers, and a Fermionic-encoding-free form of the CQE.
... Restarting the VQE optimization, which has been done in some ADAPT work, can lead to a suboptimal solution of the ACSE, or for the VQE subroutine to fail. Recent work by Liu et al.
[44]
used a reconstructed 3-RDM in the ACSE to obtain approximate residuals to seed the ADAPT algorithm. Because these approximate gradients can differ in a substantial way from the exact gradients, more terms are needed, which significantly increases the variational flexibility of the ansatz. ...
... However, unlike Liu et. al,
[44]
, it is important not to use the classical ACSE with reconstructed residuals from a reconstructed 3-RDM, as these will likely lead to convergence issues. However, the classical 3-RDM can still be obtained relatively easily on a quantum computer through a variety of techniques. ...
Accelerated Convergence of Contracted Quantum Eigensolvers through a Quasi-Second-Order, Locally Parameterized Optimization
A contracted quantum eigensolver (CQE) finds a solution to the many-electron Schr\"odinger equation by solving its integration (or contraction) to the 2-electron space -- a contracted Schr\"odinger equation (CSE) -- on a quantum computer. When applied to the anti-Hermitian part of the CSE (ACSE), the CQE iterations optimize the wave function with respect to a general product ansatz of two-body exponential unitary transformations that can exactly solve the Schr\"odinger equation. In this work, we accelerate the convergence of the CQE and its wavefunction ansatz via tools from classical optimization theory. By treating the CQE algorithm as an optimization in a local parameter space, we can apply quasi-second-order optimization techniques, such as quasi-Newton approaches or non-linear conjugate gradient approaches. Practically these algorithms result in superlinear convergence of the wavefunction to a solution of the ACSE. Convergence acceleration is important because it can both minimize the accumulation of noise on near-term intermediate-scale quantum (NISQ) computers and achieve highly accurate solutions on future fault-tolerant quantum devices. We demonstrate the algorithm, as well as some heuristic implementations relevant for cost-reduction considerations, comparisons with other common methods such as variational quantum eigensolvers, and a fermionic-encoding-free form of the CQE.
... Because the number of terms inĤ for a molecule is also quartic, the total number of measurements per iteration would naively scale as O(n 8 ) instead of the O(n 4 ) scaling of a fixed-ansatz VQE applied to a molecular problem. However, by reformulating the energy gradient in terms of the 3particle reduced density matrix, Ref.
[30]
showed that this measurement cost is actually O(n 6 ). 1 An important consideration in choosing a pool is that it should be possible to construct from it an ansatz that represents the exact ground state to arbitrary accuracy. Pools that satisfy this criterion are called "complete" [9]. ...
... If we now add two more generators, Y n−1 and Z n−1 Y n , (they generate the third operator X n−1 Y n ), then they generate new odd strings when multiplied by the even strings from Eq.
(30)
, and so the total number of odd strings becomes Odd + 3 × Even = 2 n−1 (2 n−1 + 1) 2 . ...
Avoiding symmetry roadblocks and minimizing the measurement overhead of adaptive variational quantum eigensolvers
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nicholas Mayhall
<here is a image 2df8e8336a9b1024-510e645d398d250b> Sophia Economou
Quantum simulation of strongly correlated systems is potentially the most feasible useful application of near-term quantum computers. Minimizing quantum computational resources is crucial to achieving this goal. A promising class of algorithms for this purpose consists of variational quantum eigensolvers (VQEs). Among these, problem-tailored versions such as ADAPT-VQE that build variational ans\"atze step by step from a predefined operator pool perform particularly well in terms of circuit depths and variational parameter counts. However, this improved performance comes at the expense of an additional measurement overhead compared to standard VQEs. Here, we show that this overhead can be reduced to an amount that grows only linearly with the number $n$ of qubits, instead of quartically as in the original ADAPT-VQE. We do this by proving that operator pools of size $2n-2$ can represent any state in Hilbert space if chosen appropriately. We prove that this is the minimal size of such "complete" pools, discuss their algebraic properties, and present necessary and sufficient conditions for their completeness that allow us to find such pools efficiently. We further show that, if the simulated problem possesses symmetries, then complete pools can fail to yield convergent results, unless the pool is chosen to obey certain symmetry rules. We demonstrate the performance of such symmetry-adapted complete pools by using them in classical simulations of ADAPT-VQE for several strongly correlated molecules. Our findings are relevant for any VQE that uses an ansatz based on Pauli strings.
... Because the number of terms inĤ for a molecule is also quartic, the total number of measurements per iteration would naively scale as O(n 8 ) instead of the O(n 4 ) scaling of a fixed-ansatz VQE applied to a molecular problem. However, by reformulating the energy gradient in terms of the 3particle reduced density matrix, Ref.
[30]
showed that this measurement cost is actually O(n 6 ). 1 An important consideration in choosing a pool is that it should be possible to construct from it an ansatz that represents the exact ground state to arbitrary accuracy. Pools that satisfy this criterion are called "complete" [9]. ...
Avoiding symmetry roadblocks and minimizing the measurement overhead of adaptive variational quantum eigensolvers
Full-text available
Jun 2023
V. O. Shkolnikov
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nicholas Mayhall
<here is a image 2df8e8336a9b1024-510e645d398d250b> Sophia Economou
Edwin Barnes
Quantum simulation of strongly correlated systems is potentially the most feasible useful application of near-term quantum computers. Minimizing quantum computational resources is crucial to achieving this goal. A promising class of algorithms for this purpose consists of variational quantum eigensolvers (VQEs). Among these, problem-tailored versions such as ADAPT-VQE that build variational ansätze step by step from a predefined operator pool perform particularly well in terms of circuit depths and variational parameter counts. However, this improved performance comes at the expense of an additional measurement overhead compared to standard VQEs. Here, we show that this overhead can be reduced to an amount that grows only linearly with the number n of qubits, instead of quartically as in the original ADAPT-VQE. We do this by proving that operator pools of size 2 n − 2 can represent any state in Hilbert space if chosen appropriately. We prove that this is the minimal size of such "complete" pools, discuss their algebraic properties, and present necessary and sufficient conditions for their completeness that allow us to find such pools efficiently. We further show that, if the simulated problem possesses symmetries, then complete pools can fail to yield convergent results, unless the pool is chosen to obey certain symmetry rules. We demonstrate the performance of such symmetry-adapted complete pools by using them in classical simulations of ADAPT-VQE for several strongly correlated molecules. Our findings are relevant for any VQE that uses an ansatz based on Pauli strings.
... Instead of a fixed-length ansatz, that is, where one chooses UCCSD, UCCSDT or UCCSDTQ anszatz (length equal 2, 3 or 4, respectively), variational algorithms with a variable-length ansatz have been proposed by the community [76][77][78][79]
[80]
There are two reasons for that: (1) the fixed-length ansätze use unnecessary excitations that can be considered as redundant terms as they do not contribute to a better approximation of the FCI wavefunction. This creates longer circuits and consumes a greater number of variational parameters; (2) fixed-length ansätze such as UCCSD or QUCCSD cannot provide a good chemical accuracy for strongly correlated systems 51 (i.e., see, e.g., the H 6 molecule in Section 5). ...
Open source variational quantum eigensolver extension of the quantum learning machine for quantum chemistry
Article
Full-text available
Mar 2023
<here is a image d6a643eb5606a8a6-b8c2b7b664ae8233> Mohammad Haidar
<here is a image 9df1f2f70375fbc2-39d3c9a3e8609205> Marko J. Rančić
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Thomas Ayral
<here is a image bf990ebb478e50f8-5ac77f11e402dc96> Jean-Philip Piquemal
Quantum chemistry (QC) is one of the most promising applications of quantum computing. However, present quantum processing units (QPUs) are still subject to large errors. Therefore, noisy intermediate-scale quantum (NISQ) hardware is limited in terms of qubit counts/circuit depths. Variational quantum eigensolver (VQE) algorithms can potentially overcome such issues. Here, we introduce the OpenVQE open-source QC package. It provides tools for using and developing chemically-inspired adaptive methods derived from unitary coupled cluster (UCC). It facilitates the development and testing of VQE algorithms and is able to use the Atos Quantum Learning Machine (QLM), a general quantum programming framework enabling to write/optimize/simulate quantum computing programs. We present a specific, freely available QLM open-source module, myQLM-fermion. We review its key tools for facilitating QC computations (fermionic second quantization, fermion-spin transforms, etc.). OpenVQE largely extends the QLM's QC capabilities by providing: (i) the functions to generate the different types of excitations beyond the commonly used UCCSD ansatz; (ii) a new Python implementation of the “adaptive derivative assembled pseudo-Trotter method” (ADAPT-VQE). Interoperability with other major quantum programming frameworks is ensured thanks to the myQLM-interop package, which allows users to build their own code and easily execute it on existing QPUs. The combined OpenVQE/myQLM-fermion libraries facilitate the implementation, testing and development of variational quantum algorithms, while offering access to large molecules as the noiseless Schrödinger-style dense simulator can reach up to 41 qubits for any circuit. Extensive benchmarks are provided for molecules associated to qubit counts ranging from 4 to 24. We focus on reaching chemical accuracy, reducing the number of circuit gates and optimizing parameters and operators between “fixed-length” UCC and ADAPT-VQE ansätze.
... When building a different U(θ ) at each cycle, it is currently unclear how to choose the best one for a given Hamiltonian. Adaptive methods [60]
[61]
[62][63][64] to build each operator one by one solve this problem but are computationally expensive. Due to the absence of a cost-effective way to ascertain a new U(θ ) for each cycle, we use the same one for each cycle. ...
Improved Variational Quantum Eigensolver Via Quasidynamical Evolution
Article
Full-text available
Manpreet Singh Jattana
Fengping Jin
Hans De Raedt
<here is a image 04a51ac2644be8cd-9695bfb2a58ff666> Kristel Michielsen
The variational quantum eigensolver (VQE) is a hybrid quantum classical algorithm designed for current and near-term quantum devices. Despite its initial success, there is a lack of understanding involving several of its key aspects. There are problems with VQE that forbid a favorable scaling towards quantum advantage. In order to alleviate the problems, we propose and extensively test a quantum annealing inspired heuristic that supplements VQE. The improved VQE enables an efficient initial state-preparation mechanism, in a recursive manner, for a quasidynamical unitary evolution. We conduct an in-depth scaling analysis of finding the ground-state energies with increasing lattice sizes of the Heisenberg model, employing simulations of up to 40 qubits that manipulate the complete state vector. In addition to systematically finding the ground-state energy, we observe that it avoids barren plateaus, escapes local minima, and works with low-depth circuits. For the current devices, we further propose a benchmarking toolkit using a mean-field model and test it on IBM Q devices. Realistic gate execution times estimate a longer computational time to complete the same computation on a fully functional error-free quantum computer than on a quantum computer emulator implemented on a classical computer. However, our proposal can be expected to help accurate estimations of the ground-state energies beyond 50 qubits when the complete state vector can no longer be stored on a classical computer, thus enabling quantum advantage.
... 43 Many recent works have contributed to the development of adaptive VQE algorithms to reduce circuit depth. [44][45][46]
[47]
[48] Adaptive Derivative-Assembled Pseudo-Trotter (ADAPT) ansatz 44 builds a very compact representation of electronic wave functions while maintaining high accuracy. Qubit coupled cluster (QCC) represents the electronic wave function in the qubit representation. ...
Multiscale quantum algorithms for quantum chemistry
Article
Full-text available
Feb 2023
<here is a image d9b397a949953560-5a6a05e4dc3d0f3d> Honghui Shang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Huan Ma
<here is a image 0dbe773d08aabca7-3cdc50b3a9f9d858> Jie Liu
Jinlong Yang
Exploring the potential applications of quantum computers in material design and drug discovery is attracting more and more attention after quantum advantage has been demonstrated using Gaussian boson sampling. However, quantum resource requirements in material and (bio)molecular simulations are far beyond the capacity of near-term quantum devices. In this work, multiscale quantum computing is proposed for quantum simulations of complex systems by integrating multiple computational methods at different scales of resolution. In this framework, most computational methods can be implemented in an efficient way on classical computers, leaving the critical portion of the computation to quantum computers. The simulation scale of quantum computing strongly depends on available quantum resources. As a near-term scheme, we integrate adaptive variational quantum eigensolver algorithms, second-order Møller-Plesset perturbation theory and Hartree-Fock theory within the framework of the many-body expansion fragmentation approach. This new algorithm is applied to model systems consisting of hundreds of orbitals with decent accuracy on the classical simulator. This work should encourage further studies on quantum computing for solving practical material and biochemistry problems.
... In recent years, variational quantum circuit ansatzes such as the unitary coupled-cluster (UCC) [26][27][28] and hardware-efficient ansatz (HEA) 17 have been successfully applied in quantum chemistry applications for small molecules on most leading quantum hardware platforms. [12][13][14][15][16][17][18] Circuit optimization techniques including operator reduction [29][30][31][32][33] and adaptive algorithms [34][35][36][37]
[38]
[39][40][41][42][43][44][45][46] have also been proposed to further reduce circuit depth and lower optimization overhead. ...
Quantum circuit matrix product state ansatz for large-scale simulations of molecules
Preprint
Full-text available
Jan 2023
Jie Liu
<here is a image d287075e3dbe83c4-cf3b4cc878c6d151> Yi Fan
<here is a image 35831df00c8d2e68-2714c6cb95584d37> Zhenyu Li
Jinlong Yang
As in the density matrix renormalization group (DMRG) method, approximating many-body wave function of electrons using a matrix product state (MPS) is a promising way to solve electronic structure problems. The expressibility of an MPS is determined by the size of the matrices or in other words the bond dimension, which unfortunately should be very large in many cases. In this study, we propose to calculate the ground state energies of molecular systems by variationally optimizing quantum circuit MPS (QCMPS) with a relatively small number of qubits. It is demonstrated that with carefully chosen circuit structure and orbital localization scheme, QCMPS can reach a similar accuracy as that achieved in DMRG with an exponentially large bond dimension. QCMPS simulation of a linear molecule with 50 orbitals can reach the chemical accuracy using only 6 qubits at a moderate circuit depth. These results suggest that QCMPS is a promising wave function ansatz in the variational quantum eigensolver algorithm for molecular systems.
... The scaling of the shot count is dominated by the estimation of the matrix M which scales as O(N 12 ) for both qLR(sc) and qLR(proj) approaches, where N is some measure of the system size. These requirements may be reduced by utilizing commutators which lead to the cancellations of uncontracted terms
[79]
, approximations for higher-body RDMs and taking advantage of the high symmetry of the M matrix (such as by the use of Krylov-subspace-based algorithms like the Davidson method). The pathways to reduce computational complexity will be a topic of later studies. ...
Quantum simulation of molecular response properties
Preprint
Full-text available
Jan 2023
Vibin Abraham
<here is a image 9769e18d72e6ad58-c506755f51b654cf> Ashutosh Kumar
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ayush Asthana
<here is a image a60622c6b69fc685-9d932d07278afb70> Pavel A. Dub
Accurate modeling of the response of molecular systems to an external electromagnetic field is challenging on classical computers, especially in the regime of strong electronic correlation. In this paper, we develop a quantum linear response (qLR) theory to calculate molecular response properties on near-term quantum computers. Inspired by the recently developed variants of the quantum counterpart of equation of motion (qEOM) theory, the qLR formalism employs "killer condition" satisfying excitation operator manifolds that offers a number of theoretical advantages along with reduced quantum resource requirements. We also used the qEOM framework in this work to calculate state-specific response properties. Further, through noise-less quantum simulations, we show that response properties calculated using the qLR approach are more accurate than the ones obtained from the classical coupled-cluster based linear response models due to the improved quality of the ground-state wavefunction obtained using the ADAPT-VQE algorithm.
... However, assuming the case of a second-quantized electronic structure Hamiltonian (with O(N 4 ) terms), and given there are O(N 4 ) terms in a complete pool for up to double excitation operators, measurement scaling at each outer-loop iteration could naively reach O(N 8 ). This can be reduced to O(N 6 ) if one reformulates the energy gradients in terms of the three-body reduced density matrix
[532]
. This method also allows predicting gradients from the two-body reduced density matrix of the previous iteration of ADAPT-VQE, reducing overall scaling of measurements back to O(N 4 ) albeit at a cost to accuracy. ...
The Variational Quantum Eigensolver: A review of methods and best practices
Article
Full-text available
Nov 2022
H. Chen
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jules Tilly
<here is a image 10e15f1b1ca1f5a4-0bcbf58c0053fa69> Shuxiang Cao
<here is a image 4c43a2d08008a91c-4279e1156a826a5b> Jonathan Tennyson
The variational quantum eigensolver (or VQE), first developed by Peruzzo et al. (2014), has received significant attention from the research community in recent years. It uses the variational principle to compute the ground state energy of a Hamiltonian, a problem that is central to quantum chemistry and condensed matter physics. Conventional computing methods are constrained in their accuracy due to the computational limits facing exact modeling of the exponentially growing electronic wavefunction for these many-electron systems. The VQE may be used to model these complex wavefunctions in polynomial time, making it one of the most promising near-term applications for quantum computing. One important advantage is that variational algorithms have been shown to present some degree of resilience to the noise in the quantum hardware. Finding a path to navigate the relevant literature has rapidly become an overwhelming task, with many methods promising to improve different parts of the algorithm, but without clear descriptions of how the diverse parts fit together. The potential practical advantages of the algorithm are also widely discussed in the literature, but with varying conclusions. Despite strong theoretical underpinnings suggesting excellent scaling of individual VQE components, studies have pointed out that their various pre-factors could be too large to reach a quantum computing advantage over conventional methods. This review aims at disentangling the relevant literature to provide a comprehensive overview of the progress that has been made on the different parts of the algorithm, and to discuss future areas of research that are fundamental for the VQE to deliver on its promises. All the different components of the algorithm are reviewed in detail. These include the representation of Hamiltonians and wavefunctions on a quantum computer, the optimization process to find ground state energies, the post processing mitigation of quantum errors, and suggested best practices. We identify four main areas of future research: (1) optimal measurement schemes for reduction of circuit repetitions required; (2) large scale parallelization across many quantum computers; (3) ways to overcome the potential appearance of vanishing gradients in the optimization process for large systems, and how the number of iterations required for the optimization scales with system size; (4) the extent to which VQE suffers for quantum noise, and whether this noise can be mitigated in a tractable manner. The answers to these open research questions will determine the routes for the VQE to achieve quantum advantage as the quantum computing hardware scales up and as the noise levels are reduced.
... To explore the possibilities of near-term quantum advantage, adaptive schemes within the VQE framework featuring system-specific iterative ansatz construction have been proposed. [12][13][14][15][16][17]
[18]
These approaches aim to adaptively parameterize the target electronic wavefunction to desirable accuracy with a quantum circuit as shallow as possible. Such approaches feature selection of a unitary generator from a predefined operator set ("pool"). ...
Growth reduction of similarity transformed electronic Hamiltonians in qubit space
Accurately solving the electronic structure problem through the variational quantum eigensolver (VQE) is hindered by the available quantum resources of current and near-term devices. One approach to relieving the circuit depth requirements for VQE is to "pre-process" the electronic Hamiltonian by a similarity transformation incorporating some degree of electronic correlation, with the remaining correlation left to be addressed by the circuit ansatz. This often comes at the price of a substantial increase in the number of terms to measure in the unitarily transformed Hamiltonian. In this work, we propose an efficient approach to sampling elements from the unrestricted pool of N-qubit Pauli products which minimize the onset of new terms in the transformed Hamiltonian, while facilitating substantial energy lowering. We find that utilizing an operator selection criteria which takes into account both energy gradients and expected growth can substantially reduce the number of Pauli products in effective Hamiltonians used for a subsequent VQE optimization.
... However, assuming the case of a second-quantized electronic structure Hamiltonian (with ( 4 ) terms), and given there are ( 4 ) terms in a complete pool for up to double excitation operators, measurement scaling at each outer-loop iteration could naively reach ( 8 ). This can be reduced to ( 6 ) if one reformulates the energy gradients in terms of the three-body reduced density matrix
[532]
. This method also allow predicting gradients from the two-body reduced density matrix of the previous iteration of ADAPT-VQE, reducing overall scaling of measurements back to ( 4 ) albeit at a cost to accuracy. ...
The Variational Quantum Eigensolver: A review of methods and best practices
<here is a image 10e15f1b1ca1f5a4-0bcbf58c0053fa69> Shuxiang Cao
<here is a image 4c43a2d08008a91c-4279e1156a826a5b> Jonathan Tennyson
The variational quantum eigensolver (or VQE), first developed by Peruzzo et al. (2014), has received significant attention from the research community in recent years. It uses the variational principle to compute the ground state energy of a Hamiltonian, a problem that is central to quantum chemistry and condensed matter physics. Conventional computing methods are constrained in their accuracy due to the computational limits facing exact modeling of the exponentially growing electronic wavefunction for these many-electron systems. The VQE may be used to model these complex wavefunctions in polynomial time, making it one of the most promising near-term applications for quantum computing. One important advantage is that variational algorithms have been shown to present some degree of resilience to the noise in the quantum hardware. Finding a path to navigate the relevant literature has rapidly become an overwhelming task, with many methods promising to improve different parts of the algorithm, but without clear descriptions of how the diverse parts fit together. The potential practical advantages of the algorithm are also widely discussed in the literature, but with varying conclusions. Despite strong theoretical underpinnings suggesting excellent scaling of individual VQE components, studies have pointed out that their various pre-factors could be too large to reach a quantum computing advantage over conventional methods.
This review aims at disentangling the relevant literature to provide a comprehensive overview of the progress that has been made on the different parts of the algorithm, and to discuss future areas of research that are fundamental for the VQE to deliver on its promises. All the different components of the algorithm are reviewed in detail. These include the representation of Hamiltonians and wavefunctions on a quantum computer, the optimization process to find ground state energies, the post processing mitigation of quantum errors, and suggested best practices. We identify four main areas of future research: (1) optimal measurement schemes for reduction of circuit repetitions required; (2) large scale parallelization across many quantum computers; (3) ways to overcome the potential appearance of vanishing gradients in the optimization process for large systems, and how the number of iterations required for the optimization scales with system size; (4) the extent to which VQE suffers for quantum noise, and whether this noise can be mitigated in a tractable manner. The answers to these open research questions will determine the routes for the VQE to achieve quantum advantage as the quantum computing hardware scales up and as the noise levels are reduced.
... See Refs [16,25] for discussions on operator pool redundancy, minimal complete pools, and symmetry considerations. Another approach to minimize the measurement overhead has been proposed by Yang and coworkers
[26]
, where they use an approximate reconstruction of the three-electron reduced density matrix to completely remove the measurment overhead, albeit at a slight increase in ansatz length. TETRIS-ADAPT-VQE adds multiple operators per ADAPT layer while keeping the number of operators roughly constant. ...
TETRIS-ADAPT-VQE: An adaptive algorithm that yields shallower, denser circuit ans\"atze
Adaptive quantum variational algorithms are particularly promising for simulating strongly correlated systems on near-term quantum hardware, but they are not yet viable due, in large part, to the severe coherence time limitations on current devices. In this work, we introduce an algorithm called TETRIS-ADAPT-VQE, which iteratively builds up variational ans\"atze a few operators at a time in a way dictated by the problem being simulated. This algorithm is a modified version of the ADAPT-VQE algorithm in which the one-operator-at-a-time rule is lifted to allow for the addition of multiple operators with disjoint supports in each iteration. TETRIS-ADAPT-VQE results in denser but significantly shallower circuits, without increasing the number of CNOT gates or variational parameters. Its advantage over the original algorithm in terms of circuit depths increases with the system size. Moreover, the expensive step of measuring the energy gradient with respect to each candidate unitary at each iteration is performed only a fraction of the time compared to ADAPT-VQE. These improvements bring us closer to the goal of demonstrating a practical quantum advantage on quantum hardware.
... In particular, the QEB operators were demonstrated to be able to achieve the same rate of convergence as the general fermionic operators in previous studies. [40,
46]
While, in the DMET-VQE calculations, the convergence of the QEB operators is much slower than the general fermionic operators. All calculations in the rest of this work use spin-adapted fermionic operators to construct operator pools for adaptive VQE algorithms. ...
Divide-and-conquer variational quantum algorithms for large-scale electronic structure simulations
Exploring the potential application of quantum computers in material design and drug discovery has attracted a lot of interest in the age of quantum computing. However, the quantum resource requirement for solving practical electronic structure problems are far beyond the capacity of near-term quantum devices. In this work, we integrate the divide-and-conquer (DC) approaches into the variational quantum eigensolver (VQE) for large-scale quantum computational chemistry simulations. Two popular divide-and-conquer schemes, including many-body expansion~(MBE) fragmentation theory and density matrix embedding theory~(DMET), are employed to divide complicated problems into many small parts that are easy to implement on near-term quantum computers. Pilot applications of these methods to systems consisting of tens of atoms are performed with adaptive VQE algorithms. This work should encourage further studies of using the philosophy of DC to solve electronic structure problems on quantum computers.
... Instead of a fixed-length ansätze, other types of iterative variational algorithms have been proposed by the community 74,75,76,77,
78
There are two reasons for that: (1) the fixed-length ansätze use unnecessarily excitations that can be considered as redundant terms as they do not contribute to approximate the FCI wavefunction. This creates longer circuit depth and consumes a greater number of variational parameters. ...
Open Source Variational Quantum Eigensolver Extension of the Quantum Learning Machine (QLM) for Quantum Chemistry
Quantum Chemistry (QC) is one of the most promising applications of Quantum Computing. However, present quantum processing units (QPUs) are still subject to large errors. Therefore, noisy intermediate-scale quantum (NISQ) hardware is limited in terms of qubits counts and circuit depths. Specific algorithms such as Variational Quantum Eigensolvers (VQEs) can potentially overcome such issues. We introduce here a novel open-source QC package, denoted Open-VQE, providing tools for using and developing chemically-inspired adaptive methods derived from Unitary Coupled Cluster (UCC). It facilitates the development and testing of VQE algorithms. It is able to use the Atos Quantum Learning Machine (QLM), a general quantum programming framework enabling to write, optimize and simulate quantum computing programs. Along with Open-VQE, we introduce myQLM-Fermion, a new open-source module (that includes the key QLM ressources that are important for QC developments (fermionic second quantization tools etc...). The Open-VQE package extends therefore QLM to QC providing: (i) the functions to generate the different types of excitations beyond the commonly used UCCSD ans{\"a}tz;(ii) a new implementation of the "adaptive derivative assembled pseudo-Trotter method" (ADAPT-VQE), written in simple class structure python codes. Interoperability with other major quantum programming frameworks is ensured thanks to myQLM, which allows users to easily build their own code and execute it on existing QPUs. The combined Open-VQE/myQLM-Fermion quantum simulator facilitates the implementation, tests and developments of variational quantum algorithms towards choosing the best compromise to run QC computations on present quantum computers while offering the possibility to test large molecules. We provide extensive benchmarks for several molecules associated to qubit counts ranging from 4 up to 24.
... Liu and coworkers recently proposed an efficient algorithm to reduce the number of measurements from O(N 8 ) to O(N 4 ).
167
Vanishing the energy gradient to the cluster amplitude of each UCC operator is equivalent to satisfying the corresponding anti-Hermitian contracted Schrödinger equation (ACSE) when the wave function is real. However, when the wave function is complex, only the real part of ACSE is satisfied. ...
Quantum algorithms for electronic structures: basis sets and boundary conditions
The advantages of quantum computers are believed to significantly change the research paradigm of chemical and materials sciences, where computational characterization and theoretical design play an increasingly important role. It is especially desirable to solve the electronic structure problem, a central problem in chemistry and materials science, efficiently and accurately with well-designed quantum algorithms. Various quantum electronic-structure algorithms have been proposed in the literature. In this article, we briefly review recent progress in this direction with a special emphasis on the basis sets and boundary conditions. Compared to classical electronic structure calculations, there are new considerations in choosing a basis set in quantum algorithms. For example, the effect of the basis set on the circuit complexity is very important in quantum algorithm design. Electronic structure calculations should be performed with an appropriate boundary condition. Simply using a wave function ansatz designed for molecular systems in a material system with a periodic boundary condition may lead to significant errors. Artificial boundary conditions can be used to partition a large system into smaller fragments to save quantum resources. The basis sets and boundary conditions are expected to play a crucial role in electronic structure calculations on future quantum computers, especially for realistic systems.
... However, the tensor network structure of MERA is originally constructed to capture the quantum entanglement of a particular quantum state, e.g., in a one-dimensional critical system, and therefore it is not obvious at all and is probably not appropriate that the MERA-type quantum circuit can be applied to general problems. An alternative approach in this regard is a method such as adapted variational quantum eigensolver (ADAPT-VQE) [37][38]
[39]
[40][41], where an appropriate quantum circuit is automatically generated by selecting quantum gates sequentially among a predetermined set of quantum gates accordingly to a problem to be sloved. ...
Automatic quantum circuit encoding of a given arbitrary quantum state
| https://www.researchgate.net/publication/352798443_An_efficient_adaptive_variational_quantum_solver_of_the_Schrodinger_equation_based_on_reduced_density_matrices |
RCSB PDB - 3LZ1: Crystal Structure of Nucleosome Core Particle Composed of the Widom 601 DNA Sequence (orientation 2)
Crystal Structure of Nucleosome Core Particle Composed of the Widom 601 DNA Sequence (orientation 2)
3LZ1
Crystal Structure of Nucleosome Core Particle Composed of the Widom 601 DNA Sequence (orientation 2)
PDB DOI: https://doi.org/10.2210/pdb3LZ1/pdb
NDB: NA0476
Classification: STRUCTURAL PROTEIN/DNA
Organism(s): Xenopus laevis
Expression System: Escherichia coli
Mutation(s): No
Deposited: 2010-03-01 Released: 2010-09-15
Deposition Author(s): Vasudevan, D. , Chua, E.Y.D. , Davey, C.A.
Experimental Data Snapshot
Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.319
R-Value Work: 0.269
Literature
Crystal structures of nucleosome core particles containing the '601' strong positioning sequence
Vasudevan, D.
,
Chua, E.Y.
,
Davey, C.A.
(2010) J Mol Biol403: 1-10
PubMed : 20800598 Search on PubMed
DOI: https://doi.org/10.1016/j.jmb.2010.08.039
Primary Citation of Related Structures: 3LZ0 , 3LZ1
PubMed Abstract:
Nucleosome positioning plays a key role in genomic regulation by defining histone-DNA context and by modulating access to specific sites. Moreover, the histone-DNA register influences the double-helix structure, which in turn can affect the association of small molecules and protein factors ...
Nucleosome positioning plays a key role in genomic regulation by defining histone-DNA context and by modulating access to specific sites. Moreover, the histone-DNA register influences the double-helix structure, which in turn can affect the association of small molecules and protein factors. Analysis of genomic and synthetic DNA has revealed sequence motifs that direct nucleosome positioning in vitro; thus, establishing the basis for the DNA sequence dependence of positioning would shed light on the mechanics of the double helix and its contribution to chromatin structure in vivo. However, acquisition of well-diffracting nucleosome core particle (NCP) crystals is extremely dependent on the DNA fragment used for assembly, and all previous NCP crystal structures have been based on human α-satellite sequences. Here, we describe the crystal structures of Xenopus NCPs containing one of the strongest known histone octamer binding and positioning sequences, the so-called '601' DNA. Two distinct 145-bp 601 crystal forms display the same histone-DNA register, which coincides with the occurrence of DNA stretching-overtwisting in both halves of the particle around five double-helical turns from the nucleosome center, giving the DNA an 'effective length' of 147 bp. As we have found previously with stretching around two turns from the nucleosome center for a centromere-based sequence, the terminal stretching observed in the 601 constructs is associated with extreme kinking into the minor groove at purine-purine (pyrimidine-pyrimidine) dinucleotide steps. In other contexts, these step types display an overall nonflexible behavior, which raises the possibility that DNA stretching in the nucleosome or extreme distortions in general have unique sequence dependency characteristics. Our findings indicate that DNA stretching is an intrinsically predisposed site-specific property of the nucleosome and suggest how NCP crystal structures with diverse DNA sequences can be obtained.
Organizational Affiliation
:
Macromolecules
Proteins 4 Nucleic Acids / Hybrid 2
3D Structure
Entity ID: 1 Molecule Chains Sequence Length Organism Details Image Histone H3.2 A , E 135 Xenopus laevis Mutation(s) : 0 UniProt Find proteins for P84233 (Xenopus laevis) Explore P84233 Go to UniProtKB: P84233 Entity Groups Sequence Clusters 30% Identity 50% Identity 70% Identity 90% Identity 95% Identity 100% Identity UniProt Group P84233 Protein Feature View Expand Reference Sequence
Entity ID: 2 Molecule Chains Sequence Length Organism Details Image Histone H4 B , F 102 Xenopus laevis Mutation(s) : 0 UniProt Find proteins for P62799 (Xenopus laevis) Explore P62799 Go to UniProtKB: P62799 Entity Groups Sequence Clusters 30% Identity 50% Identity 70% Identity 90% Identity 95% Identity 100% Identity UniProt Group P62799 Protein Feature View Expand Reference Sequence
3D Structure
Entity ID: 3 Molecule Chains Sequence Length Organism Details Image Histone H2A C , G 119 Xenopus laevis Mutation(s) : 0 Gene Names: h2ac14.L , h2ac14 , hist1h2aj , hist1h2aj.L , LOC494591 UniProt Find proteins for Q6AZJ8 (Xenopus laevis) Explore Q6AZJ8 Go to UniProtKB: Q6AZJ8 Entity Groups Sequence Clusters 30% Identity 50% Identity 70% Identity 90% Identity 95% Identity 100% Identity UniProt Group Q6AZJ8 Protein Feature View Expand Reference Sequence
3D Structure
Entity ID: 4 Molecule Chains Sequence Length Organism Details Image Histone H2B 1.1 D , H 125 Xenopus laevis Mutation(s) : 0 UniProt Find proteins for P02281 (Xenopus laevis) Explore P02281 Go to UniProtKB: P02281 Entity Groups Sequence Clusters 30% Identity 50% Identity 70% Identity 90% Identity 95% Identity 100% Identity UniProt Group P02281 Protein Feature View Expand Reference Sequence
(by identity cutoff) |
3D Structure
Entity ID: 5 Molecule Chains Length Organism Image DNA (145-MER) I 145 N/A Protein Feature View Expand Reference Sequence
Find similar nucleic acids by:
100%
95%
90%
80%
70%
60%
50%
40%
30%
(by identity cutoff) |
3D Structure
Entity ID: 6 Molecule Chains Length Organism Image DNA (145-MER) J 145 N/A Protein Feature View Expand Reference Sequence
Small Molecules
Ligands 2 Unique ID Chains Name / Formula / InChI Key 2D Diagram 3D Interactions MN Query on MN Download Ideal Coordinates CCD File Download Instance Coordinates SDF format, chain K [auth A] SDF format, chain P [auth I] SDF format, chain Q [auth J] SDF format, chain N [auth I] SDF format, chain O [auth I] SDF format, chain R [auth J] MOL2 format, chain K [auth A] MOL2 format, chain P [auth I] MOL2 format, chain Q [auth J] MOL2 format, chain N [auth I] MOL2 format, chain O [auth I] MOL2 format, chain R [auth J] K [auth A], N [auth I], O [auth I], P [auth I], Q [auth J], K [auth A], N [auth I], O [auth I], P [auth I], Q [auth J], R [auth J] Less MANGANESE (II) ION Mn WAEMQWOKJMHJLA-UHFFFAOYSA-N Ligand Interaction CL Query on CL Download Ideal Coordinates CCD File Download Instance Coordinates SDF format, chain L [auth C] SDF format, chain M [auth G] MOL2 format, chain L [auth C] MOL2 format, chain M [auth G] L [auth C], M [auth G] CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M Ligand Interaction
Experimental Data & Validation
Experimental Data
Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.319
R-Value Work: 0.269
R-Value Observed: 0.270
Space Group: P 2 1 2 1 2 1
Unit Cell : Length ( Å ) Angle ( ˚ ) a = 107.37 α = 90 b = 109.66 β = 90 c = 175.75 γ = 90
Software Package:
Software Name Purpose SCALA data scaling REFMAC refinement PDB_EXTRACT data extraction MOSFLM data reduction PHASES phasing
Structure Validation
Entry History
Deposition Data
Released Date: 2010-09-15
Deposition Author(s):
Vasudevan, D.
,
Chua, E.Y.D.
,
Davey, C.A.
Revision History (Full details and data files)
Version 1.0: 2010-09-15 Type: Initial release
Version 1.1: 2011-07-13 Changes: Version format compliance
Version 1.2: 2012-11-14 Changes: Database references, Structure summary
RCSB Partners
RCSB PDB Core Operations are funded by
theNational Science Foundation(DBI-1832184),
theUS Department of Energy(DE-SC0019749),
and theNational Cancer Institute,National Institute of Allergy and Infectious Diseases,
andNational Institute of General Medical Sciencesof theNational Institutes of Healthunder grant R01GM133198.
| https://www.rcsb.org/structure/3LZ1 |
NPG D47724; Morning dress, summer 1837 - Portrait - National Portrait Gallery
Morning dress, summer 1837
1 portrait matching these criteria:
- subject matching 'Fashion Plates: Activities and occasions - Undress'
<here is a image 9948b2f5b6883ee1-67872ce3561ac6a4>
© National Portrait Gallery, London
Morning dress, summer 1837
published in Le Follet, Courrier des Salons, Journal des Modes
hand-coloured etching, line and stipple engraving, published circa August 1837
8 in. x 5 7/8 in. (202 mm x 150 mm) paper size
Acquired, 1930
Reference Collection
NPG D47724
Artist back to top
Le Follet, Courrier des Salons, Journal des Modes(1829-1892), French magazine. Artist or producer associated with 89 portraits.
This portrait back to top
Also published in The Lady's Magazine and Museum, September 1837, with a description:
Négligé du Matin. This very pretty plate has been designed from one of the négligé morning dresses of her Royal Highness the Duchess of Orleans; and we are persuaded that more than one of our fair subscribers will shortly appear in a similar dress. The material of which it is composed is batiste écrue (unbleached cambric), and its very light elegant trimming consists of a few rows of fine Italian straw plait (tresses de paille d'ltalie); see plate. The corsage and skirt of the négligé are cut all in one, except at the back, where one or two additional breadths are put in the skirt, and which would necessarily render the corsage too full at back. A plain and not very deep piece is put in at the top of the neck (see plate), to which the dress is attached in full gathers; on the shoulders it is confined by a shoulder-strap. The dress has double sleeves; the inner ones are plain and tight to the arm; the upper sleeve is à-la-Lucrèce Borgia, much in the style of the Venetian sleeve, and is taken up at the front of the arm with a small silk cord and tassel; the wrist of the inner sleeve is ornamented with a pointed cuff, buttoned at the top, and with three rows of straw trimming laid on; three rows of the same go down the front and round the bottom of the dress. In place of a pelerine is a small shawl of the material of the dress, with three rows of straw trimming all round, and a light silk fringe at the edge. The cordelière round the waist is likewise of silk. Drawn capote of cambric, the front not excessively large, and the crown precisely like that of an infant's bonnet (see plate). Hair brought low at the sides, and in ringlets. Black shoes, white kid gloves.
The capote on the table is of white tulle, and ornamented with a bouquet of hyacinths.
Portrait set back to top
Fashion plates, 1770-1869
Events of 1837
Current affairs
The controversial monarch William IV dies of pneumonia in June leaving no legitimate heirs, and is succeeded to the throne by his niece Victoria, one month after her eighteenth birthday.
The Registration Act of Births, Marriages and Deaths makes it compulsory for all births, marriages and deaths to be registered at a Registry Office.
Art and science
Dickens's second novel
Oliver Twist
is serialised in
Bentley's Magazine
. The story of the orphan Oliver is an attack on the Poor Law Amendment Acts (1834), a highly contentious piece of legislation which abolished outdoor relief, effectively increasing entry in the workhouse. The novel, famously made into a musical in 1968, marks Dickens as an outspoken social critic as well as a highly popular and commercial writer.
International
The Russian poet Aleksandr Pushkin is killed in a duel with Baron Georges d'Anthès. Considered the founder of modern Russian literature, Pushkin blended Old Slavonic with vernacular Russian and was the first Russian writer to use everyday speech in his poetry. His works include
Eugene Onegin
.
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Chahaj Branch Post Office, Gangolihat 22, Pithoragarh, Uttarakhand
Chahaj Post Office, Gangolihat
Chahaj post office is located at Chahaj, Gangolihat, Pithoragarh of Uttarakhand 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 Chahaj PO is262522. This Postoffice falls under Pithoragarh postal division of the Uttarakhand postal circle. The related head P.O. for this branch office is Pithoragarh head post office and the related sub-post office (S.O.) for this branch office is Gangolihat post office.
Chahaj 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 Chahaj.
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. Chahaj 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
Chahaj Post Office & Its Pin Code
Branch Office Information
Chahaj 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
Chahaj Post Office Recruitment
Location Map
Contact Details
About India Post
Chahaj Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Chahaj Post Office has the Postal Index Number or Pin Code 262522. 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 Chahaj PO Pincode 262 522
The first digit of 262522 Pin Code '2' represents the region, to which this Post Office of Chahaj belongs to. The first two digits of the Pin Code '26' represent the sub region, i.e, Uttarakhand. The first 3 digits '262' represent the post-office revenue district, i.e, Pithoragarh. The last 3 digits, i.e, '522' represent the Chahaj Delivery Branch Office.
Branch Office Information
The Chahaj 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 Pithoragarh, which falls under Dehradun region. The circle name for this PO is Uttarakhand and it falls under Gangolihat Taluka and Pithoragarh District. The state in which this Dakghar is situated or located is Uttarakhand. The related head postoffice is Pithoragarh post office and the related sub post office is Gangolihat post-office. The phone number of Chahaj post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Pithoragarh Postal Region Dehradun Postal Circle Uttarakhand Town / City / Tehsil / Taluka / Mandal Gangolihat District Pithoragarh State Uttarakhand Related Sub PO Gangolihat Sub Office Related Head PO Pithoragarh Head Post Office
Chahaj Post Office Services
Traditionally the primary function of Chahaj 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 Chahaj 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 Chahaj and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Chahaj 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 Chahaj 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 Chahaj peoples and nearby living people. The premium services provided by Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Chahaj 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 Chahaj 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 Chahaj 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 Chahaj 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 Chahaj Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Chahaj 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 Chahaj 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 Chahaj 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
Chahaj Post Office Recruitment
For latest Chahaj post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Chahaj Branch Post Office is located in Chahaj, Gangolihat, Pithoragarh.
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 Chahaj Post Office, can be resolved at Chahaj Branch Post Office. You can send letters to "Postmaster, Chahaj Branch Post Office, Chahaj, Gangolihat, Pithoragarh, Uttarakhand, India, Pincode: 262 522". The official website of the Berhampur University Sub Office is www.indiapost.gov.in.
Chahaj Branch Office
Address: Chahaj Branch Post Office, Chahaj, Gangolihat, Pithoragarh, Uttarakhand, India
Pin Code: 262522
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.
Chahaj Post Office Summary
Dak Ghar Name Chahaj Branch Post Office Pincode 262522 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Pithoragarh Postal Region Dehradun Postal Circle Uttarakhand Location Chahaj Town / City / Tehsil / Taluka / Mandal Gangolihat District Pithoragarh State Uttarakhand Country India Related Sub Office Gangolihat Sub Office Related Head Office Pithoragarh 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
Chaurpal Post Office
| https://www.postoffices.co.in/uttarakhand-uk-ut/chahaj-gangolihat-22-pithoragarh/amp/ |
Leaving out the ugly part - Hakim Bey/Peter Lamborn Wilson | libcom.org
This article is an exposé of Hakim Bey, aka Peter Lamborn Wilson's paedophilia. A fact which many commentators conveniently brush under the carpet.
Leaving out the ugly part - Hakim Bey/Peter Lamborn Wilson
Hakim Bey/Peter Lamborn Wilson
This article is an exposé of Hakim Bey, aka Peter Lamborn Wilson's paedophilia. A fact which many commentators conveniently brush under the carpet.
The Brooklyn Rail (July-August 2004) has just published an interview of Peter Lamborn Wilson (Hakim Bey), that gives the reader a misleading and incomplete picture of the subject. The interview was then forwarded to the Research on Anarchism list-serve. "Wilson rightly became celebrated as a kind of urban prophet," the interviewer writes, "It was an identity to add the others he bears seamlessly and without contradiction: anarchist, poet, public intellectual, psychedelic explorer, artist, social critic, Sufi mystic."
The interviewer's special phrasing, "seamlessly and without contradiction," is where she begins, unintentionally, to mislead. I am writing to describe another unusual way in which Mr. Wilson has distinguished himself that may make a wrinkle or two in the average person's opinion: he is a public paedophile intellectual of international reputation, and one who mixes anarchist ideology into his paedophile discourse. Even though we're talking about a writer whose work has now been translated into French, Russian, German, Dutch, and other languages, I should like to emphasise that there is no reason why the interviewer should have already known this. The Rail's pages, however, have presented him as entirely respectable thinker, and I am writing to correct that mistake.
Peter Lamborn Wilson (who writes at least as often as Hakim Bey and makes no secret of the pseudonym), uses anarchism in an ethically warped, opportunistic way by pretending that adult-child sex is a natural freedom. It isn't, and not only would almost any anarchist disagree with him, but they'd also dispute a child-rapist's right to a non-violent remedy in many cases. As a person who is and always is, in both public and private life, as an anarchist, I feel the responsibility to simply put my disagreement on record. I do so now because the forwarding of the Rail interview creates an error of omission on the r-a list.
There is a periodical, preserved at the University of Michigan's famous Labadie Collection, that seems to make an unlikely fit with the purpose of that special archive, which is to preserve anarchist materials in particular, as well as those of other social movements, including sexual freedom and gay liberation. It is the NAMBLA Bulletin, which has been published monthly since 1983 by the North American Man-Boy Love Association. "Man-boy Love" is a term used by apologists of paedophilia. I hereafter use the term paedophilia where such people would object to its use. But why was a paedophile magazine acquired by an archive with such a charter? Most people would argue that "Man-Boy Love" is not an issue relating to gay culture at all, since paedophilia occurs no more or less frequently among gays than it does with straights. Very few people of any politics consider adult-child sex to be a legitimate lifestyle choice. But the former curator who added NAMBLA Bulletin to the Labadie was actually keeping to the central mission of the anarchist archive when he subscribed to the journal.
Beginning with the July-August 1985 issue, the magazine carried a long series of items by Hakim Bey, who was already a distinctly anarchist writer. Most of them were discussions of the paedophile obsession with a clear anarchist slant. Anarchist ideology was the mode of justification, the method of persuading children to have sex and to keep it secret. Take for example the following poem, "My Political Beliefs," from NAMBLA Bulletin's June 1986 issue, page 14:
barelegged on his bicycle in the park he rides beneatha children's fountain droplets catch his hair whichthe afternoon makes somewhat bronze, beaded with molten dew--the sunset over Jersey like an industrial krakatoa:Newark Gold, Secaucus Red, East Orange.The button on his blazer: Anarchist Bicyclistshe's in the bathtub, I seehim through a crack in the door playing with himself, he calls me in, shows meunderwater push-ups and sit-ups, except for his gallic buttocks his skin is gilt as the air over the Hudson. The touch of his wet, bath-wrinkled fingers in my hand... but then...one of his parents clumps down the hall... I suppose to make sure neither of us is raping the other...[chorus of groans] Ohhh! for aBuster-Keaton-bomb all spherical & black as coaldust with sweet sparkling with sweet sparkling fuse a mindbomb toDrop on the Idea of the Family! O for a libertarian isle of runaways! O goodnightMoon, I am lost, actually lost without himBut I didn't want this to beJust another poem about hopeless love. Pretend it's a manifesto instead. Down with School! Boy Rule OK! In the land of dreamsNo governance existsBut that of anarchs and kings, for dreamers have not yet learned to vote or think past the unfurling of the moment. He touches my cheek, runs delicate fingers through the hairs on my arm.My liege shatters all Law for a triple kiss.--Hakim Bey
Many of Hakim Bey's best-known anarchist pitches first saw print as paedophile apologies. NAMBLA published his "Association for Ontological Anarchism, communiqué #2" in July-Aug 1986, and a journal called Gayme ran "A Temporary Autonomous Zone" and "Pirate Utopias" in issues of 1993-95, along with his more obscure "Contemplation of the Unbearded."
Bey's best-known book Temporary Autonomous Zone (TAZ) describes spiritual zones in which anything goes, where the oppressive rules of the outside society need not interfere with what feels good to do. I realise that many honest people have read TAZ without taking any sleazy impression from it. I hope they'll forgive me for pointing out that paedophiles say these same things to children. In his essay "Obsessive Love" (Moorish Science Monitor, Vol. 7, #5, Summer 1995), in which he pretends to be quite the classical scholar, he talks about ancient religious views on romantic and obsessive love. "The Greco-Egypto-Islamic ferment adds a pederastic [i.e. paedophile] element... the ideal woman of romance is neither wife nor concubine but someone in the forbidden category..." He uses the term "spiritual alchemy" for witnessing the "Devine Beloved in certain beautiful boys," and remarks that, "since all homosexuality is forbidden in Islamic law, a boy-loving sufi has no 'safe' category for sensual realisation."
In fact, one of the commonest defence lawyerish lines about paedophilia is how "the Greeks did it," or how incredibly well Michael Jackson sings and dances; or how some long-dead and noteworthy author was also was in the habit of boning the baby. These are feeble and irrelevant ways to side-step the ethical issue. Knowledge is power, and children know almost nothing. But just so we go through the points, it was a minority of rich Athenian Greeks during the Classical period, not all "the Greeks," who accepted paedophilia, while, by the way, they were also proclaiming their misogyny in rhetorically gorgeous ways. Athens was a slave-owning society in which democracy was observed only between citizens not between everyone --and the use of slaves as sexual chattel carried no age-restrictions. Furthermore, in no way should artistic talent cause one to be forgiven a sexual abuse or rape. In fact, when a paedophile is very witty and well-spoken, this very same skill is used to attract young, gullible targets. To argue for paedophilia is imbecile when it is sincere. It is so logically pathetic, in fact, that one almost needs to be a child to believe that it's sincere.Pressing the anarcho-paedophile cause in another way, Wilson (Bey) reviewed the reprint of the late 19th century German-based anarchist John Henry Mackay's book Fenny Skaller and Other Poems, etc.. Bey's essay was entitled " Man-Boy Love Novel Still Relevant 100 Years On." (NAMBLA Bulletin April 1989). In "Obsessive Love," Bey again invokes Mackay (1864-1933), whose paedophilia was never known to other anarchist writers during his life: "I admit to a philosophical preference for Mackay's position..." [which means the] " giving up of all false chivalry and self-denying dandyism in favour of more 'pagan' and convivial modes of love." He closes the essay with his clearest anarcho-paedophile statement: "it has taken on a tantalising reality and filtered into my life in certain Temporary Autonomous Zones an impossible time and space and on this brief hint, all my theory is based." What he means by this is that he really has sex with children, rather than leaving the matter to fantasy, and that this is his purpose when he preaches anarchism.
Hakim Bey is the pseudonym for 59-year old Peter Lamborn Wilson, who has been based in New York City for most of his life, but is now living upstate in New Paltz. The Brooklyn Rail's interviewer, has this mistakenly reversed, giving Bey as the original name, Wilson as the pseudonym. The guy was born a WASP, and perhaps became Sufi one day while prowling the mountains of Asia. He has no occupation, and in 1994 told an interviewer (Voice Literary Supplement, New York, Feb. 1994) that he "thanks God that a trickle of family money keeps him 'independently poor.'"[1] The name Lamborn is rare in New York, and it is where the Sugar industry magnate Ody Lamborn died in 1971. It's been my impression that Hakim Bey's trust fund was originally earned by tormented labourers on sugar plantations. Whether it's from sugar or from something else, this brings us to Wilson's touching concern, about what he called "a class war situation" in the Rail interview : "Where's our support for the Mexican migrant agricultural workers?"
I have operated dangerous machinery in factories, carried lumber up flights of stairs, and I have (like most anarchists) done other boring, low-paid jobs to feed myself, starting around age thirteen. Still, I have known several anarchists who come from wealthy families, and I've thought well of them because they make the choice to use their privilege (freedom allowed by their trust fund) in good faith; perhaps to heal wounds made earlier by their own relatives. But Peter Lamborn Wilson gives me an unquiet feeling when he pretends to understand and hold concern in his heart for that other world, where he's never paid a visit, and where people work because they must work. It has the very phoney ring of someone pouring syrup into a liberal ear.
His use of his word-skills, of course, has me feeling still worse. As he conjoins his paedophile mission with anarchism, he knows very well that anarchism is now very popular among the very young. This is not "spiritual anarchism," as he entitled a public "Chaos Day" lecture in December of 2002. It is paedophile opportunism. Another device he uses a lot is exemplified in "Tectum Theatrum" (Fifth Estate, Summer 2003), in which he uses Latin phrases over and over, never to say something there's no English word for, but to impress the utterly naive reader. Having read Classical languages in college, this is especially tedious and transparent to me, but it certainly will have its desired effect on adolescent readers.
While he has no occupation, Bey/Wilson has not been idle. In Fifth Estate #363, just this past winter, he relates how, when he was in his mid-twenties, he was wandering around Persia and South Asia, smoking opium and "looking for traditional anarchism" in Sufism. Under his pseudonym (Bey), he's found some paedophile culture over in that region as well. His translation of Abu Nuwas' poetry, O Tribe That Loves Boys was published in Amsterdam in 1993.
When he was about thirty, Bey founded the Semiotext(e)-Autonomedia Publishing group in New York. It has since become one of the larger of the US-based anarchist publishers, and Bey remains with the group, which carries several of his titles. An early release was Loving Boys: Semiotext(e) Special (1980), edited by Bey. Thus he's been on this crusade, in print, for at least twenty-five years. For some time, he had a program on WBAI Radio, entitled "The Moorish Orthodox Radio Crusade."
In the letters column of Anarchy: A Journal of Desire Armed (#20/21, Nov-Dec 1989, p. 42), a letter announced a new a zine for contributors 17 and under. Wild Children, as the zine was called, solicited articles on "anarchy (of course!), sci-fi, sexuality & love, spiritual paths (or lack thereof), and anything else kids would like to submit." The letter gave Hakim Bey as the editor, at a Brooklyn PO Box. Lev Chernyi, the editor of Anarchy[2] replied that "Wild Children sounds like an interesting idea. I hope it works out. Any young readers interested?" In 1998, a 64-page anthology of this zine was published, switching over to the name Wilson as editor.[3] While the anthology is not considered a paedophile text and is carried by some anarchist bookstores without concern, it should be noted that its contents were solicited by a public anarchist-paedophile apologist during the same years (1993-1997) when he was contributing pieces of clearly anarchist-paedophile intent to the magazine Gayme, which was a bit more strident than other child-molester periodicals, and was once the target of a public prosecutor in Massachussetts. Due to legal issues relating to the its contents, in fact, the Canadian Lesbian and Gay Archives in Toronto preserves the title but will not allow scanning or copying of its pages. I have been unable to locate original copies of the zine Wild Children, but in yet another NAMBLA publication, its Journal (#7; 1986), the age "ten-and-a-half" occurs as the age of a boy in a sketch by Bey. In typical paedo-style, everything is pushed to where he can't go farther without the expectation of some angry person attacking him. But Bey takes things to the next step by using a name by which he (Peter Wilson) is actually identified. He's safe in doing so because of the extreme toleration of anarchists in general, and the shallowness of many.
Paedophilia is not the only opinion for which Hakim Bey has irritated other anarchists. One example is his views on abortion. In "Communique #9" of the Association for Ontological Anarchy, Bey wrote: "According to Chaos Theory, it does not follow that we are obliged to like or approve of murder or abortion. Chaos would enjoy seeing every bastard love-child carried to term & birthed; sperm & egg alone are merely lovely secretions, but combined as DNA they become potential consciousness, negentropy, joy... If 'meat is murder!' as the Vegans like to claim, what pray tell is abortion?"
I will not offer any reason to be offended by the paedophile literature or the misogynist position of Hakim Bey as quoted above. The ethical idiocy of both are self-evident, and neither is part of anything that should be considered an anarchist idea. I am not surprised that these opinions exist, but I am most uncomfortable for realising that there is a discreet haven for both within the anarchist culture of the United States. It makes me wonder, in fact: why did the world-wide Catholic Church sex abuse scandal go by a few years ago, without any commentary from American anarchists? Is this another dirty little anarchist secret?
As for what I mean by a "dirty little anarchist secret," here's another example: when about 7,000 priests were killed, many Catholic churches burned, and many saintly cadavers mockingly defiled at the beginning of the Spanish Revolution of 1936, it was in pretty bad taste, but there were very logical and fair reasons for people (including a huge number of anarchists) to take their anti-clerical rage into action. Many anarchists have denied that any of this happened, saying that it was all just fascist propaganda, or that it's been wildly exaggerated. Actually, there is plenty of hard evidence that it did happen. Rather than a bizarre, revisionist denial, I would rather hear us say that the current craze for anarchist soccer-teams has its roots in Spain (Madrid, I believe), where teenagers played football with the skull of a saint, out in the plaza in front of the church named after him. Why don't we just talk about it? Why can't we talk about a fairly well-known anarchist author as the paedophile personality that he most certainly is? What's the point of calling oneself "anarchist" if there's some area of discussion where it's too disturbing to ever step?
More directly intriguing to me is why I have been shut out of letters columns or declined for print in anarchist periodicals on about twenty occasions (and again now, in the Brooklyn Rail) when I cite the articles, name the issue, and express my disapproval for a man who presents child molestation as a point of anarchistic freedom. The reasons given by editors vary widely. Some reactions are hostile, taken very personally. Other cases express appreciation and some concern for the information. Certain editors have written so much thick, loving praise for Bey, and printed so much of his work that they find themselves cornered when the paedophilia item is raised. They have no sympathy for child-molestation but they frantically search for paths by which they can stay clear of its discussion, perhaps fearing that somehow, the stink of it would cling to them and their publication. They'll sometimes argue that it's unfair to link the person with the person's writings. I point to these editors, as I have here, that it's in the writings that all this is happening, with the less bold examples sometimes drooling out in their own anarchist pages.
In the present case, the writer who interviewed Lamborn Wilson recently at his green wood-frame house in New Paltz was glad to have been informed, and there was a short, respectful exchange between us. But the editors of the Rail merely tossed off a form letter: "Thank you for your input..." There was no evidence of any sort of concern, nor admission that the interview made a completely skewed impression of its subject, no hint that editors have an ethical responsibility for what they put on their pages.
Worse still is for there to be no reply, not even a private note. I was particularly disgusted by Andrei Codrescu, the (obviously anarchist) National Public Radio commentator who gave "TAZ and the Tazzerites" a glowing ten minutes of his voice on All Things Considered in July of 2003. I very respectfully wrote him about these concerns, then I confirmed that he'd received my letter, but I received no reply at all. The obvious message is that it's beneath Codrescu's consideration to acknowledge in a ten-second message - Yes the paedo-stuff is a drag but I like his other writings, sorry but I disagree or whatever he thinks. He means that Hakim Bey's 25 or more years as a public intellectual of anarchist paedophilia is not any problem for him when he tells seventy million people what cool stuff the guy writes, without reference to the paedophile origin and undercurrent of TAZ, the same item he recommended.
No one anywhere denies that Peter Lamborn Wilson (Hakim Bey) is paedophile, least of all the man himself. I state what I see on his pages, I offer my opinions as opinions only, and I make no accusation of criminal conduct. The citations are right there, for anyone to check for accuracy. Endlessly, anarchists have privately agreed that I am absolutely right, on-the-money correct, about this issue. The number who have written that opinion down where anyone else can read it is very close to zero. I am left with the impression that they are not taking responsibility for what they know. This does not speak well of the anarchists of the United States. I feel that with anarchism becoming ever more popular, the greater portion of new anarchists are just consumers of anarchist stuff. Since such people can't deal with a new ethical problem, they probably would not know what to do with that new, real revolutionary opportunity for which they pine so passionately.
The fact that a widely celebrated, living anarchist writer has smeared the anarchist tradition with a sugar-coated image of paedophilia is an issue that will continue to be raised. I feel that this is fair and relevant because I keep spotting distorted presentations of Hakim Bey and his motives, as in this last issue of the Brooklyn Rail.
FootnotesAnyone who wants a copy of the Hakim Bey paedophile bibliography (a work in progress) should just ask, and the author will email it to you.1. Erik Davis, interviewer,"The Wandering Sufi: Itroduction to the Mystic with Peter Lamborn Wilson," Voice Literary Supplement, New York, February 19942. The same editor sometimes uses the name Jason McQuinn.3. Wild Children: A Zine For Kids. New York, Scb Publishers, 1998. Peter Lamborn Wilson (Editor) and Dave Mandl (Editor).
Taken fromThe Research on Anarchism List (RA-L), which is an international forum which was started on January 1, 1996, and is devoted to book reviews, research and discussion of the theories, histories and cultures of world anarchist movements and to other topics related to anarchism.
Best of the worst
Hakim Bey
Robert Elms
Beywatch
Bibliography
Books & ArticlesWilson, Peter Lamborn. Kings of Love: The Poetry and History of the Nimatullahi Sufi Order of Iran (with Nasrollah Pourjavady), Tehran 1978._____, Angels, Thames & Hudson, London 1980._____, Weaver of Tales. Persian Picture Rugs (with Karl Schlamminger), Callwey, Munich 1980._____, The Drunken Universe. An Anthology of Persian Sufi Poetry (with Nasrollah Pourjavady), Phanes Press, Grand Rapids 1987._____, Scandal. Essays in Islamic Heresy, Autonomedia, Brooklyn, NY 1988._____, Radio Sermonettes (with the Moorish Orthodox Radio Crusade Collective), The Libertarian Book Club, New York 1992. Reprinted as Immediatism, AK Press, Edinburgh/San Francisco 1994._____, Sacred Drift. Essays on the Margins of Islam, City Lights Books, San Francisco 1993._____, Pirate Utopias. Moorish Corsairs & European Renegadoes, Autonomedia, Brooklyn, NY 1995._____, "Shower of Stars" Dream & Book: The Initiatic Dream in Sufism and Taoism, Autonomedia, Brooklyn, NY 1996._____, Escape From the 19th Century. Essays on Marx, Fourier, Proudhon & Nietzsche, Autonomedia, Brooklyn, NY 1998._____, Ploughing the Clouds: The Search for Irish Soma, City Lights Books, San Francisco 1999._____, “Sakhra-l'Assal Interviews Peter Lamborn Wilson” [in Dutch] in Buiten de Orde, Utrecht, vol. 13 # 1, March, 2002. (“Sakhra -l'Assal is independently unemployed. As a member of the Amsterdam collective for applied schizophrenics, ZZ Produkties, he was involved with translations of work by Peter Lamborn Wilson and Hakim Bey, among others. He spends his spare time drinking beer.”)_____, (editor with Robert Anton Wilson) Semiotext(e) Science Fiction Anthology (Semiotext(e) n.d.)Bey, Hakim. TAZ, The Temporary Autonomous Zone, Ontological Anarchy, Poetic Terrorism (Brooklyn, NY: Autonomedia, 1991)_____, (contributor) Poems of Love and Liberation (New York: NAMBLA, 1996)Articles in the NAMBLA Bulletin[NAMBLA Bulletin is published by the North American Man-Boy Love Association. This is a partial list of Bey’s articles for the magazine. Original copies were examined by me at the Special Collections Department, University of Michigan at Ann Arbor (United States).]
Bey, Hakim. "Japanese Scarf" (poem, reprinted from Seditious Delicious) NAMBLA Bulletin, Jul-Aug 1985_____, "Poem" NAMBLA Bulletin, Jan-Feb 1986_____, "Five Conceptual Art Projects" NAMBLA Bulletin, Apr. 1986_____, "My Political Beliefs" NAMBLA Bulletin, June 1986._____, "Association for Ontological Anarchism, Communique #2." NAMBLA Bulletin, Jul-Aug 1986_____, "The Face of God" NAMBLA Bulletin, Dec. 1986_____, "The Eroticism of Banal Architecture" NAMBLA Bulletin, Jan-Feb 1987_____, "Chaos Theory and the Nuclear Family" NAMBLA Bulletin, Mar. 1987_____, "China Sea Post-Card" NAMBLA Bulletin, Mar. 1987_____, "Divine Folly Indulges Pagan Passion" NAMBLA Bulletin, Nov. 1987
Articles in Gayme[This is a partial list of Bey’s articles for the magazine. Further citations are difficult to gather due to legal issues relating to its contents (Gayme was involved in obscenity lawsuits). The Canadian Lesbian and Gay Archives at Toronto preserves the title but will not allow scanning or copying of its pages.]
Bey, Hakim. "Contemplation of the unbearded." Gayme vol.1, no.1, 1993, pp. 16-21._____, "Temporary Autonomous Zone." Gayme vol.2, no.1, 1994, pp. 26-28_____, "Pirate Utopias." Gayme vol.2, no.2, 1995, pp. 20-23_____, "What do we do now?" Gayme vol.3, no.1, 1996, pp. 8-11_____, "The music of what happens." Gayme vol.3, no.2, 1997, pp. 6-9
TranslationsBey, Hakim. O Tribe That Loves Boys: The Poetry of Abu Nuwas [translation and biographical essay by Hakim Bey] (Amsterdam: Entimos Press, 1993)
Reviews:Bey, Hakim, "Boy-Love Novel Still Relevant 100 Years On" [a review of Fenny Skaller and Other Poems from the Books of the Nameless Love by the German anarchist John Henry Mackay] NAMBLA Bulletin, Apr. 1989
_____, "Japanese Romance on The House of Kanze by Noboku Albery"NAMBLA Bulletin, Apr.-May 1987
Editorship:Bey, Hakim (editor) Loving Boys: Semiotext(e) Special. New York: Semiotext(e), 1980
Press Exposure:Program 33 (production group of Paris), program title : "Tracks," segment title : "Pirates," broadcast on ARTE TV network, October 28 and 30, 2004 ; [also transmitted in German?]
Davis, Erik (interviewer),“The Wandering Sufi: Introduction to the Mystic with Peter Lamborn Wilson,” Voice Literary Supplement, New York, February 1994
Sample text
My Political Beliefsby Hakim BeyThis appeared in NAMBLA Bulletin, June 1986, page 14 (published by the North American Man-boy Love Association).
barelegged on his bicycle in the park he rides beneatha children's fountain -droplets catch his hair whichthe afternoon makes somewhat bronze, beaded with molten dew--the sunset over Jersey like an industrial krakatoa:Newark Gold, Secaucus Red, East Orange.The button on his blazer: Anarchist Bicyclistshe's in the bathtub, I seehim through a crack in the door playing with himself, he calls me in, shows meunderwater push-ups and sit-ups, except for his gallic buttocks his skin is gilt as the air over the Hudson. The touch of his wet, bath-wrinkled fingers in my hand... but then...one of his parents clumps down the hall... I suppose to make sure neither of us is raping the other...[chorus of groans] Ohhh! for aBuster-Keaton-bomb all spherical & black as coaldust with sweet sparkling with sweet sparkling fuse -a mindbomb toDrop on the Idea of the Family! O for a libertarian isle of runaways! O goodnightMoon, I am lost, actually lost without himBut I didn't want this to beJust another poem about hopeless love. Pretend it's a manifesto instead. Down with School! Boy Rule OK! In the land of dreamsNo governance existsBut that of anarchs and kings, for dreamers have not yet learned to vote or think past the unfurling of the moment. He touches my cheek, runs delicate fingers through the hairs on my arm.My liege shatters all Law for a triple kiss.--Hakim Bey
"John Henry Mackay (6 February 1864 – 16 May 1933) was an individualist anarchist, thinker and writer. Born in Scotland and raised in Germany, Mackay was the author of Die Anarchisten (The Anarchists) (1891) and Der Freiheitsucher (The Searcher for Freedom) (1921). Mackay was published in the United States in his friend Benjamin Tucker's magazine, Liberty"
"Using the pseudonym Sagitta, Mackay wrote a series of works for pederastic emancipation, titled Die Bücher der namenlosen Liebe (Books of the Nameless Love). This series was conceived in 1905 and completed in 1913 and included the Fenny Skaller, a story of a pederast. Under his real name he also published fiction, such as Der Schwimmer (1901) and, again as Sagitta, he published a pederastic novel of the Berlin boy-bars, Der Puppenjunge (The Hustler) (1926)."
PLW-Hakim Bey's pederastic literary output seems a mere pebble, next to the life-long avalanche of pro-pedophile propaganda which Mackay was responsible for. Would you ban this rather formative Anarchist's writings, also?
On the other hand, I believe that PLW's accounts of his early life are at least 50% fiction. I can't find any documentation for a Peter L Wilson born & raised when and where he claims, nor can I find any independent confirmations of his alleged wandering around southeast asia and the middle east. I don't believe he was born "Peter Lamborn Wilson".
There was a school teacher who lived in New Jersey in the early 1970s, who had an intense interest in libertarian anarchist philosophy, and was involved in a large scale child pornography & prostitution conspiracy. When this person vanished, in 1975, he was a wanted fugitive accused of participating in the abuse of a 10 year old boy. There are startling parallels between this person and PLW-Hakim Bey, including very unique personal interests (far more unique than simply being "pro-pedophile").
No.
PLW-Hakim Bey's pederastic literary output seems a mere pebble, next to the life-long avalanche of pro-pedophile propaganda which Mackay was responsible for. Would you ban this rather formative Anarchist's writings, also?
Maybe, unless they had some sort of value that could be wholly separated from his promotion of pederasty. As best I can tell, Bey's don't.
(Incidentally, I'm not sure what you mean by "ban", unless it's a rather confusing way of saying "reject" or "want nothing to do with". It's not like gangs of anarchists are going off burning copies of The Daily Nonce or summat...)
@jonthom -In one of the many threads, here, devoted to PLW-Hakim Bey, there was some talk of asking anarchist booksellers not to stock PLW-Bey' writings and - should they decline to co-operate - removing the books by theft or force anyway. [I would be opposed to that, simply because it would be censorship of the written word].
If you've never heard of Mackay, you might be interested in a little research on the "Free Love" movement, circa 1850-1945, especially the late 1800s & early 1900s. Here's an interesting introduction:http://www.ncc-1776.org/tle1996/le961210.html
Most Free Love advocates of that time were concerned to "get the state out of our bedrooms", in the context of consenting heterosexual relations between adults, decriminalization of birth control & abortion especially - but the movement included advocates for decriminalizing adult gay & lesbian relations, heterosexual relations between adults and adolescents, and pederasts such as Mackay advocating decriminalized relations between men and boys. [Pederasts are not the same phenomenon as Gay Men, a fact that was recognized even back in the 1800s!]
There should be no doubt, that a longing for 'sexual liberation' contributed substantially to popular support for the various radical movements of the 1800s & 1900s in Western European nations & North America (such as there was).
As for PLW-Hakim Bey...I DON'T WANT my suspicions about him, [far more than suspicions, unfortunately], to be correct. That would be a propaganda disaster for several communities of persons that I like & have respect for. One reason why I have not been more direct, why I don't just name the person I believe PLW once was, is that I keep hoping someone will dig up verifiable data proving to me that I'm full of sh*t on this matter. I'd LOVE that to happen.However, as that continues to NOT happen, I feel a responsibility to at least leave a trail in some public forum through which others could reconstruct my own research, so that I won't take this info to my grave if I were to kick the bucket in the near future. [I'm in the latter stage of my life]
How does dealing with the pedageddon operate in a libcom society? Are pitchforks allowed or does that belong to an outmoded form of production?
Fleur
but I think sometimes in history, past or present, when yeah, there's adult-child sensuality and no one gives a big fuck. It happens.
Will you please, kindly, just fuck off and die.
Signed by me, a childhood sexual abuse survivor.
I'm very sorry to hear that, Fleur :(
| https://libcom.org/comment/623489 |
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Doan, A Dodds, W Dokulil, MT Dokulil, Martin T. Domaizon, I Domaizon, I. Domis, LNS Domis, de Senerpont Domis, L.N. De Senerpo Domis, Lisette N. de Sene Domis, Lisette N. Senerpo Dong, Bo Donk, E V Dossena, M Doubek, J.P. Doubek, J.P. Doubek, K. Downing, AS Downing, Andrea S. Doyle, B. Doyle, Chris DP, Hamilton Drakare, S Duffy, C. Dugan, Hilary A. Dugan, Hilary Dugan, H. Dugan, H.A. Dugan, H. A. Dugan, H.A. Dunalska, Julita Dunalska, J Dunalska, JA Dunalska, Julita A. Dur, G. Dwulit-Smith, Jeffrey E, de Eyto E., Mantzouki Eakins, J Eckert, W. Effler, SW Eiler, Alexander Elias, Eliane C Elliott, A. Elliott, Alex Elliott, JA Elosegi, A. Engel, F Engel, F. Erina, O. Erm, A Escobar, J. Escobar, Jaime Escot, C. Evans, CD Everhart, JC Evrendilek, F. Ewing, HA Eyto, E Fakhraee, Mojtaba Fang, X Fang, X Farrell, K.J. Farrell, K.J. Fastner, J. Fatima, Uroosa Favot, Elizbaeth J. Fedorova, I. Feijoó, C. Feldbauer, Johannes Feldmann, Tõnu Feng, L Ferreira, TF Ferrer, NC Feuchtmayr, H. Feuchtmayr, H. Fey, Samuel B. Fey, S B Field, T Fierer, N Filstrup, C T Finlayson, C. M. Fischer, H Fischer, JM Fitchett, L. Flaim, G Flaim, Giovanna Flaim, G. Flaim, Giovanna Flindt, MR Folkard, A.M. Font, Raquel Arias Forest, Katrina T Fornerón, C. F. Forsberg, Philip Foulquier, Arnaud Fountain, T Fragoso, CR Fram, JP Frank, Eibe Frankenberg, C. Fránková, Markéta Frassl, M. A. Frassl, Marieke A. Frassl, M.A. Free, G Froula, Jeff Fu, C Funk, C G, Gal G, Flaim GA, Weyhenmeyer GA., Weyhenmeyer Gaeta, JW Gagliardi, Laura M Gaiser, E Gal, Gideon Gallina, Nicole Gao, G Garcia, F.C. Garcia, Sarahi L. Garcia, Sarahi L Gasol, J M GB, Arhonditsis George, A George, P Gerling, A.B. Gerten, D Gessner, MO Ghylin, Trevor W Gianuca, A. T Gilboa, Yael Giling, D.P. Gilmer, Alan Ginter, Kai Ginter, K Gionchetta, Giulia Girard, R Giuliani, M Gómez, R. Gómez, Rosa Gomez-Gener, L. Gómez-Gener, Lluís Gómiak, D Gomułka, Piotr Gonçalves, M.A. Goring, S Gorzalski, A Gougis, Darner R. Gray, Derek K. Gries, C. 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Hetherington, Amy L. Hetherington, A.L. Higgins, SN Higgins, Scott N. Hintze, Thomas Hipsey, Matthew R Hipsey, M. Hipsey, M.R. Hipsey, Matt R Hipsey, Matthew R. Hobbie, JE Hodges, B R Hoen, J Hoffman, EP Hogan, PJ Holtgrieve Hong, G S Honti, M Honti, M. Honti, M. Honti, Mark Hook, Simon Hook, S. Hori, Yukari Hori, Yukari Horrison, K.A. Hout, Y. Houtari, J. Howard-Williams, Clive Howe, Eric A. Howitt, J. A. Hoyos, N Hoyos, Natalia HP., Grossart Hsieh, Y Hu, Y-H Huamantinco Cisneros Huang, Lei Huang, W Huber, V Huot, Y. Huotari, J Huttula, T Huttula, T. Ibelings, Bas W. Ibelings, BW Ibelings, B.W. Ibelings, Bas W Idrizaj, Agron Imberger, J. Ingram, R Isles, Peter Isles, P.D.F. Istvanovics, V. Istvánovics, V. Istvanovics, V Istvánovics, V Istvánovics, Vera Izmest'eva, Lyubov R. J., Brookes Jaatinen, E Jackson, J.R. Jacquet, S Jacquet, S. Jaimes, Aline Jakkila, J Jakobsson, E. James, A Janatian, N. Janse, JH Jansen, J. Jansson, M Järvalt, A Jarvinen, M. Järvinen, O Järvinen, M Jaworska, B JC., Nejstgaard Jellison, R Jennings, E Jennings, E. Jennings, Eleanor Jennings, Eleanor Jennings, E. Jennnings, Eleanor Jeppesen, E Jia, Q Jiang, Meilan JM, Melack Joehnk, KD Joehnk, Klaus D. John, Ranjeet Johnson, RA Jokiniemi, A Jones, ID Jones, Ian D. Jones, I.D. Jones, Stuart E Jones, I. D. Jones, I. D. Jones, Stuart E. Jonsson, A JP., Doubek JS, Read Junior, E. S. Oliveir Juntunen, J. K, Rinke Kakinuma, T. Kallio, K Kallio, Kari Kang, Dongwan Kangur, Peeter Kangur, P Kangur, K Kangur, Andu Kangur, Kulli Kangur, A Kangur, K. Kangur, Peter Kara, Emily L Karakaya, N. Karjalainen, Juha Karjalainen, J. Karlsson, J. Kasprzak, Peter Kaste, O Katsev, Sergei Kawamura, T Keller, WB Keller, P. S. Keller, Philipp S. Keller, Philipp Kelly, S. Kelly, PT Kelly, S Kelly, P.T. Kelly, Sean Kemanian, A.R. Kerimoglu, Onur Keskitalo, J Ketola, M. Keuskamp, Joost Khua, J.K. Kim, B Kimura, N Kipfer, R Kirchesch, V Kirillin, G Kirillin, G. Kissman, Carrie E. H. Kitchell, JF Klaus, M. Kling, GW Klug, J. Klug, J.L. Klug, J. L. Klug, JL Klug, J. L. Knight, R Knoll, Lesley B. Knoll, L.B. Knoll, Lesley B. Knoll, L.B. Ko, T Koch, GR Koehler, B Koester, O Kõiv, Toomas Kokic, Jovana Kokorite, I Kokubo, K. Komai, K. Konstantinou, I. Kopacek, J Koreivienė, J. Kortelainen, Pirkko Koschorreck, Matthias Koschorreck, M. Kosten, S Kosten, S Kosten, S. Kosten, Sarian Kothawala, DN Kourzeneva, E Kpodonu, A.T.N.K. Kraemer, Benjamin M. Kratz, Timothy K Kratz, Timothy K. Kratz, T.K. Kritzberg, ES Kroiss Krztoń, W. Kuha, Jonna Kulbe, T Kumagai, Michio Kumari Kuoppamaki, K. Kushner, PJ Kuusisto, Esko Kwietniewski, Edward L, Lewis L, Winslow L., Seelen Laas, Alo Laas, A. Laas, A. Laas, Alo Ladwig, Robert Lagrget, B Lajeunesse, M.J. LaLiberte, G.D. Lambrecht, Nick L LANCELET, T S Langman, OC Lapiere, J.F. Laspoumaderes, Cecilia Laudon, H Launiainen, S Lauster, GH Lavender, M. Lawrence, G LC, Bruce Leach, T.H. Leach, T.H. Leach, TH Leff, L.G. Lehtorante, J Lei, R Leigh, C. Leite, N. K. Lenhardt, Mirjana Lenhardt, M Lennon, Jay T. Lenters, John D. Lenters, JD Lenters, J.D. Lepistö, Ahti Lepisto, A. Lepori, F. Leppäranta, Matti Leshkevich, George Lewandowska, A.M. Lewis, Abigail S.L. Lewis, Abigail S. L. Li, Z Li, Z Li, Y Li, Y Li, W Li, K Lima, Marla Sonaira Lima, T. C. Lin, F P Lin, Fang‐Pang Lin, C Lin, F-P Lin, Zhanju Lin, C C Lin, Z Lindsey, AM Linkhorst, A. Lischeid, Gunnar Liu, W-C Liu, W Liu, Z Liu, X Livingstone, D M Llames, M.E. LN., de Senerpont Lofton, Mary E. Lofton, M.E. Lofton, Dendy Lofton, Mary E Lohilla, A. Long, E.C. Lopes, das Neves Lottig, NR Lottig, N Lozoya, Juan Pablo Lozoya, J. Lucas, R.M. Lucy, F. Lürling, M. Lyche-Solheim, A Lyons, K. M., Beklioglu M., Honti MA, Frassl Maberly, S. Maberly, SC MacIntyre, Sally Mack, JA MacKay, M Mackay, M. Mackay, E. Mackay, E.M. Madronich, S. Magnuson, John J. Magnuson, John J. Maier, Dominique B. Makler-Pick, Vardit Makler-Pick, V Malfatti, Stephanie Malmstrom, Rex Malmstrom, Rex R Mammarella, I Mantzouki, E. Marcé, Rafael Marce, R Marcé, R. Markensten, H Maronić, D. Š. Marques, DM Marques, David da Motta Martí, Eugènia Martin, Joel Martinez-Garcia, Manuel Martma, T Maruya, Y. Marzec, G Mather, J Matsuzaki, I.S. Matthews, B Mattila, O-P May, Linda May, L McBride, C. McBride, C. G. McBride, C. G. McBride, Chris G. McBride, C.G. Mcbride, C McCarthy, V. McCarthy, V McClure, R.P. McClure, R.P. McConnell, C McConnell, C McCullough, I.M. McIntyre, Peter B. McKenzie, R.L. McMahon, Katherine D McMahon, KD McMahon, Katherine D. McMahon, K.D. ME, Lofton Meier, J. Meinke, T P Meinson, Pille Meinson, P. Melack, John M. Melack, JM Melita, M. Melles, S.J. Mello, Nelson A S T Mello, NASTD Mendonca, R Mendonça, R. F. Mendoza-Lera, C. Mendoza-Lera, Clara Merchant, C.J. Merchant, CJ Merchant, Christopher J. Merrel, Kellie Merrell, Kellie Mertens, Andrew N. Mesman, Jorrit P. Meyer, Michael F. Milack, J M Milewski, P. Milewski, P Miller, SD Miller, Todd Miller, Todd R. Mischke, U Mitchell, Mark Moatar, F Modenutti, Beatriz Moe, JS Monson, RK Monteith, DT Montoya, J M Mooij, WM Mooij, W M Moore, K Moore, Tadhg N. Moradi, Amir M. Moran, Mary A Moreira, Santiago Moreno-Ostos, E. Moreno-Ostos, E Morgan, A. Morrison, Ken M Morrow, M Motta Marques, DML Moya, Francisco MR, Hipsey Mueller-Navarra, Doerthe C. Müller, RA Munger, Z.W. Muniz, C. C. Muraoka, Kohji Mutschler, James Mutz, Michael N., Catalan Nagy, Eric Nakayama, K. Naumenko, Mikhail Naumoski, A. Naus-Wiezer, SMH Navarro, Marcela Bastidas Nes, EH Newton, Ryan J Ng, S NicAonghusa, C Niederlehner, B.R. Nielsen, A Nin, M. Nishri, A Niu, Fujun NK., Skaff Nodine, Emily R. Nodine, E.R. Nõges, T. Nõges, Peeter Noges, P. Noges, P Noges, P. Nõges, Peeter Noges, T Noges, T Nõges, Tiina Noges, Tina Noges, P Nordbo, A North, R L North, Rebecca L. North, R P Norval, M. Novo, E M L M Nurminen, L. O'Brien, K R O'Cathain, D. O'Donnell, DM O'Reilly, C O'Reilly, C. O'Rourke, Michael Obertegger, Ulrike Obertegger, U. Obrador, B. Obrador, B Obrador, Biel Obrador, Biel Ojala, A Okada, T. Olabuenaga, I Oliver, Samantha K. Olson, MH Olsson, Freya Onandia, G. Oris, JT Orkowska-Krzebietke, Agnieszka Ostrovsky, I Ott, I Oulehle, F Ouyang, Zutao Overholt, E.P. Overholt, EP Oyserman, Ben O Ozkundakci, Deniz O’Reilly, Catherine M. O’Reilly, Catherine M. P, Kortelainen Paavola, R. Pace, ML Padisák, Judit Page, T. Pall, Peeter Palmer, MA Palshin, N. Paranaíba, J. R. Park, J.-H. Pärn, O Pastor, A. Pasztaleniec, A Paterson, Andrew M Paterson, AM Pati, Amrita Patil, Vijay P. Patil, V.P. Paul, N.D. PC, Hanson Peel, Sara Perillo, G. M. E. Perillo, G. Perillo, Gerardo M.E. Pernica, P. Pernica, P Peternell, M. Peters, Jody A. Petrucio, M. M Pettersson, K Petzoldt, T Phllips, G Piccolo, M. C. Piccolo, M. Piccolo, M.L. Piccolo, Cintia Piccolo, M.C. Pierson, Don Pierson, DC Pierson, D. Pierson, D. Pierson, D.C. 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Schwientek, Patrick Scordo, F. Sczyrba, Alexander SE, Hampton Seekel, DA Seekell, D. Seekell, D. Seelen, Laura M.S. Segarra, Monique Seltmann, C.T. Semmler, T Shade, Ashley Shade, Ashley Shao, Changliang Sharma, Sapna Sharma, S. Sharma, Sapna Shatwell, Tom Shatwell, Tom Shavlik, Jude W Shen, Y Shikhani, Muhammed Shin, P Shintani, T. Shirasawa, K Shu, L. Shumilova, Oleksandra Shurin, JB Silow, Eugene Silveira, M. H Singer, Gabriel Sire, J Skijlbred, B Skoulikidis, Nikos Smagula, Amy P. Smith, P. Smith, MC Smol, JP Smolders, Alfons J. P. Smyth, R. L. Smyth, R.L. Smyth, Robyn L. Smyth, R. Smyth, R. L. Smyth, Robyn L. Sniewski, Grzegorz Snortheim, C.A. Snorthheim, Craig Sobek, Sebastian Sobek, S Solbakov, V Solomon, CT Somers, KM Somers, K M Sommaruga, R Soncini-Sessa, R Soranno, P A Soranno, P.A. Sorice, M.G. Soulignac, Frederic Souza, Maria Sol Soylu, Evren Sparber, K. Sparber, K Stachelek, J. Stacy, TL Staehr, PA Staehr, P.A. Staehr, Peter A. Staehr, P. A. Staehr, P. A. Staehr, P.A. Staehr, Peter A Stanley, Emily H Starrfelt, J Stepanauskas, Ramunas Stepien, Carol A. Sterling, S Sterner, Robert W Stevens, Sarah LR Stockwell, Jason D. Stockwell, J.D. Stockwell, Jason D. Stockwell, JD Stombaugh, J Stone, Amanda G. Straile, D Straile, Dietmar Straile, D. Strock, K.E. Sturm, M Sulzberger, B. Sumberova, K Šumberová, Kateřina Swain, HM Swanner, Elizabeth D Sweeney, C. Søndergaard, M Takamura, Noriko Tan, Zeli Tan, Zeli Tan, Z. Tanentzap, A. J. Tanentzap, A. J. Team, The Mendeley Support Temponeras, Maria Terzhevik, A Teubner, K Teubner, Katrin Teurlincx, Sven Thackeray, S.J. They, Ng Haig Thiery, W. Thomas, Perry Thomas, Quinn Tibor, G Tietjen, Todd Tietjen, Britta Tikka, M Tilak, Sameer Tominaga, K Toming, K Torgersen, T Tranvik, L Tranvik, LJ Tranvik, Lars Tremblay, Julien Trimmer, M Tringe, Susannah G Trolle, D Trolle, Dennis Tsai, J Tucker, AJ Turnbull, T Turner, A.J. Turney, DE United Nations Environment Programme, Enivonrmental Effects Assessment Panel Urrutia-Cordero, P. V., Istvánovics Vachon, D Valerio, Giulia Valesini, Fiona J. Van de Bogert, Matthew C van der Linden, Leon van Dijk, Gijs Van Loon, E. Van Wichelen, J Vanni, M.J. Vannie, MJ Velez, M. Velez, Maria I. Venail, P. Venkiteswaran, Jason J. Verburg, P. Verburg, P Verburg, P. Verburg, Piet Vernon, F Vesala, T Vetter, Mark Viik, Malle Viik, M Vilbaste, S Viljanen, M Villamizar, S R Villamizar, S. Vincent, WF Vinçon-Leite, Brigitte Vinebrooke, RD Visser, P. von Schiller, Daniel von Schiller, D. Vourenmaa, J. Voutilainen, Ari Waajen, G Wagner, J Wain, D. Waite, AM Wallin, Marcus B. Wallin, Marcus B. Wang, R Wang, Junbo Wang, H. Ward, N.K. Warnecke, Falk Warren, Susan Waterfield, Holly Watkinson, Andrew J. Watras, A.J. Watras, C.J. Watras, Carl J Watson, Simon R. Weather, K.C. Weathers, Kathleen C. Weathers, KC Weathers, K. C. Weathers, K.C. Weathers, K.C. Weathers, Kathleen C Weber, Michael Weber, E Weber, M. Weigelhofer, Gabriele Welkie, David G. Wells, Britney Wemple, B. Weng, W. Wentzky, VC Weyhenmeyer, G.A. Weyhenmeyer, Gesa A. Weyhenmeyer, Gesa A Weyhenmeyer, Gesa A. Weyhenmeyer, GA Whitaker, RJ White, D. S. White, D. S. White, M. Wickramaratne, Chaturangi Wigdahl-Perry, C. Wilk-Woźniak, E. William, Colom Williamson, Craig C. Williamson, Craig E. Williamson, C.E. Williamson, T.J. Williamson, C.E. Williamson, T.J. Wilson, H.L. Wilson, Louise Winder, M Winegardner, A.K. Winn, N Winslow, Luke Winslow, L.A. Winslow, Luke A Winslow, L. A. Winslow, L.A. Winslow, L. A. Winters, Kirsten M. Wiśniewski, Grzegorz Wittkop, Chad Wolinski, Laura Woolverton, C. Woolway, R.I. Woolway, Iestyn Woolway, RI Woolway, R.I. Woolwya, R.I. Wooward, G Worrest, R C Woyke, Tanja Wright, RW Wu, Chin H Wu, J T Wu, Chin H. Wunnemann, B Yajima, H Yan, N Yan, D Yang, Y Yao, Huaxia Yao, Huaxia Yao, X Yao, H Yao, H Yaziciaglu, S Yokota, Kiyoko Youngblut, ND Yu, J Yvon-Durocher, G Zdorovennov, R. Zdorovennova, G. Zechmeister, T Zepp, R.G. Zhang, Guoqing Zhang, Y Zhang, J Zhang, Y. Zhang, J. Zhang, Q. Zhao, L Zhu, G Zhu, Guangwei Zhu, M. Zhu, G. Zhu, Mengyuan Zhu, M Zhu, M. Zhu, G. Zhuang, Qianlai Zhuang, Q. Zhuang, Qianlai Zilio, M. Zilio, Mariana I. Zion, M Zlatanović, Sanja Zohary, T Zohary, T. Zoppini, Annamaria Zunino, J. Zwart, Jacob A. Zwart, J.A. 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TURNER v. MILLER | 301 F.3d 599 (2002) | 1f3d5991842 | Leagle.com
KANNE Circuit Judge. Roland Turner sued several State of Illinois prison officials to recover for injuries he allegedly sustained...1f3d5991842
TURNER v. MILLER
No. 01-3413.
View Case
Cited Cases
Citing Case
301 F.3d 599 (2002)
Roland TURNER, Plaintiff-Appellant,
v.
Louis MILLER, Jerome Nickerson, and Paul Morgan, Defendants-Appellees.
United States Court of Appeals, Seventh Circuit. https://leagle.com/images/logo.png
Argued May 22, 2002.
Decided August 21, 2002.
Attorney(s) appearing for the Case
Barbara J. Clinite (argued), Chicago, IL, for Plaintiff-Appellant.
Mary E. Welsh (argued), Office of the Attorney General, Civil Appeals Division, Chicago, IL, for Defendant-Appellee.
Before POSNER, KANNE, and WILLIAMS, Circuit Judges.
United States Court of Appeals, Seventh Circuit.
KANNE, Circuit Judge.
Roland Turner sued several State of Illinois prison officials to recover for injuries he allegedly sustained when he was shocked by exposed electrical wires in the showers at Stateville Correctional Center. In Count I, Turner alleged that the defendants violated his Eighth Amendment right to be free from cruel and unusual punishment by exposing him to unsafe conditions of confinement. In Count II, he alleged that the defendants were negligent under state law. After a four-day trial, a jury returned a verdict in favor of the defendants.
I. Background
Turner, a prisoner at Stateville Correctional Center, alleges that on October 25, 1997, he was shocked when he came into contact with exposed wires dangling from a missing light fixture in the showers. Turner claims that when he raised his arm to allow another inmate to step in front of him to use a showerhead, his wrist touched the exposed wires and he was shocked. According to Turner, he then fell to the ground, resulting in injuries to his hands, back, and head.
[301 F.3d 601]
At trial, Turner and several inmates testified on Turner's behalf. Turner explained that because so few showerheads were working, he shared a showerhead with fellow inmate Flaviano DeLaola. Turner alleged that after he rinsed off, he stepped back to allow DeLaola to use the showerhead. At this point, Turner claimed that he raised his arm, and the next thing he remembered was being awakened with smelling salts. However, DeLaola testified at trial that he was a couple of showerheads away from Turner at the time of the incident, and thus, did not share the showerhead with Turner. Further, although several inmates claimed to have heard Turner yell out and seen him fall to the floor, no one actually saw Turner's arm hit any exposed wires.
Turner and the inmates provided conflicting testimony about the time frame during which the exposed wires in the showers existed and about the length of the exposed wires. One inmate testified that the wires had been hanging since 1994, while another inmate testified that the first time he saw the wires was on the day that Turner was shocked. Further, while Turner testified that the wires dangled between twelve and thirteen inches, another inmate specifically testified that two exposed wires were only seven and ten inches long respectively, and yet another inmate testified that the wires were two feet long. Turner and all the inmates admitted that they had never filed a written grievance about the exposed wires.
At trial, the defendants denied all allegations against them and asserted sovereign immunity as an affirmative defense to Turner's negligence claim. Further, each defendant testified that he had no knowledge about the exposed wires in the showers and that he had never seen any wires dangling in the showers. Defendant Louis Miller, assistant Chief Inspector, testified that his responsibilities did not include inspecting the showers, and therefore, he would not have had an opportunity to notice any exposed wires. Rather, Miller explained that he was alerted to necessary repair work through work orders submitted to the engineering office, and no work order for exposed wires in the showers was ever submitted. Defendant Lieutenant Paul Morgan testified that on ninety-five percent of the days that he worked, he inspected the showers for contraband and that he had never seen any exposed wires in the showers nor had any inmate or guard ever told him that there were exposed wires in the showers. Defendant Sergeant Jerome Nickerson testified that he walked through the showers once every two or three weeks to check for cleanliness and that he never saw any exposed wires. Additionally, Nickerson testified that no inmate ever reported exposed wires to him.
The prison medical technician, John Adams, also testified on behalf of the defendants. Adams explained that when he arrived at the showers, he used an ammonia inhalant to revive Turner. Adams stated that although someone who was unconscious would normally be groggy upon revival, Turner "snapped around" immediately after being given the ammonia inhalant. Further, Adams testified that the inmates in the shower were disinterested in what was happening with Turner. Adams explained that this behavior was unusual because normally when a fellow inmate was injured, the other inmates were very interested in seeing that the injured inmate received medical attention immediately. Adams also explained that Turner had no visible wounds or injuries. Dr. Smith, the Stateville medical director who subsequently treated Turner, also testified that if Turner had lost consciousness and fallen, he would have had bruising as
[301 F.3d 602]
well as swelling. However, according to Dr. Smith, Turner had no such injuries.
The jury returned a verdict on the negligence count in favor of the defendants, and thereafter the district court entered judgment in favor of the defendants and against Turner. Subsequently, Turner filed post-trial motions pursuant to Rules 50 and 59, arguing that reversal was warranted because the verdict was against the manifest weight of the evidence or, alternatively, that a new trial was warranted due to a lack of evidence, errors in the jury instructions, and an incomplete impeachment of him by defense counsel. The district court denied Turner's post-trial motions, and Turner now appeals.
II. Analysis
We review the district court's denial of Turner's motion for judgment as a matter of law de novo,limiting our inquiry "to whether the evidence presented, combined with all reasonable inferences permissibly drawn therefrom, is sufficient to support the verdict when viewed in the light most favorable to the party against whom the motion is directed." Goodwin v. MTD Prods., Inc.,232 F.3d 600, 605-06 (7th Cir.2000) (quotations omitted). We reverse only if we conclude that no rational juror could have found for the prevailing party. See id.at 606. We review the district court's denial of Turner's motion for a new trial for an abuse of discretion. See id.
With respect to Turner's state law negligence claim, the defendants persuade us that the district court lacked subject-matter jurisdiction over this claim. Where a charged act of negligence "arose out of the State employee's breach of a duty that is imposed on him solelyby virtue of his State employment, sovereign immunity will bar maintenance of the action" in any court other than the Illinois Court of Claims. Currie v. Lao,148 Ill.2d 151,170 Ill.Dec. 297,592 N.E.2d 977, 980 (1992) (emphasis in original); see also705 ILCS 505/8(d) (1998) (waiving Eleventh Amendment immunity only in the Illinois Court of Claims).
In
Healy v. Vaupel,
133 Ill.2d 295
, 140 Ill.Dec. 368,
549 N.E.2d 1240
, 1248-51 (1990), the Illinois Supreme Court explained that the Illinois Court of Claims had exclusive jurisdiction over a student's claim that university employees' negligent performance of their duties led to personal injuries she sustained while participating in university gymnastic activities. That court emphasized that "[t]he relationship between the plaintiff and the defendants would not have had a source outside the employment status of the defendants."
Id.
140 Ill.Dec. 368, 549 N.E.2d at 1249. Six years later, in
Magdziak v. Byrd,
96 F.3d 1045
, 1049 (7th Cir.1996), we found that a state police officer who killed a third party during a high speed chase was performing a function that arose solely as a result of that officer's state employment. Thus, we explained that the Illinois Court of Claims had exclusive jurisdiction over the resulting tort claims.
See id.
Similarly, we find today that the relationship between Turner and the defendants would not have had a source outside the employment status of the defendants, and whatever duty was owed by the defendants to Turner existed because of Turner's status as a prisoner and his presence at Stateville Correctional Center.
See Healy,
140 Ill.Dec. 368, 549 N.E.2d at 1249;
see also Witt v. Corr. Officer Andrew,
2000 WL 1349246, at *3 (N.D.Ill. Sept.19, 2000) ("The court cannot imagine any set of conceivable facts where [the prison official's] negligent discharge of his shotgun while he was on duty as an armed guard in the prison could be considered outside the scope of the duties imposed upon him by his state employment.").
[301 F.3d 603]
Thus, we find that the district court improperly exercised subject-matter jurisdiction over Turner's state law negligence claim.
With regard to the matter over which jurisdiction exists — his Eighth Amendment claim — Turner contends that the district court erred in denying his motion for judgment as a matter of law or a new trial. Before considering the merits of this argument, we must address a procedural matter that became apparent on review of the trial record. The verdict form submitted to the jury by the court was three pages in length and divided into separate sections. One section dealt with the negligence claim, and a second section concerned the Eighth Amendment claim. The jury's verdict was returned only as to the negligence claim, and no verdict was returned with regard to the Eighth Amendment claim. The judgment on the verdict entered by the court simply stated "that judgment is entered in favor of the defendants and against plaintiff."
While the verdict returned concerned only the negligence claim directly, it is our view that it is reasonable to infer that the jury's verdict on that claim constitutes an adverse finding on Turner's Eighth Amendment claim. See Klapmeier v. Telecheck Int'l, Inc.,482 F.2d 247, 256 (8th Cir.1973) (affirming the trial court's use of a similar inference). *Despite lack of jurisdiction over the negligence claim, we believe such an inference is reasonable and appropriate because both claims rested on the same operative facts and because Turner needed to show more than negligence to find deliberate indifference, an essential element of the Eighth Amendment claim. See Snipes v. DeTella,95 F.3d 586, 590 (7th Cir.1996); Lunsford v. Bennett,17 F.3d 1574, 1580 (7th Cir.1994) (explaining that "[m]ere negligence does not satisfy the deliberate indifference standard").
We turn now to the merits of Turner's constitutional claim. The Eighth Amendment's prohibition against cruel and unusual punishment imposes upon prison officials the duty to "provide humane conditions of confinement" for prisoners. Farmer v. Brennan,511 U.S. 825, 832, 114 S.Ct. 1970, 128 L.Ed.2d 811 (1994). An Eighth Amendment conditions-of-confinement claim has two components — a subjective component and an objective component. See Delaney v. DeTella,256 F.3d 679, 683 (7th Cir.2001). We have previously held:
To satisfy the objective component, the deprivation alleged must be, objectively, sufficiently serious. Therefore, extreme deprivations are required to make out a conditions-of-confinement claim. The subjective component relates to a defendant's state of mind and requires a showing of deliberate indifference. At a minimum ... an inmate must allege actual knowledge of impending harm easily preventable. A failure of prison officials to act in such circumstances suggests that the officials actually want the prisoner to suffer the harm.
Delaney,
256 F.3d at 683 (internal citations and quotations omitted) (emphasis in original). With respect to the subjective prong — which requires a showing of deliberate indifference — the Supreme Court has explained that "an Eighth Amendment claimant need not show that a prison official acted or failed to act believing that harm actually would befall an inmate; it is enough that the official acted or failed to act despite his knowledge of a substantial risk of serious harm."
Farmer,
511 U.S. at 842, 114 S.Ct. 1970. In making this determination, we may consider whether
[301 F.3d 604]
"the circumstances suggest that the [official] being sued had been exposed to information concerning the risk and thus `must have known' about it." Id.
In this case, ample evidence was presented to support the conclusion that the defendants were not negligent, let alone deliberately indifferent. Turner and each of the testifying inmates acknowledged that none of them had ever filed a written grievance regarding exposed wires in the showers. Moreover, each of the three defendants denied that they had ever personally seen any exposed wires in the showers or that anyone had ever told them about the wires. A rational juror easily could have concluded that Turner failed to prove not only negligence, but by inference deliberate indifference, on the part of the defendants because he failed to present any evidence suggesting that the defendants knew of the wires or that they had been exposed to information concerning a substantial risk of serious harm. See id.Thus, the district court properly denied Turner's motion for judgment as a matter of law or a new trial with respect to Turner's Eighth Amendment claim.
Moreover, the resolution of the claim of negligence (and by inference deliberate indifference) requires a credibility determination. The jury heard Turner and his fellow inmates give inconsistent testimony about the circumstances surrounding the incident and conflicting statements concerning the length of the wires and the time frame during which the wires were allegedly exposed. Also, Turner testified that he was shocked when he stepped aside to let DeLaola use a showerhead, yet DeLoala testified that he was several showerheads away from Turner at the time of the incident. Further, neither medical technician Adams nor Dr. Smith saw any visible bruising or lacerations on Turner's body. Because the jury clearly did not find Turner's story credible, our decision to decline to alter the judgment below is further supported. See United States v. Henderson,58 F.3d 1145, 1148 (7th Cir. 1995) ("[Q]uestions of credibility are solely for the trier of fact, so such arguments are wasted on an appellate court.") (quotations omitted).
Finally, Turner argues that he is entitled to a new trial because during his cross-examination, defense counsel failed to prove up an attempted impeachment of him. However, following the trial, Turner moved for a mistrial or to have a curative instruction given to the jury regarding defense counsel's failed prove up. Both parties concede that a curative instruction was given to the jury. We have held previously that absent an overwhelming probability that the jury will be unable to disregard inadmissible evidence and a strong likelihood of a devastating effect from the evidence, we will presume that a jury will follow a curative instruction. See Raybestos Prods. v. Younger,54 F.3d 1234, 1239 (7th Cir.1995). In the present case, Turner presents no basis to conclude that the curative instruction was inadequate or that a strong likelihood of a devastating effect exists. See id.
III. Conclusion
For the foregoing reasons, it is ordered that the judgment of the district court is MODIFIED to provide as follows: "Judgment is entered in favor of the defendants Louis Miller, Jerome Nickerson, and Paul Morgan and against the plaintiff, Roland Turner, on plaintiff's Eighth Amendment claim." The judgment, as modified, is AFFIRMED. It is further ordered that plaintiff's state law negligence claim is DISMISSED for lack of subject-matter jurisdiction.
FootNotes
* This was a view apparently shared by the district court and counsel in this case.
| https://www.leagle.com/decision/2002900301f3d5991842 |
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(PDF) 2021 - Stefani-Santos et al 2021 Odonata (Insecta) communities along an elevational gradient in the Atlantic forest of southeastern Brazil
PDF | On Nov 12, 2021, Gláucia Stefani-Santos and others published 2021 - Stefani-Santos et al 2021 Odonata (Insecta) communities along an elevational gradient in the Atlantic forest of southeastern Brazil | Find, read and cite all the research you need on ResearchGate
2021 - Stefani-Santos et al 2021 Odonata (Insecta) communities along an elevational gradient in the Atlantic forest of southeastern Brazil
Authors:
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Gláucia Stefafni Santos
Instituto Federal de Educação, Ciência e Tecnologia do Sul de Minas Gerais
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Walter Francisco de Ávila Jr
Walter Francisco de Ávila Jr
<here is a image 188750c627ead602-81c3b6bf1e940ea0>
Mateus Clemente
Instituto Federal de Educação, Ciência e Tecnologia de Rondônia (IFRO)
<here is a image d27b5ef2ce117684-de4b62cd786bbed7>
Nathália Ribeiro Henriques
Federal University of Minas Gerais
Preprints and early-stage research may not have been peer reviewed yet.
178
International Journal of Odonatology, 24.2021, 178 – 196
OpenAc c ess. © 2021 Ulf Norling, published online 1 Jan 2021 by W achholtz This work is
license d under the Cr eative Commons Attribution 4.0 Public Lic ense.
OpenAccess.
OpenAc c ess. © 2021 Ulf Norling, published online 1 Jan 2021 by W achholtz This work is
license d under the Cr eative Commons Attribution 4.0 Public Lic ense.
2021 Stefani-Santos et al., published online 05 Nov 2021 by Wachholtz
OpenAc c ess. © 2021 Ulf Norling, published online 1 Jan 2021 by W achholtz This work is
license d under the Cr eative Commons Attribution 4.0 Public Lic ense.
This work is licensed under the Creative Commons Attribution 4.0 Public License.
G. Stefani-Santos 1 , W.F Ávila Jr 2*, M.A. Clemente 3 , N.R. Henriques 4, A.S.B. Souza 5,
D.S. Vilela 6and M.M. Souza 7
Odonata (Insecta) communities along an elevational gradient in the
Atlantic forest of southeastern Brazil, with the description of the
female of Heteragrion mantiqueirae Machado, 2006
https://doi.org/10.23797/2159-6719_24_14
Received: 23 January 2021 – Accepted: 19 March 2021 – Published: 05 November 2021
Abstract. Despite the important role of the order Odonata in ecosystems, there is a lack of infor-
mation about dragony communities in severalregions, high elevation sites, and environmentally
protected areas in Minas Gerais State, Brazil. Our objective was to assess the abundance and rich -
ness of dragony and damsely communities along an elevational gradient in the Atlantic Forest,
southeastern Brazil. This study was conducted in the Fernão Dias Environmental Protection Area,
Mantiqueira Mountain region, Gonçalves, Minas Gerais State, in sites covered by Seasonal Semi -
deciduous and mixed forests.Thisistherststudyof Odonata communitiesintheregion. Sam -
plings were carried out on 17 days from October 2019 to March 2020 at three elevation ranges (low,
mid, and high). A total of 293 specimens, distributed in 39 species and 9 families, were sampled.
Elevation did not inuence therichnessor abundance of dragonies butaltered communitycom -
position. Some species were found to be exclusive to high-elevation sites, such as Heteragrion
mantiqueirae Machado, 2006 , which was recorded for therst time in Minas Geraisand wepro -
vide a description and diagnosis of the single female collected in tandem. A novel species of the
genus Brechmorhoga was found to occur at midand high elevations. Thecomposition of dragony
communities depends on the degree of preservation and extension of forest areas. Therefore, con -
servation of forests in Gonçalves is crucial for preserving Odonata diversity in Minas Gerais State.
keywords: Anisoptera, altitude, diversity, dragony, preservation, Zygoptera
Introduction
The orderOdonatacomprisesinsects popularlyknownas dragoniesand damselies (Machadoet
al., 1998 ) andis composedby two suborders, Anisoptera (Epiprocta) and Zygoptera (Corbet, 1999 ),
of which 901 species, 147 genera, and 15 families occur in Brazil (Pinto, 2020). As nymphs, dragon-
ies and damselies occupy lentic and lotic freshwater environments; some species occur mainly in
1Instituto Federal de Educação, Ciência e Tecnologia do sul de Minas Gerais, Inconfidentes, Brazil;
https://orcid.org/0000-0002-1610-2920 .
2Departamento de Biodiversidade, Evolução e Meio Ambiente, Programa de Pós-Graduação em Ecolo-
gia de Biomas Tropicais. Universidade Federal de Ouro Preto, Ouro Preto, Brazil; http://orcid.org/0000-
0003-4707-0113 ;
3Departamento de Zoologia, Universidade Estadual Paulista, Rio Claro, São Paulo, Brazil; https://orcid.
org/0000-0003-4969-1335 .
4Departamento de Genética, Ecologia e Evolução, Programa de Pós-Graduação em Ecologia, Conserva-
ção e Manejo da Vida Silvestre, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais,
Brazil; https://orcid.org/0000-0002-3858-8423 .
5Instituto Federal de Educação, Ciência e Tecnologia do Paraná, Umuarama,Paraná, Brazil; https://or-
cid.org/0000-0001-9708-7402 .
6Department of Biology, University of São Paulo (USP), Ribeirão Preto, Brazil; https://orcid.org/0000-
0001-6510-7018 .
7Instituto Federal de Educação, Ciência e Tecnologia do sul de Minas Gerais, Inconfidentes, Brazil;
http://orcid.org/0000-0003-0415-1714 .
*Corresponding author. Email: [email protected].
179
Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
forests with low anthropogenic disturbances (Machado, 1988 ;Ferreira-Peruquetti&DeMarco,
2002 ; Souza et al., 2018 ) and can, therefore, be used as bioindicators of the environmental quality of
forest ecosystems (Machado, 1988 ; Gonçalvez, 2012; Oliveira-Junior et al. 2015 , 2019 a). For the pur -
poses of this study, individuals of Odonata will be referred to collectively as dragonies.
Severalinventorystudiesof dragonyspecieshavebeenconductedinMinasGeraisState,Brazil
(Santos, 1966, 1970; Ferreira-Peruquetti & De Marco, 2002; Almeida et al., 2013; Souza et al., 2013;
Bedê et al., 2015; Vilela et al., 2016; Dos Anjos 2017; Souza et al., 2017; Amorim et al., 2018; Borges
et al.,2019; Barbosa etal., 2019;Vilela etal., 2020;Silva &Souza 2020),but many localities, ecosys -
tems,andConservationUnits(UCs)oftheStatestilllackinformation oncommunitydiversityof
Odonata. Conservation Units are an important tool forbiodiversity conservation, helping to preserve
various species and environmental services (Siqueira etal., 2017; Steinke etal., 2018), whichjusties
inventory studies in UCs.
Forinstance,ina surveyofOdonatacurrentlyunderprogressintheItacolomiStatePark,Ouro
Preto, Minas Gerais, a new species of the genus Heteragrion was identiedand Cyanallagma tri-
maculatum (Selys, 1876) was rediscovered after 147 years (Ávila Jr et al., 2020 a;ÁvilaJretal.,
2020 b). The absence of biodiversity information impairsthe eectiveness of management programs
for biota conservation,even in theAtlanticForest, which isgenerallywell sampledcomparedwith
other Brazilian biomes.
TheAtlanticForestisheterogeneousbiomeandcomprisesasetofforestformationsandassociated
ecosystemsthatdierinclimateandelevation, includingDense,MixedandOpenOmbrophilousfor -
ests, Seasonal Deciduousand Semideciduousforests; restingas (coastal vegetation); mangrove swamp;
high meadows; marsh; andCaatingaenclave moist forests (Oliveira Filho, 2006 ). Additionally, this bi -
ome is one of the richest and most threatened biodiversity hotspots of the planet, in which a variety of
endemic and endangered faunal and oral species occur (Uehara-Prado et al., 2007;Maldonado-Coelho
& Marini, 2004; Ruschel, et al., 2007). Unfortunately, habitat degradation and extinction of various or -
ganisms are common, making its preservation a priority (Mayers et al., 2000 ; Steinke et al., 2018 ).
Apartfromtheexamplesdescribedabove, severalenvironmentalfactorsinuence insectdiversity
and distribution, such as water physicochemical characteristics, soil conditions, phytophysiogno-
mies,elevation,resourceavailability,andabioticvariables(Freitasetal., 2007; Fernandes, 2016 ).
Along elevational gradients, oscillation of temperature and relative humidity, low atmospheric oxy-
gen levels, and highwind speedand UV incidence are limiting factors of insect colonization (Hod -
kinson, 2005 ), particularly when combined with reduced habitat area, primary production, and re-
sourceavailability, which directlyaect species richness,abundance,andcommunitycomposition
(Lawton et al., 1987 ; Henriques-Oliveira & Nessimian, 2010 ).
Elevation eects have been the focus of various studies on dierent insects in Brazil, suchas butter -
ies (e.g., Carneiro etal., 2014; Henriques &Cornelissen, 2019 ) and social wasps (e.g., Albuquerque
et al., 2015 ; Souza et al., 2015 ; Ribeiro et al., 2019), and some international studies have instigated el -
evation eects onthe orderOdonata (e.g., Samways, 1989; Leksonoet al., 2017; Palacino-Rodríguez
et al., 2020 ). In Brazil, however, only the studies carried outby Oliveira-Junior et al. ( 2015 , 2019) and
Oliveira-Junior and Juen ( 2019 b) can be found on topic. It is known that altitude aects the composi -
tion of aquatic invertebrate communities (Tomanova et al., 2007), however the results found on the
inuenceofelevation forOdonataarestilldivergent,especially inadulthood.According toCorbet
( 1999 ) and Oliveira-Junior et al. ( 2015 ), the elevation alone maynot exert a great inuence on dragon -
y communities, especially in thosespecies with greatight capacity of Anisoptera, butif associated
with other environmental variables such as the area conservation degree or the physicochemical char -
acteristics of the water, it could aect the composition and distribution of the Odonata fauna.
This study aimed to describe abundanceand richness of dragonycommunities alongdierent ele -
vational gradients in the Atlantic Forest in southeastern Brazil and ll in gapsin knowledge concern -
ing the distribution of Odonata in mountainous regions of the country. The elevational distribution
pattern of adults of Odonata is still not well established, since most studies evaluate only the aquatic
phases. Therefore, we tested the hypothesis that species richness decrease with increasing elevation,
following the distribution pattern of species in mountains commonly described for other terrestrial
insectgroups(e.g. ants,dung beetles,butteries,termites,gallingherbivoresetc; Fernandes, 2016
and references therein). Additionally, we provide the description and diagnosis of the hitherto un-
known female of Heteragrion mantiqueirae Machado, 2006, collected during our expeditions. The
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
female belongs to Lencioni’s HeteragrionGroup A (Lencioni, 2013), which is composed of females
possessing several rows of teeth on the ventral surface of genital valves.
Material and Methods
Study site
The study wasconductedat the Fernão DiasEnvironmental ProtectionArea,locatedin Gonçalves
(-22.503611, -45.5233333), southernmost part of Minas Gerais State, Brazil(Figure 1 ). The region is
inserted in the Mantiqueira Mountain system and is covered by Seasonal Semideciduous and Mixed
forestvegetation,themostcommonphytophysiognomiesoftheAtlanticForestdomain(Oliveira
Filho, 2006 ). The climate is humid temperate (Köppen classication: Cwb), the annual average pre -
cipitation is about 1500 mm, average daily temperatures vary from 14 to 19 °C, and elevations range
from 880 to 1670 m (a.s.l.) (Melo & Salino, 2007 ).
Figure 1.Map of the study area showing low-, mid-, and high-elevation sampling sites in Gonçalves,
Minas Gerais State, Brazil.
Data sampling
Samplings were performed from October 2019 to March 2020 at low-, mid-, and high-elevation sites
(880 to 1670 m a.s.l.) located at 160 m elevation intervals (Table 1 and Figure 1). Samples were per-
formed on 17 days for 8 h a day, totaling 136 h of sampling eort equally distributed between eleva -
tion ranges. Adult dragonies were captured using entomological nets in the morning and afternoon
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
from 9:00 to 17:00 h, according to Bedê et al. ( 2015) in lentic and lotic environments and associated
terrestrial ecosystems. Sampled individuals were placed in entomological envelopes labeled with the
date and place of collection. Subsequently, dragonies were sacriced by immersion in acetone P.A.
and identied by specialists. For specimens identication we used the keys contained in Garrison et
al. ( 2006 , 2010 ) for genus level of Zygoptera and Anisoptera, Lencioni ( 2017) for specic identica -
tion ofZygoptera and additional literature foreach genera andspecies when needed. Specimens were
depositedintheBiological CollectionofSocialWaspsof theFederalInstituteofSouthernMinas
Gerais (CBVS, IFSULDEMINAS), Incondentes Campus, Brazil.
Table 1.Ecological, economic, and social characteristics of Odonata sampling sites along an elevational
gradient in the Fernão Dias Environmental Protection Area, southern Minas Gerais State, Brazil. Coordi-
nates of the sampled locations at each elevation are shown below.
CharacteristicLow elevationMid elevationHigh elevation
Elevation range 880 to 1090 m (a.s.l.)1250 to 1410 m (a.s.l.)
1570 to 1670 m (a.s.l.)
Vegetation type Semideciduous forestMixed and
Semideciduous forest
Mixed forest
Fragmentation
state
Highly fragmented Moderately
fragmented
Less fragmented
Succession stage Initial or intermediateIntermediateAdvanced
Canopy formation Rare UncommonFrequent
Pasture growth High LowLow
Eucalyptus
cultivation
PresentPresentPresent
Ecotourism
activities
Low HighHigh
Lentic ecosystemsPresentPresentPresent
River/stream width2 to 10 m2 to 5 m<2 m
Riparian forest<5 m5 to 10 m<10 m
Residential areasManyMany Few
Lotic ecosystems Present; greater water
volume and current
speed; width between
2 to 10 m
Present; greater water
volume
and current
speed; width between
2 to 5 m
Present; greater water
volume and current
speed; width <2 m
Coordinates
LocationsLow elevationMid elevationHigh elevation
Area 1 22.7007 S / 45.8453 W 22.6739 S / 45.8528 W
22.7415 S / 45.8438 W
Area 2 22.6392 S / 45.7975 W 22.7105 S / 45.8327 W
22.7359 S / 45.8195 W
Area 3 22.6552 S / 45.8207 W 22.6699 S / 45.8537 W
22.7235 S / 45.8723 W
Area 4 22.6028 S / 45.8861 W 22.6694 S / 45.8486 W
22.7447 S / 45.8923 W
Area 5 22.6164 S / 45.8793 W
Area 6 22.6422 S / 45.8030 W
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Data analysis
Toassessthefrequency ofdistributionof dragonyspecieswithinthecommunityasawhole, we
classied singletons (one individual sampled) and doubletons (two individuals sampled) as rare. Di -
versity was measured by elevation range using the Shannon diversity index ( H ′), evenness byPielou’s
index ( J , calculated from H ′), and dominance by the Simpson index (D ). Dierences between eleva -
tion rangeswere analyzed bythe Kruskal–Wallistest. Spatial variations inthedistribution of sam -
pled organisms were visually represented by nonparametric multidimensional scaling (nMDS).
Abundance data were tested for homogeneity of multivariate dispersion (PERMDISP) (Anderson et
al., 2006 ) between elevation ranges and subjected to nonparametric multivariate analysis of variance
(PERMANOVA). Cluster analysis was performed based on aJaccardsimilarity matrixconstructed
from presence/absence data. Dendrograms were constructed by unweighted pair group method with
arithmetic mean (UPGMA), where the similarity betweenthe groups isthe average of similarities -
the UPGMAlinks the smallest distances and recalculates new distances using arithmetic meansfor
a new grouping, thus linking groups by the average similarity between their elements, increasing the
ability to discriminate groups (Valentin, 2012 ), so we used this method because it best adjust for our
data. All analyses were performed using PAST software version 3.24 (Hammer et al., 2001 ).
Taxonomy
The female description of H. mantiqueirae Machado, 2006was based on a single specimen collected
in tandem in a lotic environmentof dense vegetationwithina mixed forest(Figure 2 ). The collecting
site is located at 1660 m (a.s.l.) (-22.7418361, -45.8459722).
Habitus was scanned with an Epson V600 Perfection at colored 1200 dpi with 200% magnication.
IllustrationsweremadeusingtracepaperandscannedwithEpsonV600Perfectionatblackand
white 1200 dpi with 100% magnication.
Morphological terminology follows Bota-Sierra & Novelo-Gutiérrez ( 2017); Lencioni ( 2017); Vilela
et al. ( 2019). All measurements are in millimeters (mm).
Abbreviationsinthetextareusedasfollows: AL,abdomenlength(includingcercus); DP,dorsal
plate of intersternite; FW, fore wing; HW, hind wing; Is, interternite; Pt, pterostigma; Px, postnodal
crossvein; Se, setifer; S1–10, abdominal segments 1 to 10; TL, total length (including cercus).
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Figure 2. Place of collection of Heteragrion mantiqueirae Machado, 2006, at the APA Fernão Dias,
Southern Minas Gerais State.
Results
Richness, abundance and distribution of Odonata communities
A total of 293 Odonata individuals were sampled, belonging to 39 species distributed throughout nine
families (three families from suborder Anisoptera and six families from suborder Zygoptera), includ -
ing two new records to Minas Gerais State: Hetaerina brightwelli(Kirby, 1823), and Heteragrion
mantiqueirae Machado, 2006 (Table 2 , Figure 4). Libellulidae was the family with the highest species
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
richness(16 species,41% of the total richness), followed byCoenagrionidae(eight species, 20.51%),
Calopterygidae(fourspecies,10.25%),Heteragrionidae(threespecies,7.69%),Protoneuridae(two
species,5.12%), andAeshnidae,Gomphidae,Lestidae,andMegapodagrionidae(onespecieseach,
2.56%). Libellulidae wasalso the mostabundant family ( n = 75individuals, 25.6% of the total abun -
dance), followed by Calopterygidae ( n = 77, 26.27%),Coenagrionidae ( n = 70,23.9%), Heteragrioni -
dae ( n = 42, 14.33%), Gomphidae and Megapodagrionidae ( n = 7 each, 2.38%), Protoneuridae ( n = 6,
2.04%), Aeshnidae( n= 5, 1.7%), and Lestidae ( n= 4, 1.36%). The most abundant specieswere Hetae -
rina longipes HageninSelys,1853(Zygoptera: Calopterygidae, n = 59), Heteragrion rogertaylori
Lencioni, 2013 (Zygoptera: Heteragrionidae, n = 32), Oxyagrion terminale Selys,1876 (Figure 4 a)
(Zygoptera: Coenagrionidae, n = 31), and Erythrodiplax fusca(Rambur, 1842) (Anisoptera: Libelluli -
dae, n = 17). Altogether, these four species accounted for 47.44% of sampled individuals.
Table 2.Richness, abundance, dominance, Shannon-Wiener diversity index, Pielou’s evenness, Chao-1 spe -
cies estimator, and number of exclusive species of Odonata sampled ( N= 293) by elevation range in the Fernão
Dias Environmental Protection Area, southern Minas Gerais, Brazil. *New records to Minas Gerais State.
Suborder/family/speciesElevation
LowMidHigh
Anisoptera
Aeshnidae
Coryphaeschna sp. 1 001
Rhionaeschna planaltica (Calvert, 1952) 001
Rhionaeschna punctata (Martin, 1908) 003
Gomphidae
Progomphus gracilis Hagen in Selys, 1854 007
Libellulidae
Brechmorhoga sp. nov. 032
Dasythemis mincki (Karsch, 1889) 033
Erythrodiplax sp. 002
Erythrodiplax a. avittata Borror, 1942 230
Erythrodiplax a.basalis (Kirby, 1897) 022
Erythrodiplax castanea (Burmeister, 1839) 001
Erythrodiplax fusca (Rambur, 1842) 11 51
Erythrodiplax media Borror, 1942 001
Macrothemis imitans Karsch, 1890 512
Macrothemis marmorata Hagen, 1868 103
Macrothemis tenuis Hagen, 1868 082
Micrathyria didyma (Selys, 1857) 100
Micrathyria stawiarskii Santos, 1953 103
Perithemis lais (Perty, 1834) 110
Perithemis mooma Kirby, 1889 200
Orthemis discolor (Burmeister, 1839) 300
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Suborder/family/speciesElevation
LowMidHigh
Zygoptera
Calopterygidae
Bryoplathanon globifer (Hagen in Selys, 1853)
006
Hetaerina brightwelli* (Kirby, 1823) 030
Hetaerina longipes Hagen in Selys, 1853 19328
Hetaerina rosea Selys, 1853 900
Coenagrionidae
Argia sordida Hagen in Selys 1865 629
Argia modesta Selys, 1865 104
Acanthagrion gracile (Rambur, 1842) 820
Acanthagrion cf.lancea (Selys, 1876) 100
Oxyagrion evanescens Calvert, 1909 010
Oxyagrion mirnae Machado, 2010 003
Oxyagrion terminale Selys, 1876 31216
Telebasis erythrina (Selys, 1876) 020
Heteragrionidae
Heteragrion aurantiacum Selys, 1862 120
Heteragrion mantiqueirae Machado, 2006* 007
Heteragrion rogertaylori Lencioni, 2013 11714
Lestidae
Archilestes exoletus (Hagen in Selys, 1862) 130
Megapodagrionidae
Allopodagrion contortum (Hagen in Selys,
1862)
232
Protoneuridae
Forcepsioneura itatiaiae (Santos, 1970) 004
Peristicta forceps Hagen in Selys, 1860 101
Ecological
parameters
Richness211926
Abundance80105108
Dominance0.11370.1472
0.07184
Diversity2.5292.3662.908
Evenness 0.83050.80340.8926
Chao-1 estimator 32.2519.528.14
Number of exclusive species53 11
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Figure 3.Richness and abundance of Odonata communities, stratified by suborder, at low, mid, and high
elevations in the Fernão Dias Environmental Protection Area, southern Minas Gerais State, Brazil.
High-elevation sites had thehighest richness( n = 26), abundance (n = 108), number of exclusive spe-
cies ( n = 11), and diversity ( H ′ = 2.908) (Table 2 and Figure 3 ). Six specieswere singletonsand ve
weredoubletons,indicatingthat28.2%ofthedragonyspeciescollectedwererare.Fivespecies
were exclusive to the low-elevation range ( Acanthagrion cf. lanceaSelys, 1876, Hetaerina rosea
Selys, 1835, Micrathyria didyma(Selys in Sagra, 1857) (Figure 4 b), Orthemis discolor Burmeister,
1839, and Perithemis mooma(Kirby, 1889), three species to mid elevation Hetaerina brightwelli
(Kirby, 1823), Oxyagrion evanescens Calvert, 1909, and Telebasis erythrina (Selys, 1876), and 11 to
high elevation (Table 2 ).
Elevation effect on Odonata diversity and species description
No distinct groups were formed by nMDS of species abundance. A stress value of 0.22 was observed,
indicatingadequateordination(Kruskal &Wish, 1978). Odonataabundancedidnotdierbetween
elevationranges, as assessed byboth PERMDISP ( F = 0.503,P > 0.05)andPERMANOVA ( F = 0.612,
P > 0.05). The Jaccard index revealed dissimilarity between samples taken at dierent elevation rang -
es (Figure 5 ). Two clusters were formed, one comprising low and mid elevations (0.43) and the other
comprising low + medium and high elevation ranges (0.32). No dierences in diversity were observed
between elevation ranges ( P> 0.05). Although diversity was numerically higher at high-elevation
sites, species dominance was lower ( D= 0.0718) and evenness was higher ( J= 0.8926) at this range.
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Figure 4. Some species reported in this study: (a) Oxyagrion terminaleSelys, 1876; (b) Micrathyria dydi-
ma (Selys in Sagra, 1857); (c) Acanthagrion gracile (Rambur, 1842); (d) Dasythemis mincki (Karsch, 1890);
(e) Heteragrion mantiqueirae Machado, 2006 ; (f) Macrothemis marmorata Hagen, 1868; (g)Rhionaeschna plan-
altica (Calvert, 1952); (h) Progomphus gracilis Hagen in Selys, 1854; (i) Rhionaeschna punctata(Martin, 1908).
Figure 5.Jaccard similarity among Odonata communities along an elevational gradient in the Fernão
Dias Environmental Protection Area, southern Minas Gerais State, Brazil.
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
The female of Heteragrion mantiqueirae Machado, 2006 (Figures 6 a−h)
Material studied
1♀ (in tandem). BRAZIL, Minas Gerais, Gonçalves, APA Fernão Dias (22.6708 S, 45.8669 W, 1410
m asl), 12.x.2019, M.M. Souza leg.
Head (Figures 6a,b) − Labrum pale withlight brownstripe surrounding the distal extremityto the
middle, postclypeus black with the edge pale, postfrons black with a black spot below each antenna,
antenna black, black band connecting middle of the eyes to occiput, vertex black, occipital bar and
occipital ridge black.
Thorax(Figures 6b, c,e) – Prothorax:anteriorlobe palewithblack spotinthe center; middle lobe
palewithlightovalblack spot oneachside, andblackstripinthecenter;hindlobewithrounded
margins, pale laterally with broad black spot inthe middle; propleuron pale. Pterothorax: middorsal
carinablack;humeralblackstripeaccompanyingthemiddorsalcarina;mesepisternumpalewith
light brownstripe; mesinfraepisternumwithbrown spot; mesepimeron with blackstripebelow the
mesopleural suture becoming lighter near the mesinfraepisternum; metepisternum and metepimeron
pale,black spotnearthemetapleuralfossa;antealarcrestandantealarcarinablack;interesternite
rounded, kidney-like, broader than and surpassing setifer, presence of a dorsal plate extending up
close to the rst thoracic spiracle (Figure 6 d).
Wings (Figure 6b) −hyalinewith dark brown venation;pterostigma brown,proximalside oblique,
overlying two cells in FWand three cells in HW; two post-quadrangularcells; 19 Px inFW and17
in HW.
Abdomen (Figures 6b, f−h) − S1 pale with adorsal blackspot; S2−9 connected by palebasal rings,
blackdorsally,becomingdark/lightbrowntowardstheventer;S10lightbrown;genitalvalvesof
ovipositor atthe samelevel ofS10, itsventraledgecontainingseveralrows ofteeth;cercibrown,
conical, slightly surpassing S10 length.
Measurements [mm] – TL 47.2; AL 37.8; FW 32.2; HW 31.2; Pt 2.3 .
Differential diagnosis
The female of H. mantiqueiraecan be separated from its female congeners by the following combi-
nation of characters (considering here only Heteragrion itacolomii Ávila Jr,Lencioni&Carneiro,
2020 , a Group A species with described female intersternite): hind lobe with rounded margins, pale
laterally with a broad black spot in the middle (in H. itacolomiirounded margins, pale laterally with
small black spots on the edges, broad spot in the middle); intersternite rounded, kidney-like, broader
than and surpassing setifer (in H. itacolomiinot kidney-like, dorsally curved with dorsal end elon-
gatedandrounded);presenceofacylindricaldorsalplateextendingupclosetotherstthoracic
spiracle(in H. itacolomii dorsalplateabsent); ovipositoratthesamelevel ofS10 (in H. itacolomii
slightly surpassing S10 level).
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Figure 6.Female of Heteragrion mantiqueirae: (a) dorsal view of head; (b) lateral view of female habitus;
(c) dorsal view of thorax; (d) intersternite; (e) dorsal view of mesostigmal plates and prothoracic hind
lobe; (f) S9-S10, cerci and genital valves in lateral view; (g) genital valves in ventral view; (h) S9-10 and
cerci in dorsal view. DP: dorsal plate; Is: intersternite; Se: setifer.
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Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Discussion
Richness, abundance and distribution of Odonata communities
Thetwo familieswiththehighestspeciesrichness in thisstudy, LibellulidaeandCoenagrionidae,
followed the pattern alsoobserved in other inventories (Costa et al., 2000; Ferreira-Peruquetii & De
Marco, 2002 ;De Marco& Viana 2005 ; Costa& Oldrini, 2005 ; Dalzochio et al., 2011 ; Souza etal.,
2013 ; Bedê et al.,2015 ; Amorim et al., 2018 ; Borges et al., 2019 ; Barbosa, et al.,2019 ; Silva & Souza,
2020 ; Palacino-Rodrígues et al.(2020 ). This result was expected given the large number of Libellu-
lidae and Coenagrionidae species occurring in Brazil, 237and 325respectively (Pinto, 2020 ), as they
represent more than 60% of the total of Brazilian species.
Hetaerina species areabundant in lotic environments with faster currents (Vega-Sánchez etal., 2011 ;
Amorim et al., 2018 ), H. longipes hasbeenobservedindierentelevationrangesandbiomesin
Minas Gerais (Dos Anjos, 2017 ; Borges et al., 2019; Vilela et al., 2020 ).In this study, Hetaerina were
found to be common at low and mid-elevation sites with the same environment (Table 1 ). Hetaerina
rosea is widely distributed throughout the State, occurring mainly in lotic environments, including
impactedareas(Peruquetti &De Marco,2002; Souzaet al., 2013; Bedêet al., 2015;Amorimet al.,
2018 ; Silva & Souza, 2020 ). Here H. rosea was registered at low-elevation with high pasture growth,
presenceofEucalyptuscultivationandinitialor intermediatestagesofecologicalsuccession. We
registered for therst time H. brightwellii in Minas Gerais occurring at mid-elevation and was previ-
ouslyreportedtooccurinOmbrophilousforestsandAtlanticForest sitesinRiodeJaneiroState
(Santos, 1997 ), Espírito Santo State (Storari et al., 2019 ) and São PauloState (Costa et al., 2000 ). The
high abundance of Hetaerinaindividuals may also be due to the morphological, physiological, and
functionaltraitsthatcontributetotheirlonglife span(Córdoba-Aguilar&Cordero-Rivera, 2005;
Pedraza-Hernández, 2010 ). Such factors may explain the distribution of Hetaerinaspecies along the
elevational gradient.
Oxyagrion terminale Selys, 1876 (Figure 4a) is widely distributed in Minas Gerais, occurring in
Seasonal Semideciduous forest at 900–1100 m elevation (Souza et al., 2013 ), in Campos Rupestres
(Rupestrian Fields) associated with Seasonal Semideciduous forests at1000–1400m elevation (Bedê
et al., 2015 ), andin theCerrado (Vilela et al., 2020), what explains its occurrence and frequency in
the present study. Oxyagrion evanescens Calvert, 1909, foundat mid-elevationsites, wasreported to
occur in Semideciduous forest areas in Minas Gerais (Souza et al., 2013 ; Amorim et al., 2018 ),
Heteragrion rogertaylori was recorded in dense, well-preserved areas of seasonal Semideciduous
forests by Amorim et al. ( 2018). The same pattern was found herein, with the species being more
abundantatmidandhigh-elevations(Figure 3 ) in lotic environments with dense vegetation cover.
Environments with these characteristics are commonly inhabited by the family Heteragrionidae.
Erythrodiplax fusca (Rambur, 1842) also has wide geographical distribution across lotic and lentic
environments (Ferreira-Peruquetti & De Marco, 2002 ), including shtanks (Fonseca et al., 2004 ). E.
fusca is used as an indicator of environmental impacts on watercourses and riparian forests (Mon-
teiro Júnior et al., 2013), explaining the abundance of this species at low-elevation in our study in an
environmentwith the presence of Eucalyptus cultivation, high degree of Pasture growth,and initial
and intermediate stages of ecological succession.
The species Acanthagrion cf. lancea Selys, 1876has one of the narrowest distributions among spe-
ciesexclusive tolow-elevationranges.Fewstudieshavedescribeditsoccurrence,althoughithas
been observed indierentecosystems(Santos & Machado, 1983; Vilela etal., 2016;Barbosaet al.,
2019 ; Borges et al.,2019 ), including articial environments such as sh tanks (Vale & Souza,2019 ).
On the other hand, Telebasis erythrina (Selys, 1876) was found to occur in Cerrado and Semidecidu -
ous forest regions in the State (Lencioni, 2011 , 2017 ). T. erythrina(Selys, 1876) was found in regions
of Cerrado andsemideciduous forestin theState (Lencioni, 2011 , 2017). Here, thespecies T. eryth-
rina was recorded at mid-elevation, an environment with vegetation characterized by Mixed and
Semideciduous forest with intermediate stages of ecological succession and low pasture growth, al-
though it presents Eucalyptus cultivation and high ecotourism activities.
191
Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
Orthemis discolor , M. didyma and P. mooma were exclusive to low-elevation and this same distribu-
tion patternis alsoreported inother studies(De Marco &Resende, 2002;Peruquetti & De Marco,
2002 ; Giacomini& DeMarco2008 ; Souzaet al., 2013 ; Bedêet al.,2015 ;Vilela et al., 2016 ,2020 ;
Amorim et al. 2018 ;Barbosaetal., 2019 ;Borgesetal., 2019 ;Silvaetal., 2020 ;Souzaetal., 2013 ;
Souza et al., 2017 ).
Thehighelevationrangewascharacterizedbyhighcanopycoverage.Previousstudiesidentied
three species occurring exclusively at this range in forest areas: Bryoplathanon globifer (Hagenin
Selys, 1853)which was recorded above 1600 m in a mixed forest in Serra do Papagaio State Park
(Dos Anjos, 2017 ), Oxyagrion mirnaeMachado, 2010 and H. mantiqueirae Machado, 2006 (Fig-
ure 4 e) above 1500 m in Zona da Mata Region (Machado, 2006 , 2010)
A new species of the genus Brechmorhoga ,which hadbeenmistakenly identied as B. tepeaca by
Santos ( 1946 ), was observed at high elevations. Kompier ( 2015) suggested that specimens of this spe-
cies, treated by him as B. tepeacasensu Santos, should be properly described. The results show that
these species are restricted to the highest and most conserved areas and underscore the importance
of preserving these locations in the municipality of Gonçalves.
Elevation effect on Odonata diversity
No distributionpattern wasfoundfor Odonataalongthe elevationalgradient of Fernão Dias Envi -
ronmental Protection Area. Probably other factors than altitude have a greater inuence on the drag -
ony communities in this area. Dierent bioticand abioticfactors, such as vegetation cover,resource
availability,temperature,andrelativehumidity,aredirectlyinuencedbyelevation(Fernandes,
2016 )and, therefore, analysisof altitude alonemay notprovide sucient insightintotheeects of
elevational gradient on diversity (Körner, 2007 ). We work here with categorical variables (low, mid
and high elevation)and didnot nda statistically signicant distribution pattern. However,if thedata
were categorical the resultscould bedierent and therecould bea tendencyfor dragony distribu -
tion along theelevationalgradient.Inthisstudy, dragonydistributionandcompositionalongthe
elevational gradient seemed to be inuenced by vegetation cover, fragmentation, and degree of con -
servation (Table 1 ). Such relationships wereobservedfor Heteragrionidae, which weremore abun -
dant in freshwater environments with dense vegetation, slow currents, and high conservation degree
(Machado, 1988 ; Ferreira-Peruquetti&De Marco, 2002 ), as alsopresentindierentlocationsand
ecosystems in Minas Gerais, particularly in semideciduous forests (Souza et al., 2013 ;Machado&
Souza, 2014 ; Machado, 2014 Amorim et al., 2018 ; Souza et al., 2018 ).
The Jaccard index revealed that the greater distance between high-elevation samples and other
groupsmayindicatethatthisareahasa diverse community. AccordingtoKent and Coker( 1992 ),
values above 0.5 indicate high similarity, which did not occur in the present study. The Jaccard index
measures similarity in a qualitative manner. That is, it analyzes the proportion of species shared be-
tween samples in relation to the total number of species and does not consider the number of indi-
vidualsinagivensample;rather,ittakesintoaccounttheirpresenceorabsence(Ferreiraetal.,
2008 ). This helpsto explain the occurrence ofexclusivespecies at the evaluated sites. Dierentcom -
munitieswereobservedatdierentelevationranges,particularlyathighelevation(Table 2 ), in
agreement with Leksono et al. ( 2017). Thus, elevation, degree of conservation, and forest size may
aect Odonata community composition.
Leksono et al. ( 2017 )investigatedOdonatacommunitiesoccurringatdierentelevationrangesin
Java Island,Indonesia,andfoundnodierencesinabsolutevalues ofspeciesrichness between15
and1970m(a.s.l.).However,apositiverelationshipwasobservedbetweenelevationandgeneral
abundance, with the highest abundance at the highest elevation and the lowest abundance at the low-
estelevation.Incontrast,negativerelationshipsbetweenOdonataspeciesrichnessandelevation
were observedalong a ~4000 m gradientin Ecuador (Jacobsen, 2004 ), a ~2500 m gradient in Swit-
zerland (Oertli et al., 2002 ), and a ~1120 m gradient in Mexico (Novelo-Gutierrez & Gómez-Anaya,
2009 ). In Brazil, Oliveira-Junior et al. 2015 ,2019 ) and Oliveira-Junior and Juen (2019 b) investigated
the occurrence of Odonata in Amazonian streams at 31–156 m (a.s.l.) elevation. The authors showed
192
Stefani-Santos et al.: Odonata (Insecta) communities in the Atlantic forest of southeastern Brazil
that elevational gradient alone did not inuencecommunity composition but,when associated with
degreeofconservationandvegetationcover, signicanteectsoncommunitycompositionwere
exerted.
Conclusions
Elevational gradientdid not inuence the richness or abundance of Odonata in theFernão DiasEn -
vironmental Protection Area, Gonçalves, Minas Gerais, Brazil. However, dierences in community
composition were observed along the gradient, particularly at the high elevations, where many rare
species were seen. For instance, we record,for the rst time in Minas Gerais State, H. mantiqueirae
Machado, 2006 , and we present a description and diagnosis of a single female found at high elevation
sites. Additionally, a new species of Brechmorhoga, found at mid-and high-elevation ranges is being
currently describedby some of the authors. The ndings show that, at high elevation, a high degree
of conservation resulted in a greater number of unique species, underscoring the relevance of forest
preservationinthehigherareasofthisenvironmentalprotectionunit.Forestrestorationeorts
should be directed toward mid- and, particularly, low-elevation sites.
Acknowledgements
Thiswork wassupportedbytheGonçalves CityHallfor supportunderGrant,Federal Instituteof
SouthernMinas Gerais,CampusIncondentes.We thankIsabelLirafromtheMunicipalTourism
Council(COMTUR), Councilor LeandroPiola, Secretary ofTourismRafaelaRosa. We alsothank
Bicho doMato, Espaço Kalevala, Vida Verde,and Fazenda das Rosas for providing accommodation;
the tourism agencies Tribo da Montanha, Gonçalves Radical, Conexão Gonçalves,Padaria São Fran -
cisco, Kalapalo Editora,ImobiliáriaCampesino, FlorestaBarnabé; and the localresidentsfor their
contribution and logistic support. Finally, we are grateful to the Federal Institute of Southern Minas
Gerais, Campus Incondentes, for the support.
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| https://www.researchgate.net/publication/356175142_2021_-_Stefani-Santos_et_al_2021_Odonata_Insecta_communities_along_an_elevational_gradient_in_the_Atlantic_forest_of_southeastern_Brazil |
Jones v. Hess, No. 80-2214 - Federal Cases - Case Law - VLEX 888205106
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
Jones v. Hess, No. 80-2214
Court United States Courts of Appeals. United States Court of Appeals (10th Circuit) Writing for the Court Before HOLLOWAY, DOYLE, and SEYMOUR; HOLLOWAY; ROBERT J. BELL; ROBERT J. BELL Citation 681 F.2d 688 Parties Edwin Edgar JONES, Petitioner-Appellant, v. Norman HESS and the State of Oklahoma, Respondents-Appellees. Docket Number No. 80-2214 Decision Date 01 June 1982
Page 688
681 F.2d 688
Edwin Edgar JONES, Petitioner-Appellant, v. Norman HESS and the State of Oklahoma, Respondents-Appellees.
No. 80-2214.
United States Court of Appeals, Tenth Circuit.
James A. Mitchell, Oklahoma City, Okl., for petitioner-appellant.
David W. Lee, Asst. Atty. Gen., Chief, Crim. Div., Oklahoma City, Okl. (Jan Eric Cartwright, Atty. Gen. of Oklahoma, Oklahoma City, Okl., was also on the brief), for respondents-appellees.
Before HOLLOWAY, DOYLE, and SEYMOUR, Circuit Judges.
HOLLOWAY, Circuit Judge.
In August 1971, petitioner-appellant Jones was convicted by a jury on two counts of murder and one count of shooting with intent to kill. 1 In accordance with the jury's verdict and sentencing determination, the District Court of Pittsburg County, Oklahoma, entered judgment and sentenced Jones to two terms of life imprisonment on the murder counts and a term of 20 years' imprisonment on the count of shooting with intent to kill, the sentences to run consecutively. On direct appeal, the Court of Criminal Appeals of Oklahoma affirmed the convictions in May 1973. Jones v. State, 509 P.2d 924 (Okla.Crim.App.).
Jones filed a petition under 28 U.S.C. § 2254 for a writ of habeas corpus in the United States District Court for the Eastern District of Oklahoma in March 1976. That petition was dismissed in March 1977 for failure to exhaust state remedies. On March 25, 1977, Jones filed in the District Court of Pittsburg County, Oklahoma, an application for post-conviction relief. Following an evidentiary hearing, the court denied the application in September 1977. On appeal from that decision, the Oklahoma Court of Criminal Appeals affirmed the district court's decision in April 1978.On
Page 690
June 9, 1978, however, the Court of Criminal Appeals on its own motion withdrew its order, pending further consideration. That court re-affirmed the denial of post-conviction relief on April 10, 1979, in an unpublished opinion with one judge dissenting.
The instant habeas petition was filed in May 1979, alleging nine grounds for relief. Discovery was allowed, and the federal magistrate held an evidentiary hearing. On September 30, 1980, the magistrate issued his proposed findings of fact and recommendations for disposition. The district court adopted those findings and recommendations and denied the petition on October 14, 1980.(I R. 137). This timely appeal followed.
I
We will only briefly review the facts surrounding the charges since a detailed summary of the evidence is found in the opinion of the Court of Criminal Appeals, 509 P.2d at 925-927. The state trial testimony reveals these facts:
On February 17, 1971, Jones and his cousin, William B. Franklin, stopped in Fountain Head State Park in eastern Oklahoma while en route to Texas. Franklin had once been convicted of a felony but had received a full pardon. He held a federal license to deal in firearms at the time of the events involved here. A game ranger, W. L. Pickens, had heard gunfire in the park and investigated. When he came upon Jones and Franklin, Pickens observed firearms in Jones's car and told the pair that it was against state law to possess firearms in a state park.
The weapons were placed in the back of Pickens's vehicle, and the three drove to another location. They were joined by Park Superintendent Leo Newton and Oklahoma Highway Patrol Trooper Bill Walker. Franklin telephoned a deputy sheriff in Okmulgee for whom Franklin had done undercover work to see if he would vouch for them. Walker then frisked Jones.
The testimony varied as to what happened next. According to Franklin, who had been convicted separately after a severance was granted, he attempted to hand a gun which he had been wearing to Newton. Franklin testified that he heard Newton yell, "Look out he's got a gun" and saw Walker fire at him; he then shot Walker and Newton; he was not sure that Pickens had been shot; Jones did not do any of the shooting; and over the next four days Jones tried to talk Franklin into surrendering.
Jones testified that he was unarmed during the shooting and dove for cover; he saw Franklin shoot Walker and Newton; he was in a state of disbelief during the shooting; he fled with Franklin at Franklin's urging; they unloaded and hid the weapons to prevent anyone else from being shot; and he finally succeeded in convincing Franklin to give himself up. After four days they surrendered.
Park Superintendent Newton and Trooper Walker were dead when law enforcement officials arrived. Ranger Pickens had received gunshot wounds in the head and was conscious but unable to talk. Pickens testified that he was hit on the third or fourth shot but didn't know who shot him. On cross-examination he admitted having stated at the preliminary hearing that it was Franklin who shot him "because he (Franklin) was the only one with a gun."
The jury found Jones guilty of both murders and of shooting Pickens with intent to kill. It recommended a life sentence on each of the first two counts and 20 years' imprisonment on the shooting count. (II R. 168; III R. 246; IV R. 91).
Jones alleged nine grounds for relief in this federal habeas petition. Essentially he averred unethical and prejudicial conduct on the part of the prosecution; bias and inadequacy of the trial judge; incompetency of appointed counsel; lack of meaningful appellate review due to ineffectual counsel and an apparently biased or ineffective State appellate court; total lack of evidence that Jones had knowledge of, took part in, or condoned the crimes; failure of the prosecution to fully advise him and give notice
Page 691
of the charge in violation of the Sixth Amendment and the Oklahoma Constitution; refusal to hold void for vagueness 21 O.S.1971 § 1283 (prohibiting convicted felons from carrying firearms) due to varying interpretations of the effect of pardons; failure to instruct on the elements of aiding and abetting a felon in the possession of a firearm capable of concealment, after a former conviction; and denial of due process and equal protection by lack of reconciliation of conflicting interpretations on the effect of pardons. (I R. 7-8).
The federal district court adopted the findings and recommended disposition of the magistrate, thus denying on the merits all claims except the claim of "apparent bias or inadequacy of the trial judge." That claim was dismissed without prejudice for failure to exhaust state court remedies. On appeal, Jones asserts that the district court erred in its adverse ruling on each of the nine claims.
We turn first to the background underlying the district court's dismissal, for lack of exhaustion, of the claim of "apparent bias or inadequacy of the trial judge." (Appellant's Brief in Support of Appeal at 34-39; Brief of Appellees at 13-14; Reply Brief of Appellant at 6-8). From the habeas petition and petitioner's briefs, it appears that this claim is based on the Fourteenth Amendment Due Process and Equal Protection Clauses and the constitutional right to a fair trial.
Jones points to several acts by the state trial court which allegedly demonstrate its bias and prejudice, including appointment of allegedly incompetent defense counsel, a request that the Governor appoint a special prosecutor (VII R. 64; see XII R. 496), various rulings at trial which are said to evidence prejudice, and "failure to exercise supervisory control" over alleged prosecutorial misconduct.(I R. 9-10). We note that Jones made some similar arguments in his state post-conviction proceedings. (II R. 274, 318-24, 463-64; V R. Appeal from Denial of Post Conviction Relief (filed Oct. 5, 1977) at 4-5, Brief in Support of Appeal from Denial of Post Conviction Relief (filed Oct. 5, 1977) at 35-41). However, for reasons discussed in Parts II B and III infra, we must agree with the trial court's ruling that this claim of bias or inadequacy of the state trial judge has not been exhausted in the state courts for purposes of 28 U.S.C. § 2254 .
Our basis for this conclusion requires that we examine in some detail the evidentiary showing on this issue at the federal hearing on the claim. Petitioner Jones there offered testimony and exhibits to demonstrate ex parte communications between the state trial judge and the prosecution, a substantial claim from its appearance. Jones introduced, without objection, copies of three letters (reproduced infra as Appendices A, B, and C) apparently written to the prosecuting attorney by Judge Robert J. Bell, the State trial judge, who was deceased by the time of the federal evidentiary hearing. (VII R. 1, 3, 4; XIV R. 36, 41-42, 47). The letters indicate that copies were sent to an Assistant Attorney General. Two were marked "confidential." Mr. Foor, Jones's appointed defense counsel in the state court, testified that he never received copies of these letters.(XIV R. 59, 60, 64. See XIV R. 94).
The handwritten notations at the bottom of Plaintiff's Exhibit 1 (Appendix A) are citations to authority later relied on by the prosecution at a sanity hearing which related to codefendant Franklin.(XIV R. 39-41). The letter refers, inter alia, to an intended sanity hearing and authority permitting officers who have observed a defendant to testify against commitment. The letter states that it "is written in confidence." The judge's court reporter and secretary at the time, Ms. Gwen Burba, testified that she typed the letter and that she recognized Judge Bell's signature and notations at the bottom.(XIV R. 95, 97-98).
Ms. Burba also testified that the signature on Plaintiff's Exhibit 2 (Appendix B) was Judge Bell's and that the typing was
Page 692
hers. (XIV R. 98). The letter appears to reveal defense strategy which the judge "happened to overhear", relating to a defense motion for a severance. (See XIV R. 42-44). Mr. Foor testified that seeing the letter "totally shocked" him, but that it was possible he had revealed the...
Osborn v. Shillinger, No. 86-2175 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) November 7, 1988 ...18, 19-20, 70 L.Ed.2d 1 (1981) (per curiam); Picard v. Connor, 404 U.S. 270, 275, 92 S.Ct. 509, 512, 30 L.Ed.2d 438 (1971); Jones v. Hess, 681 F.2d 688 , 693-94 (10th Cir.1982). To fulfill the exhaustion requirement, a petitioner must present his claim to a state appellate court. White v. Me......
Fontenot v. Crow, No. 19-7045 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) July 13, 2021 ...and pieces of argument to his Brady and actual innocence claims based upon the recently produced Ada police reports"); cf. Jones v. Hess , 681 F.2d 688 , 694 (10th Cir. 1982) (" ‘[B]its of evidence’ which were not before the state courts will not render a claim unexhausted." (quoting Nelson ......
Adarand Constructors v. Slater, No. 97-1304 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) September 25, 2000 ...(10th Cir. 1999) (applying Landgraf), cert. denied sub nom. Palaganas-Suarez v. Greene, 120 S. Ct. 1539 (2000); see also Jones v. Hess, 681 F.2d 688 , 695 n.9 (10th Cir. 1982) ("Generally an appellate court must apply the law in effect at the time it renders its decision where a change in la......
47 cases
Osborn v. Shillinger, No. 86-2175 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) November 7, 1988 ...18, 19-20, 70 L.Ed.2d 1 (1981) (per curiam); Picard v. Connor, 404 U.S. 270, 275, 92 S.Ct. 509, 512, 30 L.Ed.2d 438 (1971); Jones v. Hess, 681 F.2d 688 , 693-94 (10th Cir.1982). To fulfill the exhaustion requirement, a petitioner must present his claim to a state appellate court. White v. Me......
Fairchild v. Workman, No. 06-6327. United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) August 31, 2009 ...converting the claim into a new one. 291 F.3d at 670 (quoting Demarest v. Price, 130 F.3d 922, 932 (10th Cir.1997)); Jones v. Hess, 681 F.2d 688 , 694 (10th Cir.1982) (quoting Nelson v. Moore, 470 F.2d 1192, 1197 (1st Cir.1972)). But at a certain point, when new evidence so changes the legal......
Fontenot v. Crow, No. 19-7045 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) July 13, 2021 ...and pieces of argument to his Brady and actual innocence claims based upon the recently produced Ada police reports"); cf. Jones v. Hess , 681 F.2d 688 , 694 (10th Cir. 1982) (" ‘[B]its of evidence’ which were not before the state courts will not render a claim unexhausted." (quoting Nelson ......
Adarand Constructors v. Slater, No. 97-1304 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) September 25, 2000 ...(10th Cir. 1999) (applying Landgraf), cert. denied sub nom. Palaganas-Suarez v. Greene, 120 S. Ct. 1539 (2000); see also Jones v. Hess, 681 F.2d 688 , 695 n.9 (10th Cir. 1982) ("Generally an appellate court must apply the law in effect at the time it renders its decision where a change in la......
| https://case-law.vlex.com/vid/jones-v-hess-no-888205106 |
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U.S. v. Rodriguez, No. 94-3935 - Federal Cases - Case Law - VLEX 886403102
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
Federal Cases
U.S. v. Rodriguez, No. 94-3935
Court United States Courts of Appeals. United States Court of Appeals (7th Circuit) Writing for the Court Before COFFEY, EASTERBROOK and RIPPLE; RIPPLE Citation 69 F.3d 136 Parties UNITED STATES of America, Plaintiff-Appellee, v. Tomas RODRIGUEZ, Defendant-Appellant. Docket Number No. 94-3935 Decision Date 23 October 1995
Page 136
69 F.3d 136
UNITED STATES of America, Plaintiff-Appellee, v. Tomas RODRIGUEZ, Defendant-Appellant.
No. 94-3935.
United States Court of Appeals, Seventh Circuit.
Argued Sept. 13, 1995. Decided Oct. 23, 1995.
Page 138
Barry Rand Elden, Asst. U.S. Atty., Collen Coughlin (argued), Office of the U.S. Attorney, Criminal Appellate Division, Chicago, IL, for plaintiff-appellee.
Alexander M. Salerno, Berwyn, IL, argued for defendant-appellant.
Before COFFEY, EASTERBROOK and RIPPLE, Circuit Judges.
RIPPLE, Circuit Judge.
After entering a conditional plea of guilty to an indictment charging him with possession of cocaine with intent to distribute in violation of 21 U.S.C. Sec. 841(a) (1), Tomas Rodriguez now appeals his conviction. He challenges the legality of the arrest and search that led to his indictment, the district court's determination of his suppression motion without a hearing, and the district court's application of the sentencing guidelines in determining his sentence. For the reasons set forth in the following opinion, we affirm the judgment of the district court.
I
BACKGROUND
A. Facts
On June 21 and 22, 1994, Tomas Rodriguez flew from Los Angeles to Chicago's O'Hare International Airport with a stopover in Las Vegas. On the morning of June 22, agents of the Drug Enforcement Agency ("DEA") and the United States Customs Service received a tip from a confidential informant that Mr. Rodriguez would be arriving at O'Hare that morning and that he had purchased his one-way ticket with cash. Acting on this information, two officers assigned to the DEA Airport Task Force met Mr. Rodriguez' flight and observed his activities upon arrival.
When Mr. Rodriguez arrived at the gate in Chicago, he began looking nervously around the terminal. According to the agents, he appeared to be engaging in counter-surveillance. The agents then followed him to the baggage claim area and observed as Mr. Rodriguez waited until all the other passengers from his flight had retrieved their luggage before he claimed his own bag. 1
As Mr. Rodriguez walked toward the exit of the airport, one of the agents approached Mr. Rodriguez and identified himself as a law enforcement officer. Mr. Rodriguez agreed to answer a few questions; he confirmed his name for the agent and the flight upon which he had just arrived. Also upon request, he produced his airline ticket and verified his ownership of the bag he had just retrieved. In the view of one of the officers, Mr. Rodriguez became "extremely nervous" during the course of the encounter.
The agent then asked for Mr. Rodriguez' consent to search his luggage. When Mr. Rodriguez agreed, he and the agent moved away from the doorway, and Mr. Rodriguez opened his bag. In the bag agents observed two brick-shaped packages, each of which subsequently was found to contain a kilogram of cocaine.
B. Proceedings in the District Court
Mr. Rodriguez, through counsel, filed a motion seeking additional discovery and a motion to quash his arrest and suppress evidence. The district court initially granted the motion for additional discovery and set for hearing the motion to suppress. Upon the government's motion for reconsideration, however, the district court vacated its order scheduling a suppression hearing and denied defendant's motion to quash the arrest and suppress evidence. As a result of the district court's ruling, Mr. Rodriguez' request for additional discovery was rendered moot.
Page 139
The district court took the view that Mr. Rodriguez had not met his burden of making the prima facie showing of illegality necessary to entitle him to a suppression hearing. Noting that Mr. Rodriguez' motion focused on events leading up to the encounter, the court found that the record, on its face, supported a finding that the actual encounter and subsequent search was consensual.
The district court addressed Mr. Rodriguez' claim that his consent was not given voluntarily but was instead the product of trickery by officers specially trained to obtain waivers of constitutional rights. The court stated that he had not supported these allegations with definite, specific, detailed, and nonconjectural facts. Characterizing Mr. Rodriguez' allegations of illegality in this manner, the court determined that a hearing on the motion to suppress was not required.
Turning to the merits of the motion, the court determined that the lack of sufficient evidence to require a hearing on the motion to suppress foredoomed the motion itself. In reaching this conclusion, the court relied on the objective test of United States v. Mendenhall, 446 U.S. 544 , 100 S.Ct. 1870 , 64 L.Ed.2d 497 (1980): " [A] person has been 'seized' within the meaning of the Fourth Amendment ... only if, in view of all the circumstances surrounding the incident, a reasonable person would have believed that he was not free to leave."Id. at 554, 100 S.Ct. at 1877. The district court took the view that, under Mendenhall, the airport encounter did not rise to the level of a "seizure." To determine whether the search was consensual, the district court applied the factors set forth in United States v. McCarthur, 6 F.3d 1270 , 1276 (7th Cir.1993), and found that Mr. Rodriguez had voluntarily consented to the search.
The district court rejected Mr. Rodriguez' argument that his consent had been obtained through subtle psychological coercion employed by officers specially trained to employ such tactics. The district court held that, because the test is an objective one, and the focus is on what a reasonable suspect would have felt free to do, the agents' subjective motivation and training are immaterial. The court found no evidence in the record to support the conclusion that Mr. Rodriguez had not voluntarily consented to the search.
On September 1, 1994, the district court accepted Mr. Rodriguez' conditional plea of guilty to the indictment. Prior to sentencing, Mr. Rodriguez petitioned the district court to sentence him below the statutory mandatory minimum as permitted by Sec. 5C1.2 of the Sentencing Guidelines. At sentencing, however, the district found that Rodriguez had not furnished all the information within his knowledge concerning the offense, as required for downward departure under Sec. 5C1.2, and sentenced him to the statutory minimum five years' imprisonment.
II
DISCUSSION
A. Denial of Hearing
We first address whether the district court properly denied Mr. Rodriguez' motion to quash his arrest and suppress evidence without an evidentiary hearing.
Mr. Rodriguez characterizes the June 22 encounter at O'Hare as a "seizure" of his person as that term is employed in our Fourth Amendment jurisprudence. He contends that his rights were violated because the agents lacked reasonable suspicion or other articulable basis that would justify their approaching and detaining him. See Terry v. State of Ohio, 392 U.S. 1 , 30, 88 S.Ct. 1868 , 1884-85, 20 L.Ed.2d 889 (1968). In support of this contention, Mr. Rodriguez tendered an affidavit and investigator's report to establish: 1) that the officers could not have known that he purchased his one-way ticket with cash; and 2) that his luggage was placed last on the baggage carousel at the request of the government.
Mr. Rodriguez first offered the affidavit of Ms. Verity McGregor, the travel agent who had sold him the airline ticket to Chicago. In her affidavit, Ms. McGregor stated that she was not the confidential informant who provided information about Mr. Rodriguez' travel plans or ticket purchase to law enforcement personnel in Chicago. The second document offered by Mr. Rodriguez is the report of Thomas C. Scrivener, an investigator
Page 140
with the Federal Defender Program, summarizing interviews his office conducted with baggage handlers for Mr. Rodriguez' flight. The report indicates that one of the baggage handlers, Scott Mattson, told the investigator that he had been approached by a large agent and instructed to look out for a particular bag. After Mr. Mattson found the luggage, according to the report, the agent then asked him to place the luggage on the conveyor belt last.
According to Mr. Rodriguez, these documents establish that the agents could not have had any valid ground to detain him; the encounter, therefore, violated his rights under the Fourth Amendment. Because Mr. Rodriguez characterizes the airport encounter as a nonconsensual stop, 2 he contends that he met his burden of making a prima facie showing of illegality in the district court and was thus entitled to additional discovery and an evidentiary hearing to develop his allegations.
The government takes a decidedly different view of the matter. It contends that the Fourth Amendment was not implicated by the encounter leading up to Rodriguez' arrest. In its view, the objective, uncontested facts with respect to the encounter--the circumstances under which Mr. Rodriguez was approached, the questions asked by the agent and the answers given by Mr. Rodriguez--establish that the consent was voluntary and that no coercion took place. The government emphasizes that Rodriguez' subjective feeling that he was not free to leave is irrelevant under the objective Mendenhall test. It further argues that the district court correctly applied the McCarthur...
United States v. Arms, Case No. 14-CR-78 United States United States District Courts. 7th Circuit. United States District Court of Eastern District of Wisconsin June 3, 2015 ...there was a disputed issue of material fact United States v. Toro, 359 F.3d 879, 885 (7th Cir. 2004) (citing United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir. 1995)). A defendant who offers only vague or conclusory allegations fails in his burden to present a prima facie showing of ill......
U.S. v. Jerez, s. 95-1549 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) May 19, 1997 ...The test, as with the "free to leave" formulation, is an objective one and requires a contextual approach. United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir.1995); Notorianni, 729 F.2d at 522. The determination of whether an encounter is a seizure is made on the basis of the "totality o......
Lanigan v. Village of East Hazel Crest, Ill., 96-1442 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) March 28, 1997 ...through noncoercive questioning. This is not a "seizure" within the meaning of the Fourth Amendment. United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir.1995) (citations omitted). The encounter in this case falls into the second category--a brief, non-intrusive detention. Based on the spe......
79 cases
United States v. Arms, Case No. 14-CR-78 United States United States District Courts. 7th Circuit. United States District Court of Eastern District of Wisconsin June 3, 2015 ...there was a disputed issue of material fact United States v. Toro, 359 F.3d 879, 885 (7th Cir. 2004) (citing United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir. 1995)). A defendant who offers only vague or conclusory allegations fails in his burden to present a prima facie showing of ill......
U.S. v. Leveto, No. CRIM. 01-6(1). United States United States District Courts. 3th Circuit. United States District Courts. 3th Circuit. Western District of Pennsylvania November 2, 2004 ...violate his constitutional rights). The burden is on the defendant to establish the necessity for the hearing. United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir.1995). That burden can be met only upon the presentation of "definite, specific, detailed, and nonconjectoral facts." A. Affid......
U.S. v. Jerez, Nos. 95-1549 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) May 19, 1997 ...The test, as with the "free to leave" formulation, is an objective one and requires a contextual approach. United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir.1995); Notorianni, 729 F.2d at 522. The determination of whether an encounter is a seizure is made on the basis of the "totality o......
Lanigan v. Village of East Hazel Crest, Ill., No. 96-1442 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) March 28, 1997 ...through noncoercive questioning. This is not a "seizure" within the meaning of the Fourth Amendment. United States v. Rodriguez, 69 F.3d 136 , 141 (7th Cir.1995) (citations omitted). The encounter in this case falls into the second category--a brief, non-intrusive detention. Based on the spe......
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?G of ATP Hydrolysis and Cytosolic [ADP] Assessed at the End of Exercise by 31P-MRS in the Calf Muscle of Patients with Myo-Phosphorylase Deficiency FUN (Fase UNwrapping) - Validation of a 2D Region-Growing Phase Unwrapping Program (1)H-HRMAS for Quantitative Measurement of Choline Concentration in Amniotic Fluid as a Marker of Fetal Lung Maturity: Inter- And Intra-Observer Reproducibility Study B1-Insensitive Transmission Lines for RF-Safe Active Tracking of a Robotic Assistance System In Vitro Mitochondrial Labeling Using Mito-Carboxy Proxyl (Mito-CP) Enhanced Magnetic Resonance Imaging In Vivo 19F CSI of 2-Fluoro-2-Deoxy-D-Glucose and 2-Fluoro-2-Deoxy-D-Glucose-6-Phosphate in Rat Brain In Vivo and post Mortem Identification of an Atrial Septal Defect in eTbx5-KO Mice In Vivo Assessment of Canine Prostate Cryoablations with Magnetization Transfer Imaging In Vivo Assessment of Canine Prostate Thermal Ablations with Magnetization Transfer Imaging In Vivo Assessment of Trabecular Bone Microstructure of the Distal Radius Using a Compact MRI In Vivo Detection of Histone Deacetylase Inhibition by MRS In Vivo Evaluation of an Inducible MRI Reporter Gene In Vivo Localized Proton Detection of Carbon-13 Magnetization Transfer Effect of Specific Enzyme Reactions In Vivo Magnetic Resonance Microimaging in Adult Zebrafish In Vivo Measurement of 13C Isotopic Enrichment of Brain Glycogen. Effect of Adrenergic Stimulation on Glycogen Turnover. In Vivo Measurement of the Hypoxia Marker EF5 Using 19F NMR Spectroscopy In Vivo Monitoring of Local Inflammation After Acute Infarction by 1H/19F MRI In Vivo Morphological and Parametric Analysis of Stem Cell Migration on MRI: Investigation of Viable and Non-Viable Behavior In Vivo T2, T1?, and Sodium Imaging of Articular Cartilage at 3.0T: Initial Experience In Vivo Temperature Assessment Using 1H NMR Chemical Shifts of NAA-Water and TmDOTP5- T1? Imaging with Weak B1 Fields in the Presence of Frequency Offsets 1H and 31P Spectroscopy of the Liver in Patients Undergoing Long-Term Total Parenteral Nutrition (TPN) 1H MR Spectroscopy of Human Bile for Rapid and Non-Invasive Diagnosis of Pancreatic Cancer 1H MR Spectroscopy of Human Bile in the Diagnosis of Chronic Cholestatic Disorders: Primary Sclerosing Cholangitis and Cholangiocarcinoma 1H MRS Assessment of Spermatogenic Activity in Experimentally Injured Rat Testes 1H MRS During Creatine Supplementation in GAMT Deficient Knockout Mice Elucidates an Early Difference in Creatine Uptake Between Muscle and Brain 1H MRS of Cortical and Cerebellar Brain Extracts of Ataxic Migraine Mice 1H MRSI Study of Effects of Cognitive-Behavioral Therapy on Obsessive-Compulsive Disorder 1H-MR Spectroscopy at 7.0 T and Intra-Individual Comparison to 3.0 T and 1.5 T 129Xe Polarizer Commercial Prototype 13C MRS Detection of Increased Choline Metabolism Following HDAC Inhibition 13C-Edited 1H NMR Spectroscopy with Selective Resonance Suppression Using Asymmetric Adiabatic RF Pulses 31P Cardiac Magnetic Resonance Spectroscopy During Leg Exercise at 3 Tesla in Healthy Volunteers 31P Magnetization Inversion Transfer Approach for Measurements of Dynamic Parameters of Creatine Kinase and ATPase Reactions in the Human Brain at 7T: Comparisons to the Multi-Single-Site Saturation Transfer Experiments 31P MRS of the Brain Supports the Mitochondrial Hypothesis for Huntington Disease, Revealing Altered ATP Synthesis, pH Increase and Stable ATP Level 31P MR-Spectroscopy of the Human Myocardium Using Spatial Saturation Pulses and a B1-Field Correction 31P NMR of Phospholipid Metabolites in Postmortem Schizophrenic Brain 1.5T In Vivo 1H MRS for Evaluation of Fetal Lung Maturity: Technical Feasibility Study 128-Channel Body MRI with a Flexible High-Density Receiver-Coil Array 13C and 31P NMR Spectroscopy in Perfused Mouse Liver: A Novel Method for Investigating Effectors of Hepatic Fatty Acid Metabolism 13C Multi-Spectral 2D Rosette Imaging 16-Channel Parallel DTI at 7T: Initial Experiments 16-Channel TORO Knee Coil 1H MRI Assessment of Cardiac Function Following Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes for Cardiac Repair 1H MRS Detects Bilateral Abnormalities in Hippocampus of Temporal Lobe Epilepsy Patients 1H-MR Spectroscopic Imaging of the Human Brain Using Adiabatic Refocusing Pulses at 3 and 7T 1H-MR Spectroscopy in the Frontal Area in Child and Adolescent Patients with Obsessive-Compulsive Disorder and a Subgroup of Anorexia Nervosa 1H-MR Spectroscopy Utilizing a 1T Open MR System: Expanding Access to the Obese and Claustrophobic Patient Populations 1H-NMR Spectroscopy in the Diagnosis of Proteus Mirabilis-Induced Urinary Tract Infection 1T MR Imaging of Trabecular Bone at the Distal Radius Using a Dedicated RF Coil 20 Channel Coil Array for High Resolution Imaging of the Optic Nerve 21 Tesla MRI Microimaging of Rat Heart by Superparamagnetic Antimyoglobin Bound Nanoparticles 2D Accelerated Single Breath Hold 3D First-Pass Sequence for Coronary Artery Imaging Using Segmented Elliptic Centric View Ordering 2D Arbitrary Shape Selective Excitation Summed Spectroscopy (ASSESS) 2D Cardiac Function During Free-Breathing with Navigators 2D J-Resolved Spectroscopy at 7T 2D J-Resolved Spectroscopy at 7T 2D MRSI in Locally Advanced Breast Cancer: Assessment of Tumor Response in Patients Undergoing Neo-Adjuvant Chemotherapy 2D Single Echo Acquisition with an Increased Matrix Size MAMBA Array 3 Tesla MR Spectroscopy Reveals Decreased Glutamate and Glutamine Levels in Frontal White Matter in HIV-Associated Dementia 3.0 Tesla Magnetic Resonance Angiography (MRA) for Comprehensive Renal Evaluation of Living Kidney Donors: Pilot Study with Computerized Tomography Angiography (CTA) Comparison 3.0T High Spatial Resolution CE-MRA of the Pulmonary Circulation: Initial Experience with a 32-Channel Phased Array Coil Using a High Relaxivity Contrast Agent 31P MRS Study of Brain Creatine Kinase in Two Different Animal Models Simulating Human Alzheimer‘s Disease and Vascular Dementia 32 Channel Receive-Only SENSE Array for Brain Imaging at 7T 32-Element Coil Array for Highly Accelerated Clinical Cardiac MR Imaging 3D Analysis of Cerebral Vascular Patterning in Mouse Embryos with Contrast Enhanced Micro-MRI 3D Blood Flow Visualization in Patients with High-Grade Carotid Artery Stenosis and Volunteers Using Flow Sensitive 4D MRI at 3T 3D Cardiac Tissue Engineering for Embryonic Stem Cells Therapy After Myocardial Infarction: Preliminary Results 3D Cartesian and Elliptical GRAPPA Based Spectroscopic Imaging of Gliomas at 3 Tesla 3D CE-MRA of the Peripheral Arteries Featuring Surface Coil Coverage and Data Acquisition During Continuous Table Movement (TimCT) 3D Contrast-Enhanced MR Angiography in Occlusive Disease of the Central Thoracic Veins 3D Diffusion Tensor MRI with Isotropic Resolution Using a Steady-State Radial Acquisition 3D Features of Disrupted Carotid Plaque: A Multi-Plane, Multi-Contrast In Vivo High Resolution MRI Study 3D HYPR in CE MRA of the Lower Extremeties 3D kSPA for High Spatial and High Temporal Resolution fMRI 3D kSPA Image Reconstruction for Undersampled Arbitrary Trajectories 3D Live Surfaces - A New Approach for Semiautomatic Volumetry of Brain Lesions 3-D Local Frequency Estimation Inversion for Abdominal MR Elastography 3D Magnetic Resonance Electrical Impedance Tomography at 4T Using Sensivity Matrix Based Reconstruction 3D MR Flow Analysis in a Realistic Rapid-Prototyping Model System of the Thoracic Aorta: Comparison with In-Vivo Data and Computational Fluid Dynamics in Identical Vessel Geometries 3D MRI with Self-Gated Detection of Physiological Motion in the Mouse 3-D MRSI of Patients with Gliomas Using a 7T Whole Body MR Scanner 3D Myelin Water Imaging in the Spinal Cord at 3.0T 3D Phase Sensitive IR Prepared Spoiled Gradient Echo Technique with Free Breathing Navigators – A Tool for Quantitative Characterization of Scar 3D Relaxomic Analysis of a Tumor Laden Mouse Brain 3D RF Pulses for Parallel Transmission MRI Systems 3D Rigid Body Motion Correction in K-Space 3D Self-Navigated Interleaved Spiral (3D-SNAILS) for DWI 3D Spatial Excitation Using Variable-Density K-Space Trajectories 3D Spiral In/Out Arterial Spin-Labeled Perfusion Measurement 3D Visualization of RF Ablation Scarring Using Delayed Enhanced MRI Co-Registered with MRA 3D Volumetric In Vivo Spiral CSI at 7T 3D-Gradient Coil Structures for Breast Imaging Using Fuzzy Membership Functions. Part II 3-Dimensional Navigators for Motion Tracking and Correction in 3D Radial Imaging 3D-MR-Based Polymer Gel Dosimetry of Proton Needle Beams 3D-Orthogonal Phased Array Coil for High-Resolution and Low-Distortion EPI Imaging of Monkey Brain at 3.0T 3He Regional Volumetry in Pediatric Cystic Fibrosis: Pre and Post Physiotherapy 3T MRI Demonstrates Significant Decrease of Mural Inflammatory Changes in Giant Cell Arterits Under Steroid Treatment 3T MRI Detection of Contrast Reagent Extravasation in the Normal Primate Brain 3T SENSE Navigator Coronary MRA: Targeted Volume Vs. Whole Heart Acquisitions 3T VIPR-SSFP: High Isotropic Resolution MSK Imaging (0.33 mm) 4 Channel Mouse Array at 7 Tesla 4D Lung Imaging with Time-Resolved 3D MRI and Low Pitch Helical CT: Comparison of Two Techniques for the Assessment of Tumour Size and Displacement in a Ventilated Ex-Vivo Set Up 4T Magnetic Resonance Spectroscopy of the Hippocampus in Alzheimer Disease and Mild Cognitive Impairment 7T Diffusion Tensor Imaging and Q-Ball Imaging of the Human Brain In Vivo A 128 Channel Receive-Only Cardiac Coil for 3T A 14.1 Tesla Animal Coil Design for Homogenous and Focused RF Excitation A 16 Channel Transceive Surface Loop Array Coil for Parallel Imaging at 7T A 19F/1H Dual Resonant 7T Elliptic Body Coil That Double Tuned by Ellipticity A 30-Month 31P MRS Follow Up Study of First Episode Schizophrenia A 31-Channel Multi-Layer 3T Receive Head Array A 32 Channel Transmit/Receive Transmission Line Head Array for 3D RF Shimming A 3D Parallel Imaging Capable Transmit and 16-Channel Receive Array Knee Coil at 3T A 3T Head Transmitter Integrated with 3D Parallel Imaging Capable 16-Channel Receive Array Coil A 4-Channel Optical Link Transmission for RF Coil Array at 1.5T A Biplanar Shielded Gradient Coil Design for Hyperpolarized Gas Lung Imaging in the Standing Position A Breathhold Technique for T2 Quantification Utilizing Echo Sharing for Efficient Sampling A Calibration Method for Quantitative BOLD fMRI Based on Hyperoxia A Circularly Polarized Birdcage Coil with a Single Port A Combined Diffusion-Perfusion Model for the Analysis of DCE-MRI Data A Comparison Between Quantitative Models of Pulsed-MT A Comparison of Continuously Moving Table and Multi–Station 3D Whole-Body Water-Fat Separation A Comparison of Different Methods Using DWI for Breast Lesion Classification A Comparison of Effective Connectivity Results Obtained from Structural Equation Modeling, Autoregressive Analysis, and Granger Causality Using Simulated fMRI Data A Comparison of Flow Patterns in Ascending Aortic Aneurysms and Volunteers Using Four-Dimensional Magnetic Resonance Velocity Mapping A Comparison of Preoperative Prostate Cancer Staging Performance Between T2-Weighted 3T Endorectal MR Imaging and Real-Time Gray-Scale Transrectal Ultrasound A Comparison of T2- And T2*-Weighted Imaging at 7T A Comparison of Time Domain and Frequency Domain All Rank Selection Order Statistics Filtering (ARSOS) of Single Voxel 1H MRS-Signals A Comparison of Two-Compartment Models for the Quantification of Glomerular Filtration A Comparison Study of Myocardial T2* Measurement in Iron Overloaded Thalassemia Patients A Compartmental Model for Oxygen-Enhanced Magnetic Resonance Imaging of the Lung A Conservative Method for Ensuring Safety Within Transmit Arrays A Continuous Capacitance Loop Detector for High Sensitivity 7T MRI A Contrast-ENhanced Timing Robust Acquisition Order with a Preparation of the LongitUdinal Signal Component, CENTRA+, for 3D Contrast Enhanced Abdominal Imaging A Correction Method of Streak Artifacts in Gradient-Echo EPI Sequence Using a Spin Echo EPI Reference A Degenerate Birdcage Coil for Parallel Excitation A Demonstration of T2 Leakage Effects on DSC CBV Measurements A Demonstration of the Feasibility of DSC in Evaluating Breast Tumor Blood Volume A Diffusion Tensor Imaging Study on Pediatric Bipolar Disorder A Direct Modulated Optical Fiber Link for 0.3T MRI A DTI Study of Glioma Infiltration Using Fractional Anisotropy and Fiber Coherence Index A Dynamic 1H-MRS Study on Intramyocellular Lipid Accumulation in the Infusion of Lipids Differing in the Degrees of Saturated Fatty Acid Acyl Chains A Dynamic Contrast-Enhanced MRI Flow Phantom to Validate Arterial Input Function Measurements A Dynamic Nuclear Polarisation System Based on a Continuous-Flow 4He Cryostat A Fast and Accurate Off-Resonance Correction Method for Spiral Imaging A Fast Free-Breathing 3D Sequence for Delayed Enhancement Imaging of the Myocardium: Comparison with Standard 2D Breath-Hold Imaging A Fast Principal Direction Imaging Method from Diffusion Weighted Images A Feasibility Study of fMRI and EEG Activation with CHEPS (Contact Heat Evoked Potential Stimulator) A Fiber-Based Optical Excitation-Emission Fluorescence Spectrometer for MR-Guided In Vivo Tissue Characterization A Four-Pulse PRESS Sequence for Correction of the Chemical Shift Misregistration Signal Loss in Lactate Spectroscopy A Fractal Dimension for Exploratory fMRI Analysis A Framework for Evaluating the Performance of EPI Distortion Correction Strategies in Diffusion Tensor MRI A Free-Breathing Self-Gated 3D Golden-Angle Radial Technique for Abdominal Imaging and T1 Mapping A Fully Automated Selection of the Optimal Data Acquisition Window in Coronary MRA Eliminating the Need for User-Interaction A Fully Automatic Passive Marker System Localization Algorithm with Sub-Pixel Precision A Fully Integrated Framework for Inline Post Processing of MR Data in Real Time Without User Interaction A Functional Form for Arterial Input Function Modelling Including an Explicit Arterial Recirculation Phase A Generalized Dixon Method Incorporating Both T1-Contrast and Chemical Shifts A Hemodynamic Response Function for Functional MRI of the Cervical Spine Using Motor and Nociceptive Paradigms A High Order Accurate and Robust Fiber Tractography with Diffusion Tensor Imaging A High Spatial Resolution 1H Magnetic Resonance Spectroscopic Imaging Technique for Breast Cancer with a Short Echo Time A High Speed Vector Modulation Array System A Highly Sensitive MR Contrast Agent Based on Liposomal Nanocarrier Containing Superparamagnetic Iron-Oxide A High-Performance Head Gradient Coil for 7T Systems A Histogram Deconvolution Method for Trabecular Bone Microstructure Measurements Using High Resolution MRI in the Presence of the Partial Volume Effect A Histological Slice Imaging Coil for 7.0 T MRI A K-T Variable-Density Undersampling Technique (ktVDUST) for Dynamic Imaging A Learning by Example Approach for MRI Analysis of Human Brain in the Context of Mental Health A Level-Set Approach to Joint Nonlinear Registration and Segmentation Using Fast Numerical Scheme A Linear Prediction Approach to Joint Estimation of Water/Fat Images and Field Inhomogeneity Map A Log-Normal Dispersion Model for Parametric Deconvolution of DSC-MRI Images: Assessment on Simulated Data A Longitudinal Study of Myelin Oligodendryocyte Glycoprotein (MOG)-Induced EAE Using Non-Invasive Imaging Techniques A Magnetic Resonance Spectroscopic Imaging (MRSI) Mapping Technique for Radiotherapy Planning A Method for Autocalibrating 2-D Accelerated Volumetric Parallel Imaging with Clinically Practical Reconstruction Times A Method for Automatic Localization of Wireless MR Reference Markers: Feasibility and Accuracy A Method for Detecting 'Meaningful' Components in Independent Component Analyses of fMRI Data A Method for Fast Longitudinal Relaxation Rate Mapping and for Image Enhancement: Equilibrium Signal Intensity-Mapping A Method for Non-Cartesian Parallel Imaging Reconstruction with Improved Calibration A Method for T2-Selective Saturation to Cancel Out Macromolecular Magnetization Transfer in Z-Spectroscopy A Method to Correct Linear Eddy Currents by K-Space Trajectory Estimation A Method to Study Alterations in Networks of Structural Connectivity A Method to Verify the Instrument Position Realized by a Robotic Assistance System: Feasibility and Accuracy of the Biopsy Trajectory A Method with High Spatial and Temporal Resolution for Regional Analysis of Left Ventricular Torsion by MRI Tagging and HARP Tracking A Model Based Approach for Voxelwise Analysis of Multi-Subject Diffusion Tensor Data A Model of Competition Between Manganese and Iron and Their Combined Influence on R1 in Rat Brain Tissues A Model-Free Method for High-Precision MR Susceptometry A Modified PRESS Sequence Designed for Lactate Editing A MRI Investigation of Cerebral Perfusion Response to Hypothermia in Ischemic Rats with a MR Compatible Regional Brain Temperature Manipulation System A MRI System with 128 Seamlessly Integrated Receive Channels A Multicentre Study of In Vivo 1HMRS of Paediatric Brain Stem Tumours A Multi-Echo Acquisition Method with Reduced Echo Spacing for Robust IDEAL Water-Fat Decomposition at 3T A Multi-Echo Approach to Removing Task-Correlated Motion Artefacts in fMRI A Multiparameter DSC Study Demonstrates the Best Predictor of Brain Tumor Grade A Multiple Field Study of Permeability Difference Between Gray and White Matters A Multi-Scale Whole-Brain Optimized Diffusion Tensor Imaging of Dyslexics at 3.0T A Network Analysis of Acupuncture Effects by Functional Connectivity MRI A Neural Network Approach for Non-Cartesian K-Space Parallel Imaging Reconstruction A New 3D Approach for Clinical In- And Opposed-Phase MRI at 3 T A New Acquisition Strategy for Improved Signal Recovery and Artifact Suppression in Regions of Susceptibility Induced Field Gradients: Triple Spiral with Asymmetric Spin-Echo A New ASL Scheme of Repeated Labeling Based on FAIR Sequence A New Bio-Activated Paramagnetic Gadolinium(III) Complex [Gd(DOTA-FPG)] for Tracing Gene Expression A New Complex Data Analysis Method for Transition-Band SSFP fMRI (BOSS fMRI) A New Dedicated Coil Setup for In Vivo Measurement of Intramyocellular Lipids by 1H-MRS A New Dimensional Estimation Method for Group fMRI Data Reduction at Multiple Levels A New Lectin-Targeted Contrast Agent for MR and Optical Molecular Imaging of Vascular Endothelium A New Metabolic Model for Analysis of Dynamic 13C Isotopomer Time Courses in the Brain A New Metabolite Characteristic of Inflammatory MS Plaques: The First MRS Assignment of ß-Hydroxyisobutyrate in CSF A New Method for Measuring Strain Using Slice Following with Inversion Recovery (SFIR) A New Method for Optimum MRSI of Prostate at 3T Using Adiabatic RF Pulses and Internal Water Referencing A New Method for Tailored 2-D Excitation Using Frequency and Gradient Modulation Based on Rapid Passage A New Method of Motion-Compensated Spinal fMRI: Identifying Human Spinal Cord Function with Increased Sensitivity and Reproducibility A New Method to Visualize Vessels. Off-Resonance Angiography. A New MRI PARACEST Agent for Sensing Glucose A New MRI Reporter Gene: Mn Binding Protein MntR Produces T1 Weighted Cellular Contrast A New Plane Orientation Scheme for Spiral Projection Imaging A New Post-Processing Method to Remove Ringing Artifacts in Clinical MR Spectra A New Protocol for T1 Mapping of the Liver A New Robust Technique for Segmenting Different Heart Tissues Using Combined Functional and Viability C-Senc MR Images A New Route to Cellular Labelling A New Spectral Editing MRS Sequence for Lactate and GABA Using a Unique Basing Pulse Combination for Coupled-Spin Inversion at Long TE A New Spiral K-Space Sampled Time-Resolved MR Optimization Approach for 4D MR Renography A New SSFP BOLD Sequence for the Detection of Myocardial Ischemia in Patients: Feasibility Study A New Strategy for Fast Radiofrequency CW EPR Imaging: Direct Detection with Rapid Scan and Rotating Gradients A New Technique for Investigating the Biophysical Basis of “Angiogenic Contrast” in Tumors Using Susceptibility-Based MRI A Non-Invasive Study of Neurovascular Coupling A Normal Database for the Detection of Abnormal Myocardial Contraction Patterns A Novel Approach to Measure Regional Lung Ventilation Using Hyperpolarized 3He MRI - Potential in Clinical Studies A Novel Approach to Remove the Effect of Recirculation in Arterial Input Functions A Novel Class of Vanadium-Based MRI Contrast Agents Specific for Highly Glycolytic Cancer Cells A Novel Device for Image-Guided Interventional Breast Procedures Using 3D Access and Geometry A Novel DTI Method for Analyzing the Diffusion of Water in Retina A Novel Gd-Based MRI Contrast Agent Responsive to the Factor XIII Transglutaminase Activity A Novel Generation of Concentration Independent Gd(III)-Based MRI Responsive Agents A Novel Generation of Improved LIPOCEST MRI Agents with Highly Shifted Intraliposomal Water Protons A Novel Low Molecular Weight Folate Receptor Targeted Contrast Agent for Magnetic Resonance Tumour Imaging A Novel Method for Assessment and Quantification of Left Ventricular Dyssynchrony A Novel Method to Determine the Tikhonov Regularization Parameter for Pulmonary Perfusion Quantification with MRI A Novel Methodology for Non-Invasive and In Vivo Characterization of Soft Tissue Mechanical Properties Using Phase Contrast MRI and MR-Compatible Dynamometer A Novel MR Contrast Probe that Reports Amphetamine-Induced Cerebral Gene Transcription In Vivo A Novel Needle Driver for Tumor Detection and Biopsy in Magnetic Resonance Elastography A Novel Non-Contrast MRA Technique Using Time-Spatial Labeling Inversion Pulse in Combination with Flow-Spoiled FBI for the Assessment of Small Arteries of the Finger A Novel Parallel Imaging Technique for Radial Acquisitions: Parallel Rotation Operator A Novel Power MOSFET Decoupling Technique for Parallel Transmit Arrays A Novel RF Head Coil for 7T Homogeneity and Parallel Imaging Applications A Novel Series of Nitromidazole Probes for Oxygen Tension (pO2) Measurements In Vitro by 1H Magnetic Resonance Spectroscopy A Novel Soft Tissue Marker for Multimodal Breast Imaging with Positive MRI Contrast A Novel Tensor Distribution Model for the Diffusion Weighted MR Signal A Novel, Accurate Method for Computing the Density Compensation Function for Regridding Non-Cartesian K-Space Data A One Year Follow-Up Study of the Spinal Cord with Biplanar MRI in Multiple Sclerosis – Clinical and MR Aspects A PARACEST MRI Contrast Agent That Detects Esterase Enzymes A Perfusion Phantom for Diffusible and Non-Diffusible MR Tracers A Phase-Contrast Single Shot Fast Spin Echo Sequence for Lung Motion Analysis A Pilot Investigation of Voxel Based Diffusion Tensor MRI and Cognitive Correlates in Low Grade Hepatic Encephalopathic Patients A Practical Bookend Technique for Quantitative DCE-MRI Evaluation of the Liver A Preliminary MR Elastography Database of In Vivo Human Brain Viscoelasticity A Prepolarized MRI Knee Scanner A Probabilistic Model-Based Approach to Consistent White Matter Tract Segmentation A Proposed Ultra High Field RF Coil Design for Axial Human Brain Imaging A Quantitative Comparison of Dynamic Contrast Enhanced MR Perfusion Imaging of the Prostate with Dynamic Contrast Enhanced CT A Quantitative Simulation Approach for Optimization of Spiral K-Space-Sampled Time-Resolved Contrast-Enhanced MRA A Radiative Heater for Small Animal Coils to Prevent Hypothermia A Rapid Hyperpolarized 3He Q-Space Diffusion Spectroscopy Sequence for Sub-Second Breath Hold In Vivo A Real-Time System for Interactive Large FOV MR Imaging A Reconstruction Algorithm of Parallel Imaging with High Reduction Factor in SPACE RIP A Rigid Analysis and Experiments for the Complementary Modes in the Multi-Port Reception of a Volume Strip Array A Robust Alternative to Regularization in Parallel Imaging Reconstruction A Robust Spherical Inflation Technique Using the Method of Concentric Rings A Robust Spike Noise Correction Method for fMRI A Robust Technique for Measurement of Regional Partial Pressure of Oxygen in Rodents A Robust Transmitter Calibration Procedure for NMR of Hyperpolarized Nuclei A Scanner Stability Test for Diffusion Tensor Imaging A Segmentation Methodology that Accounts for the MR Physics of the RF Pulse Sequence. A Self Calibrating Pulse Sequence for Real Time Quantitative Cerebral Perfusion A Self-Resonant Inductively Coupled Skin Chamber Coil for High Resolution MR Imaging in Small Animals A Semi-Automatic Segmentation of Brain Tumor Using DTI Data Set A Shielded NMR System Suitable for Parahydrogen-Induced Polarization A Simple Method for Measuring and Removing Susceptibility Artifacts A Simple Method of Improving MPRAGE Inversion Coverage at 7T A Simple Method to Measure the Noise Figure of Preamplifiers A Simple Model of an Analog Fiber Optic Link for MRI A Simple Noniterative Principal Component Technique for Rapid Noise Reduction in Parallel MR Images A Simple, Robust, and Accurate Contusion Spinal Cord Injury Device for the Mouse Characterized by Diffusion MRI A Simulation Framework for Diffusion Weighted MRI in Digitalized Neurons: Extracting Cytoarchitectural Parameters Using a New Theoretical Model for Diffusion A Single PARACEST MRI Contrast Agent for Accurate In Vivo pH Measurements A Single Scan Two-Point Dixon Technique for Projection Reconstruction Using Bunched Phase Encoding A Six-Element Tranceive Surface Coil Array for Prostate MRI at 4.0 Tesla A Software Tool for the Combined Analysis of Angiographic and Perfusion MRI Datasets for an Optimized Diagnosis of Coronary Artery Disease A Solid Marker Material for MRI with Adjustable Relaxation Properties A Spatial Model of White Matter Fiber Tracts A Spatial Normalized Study of Diffusion Tensor Imaging in Clinically Isolated Syndrome and Multiple Sclerosis Patients A Statistical Approach to Non-Cartesian SENSE Regularization A Study of Cerebral Energetics and pHi in the Visual Cortex Using 31P MRS During Stimulation of Reduced Blood Oxygen Saturation Levels A Study of MRI Contrast Agent Effects on the Proton Resonance Frequency and on T2* A Study on the Trazodone in the Treatment of the Psychogenic Erectile Dysfunction Using fMRI A Superconducting Probe for High-Throughput Magnetic Resonance Histology at the Diffusion Limit A Symmetrically Fed Microstrip Coil Array for 7T A System for Prostate Intervention in a 1.5 T MRI Scanner in the Supine Position A T2-Weighted SSFP-TSE Hybrid: Gradient Moment Nulling and 180° Refocusing Pulses for Bright Blood Myocardial Edema Imaging A Technique for Warping MR Images to Histological Sections Based on Thin-Plate Splines with Homologous Points Optimization by Minimizing Bending Energy A Temporally Constrained Reconstruction Algorithm Applied to MRI Temperature Data A Theoretical and Experimental Investigation of the Tagging Efficiency of Pseudo-Continuous Arterial Spin Labeling A Time Efficient High Resolution Multi-Echo FLASH Sequence A Tracking Algorithm for Three Dimensional Tags in Cardiac MRI A Transient Model of Off-Resonance Saturation for Single-Coil CASL A Validation Dataset to Assess Pitfalls in DCE MRI Image Processing A Variable TR Shells Trajectory for Better Fat Suppression in CE-MRA A Voxel-Based Morphometry Study of Grey and White Matter Density Changes in MS Patients with Different Clinical Phenotypes A Whole-Body 7 Tesla RF Excitation Scheme with Much Improved B1+ Field Homogeneity and Local/Global SARs Over Quadrature Excitation A Wide Band Frequency Transverter for High Field MRI A Window for High-Resolution Post-Mortem DTI: Mapping Contrast Changes in Neural Degeneration Abdominal T2-Weighted Turbo-Spin-EchoImaging with BLADE at 3.0T: Initial Results Abnormal In Vivo Brain Temperature Gradient in Schizophrenia Patients and It's Possible Correlartion to Psychopathology - A Magnetic Resonance Spectroscopy Study Abnormal Metabolic and Structural Changes in Juvenile Myoclonic Epilepsy Using MRI Volumetry and 1H MR Spectroscopy Abnormalities in Magnesium (Mg) and ATP Levels Correlate with Muscle Dysfunction in Polymyositis About the Use of Perfusion-Weighted Magnetic Resonance Imaging to Define Patterns of Neonatal Hypoxic-Ischemic Encephalopathy Absolute Brain Temperature by 1H MRS Absolute Quantification of Myocardial Blood Flow in Patients with Acute Myocardial Infarction After Successful Percutaneous Coronary Interventions Absolute Quantification of Myocardial Blood Flow Using First-Pass Perfusion MRI: Extraction Fraction of Gd-DTPA Varies with Myocardial Blood Flow in Human Myocardium Accelerated R2 Mapping Through Undersampling and k-T Reconstruction Accelerated B1 Mapping for Parallel Excitation Accelerated Bilateral DCE 3D Spiral Breast Imaging Using TSENSE and Partial Fourier Methods Accelerated Cardiac Cine Imaging, with Retrospective Gating Accelerated Functional MRI of the Bowel with a 32-Element Coil Array: Detection of Perfusion Defects Using ceMRA and DWI Accelerated High Field CINE MR Imaging of Tongue Motion During Speech Production Accelerated Iterative Reconstruction of Temporally Regularized Dynamic MRI Accelerated Maturation of White Matter in Young Children with Autism: A High B Value DWI Study Accelerated Real-Time MRI with Distributed Computing Using Standard Scanner Hardware Accelerated Spiral Fourier Velocity Encoded Imaging Accelerated Three-Dimensional Myocardial Strain Quantification Using zHARP Accelerated Whole-Heart 3D CSPAMM for Myocardial Motion Quantification Accelerating Cardiac Perfusion Imaging – Signal-to-Noise Considerations Accuracy and Outcome Assessment for MR Guided Deep Brain Stimulator Implantation Accuracy Evaluation of a Two-Projection Respiratory Self-Gating Technique for Coronary MRA Accuracy of DSC-pMRI in Assigning Percentages of High-Grade Malignant Features in Masses Recurring After Surgical and Radiation Treatment of Brain Neoplasms Accuracy of Gadobenate Dimeglumine-Enhanced MR Angiography in the Evaluation of Renal Artery Stenosis: Comparison with Unenhanced Time-Of-Flight MR Angiography Versus Digital Subtraction Angiography (DSA) Accuracy of MR Imaging for the Detection of Hepatocellular Carcinoma in Patients with Cirrhosis: Correlation with the Whole Explanted Liver Accuracy of Using Real-Time MRI for Joint Motion Measurements: A Phantom Study Accurate and Automatic Slice Repositioning for Longitudinal Carotid Imaging Studies Accurate and Precise T1 Relaxometry with Reduced Data Acquisition Requirements Accurate Estimation of Physiologic Noise Using Temporal ICA-Derived Spatial Measures Accurate Measurements of Small J Coupling Constants in Inhomogeneous Fields Accurate Noise Bias Correction Applied to Individual Pixels Accurate Reconstruction in PR-MRI Despite Truncated Data Acetate Utilization Is Rate-Limited in the Rat Brain Acoustic Noise Suppression: Gradient Self-Help? Acquisition Strategies to Improve the Specificity of Block-Design fMRI Studies of Overt Speech Acquisition-Weighted CSI with a Small Number of Scans Activation Induced BOLD and CBF Responses Vary with Caffeine Dose Activation Signal Recovery in fMRI Using an Efficient Signal Drop-Out Correction Method Active Digital Decoupling for Multi-Channel Transmit MRI Systems Activity Mappings in Olfactory Bulb of Newborn Rabbits Elicited by Odor Stimulation Using Quantitative Manganese Enhanced MRI ACT-MR: ACoustically Triggered Cardiovascular Magnetic Resonance Imaging Acute Axial Diffusivity Changes Predict Long Term Locomotor Function Recovery After Spinal Cord Injury Acute Effects of Brain Radiation in Children Evaluated by Diffusion Tensor Imaging Acute Ischaemic Stroke in Rat Imaged by T1? and T2? MRI Using Adiabatic Pulses Acute Nicotine Stimulates GABA Synthesis in Human Brain Adaptive fMRI Data Filtering Based on Tissue and Signal Similarities Adaptive Phase-Unwrapping Improves Myocardial Motion Tracking with Displacement-Encoded MRI Adaptive Prediction of RR Interval for Online MR Parameters Changes ADC Decrease in Histology Identified Prostate Cancer ADC Value and Diffusion Tensor Imaging of Prostate Cancer; Therapeutic Changes with Heavy Ion Charged Particle Radiation Therapy Additional Value of Image Fusion Between MR and PET for Initial Staging in Patients with Head and Neck Cancer: Preliminary Results. Additive-Angle' Method for Fast Large-Tip-Angle RF Pulse Design in Parallel Excitation Adiabatic Refocusing Pulses in 3T and 7T Diffusion Imaging Adipose-Derived Stem Cells Improve Global and Regional Function of the Infarct Hearts Administration of Selective Serotonin Reuptake Inhibitors Changes Amygdala Activation During Facial Emotion Processing Advanced Quantitative Flow and Wall Shear Stress Analysis at 3T: 2D Vs 3D Time-Resolved MR Velocity Mapping Advances in Human Skin In-Vivo MRI with a Miniature HTS Surface Coil and a New-Generation 1.5 T Body Scanner Advantages of Parallel Imaging for DTI-Based Fiber Tracking at 3T Age Dependence in Phase Images of Human Brain at 3T and 7T: Implications for High Field Contrast Mechanisms Age Effect on Intramyocellular Lipid Composition in Db/db Mice Using In Vivo 1H-MR Spectroscopy Age Related Changes in DTI of the Brain White Matter Associated with EEG Measures Age Related Cognitive Decline and Regional Brain Changes Studied by Diffusion MRI Age, Gender, and Iron Overload Effects on Cardiac Systolic and Diastolic Function in Thalassemia Major Agenesis of Arcuate Fasciculus in Children with Global Developmental Delay of Unknown Etiology: A Diffusion Tensor Imaging Study Age-Related Changes in Structural Integrity of the Corpus Callosum Demonstrated by Diffusion Tensor Tractography Age-Related Changes of Normal Subthalamic Nucleus: Evaluation with High Resolution MR Imaging at 3.0 T Age-Related Diffusivity Changes in Brain White Matter Fiber Bundles Age-Related Patterns of Change in Brain Microstructure by Diffusional Kurtosis Imaging Airway Behavior Following a Methacholine Challenge Observed Using Hyperpolarized 3He MRI and High Resolution CT Airway Segmentation in 3D Using Dynamic Hyperpolarized He-3 Multi-Echo VIPR Algorithm and SNR Dependence of DTI Fiber Tractography Algorithms for Automatic Calculation of Quality Control Metrics for ACR Accrediatation Compliance Alterations in Brain Microstructure in ADHD by Diffusional Kurtosis Imaging Alterations of Phosmomono- and Phosphodiesters in the Brain of Patients with Major Depression Detected with 3D 31P RINEPT Altered Basal Ganglia Activation During Complex Finger Tapping Tasks in Patients with MS Altered Fiber Radial Diffusivity in Schizophrenia Revealed by Diffusion MRI Altered Functional and Structural Connectivities in Patients with Multiple Sclerosis: An Fmri and MR Tractography Study at 3 T Alternatives for Standard T1-Weighted Images in Brain Atrophy Measurements in Multiple Sclerosis Using SIENA and SIENAX Amide Proton Transfer (APT) Imaging for the Monitoring of Heating Treatment by High Intensity Focused Ultrasound (HIFU): Phantom Experiments Amide Proton Transfer (APT) Imaging Using Saturation Transfer Versus Inversion Transfer -- Which Is Better? Amide Proton Transfer Imaging and Magnetization Transfer Imaging for Characterizing Rat Brain Tumors Amphetamine PharmacoMRI in the Rat Under Isoflurane Anesthesia Amplitude of Low Frequency Fluctuation in Treatment Naive Schizophrenia Revealed by Resting-State Functional MRI Amygdala Anisotropy Correlates with Aggression and Impulsivity Amygdala Hypersensitivity in Tourette's Patients An 8 Channel 23Na Heart Array for Application at 3 T An 8 Channel Geometry Optimized RF Coil Array for Imaging of Fish at 3T An Adaptive Regularization of Richardson Lucy Spherical Deconvolution to Reduce Isotropic Effects An Algorithm for Lipid-Water Separation in the Presence of T2* Decay An Alternative Concept of Selfnavigation for Patient Respiration Monitoring An Alternative Interpretation for Stimulus-Related Signal Changes in Diffusion-Weighted fMRI An Analysis of Reciprocity in Parallel MRI An Analytical Tool for Modeling High-Field RF Coils An Anionic Surface Charged PAMAM Dendrimer Based Contrast Agent for MR Imaging of Her-2/neu Receptors by a Three-Step Pretargeting Approach An Automated, Web Based MR Quality Control Program in Compliance with the American College of Radiology Accreditation Guidelines An Autopsy Brain of Alexander Disease Studied by Comparison of Histology with High Resolution T2*-Weighted MRI at 7T An Easy-To-Made Double Tuned 23Na / 1H, Inductively Driven, Quadrature Birdcage, for Small Animal MRI at 4.7 Tesla An Echo-Dephased SPGR Approach to Generate Positive Contrast Due to Paramagnetic Marker: An Interventional MRI Application An Economical Laboratory-Scale System for Purifying 3He An Efficient and General GRAPPA Reconstruction Method for Non-Cartesian Parallel Imaging An Efficient Interpretation of DCE-MRI Data for Cancer Treatment Assessment An Efficient Multiple Field of View Gradient Coil Set An Eight-Channel 3D-Segmented RF Coil for Parallel Transmission at 3T An Energy Competing Regime for Active Contour Segmentation of Liver Boundary An Event-Related fMRI Study on Phase Specific Patterns of Cortical Activity for Working Memory in Schizophrenia Patients An Experimental Verification of a Hybrid MoM/FEM Method for RF Simulations in MRI An Extensible, Graphical Environment for Pulse Sequence Design and Simulation An Improved Approach of Quantifying Magnetic Moments of Small In-Vivo Objects An Improved Imaged-Based Finite Difference Method for Studying Water Diffusion in Tissues An Improved Phased-Array Surface Coil for Carotid Vessel Wall Imaging An Improved Pyrolytic Graphite Foam for Tissue Susceptibility Matching in MRI An Improved QUASAR Sequence for User-Independent Quantitative and Reproducible Perfusion Measurements An Improved Technique for Measurement of Gas Diffusion Anisotropy in Lung An Independent Spectrometer and Coil Insert for Research on Clinical MR Systems An Index of Blood-Brain Barrier Permeability Measured by Serial MRI in Experimental Stroke An Integrated Approach for the Quantification of Renal Perfusion and Filtration An Inverse Method for Designing RF Phased Arrays with Optimal Coil Geometry An Investigation of Human Brain Tumor Lipids by HRMAS 1H MRS and Histological Analysis An Iterative Active Deformational Methodology for Tumor Delineation An Iterative Off-Resonance and Signal Decay Correction for Improved R2* Mapping An Iterative, Non-Linear Mouse Atlas for Mouse Brain Phenotyping in a Huntington's Disease Model An MR Compatible Setup for Simultaneous Measurements of Skeletal Muscle Performance and 31P MRS in the Mouse An MR-Compatible Haptic Device for fMRI Investigations of Force Control An MRI Comparison of Quantitative Left Ventricular Structure, Function and Measurement Reproducibility in Patient Cohorts with a Range of Clinically Distinct Cardiac Conditions An MRI Determination of Vascular Transfer Constant Predicts Response to Therapy in a Cerebral Glioma Model An MRI Endoscope? An NMR-Compatible, Minimally Invasive Electrical Stimulation Method to Study Rat Skeletal Muscle Function In Vivo An Open 16-Channel Transmission Line Array for 7T An Optical Based Device for Dual Cardiac and Respiratory Synchronization for Small Animal MRI An Optimal Framework for T1 Estimation in an SPGR Acquisition An Optimised Dual-Loop Labeling Coil for Whole-Brain Perfusion Studies An Optimized 3D Inversion Recovery Prepared Fast Spoiled Gradient Recalled Sequence for Carotid Plaque Imaging An Optimized Tensor Orientation Strategy for Non-Rigid Alignment of DT-MRI Data Analysis and Refinement of PROPELLER MRI Motion Correction Analysis of Amphetamine-Induced BOLD fMRI Signals in Striatum Indicate Novel Temporal Regulation by Insulin Analysis of High B-Value Diffusion Data May Highlight In Vivo Cellular Changes Analysis of In Vivo Myocardial Oscillations Using High Temporal Resolution Cine MR Elastography Analysis of MRI Data Compression Using Principal Component Analysis Analysis of Multi-Site Structural Neuroimaging Data Using VBM: A Case Study in Childhood Absence Epilepsy Analysis of Quantitative MT Using Principal Component Analysis Analysis of Segmental Gastrointestinal Motion in an Animal Model Using Dynamic MRI and Active Shape Models Analysis of Streak Artifacts in Gradient-Echo EPI Sequence Using 1.5T MRI System Analysis of Structural Connectivity of the Human Language Pathways Using Diffusion and Functional Magnetic Resonance Imaging Analysis of the BOLD Signal Characteristics in Balanced SSFP fMRI: A Monte-Carlo Simulation Analysis of the Utility of MR-DWI-Lymphography in Detecting and Distinguishing Lymphoma from Other Lymphadenopathies in the Body Analysis of Timing Dependence on Cardiac T1 Measurements in Amyloid Patients Analysis of Wall Shear Stress of Carotid Bifurcation Using Time-Resolved Three-Dimensional Phase-Contrast MR Imaging Analytical Assessment of Kinetic Model Selection, Noise and Aliasing on Physiological Parametric Estimation in Dynamic Contrast-Enhanced MRI Analytical Description of WALTZ-PARACEST Experiments Analytical Sampling Density Compensation for PROPELLER MRI Analyzing Perfusion in Human Gray Matter Analyzing Rapid Flow from SEA-Tagged MR Images Using Harmonic Phase (HARP) Analyzing Structural and Functional Imaging Data on the Cortical Surface Anatomical Connectivity Mapping Anatomy of Long-Lived Hyperpolarized States in Parahydrogen-Induced Polarization Anesthetic Effects of Sevoflurane and Propofol on Regional CBF: A Comparative MRI Study on Normal Subjects and Implications Animal Imaging in Drug Discovery and Development Anisotropic Field-Of-Views for PROPELLER MRI Anisotropy Induced by Macroscopic Boundaries: Surface Normal Mapping Using DWI Anterograde and Retrograde Degeneration of White Matter Tracts Following Stroke Anti-VEGF (Avastin) Therapy Monitoring in Recurrent Glioblastoma Multiforme Using Dynamic Contrast-Enhanced (DCE) MRI Aortic Compliance and Pulse Wave Velocity by MRI: Effects of Pulse Pressure Amplification and Reflection Aortic Compliance of Mice at 7T Using Radial Phase Contrast Cine Imaging Aortic Morphology and Function in Ehlers Danlos Syndrome Type IV Apparent Diffusion Coefficient and Fractional Anisotropy May Predict Newly Diagnosed Low-Grade Glioma Subtypes Apparent Diffusion Coefficient Measurements in Chemoembolized Hepatocellular Carcinoma Apparent Diffusion Coefficient of Benign and Malignant Salivary Gland Tumors and Histologic Correlation: Influence of Tumor Cellularity and Myxoid Matrix Apparent Diffusion Coefficient of Breast Cancer Metastases in Bone as a Predictor of Therapeutic Response Apparent Diffusion Coefficient Value for Differentiating Tumors in Uterine Cervix at 3 Tesla Appearance of Colorectal Hepatic Metastases at Diffusion-Weighted MR Imaging Compared with Histopathology Applicability of Bioluminescence and MRI for Monitoring Cell-Based Therapy of Demyelination Application of 2D-SENSE to 3D MP-RAGE with Elliptical-Centric Phase-Encoding Application of Geometric Indices of Diffusion Tensor Imaging on Ischemic Cerebral Infarction: Comparison of Two Definitions Application of Geometrical Diffusion Tensor Imaging on Acute Ischemic Cerebral Infarction Application of Signal-Time Analysis for Perfusion Imaging with High Temporal Resolution Application of T2* Map to the Liver Before and After SPIO Administration: Correlation with Liver Function Applications and Limitations of Whole-Brain MAGIC VASO Functional Imaging Applications of Diffusion-Weighted MRI in Uterine Tumors: Signal Intensity and ADC Value Based Ability in Demonstration and Differentiation Applications of fMRI in Experimental and Clinical Medicine Applications of Off-Resonance Positive Contrast Imaging Using FLAPS Applying Data Mining for the Characterization of Acute Stroke Applying MRI-Based Multiparametric Algorithms to a Randomized Placebo-Controlled Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke Aqueductal Flow Measurement in a Rat Model of Communicating Hydrocephalus Using Gadolinium Enhancement Array Compression for MRI with Large Coil Arrays Array SNR and Coupling Versus the Input Impedance of the Preamplifiers Array-Optimized Composite Pulse for Homogeneous Whole-Brain Inversion in High Field MRI Arterial Input Function Measurements in the MCA: A Numerical Model Compared with Phantom Experiment Results Arterial Spin Labeling Perfusion Imaging of the Thyroid Gland Arterial Spin Labeling Perfusion Imaging: Value in Diagnosis of Hemangioblastoma Arterial Spin-Labeling Perfusion MRI in Pediatric Arterial Ischemic Stroke Artery-Vein Separation of Ultra-High Resolution Contrast-Enhanced MRA Using a Blood Pool Agent Artifact Reduction inT1?-Weighted Images: An Algorithm to Predict Artifact Reduction in Pulse Clusters Artifacts in T1?-Weighted Imaging: Compensation for B0 and B1 Field Imperfections ASL-MRI Assessment of the Effect of Hemorrhagic Shock on Cerebral Blood Flow After Experimental Traumatic Brain Injury in Mice Assessing Choline Kinase Activity in Cancer Cells Using a 31P NMR Enzymatic Assay Assessing CO2 Reactivity in Patients with Carotid Artery Disease Using BOLD fMRI Assessing Disease Severity in Late Infantile Neuronal Ceroid Lipofuscinosis Using Quantitative Magnetic Resonance Diffusion-Weighted Imaging Assessing Human Conceptual Representation with fMRI Assessing the Influence of Negative Mood on Brain Processing of Visceral Sensation Assessing the Mass Effect of Tumors on Adjacent Tissue: Initial Feasibility Study in a Phantom Model Assessing the Potential of 1H MRS in Analyzing the Effects of Various Dietary Fatty Acids on Normal Colon Assessment and Correction of Subject Motion in Physiological Noise Regression Assessment of Abnormalities in the Cerebral Microstructure of Schizophrenia Patients: A Diffusional Kurtosis Imaging Study Assessment of Aggressiveness of Prostate Cancer: Correlation of MR Signal Intensity with Gleason Grade Based on Step-Section Pathologic Analysis After Radical Prostatectomy Assessment of Brain Microstructure in a Transgenic Mouse Model of ß-Amyloid Deposition Assessment of Cellular Growth in a Double Microbead Alginate Construct Via MR Microscopy Assessment of Cerebral Hemodynamic in Patients with Schizophrenia by DSC-MRI Quantitative Imaging Assessment of Cerebral Metabolic Change in Patients Undergoing Carotid Endarterectomy Using Magnetic Resonance Spectroscopy Assessment of Fetal Lung Development by in Utero Magnetic Resonance Imaging Assessment of GABA and Glutamate/Glutamine Using the J-Edited Spin Echo Difference Method at 3 Tesla in Patients with Major Depressive Disorder Assessment of Global and Regional Myocardial Velocities in Patients with Left Ventricular Hypertrophy Using High Temporal Resolution MR Tissue Phase Mapping Assessment of Human Brain Temperature During Brain Activation and Hypercapnia by 1H MRS Assessment of Inhibitory Potency of Antibiotics by Measurement of Apparent T2 in Bacterial Cultures Assessment of In-Vitro Lung Structure Using Hyperpolarized He-3 ADC MRI: Comparison with In-Vivo Measurements and Repeatability Assessment of Kinetic Model Selection, Sampling Rate and Injection Duration on Physiological Parametric Estimation in Dynamic Contrast-Enhanced MRI Assessment of Longitudinal Blood-Brain Barrier (BBB) Changes Using MR Tracer Kinetics in Human Brain Infarction Assessment of Lung Volumes Using Hyperpolarized 3He MR Imaging in Rodents: Comparison with Xenon-Enhanced X-Ray CT Assessment of Magnetization Transfer Effects in Myocardial Tissue Using Balanced Steady State Free Precession Assessment of Neuronal Marker and Brain Iron in Aphakia Mice Model for Parkinson’s Disease Using Novel MRI Contrasts Assessment of Non-Rigid Registration in Diffusion Tensor Tractography of Human Spinal Cord at 3T Assessment of Ocular Dominance Plasticity with Functional MRI at 3 Tesla Assessment of Oxidative Stress and Neuronal Viability in Friedreich’s Ataxia by 1H MRS at 4 Tesla Assessment of Physiological Parameters Estimated by DCE MRI with Delayed or Dispersed Arterial Input Function Assessment of Pulmonary Lesion Using Fast Dynamic Contrast Enhancement MR Imaging Assessment of Renal Function from Motion-Corrected 3D DCE-MRI Using Clustering and Independant Componant Analysis Assessment of Respiration- and Cardiac-Related Flow Patterns of Cerebro-Spinal Fluid Using Balanced Steady-State Free Precession and Breathing-ECG Synchronization Assessment of the BOLD Effect and Vascular Reactivity During Visual Stimulation in the Presence of Hypoxic Hypoxia Assessment of the Flow Dynamics Changes in Splanchnic Arteries in Patients with Median Arcuate Ligament Compression Using Time-Resolved Three-Dimensional Phase-Contrast MRI (4D-Flow) and a New Flow Analysis Application (Flova) Assessment of the Limiting Resolution in MRI Assessment of the Protective Effect of L-Carnitine in Hepatic: Improvements of Muscle and Brain Mitochondrial and Fatty Acid Metabolism Assessment of the Separability of Physiologic Noise Using Spatial ICA Assessment of the Uterine Myometrium Using T2* Relaxometry with a Correction of Magnetic Filed Inhomogeneity Assessment of TOF- And CE- MRA in the Visualisation of Small Cerebral Vessel-Structures at 3.0 T Assessment of Treatment Response with Functional Magnetic Resonance Imaging in Metastatic Thyroid Carcinoma Assessment of Vascular Permeability in Calf with Dynamic Contrast MRI Assessment of Ventilation Function and Airway Structure in Mesothelioma Using Hyperpolarized 3He MRI Assessment of White Matter Damage in Cerebral Palsy Using Quantitative Diffusion Tensor Imaging Assessment on Clinical Data of Nonlinear Stochastic Deconvolution Versus SVD and Block-Circulant SVD Methods for Quantitative DSC-MRI Association Between Adventitial Vasa Vasorum and Atherosclerosis: A Dynamic Contrast-Enhanced Magnetic Resonance Imaging Study Association of Blood-Brain-Barrier Permeability with Future Development of Brain Atrophy: A Longitudinal Voxel-Based Morphometry (VBM) Study in a Canine Aging Model Association of Neurodegenerative Markers with T2 Hypointensities in the Basal Ganglia Association of Regional Atrophy, MRI-Guided SPECT Perfusion, and Memory Performance in Patients with Mild Cognitive Impairment Compared to Healthy Elderly Controls Assymmetric Brain Development in Children with Sturge-Weber Syndrome Demonstrated by Volumetric MRI Asymmetric Pacemaker Lead Tip Heating Along the X-Axis in 1.5T and 3T Systems Asymmetrical Inferior Fronto-Occipital Fasciculus in Chinese Children: Correlation with Chinese Reading Atherosclerotic Plaque Imaging with Ultra Short Echo Time (UTE) MRI Atlas Based Segmentation of White Matter Tracts of the Human Brain Using Diffusion Tensor Tractography and Comparison with Classical Dissection Attention Inhibitory Process Decline During Life Span: A Functional MRI Study Autocalibrated Phase-Contrast Imaging Automated Algorithm for Calculation of Lung Defect Volume Using Hyperpolarized He-3 MRI and Proton Magnetic Resonance Imaging Automated Arterial Input Function Selection Using Spatial Information and Feature Space Reduction Automated Characterization of Normal and Diseased Regions of Calcified Layers in Human Patella from Ultrashort Echo Time (UTE) Imaging on a 3T Clinical System Automated Data Processing for Quantitative Cerebral Hemodynamics with Dynamic Susceptibility Contrast Perfusion-Weighted Imaging Automated Edge-Driven Markov Random Field Segmentation of ex Vivo Mouse Brain MRM Images Automated Hippocampal Volumetry in Alzheimer’s Disease, Mild Cognitive Impairment and Normal Aging Automated Hyperpolarized 129Xe Gas Generator for Biomedical MRI/MRS Applications Automated Identification of Alzheimer's Patients Based on Support Vector Machine Learned by Image Features Related to Cerebral Atrophy Determined in 3-D MR Images Automated Judgment of Image Quality for Diffusion Tensor Imaging Automated Segmentation of 4D Cine MRI: Application to the Aortic Root and Quantitative Comparison of Normal Subjects and Patients with Marfan Syndrome Automated Single-Volume Shimming in the Presence of Shim Field Imperfections Automated Slice-Dependent Z-Shim for fMRI: User-Independent Reduction of BOLD Sensitivity Losses Automated White Matter Hyperintensity Detection Using a False Discovery Rate Method Automatic 3D Non-Rigid Registration of Whole Body Serial MR Animal Images Automatic Calculation of Gradient Delays for Center-Out Radial Trajectories Using an Entropy Metric Automatic Cardiac Motion Estimation from Tagged MRI Using Multiple Source Non-Rigid Registration Techniques Automatic Compensation of Local Susceptibility-Induced Signal Loss in EPI Using a Common Gradient Template and Automatic Slice Positioning Automatic Correction of Intensity Inhomogeneity in Multi-Station MR Angiography of the Peripheral Vessels Automatic Cortical Segmentation for Developing Neonates with the Correction of Mislabeled Partial Volumes (MLPVs) Automatic Extraction of the Low-Motion Phases of the Heart Automatic Image Registration Based Upon an Elastic Finite Element Formulation Automatic Kernel Selection for Optimal GRAPPA Reconstruction Automatic Measurements of Brain Tissue Volumes and Volume Distributions Automatic Passive Tracking of a Prostate Biopsy Device Using Phase-Only Cross Correlation Automatic Peripheral Vessel Tracking in 3D Contrast-Enhanced MR Angiography Automatic Plaque Characterization Employing Quantitative and Multicontrast MRI Automatic Prospective Spectroscopy VOI Placement Based on Brain Segmentation Automatic Reference Selection Method for Unsupervised Artery/Vein Separation in Time-Resolved Contrast-Enhanced Magnetic Resonance Angiography Automatic Registration and Segmentation of Pancreatic Images Automatic Registration of Lung Nodules on 4D Dynamic Contrast Enhanced MR Images Automatic Segmentation in Dobutamine Stress Magnetic Resonance Automatic Segmentation of Human Brain, Grey and White Matter in MRI: A Robust and Accurate Algorithm Based on the Tissues' Features Analysis Automatic Slice-Dependent Frequency Adjustments for SSFP fMRI Automatic Volume Field of View Detection in Non-Selective, Scoutless, Multi-Station MRA AV Ratio and SNR Tradeoffs for Composite Image Selection in Application of HYPR PR-TRICKS on Contrast Enhanced Cerebrovascular MRA Avastin Is Effective in Reducing rCBV in Fast Growing Human Tumor Xenografts Avidin Induced Clearance of Biotinylated Paramagnetic Liposomes for Improved Magnetic Resonance Molecular Imaging Avoiding Resonant Lengths of Wire with RF Chokes at 4 Tesla Axial and Radial Diffusivities as Potential Markers for Characterization of White Matter Lesions and Predicting Lesion Outcome in a Neonatal Rat Hypoxia-Ischemia Model Axial and Radial Diffusivity as MR Biomarkers of Axonal and Myelin Injury in Ex-Vivo Cervical Spinal Cord from Multiple Sclerosis Patients Axial Diffusivity Detects Axonal Injury Live and Postmortem Before But Not After Formalin Fixation Axonal Transport Deficits Occur Prior to Behavioral Deficits in Response to GM2 Accumulation in the HexB-/- Mouse Model B0-Correction in Parallel Imaging with Arbitrary K-Space Trajectories B1+ Homogeneity and SAR Reduction for Localized Excitation at 7T B1+ Region of Interest Localization Through Convex Optimization B1-Insensitive SSFSE Using Adiabatic Preparation of the Echo Train B0 Field Mapping for Diagnostic Purposes in Breast Cancer MR Imaging B0-Field-Driven Capsule Endoscope with Swimming Tails for Propulsion: Design Study B1 Homogeneity of Re-Entrant Cavity Resonator B1 Transmit Field Manipulation at 7 Tesla Using Controlled Decoupling of Array Coil Elements (CODACE) B1-Gradient Based MRI Using a Multi-Element Transmit System Balancing Noise Sources and Coupling in Phased Array Coils Ballistocardiogram Artifact Removal from EEG Signals Using the Real-Time Kalman Filter Baseline Cerebral Venous Oxygenation Determines Response Amplitude to Functional Activation Basis Selection for Wavelet Processing of fMRI Data Bayesian Analysis of Uncertainty in Q-Ball Imaging Bayesian Inference of Kinetic Curve Models for ASL Perfusion Measurements Bayesian Inference of Multi-Modal Perfusion fMRI Data Bayesian Mixed-Effect Model for Breast Cancer Treatment Studies Benchmarking SAP-EPI and PROPELLER for Diffusion Imaging Benefit of Parallel Imaging Techniques for Silent EPI Benefits of Cryogenic Coils for Routine In-Vivo Mouse Brain Imaging and Spectroscopy at 9.4 T Benign Prostatic Hyperplasia: Evaluation of Vascular Characteristics with Dynamic Contrast-Enhanced T1 Weighted MRI Bias Field Correction of Surface Coil MR Images of Rodent Brain Acquired at High Field Bi-Exponential T2 Decay in Hydrodynamic Vascular Gene Therapy Bilateral Time-Resolved Contrast-Enhanced MR Angiography of the Hands at 3.0 Tesla Biliary Anatomy Evaluation of Potential Living Liver Donors: Comparison of High-Resolution Magnetic Resonance Cholangiography and Multislice-CT Cholangiography Biochemical Characterization of Lymphadenopathy in Tuberculosis, Sarcoidosis and Metastasis Using in Vitro MRS Biochemistry of Soft Tissue Tumors: An in Vitro NMR Study Biopsy-Based 1-H and 31-P NMR Shows Regional Metabolic Heterogeneity Within Canine Spontaneous Tumors Bleomycin-Induced Lung Injury Assessed Non-Invasively and in Spontaneously Breathing Rats by Proton MRI Block Circulant Band Diagonal Property for Parallel Imaging Reconstruction in Cartesian K-Space Block-Wise FFT: A Memory Efficient FFT Technique for Magnetic Resonance Imaging Blood-Oxygen Level Dependent (BOLD) MRI of Healthy Human Liver Blood-Pressure Dependent T2*-Mapping BOLD and Sodium MRI of the Human Kidney: Preliminary Experience with Patients BOLD Contrast-To-Noise Ratio Across Field Strengths Under Global Stimulus BOLD Correlates of Human Alpha and Beta Rythms: A Simultaneous EEG-fMRI Study BOLD fMRI Response in the Motor Cortex Is Strongly Linked with CO2 Reactivity in Patients with Carotid Artery Disease. BOLD Low Frequency Fluctuations During Slow Wave Sleep: An EEG/fMRI Study BOLD MRI for Assessment of Tissue Supply During Reactive Hyperemia in Diabetic Patients with Severe Peripheral Arterial Occlusive Disease Bootstrap in MRSI: A Non-Parametric Way to Assess Quantification Standard Error Border Zone Pacing Improves Global and Regional Function as Assessed by Tissue Tagged MRI Boundary Element Method for Calculation of Induced Electric Fields Due to Swiched Magnetic Field Gradients and Movement in Strong Static Fields Brain 1H-MR Spectroscopy of Patients with Leber's Hereditary Optic Neuropathy and Non-Affected Carrirs of mtDNA Mutations Brain Activation in Overactive Bladder Patients Evaluated by Pharmacological fMRI Brain Atrophy Analysis of Relapsing-Remitting Multiple Sclerosis Patients Treated with Pioglitazone Brain Diffusion Weighted Imaging Study of Friedreich Ataxia Patients Brain fMRI Correlates of Pain in Diabetes Brain Iron and Neuronal Integrity in Patients with Parkinson’s Disease Probed by Novel MRI Contrasts Brain Iron in MR Imaging: R2* and Phase Shift at Different Field Strengths Brain Morphometry with Multiecho MPRAGE Brain MRI of Moving Subjects: Snapshot Images with Volume Reconstruction (SVR) Extended to Multi-Shot Sequences and Applied to Neonates and Adults Brain MRSI Metabolic Study of Patients with Remethylation Deficiency Brain Perfusion During Sleep - Determination with Quantitative Perfusion MRI and EEG with Online Artefact Removal Brain State Classification of Rapid Event-Related fMRI Using Mixed Models Brain Tissue Decomposition and Its Effects on Diffusion Tensor Images Brain Tissue Water Content Measured by MRI: Pre- Vs. Post-Shunt Chronic Hydrocephalus Brain Tumor Detection Using Scale Invariant Feature Transform Brain Tumor Nosologic Maps Obtained from T2-Weighted Images Breast Cancer Exhibits Liquid-Like Mechanical Properties – a Comparative Study Between MR-Mammography and MR-Elastography Breast Coil for Real Time MRI Guided Interventional Device Breast MRI Screening for Asain Women, a Preliminary Result Breath-Hold 3D SSFP Coronary Imaging with Simultaneous Fat and Water Separation at 3T Broadband Proton-Decoupled Proton Spectroscopy of Cancer Cell Extract Bulimia Nervosa Is Associated with Visceral Adipositas and Big Adrenal Glands - Initial Results Bulk Motion Independent Analyses of Water Diffusion Change in Brain During Cardiac Cycle Butterfly: A Self Navigating Cartesian Trajectory Caffeine Induced Uncoupling of Cerebral Blood Flow and Metabolism: A Calibrated-BOLD Study Calculation of Aorta Pressure Waveform from MRI Blood Flow Velocity Measurement Calculation of SNR Degradation with the Consideration of Reference Data Calf Muscle Perfusion Measurement by Rapid Time-Resolved Spiral FAIR-ASL Calibrated BOLD in the Medial Temporal Lobe During a Memory Encoding Task Calibrated-BOLD fMRI: The Effect of the BOLD Post-Stimulus Undershoot on the Calculation of the Flow/metabolism Coupling Ratio Calibration of BOLD fMRI Signal Changes Using Cued and Spontaneous Breathing Variations Calibration of RF Transmitter Voltages for Hyperpolarized Gas MRI Calibration Tools for RF Shim at Very High Field with Multiple Element RF Coils: From Ultra Fast Local Relative Phase to Absolute Magnitude B1+ Mapping Calorimetric Calibration of SAR Estimates Displayed on GE MR Scanners Can Connectivity Information from DTI Improve Cortical Parcellation for Resting-State Analyses? Can Functional Signal Change Act as a Filter for Extracortical Vein Effects? Evidence from Smoothing High Resolution fMRI Data Can High Field Functional MRI Detect Interhemispheric Transfer of Visual and Motor Information? Can Man Still Beat the Machine? Automated Vs. Manual Pattern Recognition of 3D MRSI Data of Prostate Cancer Patients Can Regional Cerebral Blood Volume Be Extracted from T2-Decay Curves? Can Relative Coil-Subject Motion During Acquisition Improve Parallel Imaging? Can We Expect Reproducible and Unbiased Information from Denoised Diffusion Tensor Imaging with Low SNR? Cancer Cells Induce Lymphatic Endothelial Cell Migration Cancer Detection in Mice Using Dendrimeric Gd-Peptide Nucleic Acid-Peptide Molecular Probes Cardiac Function and Myocardial Perfusion Immediately Following In-Room Maximal Treadmill Exercise Cardiac Gated ASL: Effects of CBF Pulsatility on the ASL Perfusion Signal Cardiac Imaging at 7T Cardiac Magnetic Resonance Imaging of Master Marathon Runners: Prevalence and Ethiology of Myocardial Late Enhancement Cardiac Magnetic Resonance Imaging Permits Visualization of Coronary Microembolization in Swine Cardiac MR Imaging of Apical Left Ventricular Aneurysm and Thinning Associated with Hypertrophic Cardiomyopathy Cardiac Specific Plasmid-VEGF Increases Myocardial Angiogenesis, Perfusion and Infarct Resorption Cardiac Stress P-31 MRS at 3T for Type-I Diabetes Mellitus Patients Carotid Artery Imaging at 3T: More Signal from 3D Imaging Using a New 4-Element Coil Carr-Purcell-Meiboom-Gill (CPMG) Imaging of Prostate Cancer; Trading Time for Information: High Quality T2 Images and Quantitative T2 Values for Cancer Discrimination Cartesian Continuous Sampling with Unequal Gradient Strengths Cartilage T2 Assessment at 3 Tesla: In Vivo Differentiation of Normal Hyaline Cartilage and Reparative Tissue in Patients After Different Cartilage Repair Procedures Cascaded Segmentation of Brain Tumors Using Multi-Modality MR Profiles Causality Analysis Using Resting State BOLD fMRI in Normal and Ischemic Rat Brains CDII Performance at Low Conductivity Contrast Cell Swelling Model Reproduces DWI Signal Change in Acute Stroke Cellular Labeling with Gadolinium Containing Imaging Probes. A Method for Checking the Release of Gd3+ Ions in the Cellular Environment Cellular MRI of Monocyte Infiltration: In Vitro Vs In Vivo Labeling Cellular MRI of Neural Stem Cell Therapy in a Rat Glioma Model CE-MRA and MR Velocimetry in the Determination of Hemodynamic Forces in Longitudinal Studies of Intracranial Aneurysm Growth CE-MRA and Numerical Modeling of the Flow in Intracranial Aneurysms: Prediction of Regions Prone to Thrombus Formation Cerebellar White Matter Development Lags Supratentorial White Matter Cerebral Blood Flow Estimation Using Local Tissue Reference Functions Cerebral Blood Volume Decreases Demonstrated During Breath Hold with Vascular Space Occupancy (VASO) and VASO-FLAIR fMRI Cerebral Blood Volume Fraction Mapping in a C6 Brain Tumor Model Using RSST1-MRI with an Intravascular Contrast Agent: Gd-ACX Cerebral Metabolic Deficits in Young Patients with Tourette Syndrome Assessed by Proton MRSI Cerebral Metabolic Effect of Acute Inhibition of Aspartate Aminotransferase Measured by 1H MRS Cerebral Metabolism of Adult Marmoset Monkeys After Intrauterine Hyperexposure to Dexamethasone Cerebral Microbleeds on Brain MRI in the General Elderly Population: Prevalence and Relation to Small Vessel Disease. Cerebral Perfusion in Alzheimer's Disease Using Dynamic Susceptibility Contrast MRI Cerebrospinal Fluid Lactate in P. Falciparum Malaria: Measurement by Chemical Shift Imaging at 3 Tesla Cervical Carcinoma on High-Resolution MRI: Implication for Fertility-Preserving Surgery Cervical Cord Is Vulnerable to Aging: A Diffusion-Tensor Mri Study Cervical Spinal Cord Injury in the Rat: Longitudinal MRI Comparison of Two Injury Severity Levels Cervical Spinal fMRI Study: Modulation of Functional Activation Signal by Task Difficulty, Hand Skill and Handedness Change in Knee Cartilage T2 in Response to Mechanical Loading at 3.0 T Changes in Brain Energy Metabolism After Carotid Artery Stenting by In Vivo 31P NMR Spectroscopy Changes in CBVa and CBF Haemodynamic Response with Stimulus Duration of 4.8 and 9.6 S. Changes in Coronary Sinus Size Throughout the Cardiac Cycle: Implications for Coronary Vein Imaging Changes in DTI Metrics in Normal Appearing White Matter and Gray Matter After Radiotherapy in Patients with Low Grade Glioma Changes in Metabolic Profile of Colorectal Cancer Undergoing Chemoradiation Therapy Assessed by High-Resolution Magic Angle Spinning Spectroscopy Changes in Perfusion Underlie Negative Bold Responses (NBR) in Epilepsy Patients with Generalised Spike Wave Activity Changes in Serum Albumin Measured by Electron Spin Resonance: In Vitro Diagnostic EPR Test Changes in the Tumor Micro-Environment Induced by Xanthinol Nicotinate: Characterization of the Hemodynamic Parameters and Their Consequences for Cytotoxic Therapies Changes of Proton T1 and T2 Relaxation Times of Cerebral Metabolites Induced by Repeated Manganese Treatments in Rat Changes of Rate Constant of Creatine Kinase Reaction in Human Brain During Hypoglycaemia Measured by 31P NMR Saturation Transfer Changes of T2 Values of Patellar Cartilage in Subjects with Osteoarthritis Over a One Year Time Period Changing Enhancement Patterns Over Time of Small Breast Cancers in Women at High Genetic Risk of Breast Cancer Channel Compression and Denoising Characterisation of a New Brain Metastases Model in the Nude Rat Characterisation of Brain Anisotropy Using Diffusion MRI Characterisation of Lung Edema Over Time by 1H MRI Using Preferential Averaging of K-Space Characterisation of the Time Course of the Superior Mesenteric, Aorta and Internal Carotid Arteries’ Blood Flow Response to the Oral Glucose Challenge Test Characteristic Breast MRI Findings Following Accelerated Partial Breast Irradiation Either by Intra-Operative Radiotherapy or Three-Dimensional Conformal External Beam Radiotherapy Characterization of a Prostate Cancer Xenograft in Orthotopic and Subcutaneous Sites Characterization of a Rodent Model of Metabolic Syndrome by MRS and MRI Characterization of Adrenal Tumors with Single Breath-Hold In-Phase/Opposed-Phase MR Imaging at 3.0 Tesla: Comparison of Different Echo Time Pairs Characterization of Age Induced Brain Changes Using MRI in Rats Characterization of an Experimental Setup to Study in Vitro Permeability Properties of Macromolecular Contrast Agents by DCE-MRI Characterization of an Intrinsic Low-Frequency Component at Around 0.025 Hz in Steady-State fMRI Signals Characterization of Atherosclerosis Lesions with TrueFISP Intravascular MRI Characterization of Bone Tumors with In-Vivo 1H MR Spectroscopy Characterization of Cerebellar Metabolic Alterations in Ataxia with Oculomotor Apraxia (AOA2) Characterization of Cortical Activation Patterns in Action Induced Focal Dystonia by 3.0 T fMRI Characterization of Gliomas Using MR-Derived Cerebral Blood Volume Maps in Combination with Metabolic Ratios from Proton MR Spectroscopy Characterization of Liver Neoplasms with a Fast Radial-FSE Imaging Technique. Characterization of Metabolism in Rat Olfactory Bulb by In Vivo 1H and 1H-[13C] NMR Characterization of Myelin Damage in Multiple Sclerosis Using Myelin Water Imaging: Insight from Simulations on a Four Pool Model of White Matter Characterization of Neurodegeneration in Experimental Autoimmune Encephalomyelitis Induced Rat Using High Resolution DTI Characterization of Paramagnetic Lanthanide Ion Complexes as MRI Contrast Agents as a Function of Magnetic Field Strength Characterization of Passband SSFP FMRI: A Comparison with GRE at Multiple Field Strengths Characterization of Renal Masses with Diffusion-Weighted MR Imaging -- A Preliminary Experience Characterization of Solid State Dynamic Nuclear Polarization for Metabolic Imaging Characterization of T1 Hyperintense Renal Lesions with Diffusion-Weighted Imaging: Preliminary Experience Characterization of the 6-OHDA Model of Parkinson’s Disease Using Manganese-Enhanced MRI Characterization of the BOLD Post-Stimulus Undershoot Characterization of the Dynamic Shear Properties of Hyaline Cartilage in Vitro Using MR Elastography Characterization of the Motional Spectrum of Nuclear Spins by Means of Spatial Independent Component Analysis (SICA) Characterization of the Substantia Nigra in Elderly Subjects by Multi-Modality MRI Characterization of Transmission Line Coil Elements Characterization of Transmural Myocardial Wall Motion in Mouse Using High Resolution MR Tagging Characterizing DTI Image Quality and the Efficacy of Dyadic Sorting with a Capillary Phantom Characterizing the Differential Effects of Selective Cannabinoid Agonists on Brain Activity in Awake Rats Using Pharmacological MRI Chemical Shift Artifact in Center-Out Radial Sampling: A Potential Pitfall in Clinical Diagnosis Chemical Shift Correction in Bipolar Multi-Echo Sequences for Water and Fat Separation Chemical Shift Imaging of Glycogen Storage Disease Patients Showing Increased Liver Fat Contents at Young Age Only Chemical Shift Independent Imaging of 19F Contrast Agents Using Ultrafast MRSI (F-uTSI) Chemical-Shift Artifact Reduction in Hadamard-Encoded MR Spectroscopic Imaging at High (3 and 7 T) Magnetic Fields Chemotherapy-Induced Changes of Intracellular Water Diffusion in Cultured Cells Childhood Parental Nurturance Affects Later Brain Morphology in Adolescents Choline Metabolism in Breast Cancer; the Influence of the Microenvironmental Conditions Choline Phospholipid Characterization of Hox B7 Overexpressing MCF-7 Cells Chromium(VI)-Enhanced MRI of White Matter in Mouse Brain Chronic and Incremental Effect of Hypoxia Due to Extreme High-Altitude Exposure Relate with Atrophy in Motor-Function Related Brain Areas Chronic Cigarette Smoking Modulates Injury and Short-Term Recovery of the Medial Temporal Lobe in Alcoholics Chronic Unpredictable Stress and Riluzole Treatment Alters Glutamate Metabolism in Rat Prefrontal Cortex Cine MRI Flow-Analysis in Phantom Model of Cranio-Spinal Axis In-Vivo Studies CIRcumferential COMpression Encoding (CIRCOME) Citrate in Pediatric CNS Tumors Classification of the Quality of In Vivo 1H Spectra from Human Brain Tumours Using ICA Clinical Application of Susceptibility Weighted Imaging (SWI) in Cerebrovascular Disease Clinical Application of Whole-Heart Coronary MRA Using "Paddle-Wheel" Balanced SSFP Clinical Application Study of MR Perfusion Imaging and Diffusion Tensor Imaging in the Tumor Like Lesions of the Cervical Spinal Cord Clinical Applications of Susceptibility Weighted Imaging Clinical Evaluation of Vessel Size Imaging in 31 Cases of Human Glial Brain Tumor Clinical Experience of Large FOV Accelerated Time-Resolved 3D Contrast-Enhanced MR Angiography at 3T in 105 Patients Clinical Experience of the Use of Gadolinium Contrast Agents for T1-Weighted 3D High Resolution Neurological Imaging Clinical Feasibility of a 3D Dual Echo Dixon Technique for Abdominal MRI Clinical Field-Strength MRI of Transplanted Pancreatic Islets in a Large Animal Model Clinical Significance of Global Versus Local fMRI Autocorrelation Estimation Clinical Utility of Flow Encoding Phase Contrast - MRI to Quantify the Exercise Induced Flow Reserve in Lower Extremities Clinical Value of a Single Breath-Hold 3D Delayed Hyperenhancement Cardiac MRI with Sensitivity Encoding Clnical Value of Proton Spectroscopy Added to High Spatially Resolved Gd-Enhanced MR of the Breast Cluster Analysis from Multiple MR Image Classes Can Reduce User Bias and Improve Glioma Grading Cluster Analysis of fMRI Activation Pattern in a Visual and Auditory Naming Task Clustering fMRI Data Using a Spatiotemporal Geodesic K-Means Algorithm Cocaine-Induced Cerebral ADC and Hemodynamic Changes Between Cocaine-Naïve Rats and Rats with Repetitive Cocaine Treatment Cognitive Coping Style Modulates Neural Responses to Emotional Faces – a 3T fMRI Study Cognitive Modules Utilized for Covert Verb Generation in Children: A Functinal Magnetic Resonance Imaging Study Cog-Wheel Imaging: A Rapid Echo Shifted Technique Coherent Motion Preparation of the Magnitude Signal in MR Elastography Coil Selection Optimization Using Mean-Field Annealing and Its Application to 128-Channel Imaging Collagen Binding MR-Detectable Liposomes Colour Coding in LGN and V1 Revealed by fMRI Pattern Classification Combination of 18FDG-PET, 13C MRS and 31P MRS Provides a Highly Consistent Picture of Brain Energy Metabolism, from Glucose Breakdown Up to ATP Synthesis Combination of IDEAL and ARC Imaging to Obtain Homogeneous Fat Saturation in the Brachial Plexus Within Clinically Acceptable Time Parameters Combination of Multinuclear and Multiparametric Breast MRI with ISODATA Analysis Combination of Proton MRSI of the Brain Acquired Using a Multichannel Coil Without Water Suppression Combinatorial Fiber-Tracking of the Human Brain Combine ASL Perfusion and BOLD fMRI for Imaging Risk in the Human Brain Combined Adenosine Stress Perfusion and Tagging Protocol for Detection of Coronary Artery Disease at 3 Tesla Combined Clinical MR/PET: Feasibility of Simultaneous Imaging Combined Correction with Regression for Measured Respiratory, Cardiac, and Capnometry Variations in Pain FMRI Studies Improves Model Fit Combined Diffusion Weighted and Dynamic Subtraction MRI for Prostate Transition Zone Cancer Diagnosis: Correlation with Histopathology Combined EEG and MRI Measurements in a Rat Model of Neonatal Hypoxia-Ischemia Combined HR MAS MR Spectroscopy and Gene Expression of Breast Cancer Tissue Combined In Vivo Imaging and Delivery of siRNA to Tumors Combined Magnetic-Resonance and Bioluminescence Imaging of Live Mice Combined MR and Diffuse Optical Tomography for Dynamic Contrast Enhanced Imaging Combined Proton Magnetic Resonance Spectroscopic Imaging Index Predicts Survival of Children with CNS Tumors Better Than Histology Combined Quantitative Approach for Brain Tumor Fingerprinting Combined Rotational/Translational Motion Correction Using EXTRACT for High-Resolution Trabecular Bone Imaging Combined T2 and Diffusion Weighted MRI for Localization of Prostate Cancer Combined Volumetric MRI and MR Spectroscopic Analyses of the Cerebellum in Developmental Dyslexia Combining 31P-MRS with Near-Infrared Spectroscopy to Measure the Concurrent Changes in Energy Metabolites and Cerebral Oxygen Consumption Following Hypoxia Ischemia Combining 3T, SENSE and K-Space Segmentation for Robust Coronary Sinus Flow Quantification Combining Contrast Enhanced In Vivo and Ex Vivo MRI for Characterizing Vulnerable Plaques in a Rabbit Model of Atherothrombosis Combining fMRI and Probabilistic Tractography in the Temporal Lobe Combining Voxel-Based Morphometry and 1H Magnetic Resonance Spectroscopy in Myotonic Dystrophy Type 2 and Type 1 Combining Voxel-Based Morphometry and Diffusion Tensor Imaging to Probe Neural Substrate of Schizophrenia on First Episode Treatment Naive Patients Comparative Analysis of Morphological MR Imaging Features in Human Epidermal Growth Factor Receptor (HER-2/neu Receptor) Positive and Negative Invasive Ductal Carcinoma Comparative Analysis of Predictive Capability of Dynamic Perfusion MRI, Quantitatively and Qualitatively Assessed CT, and Perfusion SPECT for Postoperative Lung Function in Lung Cancer Patients Comparative Response to Focal Cerebral Ischemia of C57Blj6, Trek-1-/- And Traak-/- Mice Comparative Study of Coronary MRA, CTA and X-Ray Angiography Comparing Automatic Deformation-Based Techniques Against Manual Volumetry in a Mouse Model of Alzheimer's Disease: A Longitudinal In Vivo Study Comparing Functional Connectivity in Default Mode of Brain Between Adult and Children During Mental Calculation Comparing MRSI, PWI and DWI of Meningiomas and Glioblastoma Multiforme at 3T to Find a Marker for Diffuse Infiltrative Brain Tumor Tissue Comparing Rodent Forepaw Stimulation Under Two Levels of Domitor Anesthesia Using Laser Doppler and fMRI at 9.4T Comparison Between 2D and 3D Black Blood Imaging of the Clinically Significant Carotid Atherosclerotic Plaque Comparison Between Broadband Decoupling Methods for Microstirp Array Comparison Between the Blood Pool Agent Vasovist and Conventional Gadolinium Agents for Dynamic Moving Table Peripheral CE-MRA – A Preliminary Study Comparison of 129Xe Pulmonary Gas Exchange Measured by Two Techniques: XTC and CSSR Comparison of 3D FSE-XETA with 3D FIESTA-C and 3D FRFSE for Imaging of the Internal Auditory Canal at 3T Comparison of 3D Look-Locker Technique Against 2D IR-FSE for dGEMRIC Comparison of Array Decoupling Mechanisms on Rat Arrays at 1.5 T Comparison of Cardiac Iron Overload Assessment by MRI Susceptometry and R2* in Thalassemia Patients Comparison of Choline and Pharmacokinetic Parameters in Breast Cancer Measured by MR Spectroscopic Imaging and Dynamic Contrast Enhanced MRI Comparison of Conventional and Phase Enhanced T2* Weighted Gradient Echo Imaging for the Detection of Iron-Oxide Nanoparticles at Low Nano-Molar Concentrations Comparison of Current B1-Mapping Techniques Comparison of Different Field Insensitive Saturation Pulses for 3T Cardiac First Pass Perfusion Comparison of Diffusion Tensor and Q-Ball Imaging of the Canine Myocardium Comparison of Diffusion Weighted Image Distortion Correction Comparison of Diffusion-Weighted with Necrosis Avid Contrast Agent–Enhanced MRI for the Assessment of Spontaneously Developed Necrosis in a Rat Rhabdomyosarcoma Model Comparison of Distortion Correction Methods for EPI Diffusion Tensor MRI Comparison of DTI and Growth-Associated Protein Expression as Markers of Neuronal Plasticity After Stroke Comparison of Four Clinically Approved Gadolinium-Based Contrast Agents for Imaging of Experimental Atherosclerosis in a Rabbit Model Comparison of Four Quantitative Pulsed ASL Methods for Mouse Brain Perfusion MRI Comparison of FP, VCSEL and DFB Laser Diode in Optical Transmission for MR RF Coil Array Comparison of Functional MRI- And PET-Techniques to Assess Tumor Heterogeneity in Malignant Gliomas Comparison of GE and SE BOLD fMRI Techniques in Temporal-Encoding Iso-Orientation Maps. Comparison of In Vivo and Ex Vivo R1-Map-Based Percent-Infarct-Mapping Using Gd(DTPA) Comparison of In Vivo MRI Methods for Examining White Matter Abnormalities in Schizophrenia Comparison of Left and Right Ventricle Functional Measurements Using Steady State Free Precession-Short Axis Versus Four Chamber Analysis Comparison of Linear and Non-Linear Fitting Methods for Estimating T1 from SPGR Signals Comparison of Linear Combination Filtering to DTI and MTR in Whole Brain Myelin-Water Imaging Comparison of Magnetic Resonance Electrical Impedance Tomography at 4T and 7T Field Strengths Comparison of Measured and Estimated Induced Voltage on Implanted Cardiac Leads Due to MRI Gradient Magnetic Fields Comparison of Micro-Architectural Differences Between the Breast Harboring Cancer and the Normal Contralateral Breast Comparison of MR Elastography and FibroScan for the Non-Invasive Assessment of Liver Fibrosis Comparison of MR Imaging Features Between Estrogen Receptor Positive and Negative Breast Cancers Comparison of MR Lesion Morphology and Contrast Enhancement Kinetics in Patients with Recurrent Breast Cancer and Non-Recurrent Lymph Node Positive Vs. Negative Breast Cancer Comparison of MRI (dGEMRIC) and CT (DICE-CT) for Molecular Imaging of Cartilage Glycosaminoglycan Comparison of MRI and Histopathologic Methods of Quantifying Hepatic Fat Fraction Comparison of MRI Features Between Invasive Ductal Carcinoma, Invasive Ductal Carcinoma with Lobular Involvement and Infiltrating Lobular Carcinoma Comparison of Navigator-Gated and Breath-Held Measurements of R2, R2*, and R2' for the Assessment of Hepatic and Myocardial Iron Content Comparison of Optimized Fast Spin Echo (FSE) Magnetic Resonance (MR) Imaging to View Angle Tilt (VAT) FSE in the Reduction of Metallic Susceptibility Artifact Surrounding Arthroplasty Comparison of Pharmacokinetic Models in Quantitative Analysis of T1-Weighted Dynamic Contrast-Enhanced Magnetic Resonance Imaging Comparison of Phase and Magnitude Images Using PSIR Sequence in the Study of Infarct Size with Delayed-Enhancement Cardiac Magnetic Resonance Imaging at 3 Tesla Comparison of Phase-Sensitive and Alternating Repetition Time SSFP for Flow-Independent Peripheral Angiography Comparison of Qualitative Assessment of Knee Osteoarthritis on Three 3.0T MR Systems from Different Manufacturers. Comparison of Quantification of Clinical MR Spectra by LCModel and the Scanner System Software Comparison of Quantitative DSC and ASL Perfusion Methods in Human Subjects at Risk for Alzheimer’s Disease Comparison of Seed-ROI Based Correlation Analysis and Independent Component Analysis in Quantification of Resting-State Brain Networks Comparison of Sensitivity and SNR Between 25mm, 50mm and 75mm Diameter Round Coils for Head Imaging on 7T Comparison of Spin Echo and Balanced Steady State Free Precession in MR-Elastography - A First Step to Cardiac MR-Elastography Comparison of Spinal Vasculature in Mouse and Rat: Investigations Using Magnetic Resonance Angiography Comparison of T1-Weighted 3D High-Resolution Anatomical Sequences for the Brain at 3 Tesla: FLASH, MP-RAGE and MDEFT Comparison of Techniques for Pulse Wave Velocity Calculation by MRI Comparison of the Effectiveness of Saturation Pulses for Quantitative First-Pass Cardiac Perfusion MRI at 1.5T and 3T Comparison of the Goodness of Fit Provided by Models Commonly Used to Characterise DCE-MRI Data Comparison of the Noninvasive Techniques to Evaluate Intracranial Compliance and Pressure Based on MR Flow Quantification Comparison of the Tensor Estimation Quality for Icosahedral Gradient Encoding Schemes Comparison of the Uniform and Golden Angle Projection Reconstruction Schemes Using a Dynamic Sampling Simulation Comparison of Three Transmit Arrays for Parallel Transmit Comparison of Transceive Phased Array with TEM Volume Coil for Human Brain Imaging at 4 T. Comparison of Tumor Permeability/Perfusion Measured by Dynamic Contrast Enhanced CT and MRI Analyzed with a Novel Arterial Input Function Estimation Method Comparison of Unilateral and Bilateral Complex Finger Tapping-Related Activation in the Precentral Gyrus Comparison of Whole Body MR-DWI and Scintigraphy in Detecting Bone Metastases Comparitive Evaluation of a Multi-Echo fMRI Acquisition Technique Using Parallel Imaging Compartment-Specific Q-Space Analysis of Isolated Nerves Compensation of Abdominal Breathing Artifacts in Multi-Shot Acquisitions Using Parallel Imaging and Automatic Coil Weight Selection from Adjacent Slices Compensation of Confounding T1 and T2 Dipolar and Residual Susceptibility Effects in DSC-MRI Using Dual-Echo SPIRAL Complex Analysis of ASL fMRI Data Yields More Focal Activation Composite Shim Coil Design for System-Specific Field Corrections Comprehensive Quantitation of Myocardial Infarct Size by Cardiac Magnetic Resonance Imaging Predicts Future Cardiovascular Events in Ischemic Cardiomyopathy Patients Considered for Revascularization Comprehensive Valve Evaluation System Computation of 3He Apparent Diffusion Coefficient in a Simple Model Acinus Computer-Aided Detection of Skeletal Metastases in MRI STIR Imaging of the Spine Concept for RF-Safe Electrophysiology Pacing Catheters Using a Transformer-Based Transmission Line Concreteness Effects in Dominant Hemisphere Temporal Lobe Epilepsy Congruence Between BOLD Activation Pattern and the Maximal Suppression Effect by TMS During a Simple Visual Discrimination Task Conjugate Gradient Correction and Reconstruction of Multishot Diffusion Weighted Variable Density EPI Conjugate Symmetry for Improved Parallel Imaging with GRAPPA Connectivity Analysis During Motor Imagery and Motor Execution Using DCM Conservative Electric Fields Can Dominate Sample Loss in High Field Microimaging Conserved Patterns of White Matter Hyperintensity Distribution in Alzheimer's, Cerebral Amyloid Angiopathy, and Healthy Aging Consistency Based Ghost Busting (CBGB) Consistency of DT-MRI to Assess Quality of MRI Inter-Subject Registration Consistent Automated Scan Planning of Spine Consistent Negative BOLD Responses in SI of Primate Cortex Produced by Tactile Stimulation Constant Phase Statistical Method Better Localizes Activations Than Phase Regressor Statistical Method Construction and Experimental Evaluation of a Planar Gradient Coil Set for a Compact Permanent Magnet Contactless Measurements of Liquid Sample Electrical Conductivity for Estimating Specific Absorption Rate in MR Applications Contamination Reduction in the Reconstruction of SLIM (CORRECT-SLIM) and Its Application to Quantitative Cardiac 31P-CSI Contiguous-Slice Diffusion Tensor Imaging of the Optic Nerve with CSF Suppressed IR CO-ZOOM Continuous 2D GRAPPA Kernel for Propeller Trajectories Contrast Between Grey and White Matter in 7 T Phase Images and Its Potential for Segmentation Contrast Enhanced Coronary MR Angiography Using Vasovist ® - Comparison with T2 Prepared bSSFP Acquisition in Pigs Contrast Enhanced MR Angiography at 7 Tesla: Challenging the Limits of Spatial Resolution Contrast Enhanced MR Angiography in Intracranial Arterial Stenosis Reveals Collateral Circulation and Angiogenesis Contrast Enhanced MR Imaging of the Brain Using T1-FLAIR with BLADE Compared with Conventional Spin Echo Sequence Contrast Enhanced Real-Time MRCA Contrast Optimization by Data Weighting in Propeller Imaging Contrast Optimization of Black-Blood Viability Imaging Contrast Resolution Between Myocardial Delayed Enhancement and Intraventricular Blood Using a Single (0.1 mmol/kg) Dose of a High-Relaxivity Contrast Agent (Gd-BOPTA) Contrast Similarity Between FA and T2* Studied in White Matter of the Human Brain at 3.0 and 7.0 T Contrast-Enhanced First Pass Perfusion MR Imaging in Patients with Subclinical Hepatic Encephalopathy Contrast-Enhanced Magnetic Resonance Mammography (MRM): Improvement in Breast Lesion Detection and Characterization with Gadobenate Dimeglumine (Gd-BOPTA) Compared to Gadopentate Dimeglumine (Gd-DTPA) Contrast-Enhanced MRA of the Abdominal and Peripheral Vessels: Is There a Need for Blood Pool Agents? Contrast-Enhanced MRI of Blood-Brain Barrier Disruption in CCL2 Transgenic Mice During Pertussis Toxin-Induced Inflammation Contrast-Enhanced Single-Echo Acquisition Imaging Using Single-Point Dixon Contribution of Cardiac-Induced Brain Pulsation to the Noise of the Diffusion Tensor in Turboprop-DTI Contribution of Gliosis, Neurodegeneration, and Axonal Spouting to the Manganese Enhancement MRI Contrast in the Rat Hippocampus After Systemic Mn Administration Contribution of Myocardial Vascular Compartment to Water Diffusion Controlled Aggregation of Ferritin for MRI of Actin Polymerization Controlling J-Coupling Evolution During Selective RF Pulses Conversion from Signal Intensity to Gd Concentration May Be Unnecessary for Perfusion Assessment of Tumors Using DCE-MRI Convertible Manganese Contrast for Molecular Imaging Coronary Blood Flow Measurement Using 3.0T Phase Contrast Magnetic Resonance Coronary Magnetic Resonance Vein Imaging Coronary Vessel Wall Contrast Uptake at MR Imaging: Comparison of Patients with Stable Angina Compared to Age-Matched Healthy Controls Corpus Callosum Morphometry in Childhood-Onset Schizophrenia Correcting Artifacts in High Temporal- and Spatial-Resolution Dynamic Abdominal Studies Using UNFOLD: A Potential Tool for Improving Perfusion Quantification of DCE-MR Investigations Correcting for Center Frequency Variations in MRSI Data Using the Partially Suppressed Water Signal Correcting for Expired Carbon Dioxide Level Does Not Improve fMRI Repeatability for Motor Studies Correcting for Translational Motion in 3D Projection Reconstruction: Revisited Correcting Static Interventional Roadmaps for Subject Displacement in Real-Time Using One-Dimensional Projections Correcting Strain Measurements of Strain-Encoding (SENC) MRI with Slice Following Correction for Gradient-Echo EPI Distortions Using Embedded Low-Resolution Field Mapping and K-Space Energy Spectrum Analysis Correction for Image Artifacts in T1?off-Weighted Imaging Correction of Contrast Agent Extravasation Effects in DSC-MRI Using Dual-Echo SPIRAL Provides a Better Reference for Evaluating PASL CBF Estimates in Brain Tumors Correction of Geometric Distortions Due to Static Magnetic Field Inhomogeneities and Eddy Currents in SENSE DTI Correction of Macroscopic Field Gradient Effect for Magnetic Field Correlation Imaging Correction of Physiological Noise on fMRI Time Series Using a Cyclic Retrospective Correction at Short TRs Corrections to Accelerated Propeller Acquisition to Maintain Contrast and Reduce T2 Decay Artifacts Correlating In Vivo MRI with 3D Post Mortem Information in Rat Brain Correlating Longitudinal In Vivo Images of Beta-Amyloid Plaques with Morris Water Maze Test Results in a Mouse Model of Alzheimer’s Disease Correlating MRI to the Gold Standard of Pathology in Invasive Breast Cancer Correlating Muscle Structure and Function with MRS and DTI Correlation Between Brain Metabolites and Very Long Chain Fatty Acid Levels in Asymptomatic Boys with X-Linked Adrenoleukodystrophy Correlation Between Choline and Contrast Enhancement in Human Breast Cancer Measured by Quantitative 1H Single-Voxel MR Spectroscopy and Dynamic Contrast-Enhanced MRI Correlation Between Choline Concentrations and Trace Values in Human Brain Tumors Correlation Between Metabolite Alterations in 1H-MR Spectroscopy in Hippocampal Sclerosis Correlation Between Plaque Neovascularization, 18 FDG-PET Plaque Uptake and Dynamic Contrast Enhanced MRI Perfusion Parameters in a Rabbit Model of Atherosclerosis Correlation Between Single Quantum and Triple-Quantum-Filtered 23Na MRI Signal Intensities, Water ADC and Histology Changes in Control and 5-Fluorouracil Treated RIF-1 Tumors Correlation Between the Apparent Diffusion Coefficient and the Oxygen Depletion Rate in COPD Disease: A Case Study Correlation Between XRA and Radial Sliding Window MRA of Arteriovenous Malformations Correlation of ADC Values for Tumour and Non-Tumour Areas of Prostate Cancer as Defined by Histopathology at Prostatectomy Correlation of Changes in Venous Cerebral Blood Flow After Trauma in Rats Measured by Susceptibility-Weighted Imaging and Fractional Anisotropy in Diffusion Tensor Imaging Correlation of Diffusion Tensor Imaging with Neuro-Chemical Changes in Low Grade Hepatic Encephalopathy Correlation of Diffusion WI to Histopathological Findings of Lymph Node in Rectosigmoid Cancer Correlation of Dynamic Contrast-Enhanced MRI Parameters and Clinical Outcome for Locally Advanced Breast Cancer Patients Correlation of Fractional Anisotropy with Histology for Diffuse Axonal Injury in a Rat Model Correlation of Gadolinium Enhanced Time Resolved MR Nephro-Urography and Inulin Measurements of Glomerular Filtration Rate in Sickle Cell Disease Nephropathy Correlation of Hyperpolarized 3He Q-Space Diffusion MRS Parameters with in Vitro Lung Data Across Animal Species Correlation of In Vivo MRS and Ex Vivo HR MAS Metabolic Profiles and Clinical Outcome for Brain Metastases Patients Correlation of Insulin Sensitivity and Replenishment of Intramyocellular Lipids (IMCL) as Observed by 1H-MRS Correlation of Microvascularity Identified Within Human Gliomas on High Resolution 8T Gradient Echo MRI and Directed Biopsy Correlation of Pre- And Post-Treatment MRI and Pathological Response Grading in Rectal Cancer Patients Correlation Time Mapping of the Human Brain: A New Application of the Mixed-TSE Pulse Sequence Correlations Between Functional Diffusion Maps and Anti-Angiogenic Treatment Response in Glioblastoma Corresponding Non-Invasive 1H and 23Na MRI of Ancient Mummified Human Tissue Cortical Activation in Reduced During Motor Imagery in Amyotrophic Lateral Sclerosis Cortical Activation of a Distraction Task in Tinnitus Patients and Controls Studied with fMRI Cortical Brain Mapping of the Rat Forelimb Using fMRI at 9.4T by Direct Nerve Stimulation Cortical Connectivity Observed in Normal and Healthy Neonates, 1 Year and 2 Years Old Children Using Low-Frequency BOLD Fluctuation Cortical Curvature and Allometric Scaling of Cerebral Cortex in Preterm Infants Cortical Expression of Cognitive Control in the Bipolar Disorder Revealed by fMRI Cortical FA Mapping of Developing Rat Brains Cortical Surface Reconstructions for Developing Neonates Cortical Thickness Analysis in Patients with Adolescent-Onset Schizophrenia Coupling Between Simultaneously Recorded BOLD Response and Neuronal Activity in the Rat Somatosensory Cortex Under Different Anesthetics Covalidation of Anisotropy Using Polarized Light Microscopy and Diffusion Tensor Imaging in White Matter of a Mouse Cranial Nerve Tractography with 3T PROPELLER Diffusion Tensor Imaging Creatine Kinase Over-Expression Improves Myocardial Energetics and Function in Failing Mouse Hearts Criterion to Accelerate Time-Resolved MRI Based on the Corners of a 4D K-Space Cross-Sectional and Longitudinal Brain Morphometry in HIV Associated Cognitive Impairment Cross-Validation of Brain Parenchymal Volumes Between SPM5 and SIENAX Curvilinear Myocardial Signal Response to Gadolinium Results in Underestimation of Absolute Myocardial Perfusion by Magnetic Resonance First-Pass Imaging Cylindrical-FSE for Rapid, Quantitative T2 Mapping in Alzheimer’s Mice Cytosolic pH Buffering in Muscle of Patients with McArdle’s Disease Daidzein-BSA-GdDTPA/CyTE777 a Novel Contrast Material for Functional and Molecular Targeting of Ovarian Carcinoma Tumors Dark Blood Delayed Enhancement in Humans by Double Preparation and Gradient-Echo or Turbo-Spin-Echo Readout Data Acquisition Considerations for Compressed Sensing in MRI DCE and Intrinsic Susceptibility-MRI Investigations of Prostate Gland Physiological Changes with Androgen Deprivation DCE-MRI Analysis of Radiotherapy and Combretastatin-A4-Phosphate (CA4P) Effects on the Cancerous Prostate Gland DCE-MRI and Fluorescence Microscopy of Microvascular Permeability DCE-MRI of Polyamidoamine Dendrimer-Nanoparticle Permeability in the RG-2 Rodent Malignant Glioma Model DCE-MRI Parameters Are Predictive of Tumour Regression in Cervix Cancer Deactivation Network of Working Memory in Schizophrenia: Functional MRI Study with Parametric Digit N-Back Task Deactivations in Primary Visual Area Which Correspond to Activations in Extrastriate Visual Areas Studied by fMRI Dealing with Spatially Varying Noise in T2* Mapping with SENSE Decline in Extent Macroscopic Cerebral Vasculature with Age Quantified Using Computerized Automatic Vessel Tracking Decomposition of 1H NMR Spectra of Blood Plasma for Identification of Complex Metabolic Response to Glucose Uptake Deconvolution Approach to Multi-Compartmental Modeling: Characterizing Intra-Renal Transport of Gadolinium Contrast Deconvolution-Based Dynamic Contrast Enhanced MR Imaging of Breast Tumors: Correlation of Perfusion Parameters with HER-2 Gene Amplification and Hormonal Receptor Status Decoupling of a Multi Channel Transmit/Receive Coil Array Via Impedance Inversion Decrease in BOLD fMRI Activation Volume Due to Abnormal Neovasculature and Metabolite Levels in Brain Tumor Patients Decrease in Tumor Cell Oxygen Consumption After Treatment by Vandetanib (ZD6474), an Inhibitor of VEGFR-2, EGFR and RET Tyrosine Kinases, and Its Effect on Responses to Radiotherapy Decreased Anisotropy in the Corpus Callosum of Patients Suffering from Limb Kinetic Apraxia Decreased Axial Diffusivity as a Biomarker of Axonal Injury in the Spinal Cord White Matter of Mice with EAE Validated with Immunofluorescence Decreased Glutamate Levels with Acute Exposure to Anesthetic Agent Propofol: A Preliminary In Vivo 1H Spectroscopy Study Decreased T1 and T2 in the Brain of APP/PS2 Mice, a Model for Alzheimer's Disease Deep Gray Matter ‘Black T2’ Correlates with Disability in the Minocycline Treated Multiple Sclerosis Patients Default Brain Function in Young Adults Revealed by CASL Perfusion fMRI Deformable Image Registration of PET-CT and MRI Using a BSpline Algorithm Deformable Models (Snakes) for Fractal Analysis of Brain Tumors on T2-Weighted Images Degeneration of Subcortical White Matter in Alzheimer's Disease: Topographical Analysis Degeneration-Induced Depth-Wise Variation in T2 Relaxation Time of Human Patellar Cartilage at 1.5T Degree of Unsaturation: A Potential Biomarker for Investigating Human Obesity Delayed Conscious Access Related to Associative White Matter Fiber Tracts Injury in Patients with Early Relapsing Remitting Multiple Sclerosis Delayed Contrast Enhanced MRI of Cartilage: Comparison of Ionic and Non-Ionic Contrast Agents Delayed Hyperenhancement MR Coronary Vessel Wall Imaging in Patients with Stable and Unstable Coronary Artery Disease Delayed Maturation of the Cortico-Spinal Tract of Premature Newborns: A Preliminary Study with Quantitative DTI-Based Tractography Dendrite Density from Magnetic Resonance Diffusion Measurements: Comparison with Histology Denoising of Perfusion Arterial Spin Labeling Data by Wavelet-Domain Filtering Denoising of Sub-Millimeter Event-Related fMRI at 3T for Robust Detection of BOLD Contrast Dependence of Eigenvector Coherence on B-Value Range Using the Bootstrap Method Dependence of Temperature Increase on Pulse Sequence with Equivalent Time-Average SAR Dependency of Gas Diffusion Measurements in Lung on Respiratory Pressure–Volume Dependency of Parameter Estimates for the Tofts Model on Temporal Sampling Rate and on Bolus Arrival Time Dependency of the Venous Phase Shift Upon Positioning Angle in Susceptibility Weighted Imaging Dephased FLAPS MRI for Real-Time Guided Biopsy: Feasibility and Accuracy Study in Ex-Vivo Liver Tissue Dephasing Around Variably Shaped Arteries: Simulations and In Vivo Data Depolarizing Hyperkalemic Arrest Reduces Mn2+-Induced MRI Signal Enhancement in Pig Hearts Deriving Scalar Maps from Diffusion Spectrum MRI Description and Preliminary Results of an MR-Compatible PET System for Molecular Imaging Studies Design and Implementation of a Z0 Vibration Compensation Unit Design and Test of a Magnet and Gradient System for Hyperpolarised Gas Lung MRI at Ultra-Low Field Design of a Highly Sensitive 12-Channel Receive Coil for Tongue MRI Design of Linear Class Large-Tip-Angle Multidimensional RF Pulses for Parallel Transmit Design of Linear-Phase Frequency-Modulated Broadband Refocusing Pulses Design of Refocusing Flip Angle Modulation for Volumetric 3D-FSE Imaging of Brain, Spine, Knee, Kidney and Uterus Design Optimization and SNR Performance of 3T 96 Channel Phased Array Head Coils Designing Active Feedback-Based Contrast Enhancement for In Vivo Imaging Designing Fast 3-D RF Excitations by Optimizing the Number, Placement and Weighting of Spokes in k-Space Via a Sparsity-Enforcement Algorithm Designing RF Pulses with Optimal Specific Absorption Rate (SAR) Characteristics and Exploring Excitation Fidelity, SAR and Pulse Duration Tradeoffs Detailed Anatomic Microimaging of Early Stage Human Embryos Detecting CBF Changes Distant from Cerebral Infarct (Diaschisis) Using CASL MRI Detecting Emphysematous Lung in a Rabbit Model Using XTC MRI Detecting Myocardial Oxygen Deficits Due to Coronary Stenosis in a Canine Model at 3.0 T with Steady-State Free Precession Imaging Detecting Oligodendroglioma Genotype Non-Invasively Using MR Imaging Detecting Radiation-Induced Lung Injuries Using XTC MRI: Initial Findings Detecting Responses to Single Light Flashes in the Rodent Brain Using Laser Doppler and fMRI at 9.4T Detecting Tumor Cell Response to Therapy Using Hyperpolarized 13C MRS Detection and Characterization of Focal Liver Lesions Comparison of 1.5-T and 3.0-T MR Imaging in the Same Patient Detection and Classification of Leukemia Using MRI and NMR Techniques Detection and Correction of Spikes in fMRI Data Detection and Measurement of Data Loss Due to Mri Interleave Positioning Errors Detection by 1H MRS of Altered Phosphatidylcholine Metabolism in Human Ovarian Cancer Cells Detection of Axon Regeneration by Manganese Enhanced Magnetic Resonance Imaging in the Adult Rat Optic Nerve After Intravitreal Peripheral Nerve Grafting Detection of Cardiac Developmental Failures in Hey-Gen Knockout Mouse Embryos with Rapid 3D MRI Microscopy Detection of Gray Matter Damage in Neonatal Rat Model of Mild Hypoxic-Ischemic Insult by Manganese-Enhanced MRI Detection of Hippocampal Lesions in Multiple Sclerosis with 3D-DIR Detection of Invasive Breast Cancer: Increased Specificity with High-Resolution 3.0T MRI Angiography Detection of Iron in an Animal Model of Hepatic Iron Overload Using T2*-IDEAL Detection of LacZ and Luciferase Double Gene Expression in Breast Cancer Xenograft by MRI and BLI Detection of Metabolic Effects of Fatty Acid Synthase Inhibition by Magnetic Resonance Spectroscopy Detection of MRI Contrast Based on Chemical Exchange Saturation Transfer (CEST) in the Presence of the T2/T2* Contrast Agent Feridex Detection of Proteoglycan Depletion in Mechanically Loaded Cartilage with T1? Imaging Detection of Reactive Gliosis Using Manganese-Enhanced MRI (MEMRI) Detection of Recent Myocardial Infarction Using Precontrast T1 Weighted Edema Sensitive Imaging Detection of Resolved Glutamate and/or Glutamine Using Optimized STEAM at 3T – a Verification Study by Phantom Experiments Detection of Structural and Functional Changes in the Cortex of Bassoon-Mutant Mice by MRI and 1H-NMR-Spectroscopy Detection of the Stria of Gennari Using Turbo Spin Echo Imaging at High Field Detection of Transient Cardiac Hypertrophy Induced by Isoproterenol in Mice Detection of Tuning and Discrimination of Visual Signal by Human Cortex Determinants of Disability in Multiple Sclerosis: A Cross-Sectional, Multiparametric, Quantitative Mr-Based Study of Disease Phenotypes Determination of Arterial Input Function in Mouse-Model Using Clinical MRI Determination of CBF and CBV Using Short and Long TR Vascular Space Occupancy (VASO)-MRI Determination of Cut-Off Value of Metabolite Ratio in Prostate Caner Prior to Biopsy - A 3D MRSI Study Determination of Hypothetic Blood Volume and Vascular Permeability of Breast Cancer Bone Metastasis by DCE-MRI in a Nude Rat Model, Preliminary Results Determination of Inversely Correlated Resting State Brain Functional Networks Using Cluster Analysis Determination of Laminar Specific Tracing of Somatosensory Pathways Using Manganese Enhanced MRI Determination of Odor Concentration Dependent Responses in Olfactory Circuitry Using Manganese Enhanced MRI Determination of Optimal Temporal Resolution and Optimal Total Acquisition Time for MR-Renal Perfusion and Filtration Measurements Determination of T1-DCE MRI Based Blood Flow Heterogeneity in Normal Kidneys and Renal Pathology Determination of Transmural, Endocardial and Epicardial Radial Strain and Strain Rate from PCMR Velocity Data Determining Optimum B Maximum Values for Diffusion Spectrum Imaging and Q-Ball Imaging in Clinical MRI System Determining the Age of Multiple Sclerosis Lesions Using Myelin Water Imaging Determining the Correlation of Cortical and Medullary Oxygenation and Perfusion in Transplanted Kidneys by Functional MRI Development and First Clincal Use of the MR Compatible Robotic System Innomotion Development of a Catheter for MRI-Guided Intramyocardial Injection Development of a Compact MRI Using a Permanent Magnet for Trabecular Bone Microstructure Measurements Development of a Dark Blood MRI Protocol for Femoral Plaque Imaging Development of a Modular MR-Compatible Robot System Development of a MRI Phantom to Emulate the Relaxation Times of the Neonatal Brain at 3 Tesla Development of a New fMRI Compatible Pneumatic Vibrotactile Stimulator Development of a Temperature Controlled Anisotropic Diffusion Phantom Development of a Two-Room MR/OR Suite: Concept to Clinical Implementation Development of All-Plastic Needle Coils Made Using Silicon Technology Development of an Algorithm for Segmentation of Cerebral Cortex in T2 Weighted Neonatal Brain MRIs and Its Use to Construct Prototype Age Specific Surface Atlases Development of an Inguinal Lymph Node Clinical Target Volume with Ferumoxtran-10 Enhanced Magnetic Resonance Imaging for Precision Radiotherapy Treatment Development of an Interventional Endo-MRI: Toward the Therapy of Pancreaticobiliary Diseases Development of Breast MRI Computer-Aided Diagnosis System: Automated Segmentation and Selection of Unspecific Morphology and Texture Features Development of Central Atrophy May Lead to Underestimation of Lesion Accrual in Patients with Multiple Sclerosis Development of Micro-Pellets Holding EPR Oxygen Sensors Development of MR-Compatible SPECT System: A Feasibility Study Development of Novel Parameter That Reflects Xe Transfer Rate in Mouse Lung from Hyperpolarized 129Xe Dynamic Study Under Spontaneous Respiration: Definition and Application to Murine Tumor B16BL6 Melanoma Development of Ultra Short Echo (UTE) Imaging for In Vivo Application at High Field Strength Developmental Changes in White Matter Microstructure in Adolescence Developmental fMRI Patterns Associated with Visuospatial Working Memory and Response Inhibition dGEMRIC of the First Carpometacarpal (1CMC) Joint: Initial Results Diagnosis of Hepatic Fibrosis by Magnetic Resonance Elastography: Sensitivity and Specificity Diagnostic Accuracy of Diffusion Weighted Imaging for Detecting Nodal Metastasis in Gynecologic Oncology Patients: Comparison with Histopathology Evidence Diagnostic Features of Acute DWI Abnormalities of Different Origin in the Hippocampus Diagnostic Magnetic Resonance Imaging in Crohn's Disease of Small Intestine: Comparison Air-Infused MR Enteroclysis with Hydro-MRI Diagnostic MR-Electrophysiology Catheter with Highly Resistive Wires for Reduction of RF-Heating Dietary Lifestyle Intervention – Influence of Fiber Intake on Hepatic Lipids and Visceral Adipose Tissue Differences Between Boys and Girls in the Development of Neuroanatomical Functional Connectivity Underlying Intelligence Found Using Bayesian Connectivity Analysis Differences in mCPP-Induced BOLD Signal Response Between Anti-Social Personality Disorder Individuals (ASPD) and Healthy Volunteers Different Contribution of Early Visual Areas to Perceptual Process of Contextual Modulation Different Distribution Functions of Magnetization Transfer Pulses for High Resolution MT Imaging of the Knee at 3 Tesla Different Pattern of Atrophy in Early- And Late-Onset Alzheimer's Disease Differential Cellular Metabolism Following Traumatic Brain Injury Differential Effects of Age on Tissue Water-Referenced Proton Metabolites in Basal Ganglia, Pons, and Cerebellum Using an MRS Sequence Optimized for Glutamate Detection Differential Effects of VEGF Overexpression on Angiogenesis and ECM Integrity in Breast Cancer Xenografts Pre-Selected for Their Invasiveness Differentiating Glial Tumours from Demyelinating Disease with SV MRS at 1.5T. a Multicentre Study Differentiating Tumor and Fibrosis Post-Treatment in Patients with Bladder Cancer Using Quantitative DCE-MRI Differentiation Between Autoimmune Pancreatitis and Pancreatic Carcinoma by Using Diffusion Weighted MR Imaging Differentiation Diognosis of Central Lung Tumor from Postobstructive Lobar Collapse or Postobstructive Pneumonitis by Magnetic Resonance Imaging: A Companion with CT Differentiation of Fungal, Tubercular and Pyogenic Brain Abscesses with Conventional, Diffusion MR Imaging and Proton MR Spectroscopy Differentiation of Infective from Neoplastic Brain Lesions by Dynamic Contrast Enhanced MRI Diffuse Axonal Injury in Corpus Callosum and Internal Capsule in Moderate to Severe Traumatic Brain Injury Diffusion and Chemical Shift of Intracellular Cesium Ions Within Perfused HeLa Cells Diffusion and Perfusion Changes During Long-Term Recovery After Prolonged Hypoxia Diffusion Effects in Passband Balanced SSFP fMRI Diffusion in the Rat Cerebral Cortex During Pilocarpine-Induced Status Epilepticus Diffusion Patterns of the Putamen and Globus Pallidus, Evaluated with DTI Diffusion Spectrum Imaging Resolves Complex 3-Dimensional Myocardial Fiber Architecture in Normal and Infarcted Myocardium Diffusion Tensor Imaging and Tractography of Cervical Cord in Normal and Spinal Cord Compression: A Preliminary Study at 3.0 T MR Diffusion Tensor Imaging as an Early Marker for Osteoarthritis Diffusion Tensor Imaging at 7 Tesla: Initial Application to Multiple Sclerosis Diffusion Tensor Imaging Detects and Quantifies Changes in Permeability in the Murine Retina Diffusion Tensor Imaging in Assessing Anti-Angiogenic Treatment in Glioblastoma Diffusion Tensor Imaging in Mild and Moderate Pediatric Traumatic Brain Injury Diffusion Tensor Imaging in Niemann-Pick C Disease on 3T Diffusion Tensor Imaging in Parkinsonism – Analysis of Corticospinal Tracts and Association Bundles in Patients with Essential Tremor Vs Parkinson´s Disease by Quantitative Spatially Normalized DTI at 3.0T Diffusion Tensor Imaging in Patients with Acute-On-Chronic Liver Failure Diffusion Tensor Imaging in Patients with Fulminant Hepatic Failure Diffusion Tensor Imaging in the Evaluation of Traumatic Spinal Cord Injury Diffusion Tensor Imaging Measures of White Matter Integrity Dissociate Damage to Memory Versus Attention Networks in Mild Traumatic Brain Injury Diffusion Tensor Imaging Measures Therapeutic Effects in a Mouse Model of Niemann-Pick Type C Disease at 23 Days of Age Diffusion Tensor Imaging of Auditory Neural Pathway in Patients with Sensori-Neural Hearing Loss Diffusion Tensor Imaging of Left Ventricular Remodeling in Response to Myocardial Infarction in the Mouse Diffusion Tensor Imaging of Muscle Degeneration in a Mouse Model of ALS Diffusion Tensor Imaging of Prostate Cancer: Comparison with Systemic Prostate Biopsy Diffusion Tensor Imaging of Refractory Partial Epilepsy at 3.0T Diffusion Tensor Imaging of Spinal Cord Injury: Regional Differences in White Matter Damage During the Hyperacute Phase Diffusion Tensor Imaging of the Human Cervical Spinal Cord at 1.5 and 3.0T Diffusion Tensor Imaging Reveals Nigrostriatal Degeneration in the 6-Hydroxydopamine Rat Model for Parkinson’s Disease Diffusion Tensor Imaging Reviles the Evolution of Neuronal Cell Membrane Damage in Stroke Patients: A Simulation Study Diffusion Tensor Imaging Studies of Morphological Changes in Developing Cerebral Cortex and White Matter of the Early Postnatal Ferret Diffusion Tensor Imaging with Tract-Based Spatial Statistics (TBSS) Reveals Local White Matter Abnormalities in Preterm Infants at Term Equivalent Age Diffusion Tensor MRI: Combination of Signals from Phased Array Coils Diffusion Tensor Representations and Their Applications to DTI Error Propagation Diffusion Tensor Shape and Size Encoded Colormaps Reveal Fiber Features in Human Brain Diffusion Tensor Magnetic Resonance Imaging Diffusion Tensor Spectroscopy and Imaging of Arcuate Fasciculus Diffusion Toolkit: A Software Package for Diffusion Imaging Data Processing and Tractography Diffusion Weighted Images in the Cat Visual Cortex at 9.4 T Reveal Extravascular Related ADC Decreases During Activation Diffusion Weighted Imaging Differentiates Corticobasal Degeneration from Progressive Supranuclear Palsy and Parkinson’s Disease Diffusion Weighted Imaging in Stage 1 Cervical Cancer: Potential Value in Differentiating Tumour from Post Biopsy Granulation Tissue Using an Endovaginal Technique Diffusion Weighted Imaging of Androgen Deprivation Hormone Therapy for Prostate Cancer Diffusion Weighted Imaging of Human Prostate at 3T: Evaluation of Diffusion and Microperfusion Contributions. Diffusion Weighted Imaging Using a Reduced-View Projection Reconstruction Imaging (RV-PRI) Diffusion Weighted Imaging with a Limited Field of View Using Interleaved Multi-Slices Inner-Volume-Imaging DW HASTE Diffusion Weighted Imaging with Reduced Susceptibility Artifact, Using 2D Singleshot DW-STimulated EPI (2D Ss-DWSTEPI) Diffusion Weighted MR Imaging of Peritoneal Tumor: Comparison with Conventional MR Imaging, and Surgical and Histopathologic Findings Diffusion Weighted MRI of Closed Head Injury and Treatment with PEG (Polyethylene-Glycol) in Rats Diffusion-Weighted Balanced-FFE Imaging Using Eddy-Current Compensation Diffusion-Weighted Imaging and Apparent Diffusion Coefficient Values for Differentiation of Residual or Local Recurrent Tumor from Posttreatment/Postbiopsy Changes in Patients with Primary Head and Neck Squamous Cell Carcinoma Diffusion-Weighted MR Imaging of Colorectal Liver Metastases: Repeatability and Reproducibility of Apparent Diffusion Coefficients and Implications for Therapeutic Monitoring Diffusion-Weighted MR Imaging of Mucinous Pancreatic Tumors: Doughnut Sign on ADC Map Diffusion-Weighted Perfusion MRI: Initial Experience in Application to Brain Tumor Diffusion-Weighted Spectroscopy Allows to Probe 13C Labeling of Glutamate Inside Distinct Metabolic Compartments in the Monkey Brain Diffusion-Weighted Whole Body MR Imaging with Background Body Signal Suppression: A Feasibility Study at 3.0 Tesla Diffusivity and Diffusion Anisotropy of Cerebellar Peduncles in the Cases of Spinocerebellar Ataxia. -Short-Range Tractography Based Analysis in Order to Avoid Crossing Fiber Problem- Digital Tuning to Suppress Ghost Artifacts in EPI by Minimization of Total Variation Digital Wireless Transmission for MRI Signals Diminished Venous Vasculature on Susceptibility Weighted Imaging Venography in Multiple Sclerosis Direct Comparison of Multi-Echo BOLD and VASO Based fMRI Direct Comparison of T2 and T2? Image Contrast in a Rat Model of Acute Cerebral Ischemia Direct Detection of Hydrogen Peroxide Via 1H CEST-MRI Direct Detection of Neuronal Magnetic Field Changes Using MRI:Timing Effect of Stimulation Direct Molecular Solution of Hyperpolarized 129Xe Through Hollow Fiber Membranes Direct MRI of Human Teeth by SWIFT Direct Respiratory Tracking and Motion Correction for Free-Breathing Whole-Heart Coronary Angiography Direct Visualization of Normal Subthalamic Nucleus with High Resolution MR Imaging at 3.0 T: Comparison Between FSE T2-WI and Fast STIR Image Direction Dependent Overestimation of Local Wavelengths in MR Elastography by Discretized Helmholtz Inversion Direction-Sensitive Perfusion with Q-Space MRI: Phantom Validation and Calf-Muscle Probing Disambiguation of Complex Subvoxel Fibre Configurations in High Angular Resolution Fibre Tractography Discrepancies Between the Fate of Human Myoblasts Transplanted Into Immunocompetent Mice After Loading with Gd-Chelates or with SPIO and the Time-Course of Label Detection by In Vivo NMR Imaging Discriminating Multiple-Sclerosis Patient Groups : A Principal-Component Analysis of CSF Metabolite Profiles Discrimination of Malignant Ascites from Cirrhosis Associated Ascites in a Multivariate Analysis Model: 1H NMR Analysis of Ascitic Fluid Disorders in Methylated Species in Response to Nitrosourea in a Melanoma Tumor Model: Demonstration Using 1H-13C HRMAS NMR Spectroscopy and L-[methyl-13C]methionine Displacement of Neurovascular Bundles Before and After MRI-Guided Prostate Brachytherapy Displacement-Encoded 3D Imaging Sequence Using Pre-Section Encoding for Section-Following and Sparse Phase-Cycling Dissociating Bottom-Up Responses in the Amygdala from Top-Down Processing in the Orbitofrontal Cortex Using an Event-Related Emotion Rating Paradigm Distortion Reduction for Spiral-fMRI: Comparison of Iterative and Non-Iterative Parallel Imaging Reconstruction Algorithms Distortion Reduction in EPI Based on Minimal Field of View Distributed Capacitance Method in RF Coils - The Advantages and Potential Distribution and Progression of Cerebral White Matter Hyper-Intensities Per Flow Territories in a Large Population of Elderly Subjects Distribution of AHA Type VI Atherosclerotic Lesions in the Carotid Artery and Relationship to Quantitative Plaque Measurements: An In Vivo MRI Study Dixon Fat-Water Separation by Dual-TR bSSFP Sequence Do Adenylate and Creatine Kinase Activity Contribute to Saturation Transfer Effects Among ADP and ATP Resonances in 31P MRS of Skeletal Muscle? Do DCE-MRI Parameters Obtained During Neoadjuvant Chemotherapy Provide an Insight Into Long Term Survival? Do Differences in BOLD and CBV Responses to Cortical Stimulation During mGluR5 Blockade Reflect Regional Differences in Neurovascular Coupling Mechanisms? Do Differences in the Left-Right Fractional Anisotropy in the Language Tracts of Right Handed Individuals Correlate with Laterality of Functional Activation? Dobutamine Stress Cardiovascular MR Imaging in Patients After Coronary Revascularisation with Stent Placement Does Changes in Gradient Duration Influence Q-Space-Based Determinations of Displacement In Vivo? Does Diazepam Influence the BOLD Response? Does Diffusion Weighted Imaging Have a Role in Predicting Response to Neoadjuvant Chemotherapy? Does MEMRI Detect Apoptosis in the Rat Neonatal Hypoxic-Ischemic Stroke Model? Does Social Isolation Rearing Induce Prefrontal Cortex Volume Loss – A MR Volumetry Study in Rats at 7T Does the Modulation of the Insular Activity Affect Our Emotional Involvement? A Real-Time fMRI Study During Emotional Pictures Processing Does the Presence of an Intravascular Contrast Agent Affect the Analysis of DCE-MRI Data? Dorsal Striatum Activity Is Correlated with Learning Efficacy of Subjects Performing an Instrumental Conditioning Task Dose Dependence of Alfentanil Analgesia Double Inversion Recovery First-Pass Myocardial Perfusion Imaging at 3 Tesla Downregulation of Uncoupling Protein-3 Is Linked to Changes in Muscle Mitochondrial Energy Metabolism In Vivo as a Result of Capsiate Administration Dramatic Changes in the 23Na Signal in Cartilage of Excised Human Osteoporotic Femoral Heads Drug-Anaesthetic Interaction in Pharmacological MRI: The Case of the Psychotogenic Agent Phencyclidine DSC-MRI: How Accurate Does the Arterial Input Function Need to Be in Practice? DTI and Fiber Tracking of the Median Nerve Using an Adjustable Wrist Coil Array DTI and MTI Parameters Correlate in Periventricular White Matter Hyperintensities in Old Age DTI Demonstrates Non-Linear White Matter Tract Development from Childhood to Adulthood DTI Evidence of Persistence of the Ventricular Zone in Human Preterm Infants DTI Fiber Tracking and Fractional Anisotropy-Reaction Time Correlations in Visual Word Recognition DTI in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI): Rapid Reproducible Analysis of Corpus Callosum Fiber Integrity Can Predict Conversion from MCI to AD DTI Study of Postinfarct Myocardium Structural Remodeling in Porcine Model DTI VBM Analysis of Pathological Progression in HIV Patients Underwent Associated Dementia DTI-Based Analysis Facilitates the Understanding of a Peculiar Neuropsychological Dissociation in a Patient with Bilateral Thalamic Damage Dual Transfer of Gene and MR Contrast Agent Into Stem-Progenitor Cells: Toward In Vivo MR Imaging of Stem Cell-Mediated Gene Therapy Dual Tuned, 13C/23Na Low Pass Birdcage Coil Dual Voxel Two-Dimensional MR Spectroscopy of Hepatic Encephalopathy and Correlation with Neuropsychological Abnormalities Dual-Band Adiabatic Selective Refocussing for Signal Suppression in High Field MR Dual-Echo Gradient Echo (DEGE) Phase Contrast (PC) Imaging for High Temporal Resolution Flow Studies in Flow Phantom, Aneurysm Models and In Vivo Human Carotid Artery DW Imaging in Prostate Cancer: Determination of Cut-Off Value of ADC for the Peripheral Zone to Predict Malignancy DWI of Rectal Cancer at 3T DWI Tractography Based Parcellation of Human Lateral Premotor Cortex Identifies Reproducible Subregions with Distinct Fronto-Parietal Connectivity DW-MRI of Perfused and Thermally Controlled Neuronal Organotypic Cultures DynaMammoAnalyst: Simultaneous Dynamic and Morphologic Analysis Software for MR Mammography Dynamic 3D Lung MRI Using a 32-Channel Coil Array for the Construction of Respiratory Motion Models Dynamic Arterial Spin Labeling Perfusion Imaging at 4T Using Parallel Imaging: Effects on Parametric Mapping Dynamic Cardiac Imaging Using Phase-Modulated Undersampled X-F Spectra from Multiple Cardiac Cycles Dynamic Changes in Murine Vessel Geometry Assessed by High Resolution Magnetic Resonance Angiography Dynamic Contrast Enhanced (DCE) -MRI and 18Fluoromisonidazole (18F MISO) PET Imaging in Head and Neck Squamous Cell Carcinoma: Initial Evaluation of Perfusion and Hypoxia in Nodal Metastasis Dynamic Contrast Enhanced MRI Assessment of Synovitis in Hemophilic Arthropathy Dynamic Contrast Enhanced MRI of Rheumatoid Arthritis and Anti-TNFalpha Treatment. Dynamic Contrast Enhanced MRI of Solid Tumors Treated with NGR-TNF, a Novel Vascular Targeting Agent Dynamic Contrast Reagent Induced Differences in Transverse Relaxation and Susceptibility Shift Observed by Echo Planar Spectroscopic Imaging Dynamic Contrast-Enhanced MRI and Vessel Size Imaging Sensitively Indicate Antiangiogenic Therapy Effects on Tumor Xenografts in Mice Dynamic Contrast-Enhanced MRI for Breast Cancer Detection Dynamic Coronary MRA During Localized Intra-Arterial Infusion of the Intravascular Agent Gadomer Dynamic Diffusion Process of MRI Contrast Agents Into the Brain Following Blood-Brain Barrier Disruption Dynamic Displacement in Human Brain Studied Using Q-Space Diffusion MRI at a 3T Clinical Scanner Dynamic End-Tidal Forcing of Carbon Dioxide and Oxygen During FMRI Dynamic Glu+Gln Alterations in a FOS Patient Investigated by 1H-fMRS and CSI Dynamic Magnetic Resonance Inverse Imaging Using Linear Constrained Minimum Variance Beamformer Dynamic Magnetic Resonance Ureterography: Initial Experience with Contrast-Enhanced, Highly Time-Resolved Evaluation of Ureteral Peristalsis Dynamic Measurement of Functional Changes in Venous Cerebral Blood Volume at 3 T Dynamic MR Imaging of Injured Rabbit Aortic Wall with a Blood Pool (MS-325) and Conventional ECF Agent: Similarities and Differences Dynamic MRI Encodes Differential Contraction of Extraocular Muscle Segments in Healthy Subjects Dynamic Oxygen-Enhanced MR Imaging Vs. Quantitative CT: Efficacy of Pulmonary Functional Loss Assessment and Clinical Stage Classification of Smoking-Related COPD Dynamic Parallel MRI by Generating Sparse Data: Tracking Temporal Changes Dynamic Parallel MRI Using the Temporal GRAPPA-Operator (TGRAPPA-Operator) Dynamic Perfusion Evaluation Based on a Tissue Model Dynamic Real Time Magnetic Resonance Imaging of the Pharynx and Larynx Evaluating Swallowing and Stridor at 3 Tesla Dynamic Registration of Cardiac MR Images Dynamic Response of the Livers of Chronic Ethanol-Treated Rats to Oxygenation Changes: An fMRI Study Dynamical 17O Imaging in Tumor Bearing Mice at 7T Dynamics of Lactate Concentration and BOLD Effect Upon Repeated Identical Visual Stimuli Dynamics of the Blood Oxygenation Response: Tissue CMRO2 Contributions and Impact for Functional MRI Early ADC Changes Following Treatment with Doxorubicin Containing Anti-HER2 Immunoliposomes Predict Tumor Growth Inhibition Early and Late Improvement of Left Ventricular Function After Drug Eluting Stent Implantation for Chronic Total Occlusions Early Changes in the Apparent Diffusion Coefficient Following Ischemic Stroke in Canines Early Life Stress Leads to Depressive Like Symptoms and a Reduced Response to a 5-HT1A Receptor Agonist as Revealed by Pharmacological fMRI in Adult Mice Early Prediction of Tumor Responses to Therapy by MR Diffusion and Magnetization Transfer Methods Early Reductions in Diffusion Anisotropy Are Apparent in Pediatric Epilepsy Easy Access to Polarized 3He by Centralized Large Scale Production Echo Like Inline Display of ECG and Respiratory Signals - Enhancing Diagnostic Capabilities in Cardiac MR Imaging Echo-Planar Imaging with Multiple Echo Trains in a Single-Shot Using Stimulated Echoes Echo-Shifted Proton Resonance Frequency Temperature Mapping Edge Detection Using Sub-Sampled K-Space Data: Application to Upper Airway MRI Edge Preserving Bayesian Reconstruction Method for Parallel Imaging and Application in Cadiac MRI EEG Based Time Points for Longitudinal Diffusion MRI Studies in Neonates with Hypoxia-Ischemia Effect and Mitigation of a NIOBE Magnetic Navigation System on a Proximal MR Imager Effect of AIF Distortion and Delay on CBF Estimation Using FT Based MMSE Deconvolution Technique Effect of Computer-Aided Diagnosis System on Diagnostic Accuracy and Reading Time in Detection of Intracranial Aneurysms on MR Angiography Effect of Considering Physiological Response in Temperature Calculations for MRI of the Human Head Effect of Contrast Media on the Signal Intensity of Single-Shot EPI for Diffusion Imaging of the Body Effect of Deep Brain Stimulation Lead Resistivity on Specific Absorption Rate at 3 T MRI Effect of Diet and Exercise on MR Outcomes of a Model of Vascular Dementia in Aged Rats Effect of DTI Bootstrap Bias on the DTI Uncertainty Measurements and Probabilistic Tractography Effect of Head Size to B1, SNR and SAR Effect of Hypothyroidism in Metabolic Profile of Rats After Cerebral Ischemia/reperfusion: A 1H NMR Study Effect of Initial Hepatic Glycogen Concentration and Resulting Plasma Glucose Concentration on the Route of Glycogen Synthesis In Vivo in Wistar Rats: A 13C NMR Study Effect of iNOS on Cerebral Blood Flow After Head Trauma Effect of In-Ovo Immobilization on Development of Chick Hind Limb Articular Cartilage: An Evaluation Using Micro-MRI Measurement of Delayed Gadolinium Uptake Effect of Ischemia on Muscle Metabolites Assessed with Functional Magnetic Resonance Spectroscopy (fMRS) During Electrically Imposed Exercise Effect of Maternal and Early Dietary Intake on Body Composition and Function Effect of Registration of Diffusion Weighted Images on Fractional Anisotropy Effect of Scanner Signal Drift on Evaluation of Baseline Connectivity Effect of Superparamagnetic Iron Oxide on High-B-Value Diffusion-Weighted Imaging for Evaluation of Focal Hepatic Lesions Effect of the Phase Increment on the Accuracy of T1 Measurements by the Variable Flip Angle Method Using a Fast RF Spoiled Gradient Echo Sequence Effective T1 Based Intensity Compensation of Spin Saturation Effect Due to Out-Of-Slice Head Motion in fMRI Time Series Obtained Via the MSV Motion Correction Algorithm Effective Velocity Spoiling for Black Blood Imaging of the Heart Effects of 48hr Sleep Deprivation on Cerebral Blood Flow Measured with Arterial Spin Labeling MRI Effects of Acute Serotonin Elevation on Brain Glucose and Neurotransmitter Metabolism : A 13C MRS Study in Rats of Citalopram Administration Effects of Anesthesia on Resting-State Functional Connectivity in Rat Brain Effects of Arterial Input Function Determination on Pharmacokinetic Modeling of Osteosarcoma DCE MRI Data Effects of Arterial Input Functions on Dynamic MRI Kinetic Parameters Estimates: An Analysis of Parameter Variability and Model Fitting in Breast Cancer Patients Effects of Capillary Orientation on Muscle T2/T2*: Comparison of Numerical Simulations with Empirical Data Effects of Cardiovascular Disease Risk Factors on Regional Cerebral Blood Flow in Dementia Effects of Citalopram on Effective Connectivity During the Go/No-Go Task Effects of Diet Manipulation on Muscle Mitochodrial Activity as Assessed in Rat by 31P Saturation Transfer Effects of Exercise Training on Myocardial Perfusion Reserve in Patients with Post Myocardial Infarction Effects of Exercise Training on the Performance of Diabetic Heart Effects of Fetal Nicotine, Dexamethasone Exposure and Caloric Restriction on the Neurochemical Profile of the Postnatal Rat Effects of Gender and Handedness on Corticospinal Tracts: Tract Specific Analysis of Fractional Anisotropy Based on Diffusion Spectrum Imaging Effects of Gradient Amplitude and Duration on Q-Space Imaging Effects of Limited Volume Coverage on Accuracy of MR-Electrical Impedance Tomography Effects of Naproxen and Naproxcinod on Intra-Renal Oxygenation During Water-Loading as Evaluated by BOLD MRI Effects of PCP on the Prefrontal Cortex Metabolism in Intact, Anesthetized Rats Effects of Several Carbogen Concentrations on Signal Changes in Susceptibility Weighted Imaging (SWI) Effects of Short-Term High Fat Diet on Rat Liver Triglyceride Content Using In Vivo 1H MRS Effects of Simultaneous EEG Recording on MRI Data Quality Effects of Static Magnetic Field Strength on Heart Rate Effects of T1, T2, and Spectral Complexity on In- And Out-Of-Phase Imaging: A Systematic Approach by Computer Simulation Effects of Temperature and Time on Cholines Observed by HRMAS 1H MRS of Rat Brain and Human Brain Tumor Samples Efficiency of Cell Labeling with Different Perfluoro-15-Crown-5 Ether Nanoparticles for 19F MRI Efficient 1H to 31P Polarization Transfer on a Clinical MR System with a Single RF Transmit Channel Efficient All-Direction Eddy Current Correction for DTI Using Orthogonal Basis Sets Efficient RF Coil Simulations with Curvilinear Quadrilateral-Element Method of Moments Efficient Simultaneous Multiple Volume Free Breathing Black Blood Cardiac MRI Efficient Slow-Flowing Blood Suppression Technique in Atherosclerosis Imaging with Motion Sensitized Driven Equilibrium (MSDE) TSE Sequence at 3T Efficient Solving for Arbitrary Susceptibility Distributions Using Residual Difference Fields Efficient Trajectory Design for Measuring Velocity Distribution or Spectra from MR Images Efficient Velocity Mapping by Accelerated Acquisition of Phase Reference Data Efficient Volumetric Brain MR Imaging with Ultrashort Echo Times EGF Receptor Expression Imaging Using Antibody-Conjugated Enzymes and a Paramagnetic Substrate Eight-Fold K-T BLAST Accelerated DCE-MRI for High Resolution Assessment of Myocardial Perfusion Elastic Registration Based Interpolation of MRI Images in 3D Electrodynamic Constraints on Minimum SAR in Parallel Excitation Electrophysiological Properties of the Effect of USPIO-Labeling on Embryonic Stem Cells Elliptical Field of View in PROPELLER MRI Elliptical SENSE with Effective 9 Fold Scan Time Reduction for Small FOV 3D MR Spectroscopic Imaging of Glioma Patients at 3T Encoding of EEG in MR Images Endometrial Imaging at High Magnetic Fields: Feasibility of In-Vivo Studies at 7 T Endorectal MR Imaging and Proton Spectroscopy for Preoperative Evaluation of Clinical T1c Prostate Cancer Energy Coupling Between RF Electric Fields and Conductive Wires: Image Artifacts and Heating Enforcing Strict Constraints in Multiple-Channel RF Pulse Optimization Enhanced Diffusion Weighting Generated by Selective Composite Adiabatic Pulses Enhanced T1 Contrast Imaging with Region Growing Method Enhancement of In Vivo iZQC Signal by Spin Locking Pulse Enhancing Endogenous CBV-Weighted fMRI Contrast at 9.4 T: A VASO Study with Slab-Selective Inversion-Recovery Entropy-Based Characterization of Diffusion Anisotropy Enzyme-Responsive PARACEST MRI Contrast Agents That Assess Subsets of the Human Degradome EPI Magnitude Signal Formation in the Proximity of Straight Conductor Subjected to a Weak Electric Current. EPSI Sampling Strategies for Spectroscopic Imaging of Sparse Spectra: Applications for Hyperpolarized 13C Imaging Equivalence of Fourier and oSVD Deconvolution in Dynamic Perfusion Measurements: Mutual Filter Transform Erythropoietin Protects from Posttraumatic Edema in the Rat Brain: MRI and Gravimetric Studies Esophagus Imaging by 3D FSE with Combination of Inner Volume Excitation and Variable Refocusing Flip Angles Estimating DCE-MRI Vascular Parameters of Tumours Using a Tractable Input Function Formulation: Model Calculations and Results Estimating Number of Fiber Directions Per Voxel for Multiple Fiber DTI Tractography Estimating Single Kidney Glomerular Filtration Rate from MR Renography: Is Cortical and Medullary Segmentation Necessary? Estimating SNR Efficiency in Non-Cartesian Trajectories: Cartesian Is to Apples as BLADE Is to Schnitzel Estimation of % Tumor Necrosis by 3D Compartmental Analysis of Dynamic Contrast-Enhanced MRI in Spontaneous Canine Osteosarcomas Estimation of Brain Connectivity Using Diffusion Tensor Imaging and Resting Temporal Correlations Estimation of Compartmental Signals from Limited Fourier Samples Estimation of Eddy Current Induced Phase Error in EPI Estimation of Fractional Contributions of White and Gray Matter by Cross-Regularized Inverse Laplace Transform Estimation of Gd-DTPA Concentration In Vivo for MR Perfusion Measurements in Pig Lungs by Means of Computed Tomography Estimation of Hemodynamic Impairment Using Dynamic Susceptibility Contrast Perfusion Imaging Estimation of Hepatic Perfusion Using an Optimised Dual-Section Saturation Recovery Sequence Estimation of T1 and T2 of Deep Radial and Calcified Layers in Human Patella from Ultra Short Echo Time (UTE) Imaging on a 3T Clinical System Estimation of Tissue Iron Contribution to 1H2O R1 Values in Human Brain Evaluated Angiogenesis and Its Maturation in Hepatocellular Carcinoma by Using Diffusion-Weighted Imaging at 3.0 Tesla Evaluating Aortic Valve Remodeling in a Rabbit Model Using High Resolution MRI Evaluating Carboxypeptidase G2 (CPG2) Based Gene-Directed Enzyme Prodrug Therapy Using19F Magnetic Resonance Spectroscopy: 3,5-Difluorobenzoyl-Glutamic Acid as a Potential In Vivo reporter of CPG2 Activity Evaluating Cirrhosis on High-Resolution 3D MRA of the Liver Evaluating Dose Timing Effects of Gefitinib (An EGFR Inhibitor) in a Breast Cancer Model Using ADC and T1 Evaluating Strategies to Deal with Motion in fMRI Using Independent Component Analysis Evaluating Structural Brain Changes in Adolescence with Magnetic Resonance Imaging and Deformation Based Morphometry Evaluation of 3D-EPI PULSAR with and Without Background Suppression Inversion Recovery Pulse Evaluation of a Degenerated Birdcage Coil for Parallel Imaging Evaluation of a Possible Risk Association Between Nephrogenic Sclerosing Dermopathy (NFD) and Gadolinium Enhanced MRI Evaluation of Accelerated Single Shot Fast Spin Echo (SSFSE) for Imaging of the Appendix Evaluation of Affected Fiber Structures in Rat Infiltrative Glioma with Diffusion-Tensor MR Fiber Tracking Method: Immunohistochemical Correlation Evaluation of an MR-Compatible Guidewire Made in a Novel Micro-Pultrusion Process Evaluation of Anatomic Variation in Macromolecule Contribution to the GABA Signal Using Metabolite Nulling and the J-Editing Technique at 3.0 T Evaluation of Anterior Choroidal Artery on 3T 3D TOF MRA Evaluation of Bioreactor-Cultivated Bone by Magnetic Resonance Microscopy Evaluation of Brain Iron In Vivo with Susceptibility Weighted Imaging Evaluation of Chronic Cryo Prostate Lesions by Diffusion-Weighted MRI Evaluation of Computer-Aided-Diagnosis (CAD) Software Tools for Tumor Detection Using Dynamic Contrast Enhanced MRI Evaluation of Contrast Mechanisms in the Substantia Nigra, Red Nucleus and Adjacent Brain Stem Structures at 7T Evaluation of Crohn's Disease Activity Using MRI: Correlation with T2 Signal Intensity on Fat-Suppressed Single Shot Imaging Evaluation of Dynamic MRI as Indicator of Disease Activity in Perianal Fistulizing Crohn’s Disease Evaluation of Early Response of Docetaxel in MCF7 Xenografts Using Ex Vivo HR MAS MRS, In Vivo MRS and DCE-MRI Evaluation of Glaucomatous Optic Nerve Using In Vivo Manganese-Enhanced MRI Evaluation of Heart Wall Motion from Tagged MRI Using Gabor Filter Bank Evaluation of HYPR PR-TRICKS for Contrast Enhanced Cerebrovascular MRA Evaluation of Initial Active Phase Laminitis in Equine Hoofs Using MRI Evaluation of Intracranial Aneurysms with 3T TOF MRA: Compared to 64-MDCTA Evaluation of Intratumoral Virus Delivery in Brain Tumor Oncolytic Virus Therapy Using Diffusion Tensor Imaging Evaluation of Ischemic Threshold for Cell Death in Acute Stroke Patients Evaluation of Minimal Angular Discrimination for Q-Ball Imaging: A Phantom Study Evaluation of MR Diffusion-Weighted Imaging as a Modality to Study Pancreatic Carcinoma Evaluation of MR Image Overlay for Spinal Interventions Evaluation of MR Markers That Predict Survival of Pre-Treatment GBM Patients Evaluation of MRI-Based Measurement for Quantifying Prostate Development in Mice with Prostate-Specific PTEN Deletion Evaluation of Oncolytic Virus Induced Vascular Leakage in an Experimental Rat Glioma Model on 8.0 Tesla MRI: Correlation with Histopathology Result Evaluation of Parallel Transmit RF-Shimming Performance for 3 Tesla Whole-Body Imaging Evaluation of Principal Component Analysis for Highly Undersampled Radial DCE-MRI Evaluation of Quality Assurance Using Daily MR Quality Image – Can We Measure Planned Maintenance? Evaluation of Radiation Dose Distribution in Lithium Formate Pellets Using EPR Imaging Evaluation of Radiation Lung Injury from Tomotherapy Using Hyperpolarized Helium-3 Diffusion MRI Evaluation of Regions of Increased CBV in Gliomas Using MRI Without Contrast Injection Evaluation of Regurgitation and Turbulence of In-Plane Flow in Branch Pulmonary Arteries After Repair of Tetralogy of Fallot by Means of Phase-Contrast MR Imaging Evaluation of Renal Function with Diffusion Weighted MRI of the Kidneys Evaluation of Serial MRI / MRSI of the Prostate in Prostate Cancer Patients Receiving Dutasteride, an Antiandrogen Therapy Evaluation of SNR/Resolution Tradeoffs Using the Theoretical Information Content Evaluation of Subacute and Chronic Cryotherapy Lesions Using Histopathology and Contrast Enhanced MR Images in the Dog Prostate Model Evaluation of Sub-Pixel Fiducial Tracking Using Image Processing Evaluation of the Applicability of Magnetization Transfer Contrast as an Indicator of the Degree of Liver Fibrosis in Rats with Carbon Tetrachloride (CCl4)-Induced Liver Fibrosis/Cirrhosis Evaluation of the Articular Cartilage of the Knee Joint at 3T Using Vastly Undersampled Isotropic Projection Steady-State Free-Precession (VIPR-SSFP) Imaging Evaluation of the Higher Order Tensor Estimation Quality for Established Gradient Encoding Schemes Evaluation of the Kidneys Oxygenation in Normal Subjects and Patients with Renal Transplant by BOLD MRI Evaluation of the Safety of Hyperpolarized Helium-3 Gas as an Inhaled Contrast Agent for MRI Evaluation of Tractography-Based Parcellation with Human Thalamus Evaluation of Tumor Angiogenesis and Growth Rate in Lung Cancer Overexpressing Four Different VEGF Isoforms in a Murine Xenograft Model Evaluation of Uterine Anomalies with 3D-FSE-XETA (eXtended Echo Train Acquisition) Evaluation of Variability in Bioluminescence Measurements in Orthotopic Bladder Tumors with Dynamic Contrast Enhanced MRI (DCE – MRI) Evaluation of Vector Mediated Gene Therapy of Experimental Gliomas Using Multi-Modal Imaging Techniques Evaluation of Vessel Wall Enhancement in Vasculitis with Myocardial Delayed Enhancement Sequences: Feasibility and Preliminary Results Event Related fMRI of Primary- And Higher Cognitive Cerebral Function Using Pulsed Arterial Spin Labeling Perfusion Event Related fMRI of Successfully Implicitly Encoded Negative and Neutral Words in Major Depressive Disorder. Preliminary Results from the NESDA Neuroimaging-Study Evidence for a Vascular Component in the Diffusion FMRI Signal: A Hypercapnia Study Evidence for Cortical Hypoperfusion by Quantitative Arterial Spin Labeling Perfusion MRI in a Mouse Model of Alzheimer’s Disease Evidence for Systematic Within-Subject Head Motion in fMRI and Its Measurement with Maximum Voxel Displacement Evidence of Decoupling Between Perfusion and Diffusion in Skeletal Muscle: An MR Study with Arterial Spin Labeling and Diffusion-Weighted Imaging Evidence of the BOLD Post-Undershoot Rebound Evidence That Diffusion Tensor Imaging (Tractography) Predicts the Natural History of Regional Recurrence in Patients Irradiated Conformally for Primary Brain Tumors Evolution of Mice Brain Metabolism After a Convulsive Dose of Soman : A HRMAS 1H-NMR Study Examination of Frequency Dependant Signal Fluctuations in Resting State Examinations Measured with MR-Encephalography Examination of the Role of Glutamine in Human Glioma Cell Metabolism with 13C and 15N NMR Spectroscopy Examining Myocardial Tissue Properties with 3T MRI Exogenous Perfusion Imaging in Cortical Developmental Malformations Experience-Dependent Plasticity of Rat Whisker Cortical Maps Imaged with BOLD fMRI Experimental Determination of Human Peripheral Nerve Stimulation Thresholds in a 3-Axis Planar Gradient System Experimental Investigation of One-Dimensional "DESIRE" for NMR Microscopy Experimental Parameters and Diffraction Patterns at High Q Diffusion MR: Experiments and Theoretical Simulations Experimental Phased-Array Excitation Guided Utilizing a Computational Electromagnetic Model: Initial Findings Exploiting Peak Anisotropy for Tracking Through Fanning Structures Exploration of the Use of Multiple Decoupling Preamplifiers on a Single Loop Exploring and Exploiting Signal Correlations for Reconstructing Undersampled Dynamic Data Exploring the Feasibility of Simultaneous EEG/fMRI at 7T Exploring Transverse Relaxation Mechanisms by Simulation at the Nano Scale: Introduction of a High Speed Monte Carlo Algorithm Exponential Diffusion Tensors for Efficient Higher-Order DT-MRI Computations Extended Experience in the Preoperative Assessment of Pregnant Patients with Suspected Acute Appendicitis: Impact of MR Imaging on the Negative Laparotomy and Perforation Rates Extension of 8 Step Phase Cycling Scheme for Improved Lipid Suppression Using Four-Pulse PRESS MRS Sequences Extension of the Magic Gradient Amplitude Ratio Method Used to Minimize Background Gradient Cross-Terms in Diffusion-Weighted MR External Diamagnetic and Paramagnetic Passive Shimming of the Human Brain Extracting the Resting-State BOLD Signal from an Event-Related fMRI Study Extraction of Lesion Features from Contrast-Enhanced MR Mammograms Using Initial and Post-Initial Enhancements Extravascular BOLD Effect for Different Size Blood Vessels Over a Large Range of Magnetic Fields Ex-Vivo MR Imaging of Trabecular Bone Structure at 1.5T and 3T FA and Directional Diffusivities of Normal White Matter Maturation from Late Childhood to Young Adulthood Factors Affecting the Effectiveness of a Projection Dephaser in 2D Gradient-Echo Imaging Factors Relating to Development of Nephrogenic Systemic Fibrosis Following Gadolinium Fast 1H Missing-Pulse SSFP Chemical Shift Imaging of the Human Brain at 7 Tesla Fast 3D EPR Imaging Using Spiral Magnetic Field Gradient Fast 3D Proton MR Spectroscopic Imaging of the Human Brain In Vivo at 7 Tesla Using "Spectroscopic Missing Pulse – SSFP": First Results Fast 3D Proton MR Spectroscopic Imaging of the Human Prostate In Vivo at 3 Tesla Using "Spectroscopic Missing Pulse – SSFP" Fast 3D Reduced Field of View Carotid Imaging at 3T Fast 4D Coronary MRA with K-T GRAPPA Fast Absolute Quantitation Using FID Echo Planar Chemical Shift Imaging (FID EP-CSI) Fast Acquisition of High-Resolution MRS in Inhomogeneous Fields Via Intermolecular Single-Quantum Coherences Fast and Quantitative Imaging of Deep Vein Thrombosis Fast and Robust HARP Tracking Using Region Growing Fast and Super Fast Estimation of Quantitative Parameters in DCE-MRI Fast Brain Imaging with Spin Echo and Spatio-Temporal Correlation (K-T) Approaches for Distortion-Free fMRI Fast Breath-Held Three-Dimensional Cine Imaging Using K-T BLAST for Left Ventricular Volume Assessment Fast Cardiac Imaging Using a Combination of HYPR, Center of Masses, and McKinnon-Bates Algorithms Fast Chemical Shift Imaging with Ultra Short Echo Time Fast Conjugate Phase Reconstruction Using Taylor Series Approximation Fast Decomposition of Water and Lipid Using a GRASE Technique with the IDEAL Algorithm Fast Dynamic Parallel Phase Contrast MRI with High Acceleration Factors and Optimized SNR Fast Image Registration for Real-Time Cardiac MRI Guided Intervention Fast Imaging by Using a Diagonal Covariance Matrix Fast Imaging for Magnetic Resonance Electrical Impedance Tomography Fast Imaging of Dynamic Objects Using POCS Based Partial Fourier Reconstruction Along Time Fast Low Angle Positive Contrast Steady-State Free Precession (FLAPS) Imaging: Theory and Experiment Fast Mapping of Highly Inhomogeneous RF Fields Fast Mapping of RF-Induced Heating Along Conductive Wires by MRI Thermometry Fast Nosological Imaging of 2DTSI Brain Data Using Canonical Correlation Analysis Fast Parallel Spiral Chemical Shift Imaging at 3 Tesla Using Iterative SENSE Reconstruction Fast Parametric Imaging of the Spine with Radial IDEAL-GRASE Fast Registration for Motion Correction of Breast MR Images Fast Segmentation of MR Brain at 3T Using Phase Sensitive Inversion Recovery Images Fast Separation of Multiple Metabolites with Radial Undersampling Fast Sequence Optimization for Superior Signal Suppression with Multiple Hyperbolic Secant Pulses Fast Single Breath-Hold 3D Abdominal Imaging with Water-Fat Separation Fast Slice-Selective B1 Mapping Fast Spatial-Spectral Imaging of Hyperpolarized 13C Compounds Using Partial-Fourier Multiple Echo 3DFIESTA Fast Susceptibility Weighted Imaging (SWI) with an Echo-Shifted FLASH Sequence Fast T1? Measurements by Spin-Lock Pre-Encoded HASTE and bSSFP (SLIPS) Fast T1-Mapping to Study Biodistribution of Nanoparticulate Contrast Agents Fast Three-Dimensional Assessment of Delayed Enhancement MRI in a Single Breathhold: Comparison with the Conventional Two - Dimensional Technique Fast Three-Dimensional Magnetization Transfer Imaging at 3T Fast Two-Point Mapping of the Bound Pool Fraction and Cross-Relaxation Rate Constant in the Human Brain Fast Whole-Brain Perfusion fMRI Using 3D GRASE Slab-Selective IR with Background Suppression Faster Dixon Fat-Water Imaging with Multiplex RF Pulses Faster Needle Insertion Using a 1.5 T Interventional Scanner and Tri Orthogonal Plane Guidance Fat Infiltration in Duchenne Muscular Dystrophy: Quantification on T1-Weighted Images for Steroid-Treated DMD Boys and Control Subjects Fat Suppression for 1H MRSI at 7T Using a Spectrally Selective Adiabatic Inversion Pulse Fat Suppression with Weighted-Combination SSFP Fat Water Separation in Mice Fat-Fat Interations in Dixon-Variant Imaging Fat-Water Separation in Alternating Repetition Time (ATR) Balanced SSFP Fat-Water Separation in Dynamic Objects, Applied to Cardiac Cine Imaging Faulty Trigger and Motion Artifact Canceling in Cardiac MRI Using SPACE-RIP FDTD Simulations of Implantable Devices at 3 and 7 Tesla FDTD Simulations of RF Inhomogeneities in Ultrahigh-Field MRI Systems of Up to 11.7 T Feasibility of Full RF Current-Vector Mapping for MR Guided RF Ablations Feasibility of an Animal Model of Hepatic Steatosis for In Vivo Fat Imaging with IDEAL Feasibility of Arterial Spin Labeling in the Measurement of Breast Perfusion Feasibility of cNGR Labeled Paramagnetic Quantum Dots for Molecular Magnetic Resonance Imaging and Two Photon Laser Scanning Microscopy of Neovascularization Feasibility of Contrast Enhanced Time-Resolved Whole-Heart (4D) Coronary MR Angiography in Humans Feasibility of Fully Simultaneous EEG/PASL/BOLD-fMRI for Characterisation of Hemodynamic Responses to Pathophysiologic and Physiologic Neuronal Activation in Epilepsy Patients Feasibility of High Resolution Partial Parallel Imaging in the Distal Tibia for Improved Structural Anisotropy Analysis Feasibility of Integrating High Spatial-Resolution, 3D Whole-Heart Viability Imaging and Coronary MRA at 3 Tesla Feasibility of Pulse Wave Velocity Measurement Using ECG-Triggered Two-Dimensional Half-Fourier FSE Feasibility of Simultaneous Evaluation of Coexistant Liver Iron and Fat Content with T2*-IDEAL Feasibility of Using Predicted Cramer Rao Lower Bounds for the Design of Optimized In Vivo MR Spectroscopy Sequences Targeting Multiple Metabolites Feasibility Study of the Cerebrospinal Fluid Flow Circulation in the Brain of Dogs with H217O Using Magnetic Resonance Imaging FeCo/Graphitic Carbon-Shell Nanocrystals as MRI Contrast Agents for Cellular and Vascular Imaging Feedback Controllers for Suppression of Acoustic Noise Response of a 4T MRI Scanner Feedback-Enhanced MRI by Fixed-Point Dynamics and Nonlinear Spin-Locking Femoral Artery Stress in the Adductor Canal Due to Leg Muscle Contraction Ferumoxide Labelling of CD133+ Cells for Targeted Re-Endothelialisation Fiber Statistics in the Corpus Callosum Fiber Tracking of Extraocular Muscles In Vivo Field Propagation Phenomena in Ultra High Field NMR: A Maxwell-Bloch Formulation Field Strength Dependence of BOLD Contrast in Motor Cortex Field-Encoded SSFP: A New Method for Positive-Contrast Visualization of Paramagnetic Agents Fine-Grained Comparison of Anisotropy Differences Between Groups of White Matter Tracts Fine-Grained Topography of Human Thalamo-Prefrontal Connectivity Revealed by Multi-Fibre Probabilistic Tractography Finer Discrimination of Brain Activation Finger-Tapping Modulates Functional Synchrony in the Motor Cortex Network Finite Element Modeling and Experimental Validation of Transverse Relaxation and Apparent Diffusion Coefficients of Hyperpolarized Noble Gases in Rodent Lung Finite Element Modeling of the Human Triceps Surae Aponeurosis Based on Force-Diplacement Data from In Vivo Motion Tracking with Phase Contrast MRI First Demonstration of Diffusion Weighted Imaging of In Vivo Carotid Plaque at 1.5T First Order Dynamic Shimming for 7 Tesla Human Imaging First PET Images Using a Prototype Small Animal Field-Cycled MRI/PET Imaging System First Protocol for High Field MRI of the Knee at 7.0 Tesla First Results of Proton Decoupled and NOE Enhanced 31P MRSI of the Human Brain at 3T Exhibit Correlations with Age First Results of Real-Time fMRI at 3T and 7 T First Study of Therapy Follow-Up of Creutzfeldt-Jakob Disease by Magnetic Resonance Diffusion and Spectroscopy First-Pass Whole-Body MRA Using the Blood Pool Contrast Medium Gadofosveset Trisodium: Comparison to Gadopentetate Dimeglumine Fitting of the Piecewise Linear Function to Signal Intensity Time Curve and Its Application in Improving the Analysis of Concentration Time Curve of Dynamic Contrast Enhanced-MRI Data Fitting to Signal Intensity Time Course Data with Intrinsic Conversion to Gd-DTPA Concentration Improves the Accuracy and Precision of Model Parameter Estimates Flexible and Retrospective Trade-Off Between Temporal and Spatial Resolution in Dynamic MR Imaging Flip Angle Calibration for High Resolution Mapping of the Long Range Diffusion Coefficient by Hyperpolarized 3He MRI Flow ENhancement of Signal Intensity (FENSI): Validation of Localized Flow Measurements Flow Measurements and Evans Index in Normal Pressure Hydrocephalus and White Matter Lesions Flow Mediated Vasodilatation Induced Brachial Artery Area Change Versus Atherosclerotic Risk Factors Flow Quantification by Dual Echo Phase Contrast SSFP Flow Quantification in Real-Time with Golden Angle Acquisition and K-T BLAST Reconstruction Flow-Preparation and Flow-Saturation-Preparation Pulses for Abdominal Non-Contrast-Agent MR Angiography Flow-Saturation-Preparation Pulse for Lower Extremity Non-Contrast-Agent MR Angiography Flow-Sensitive Inversion-Prepared SSFP Coronary MR Angiography Flow-Sensitive Susceptibility-Weighted Imaging Flow-Sensitive Susceptibility-Weighted Imaging of the Brain: Initial Experience in Ischemic Lesions Fluorine-19 MRI for Visualization and Quantification of Cell Migration in a Diabetes Model Fluorine-19 MRI of the Lung: An In Vivo Comparison of Fluorinated Gases fMRI at 7T: Whole Brain Coverage and Signal Advantages Even Infratentorially? fMRI Investigation of Central Olfactory Deficit in Early Alzheimer’s Disease fMRI of Acupuncture for Salivation fMRI of Brain Activity During Active Place Avoidance in a Task of Divided Attention fMRI Reveals Altered Auditory Sensory Integration in Manifest and Premanifest Huntington’s Disease FMRI Reveals that Peak Activated Regions in the Primary Sensorimotor Cortex and Premotor Regions are the Same for Multiple Sclerosis Patients and Controls During Complex Finger Tapping fMRI: From Mapping to Mechanisms fMRI-Guided MRS Studies of Cortical Reorganization Following Sub-Cortical Stroke Focal Lesions Detected by B Ultrasound but Not by MRI in Liver: Follow-Up Study Focused Parallel Imaging Array for Mouse Brain Imaging at 11.1T Folate Targeted Paramagnetic Liposomes for Magnetic Resonance Tumour Imaging Follow-Up After Endovascular Therapy of Cerebral Aneurysms: A Comparative Study of Angiographic CT Versus Time-Of-Flight MR-Angiography at 1.5 and 3 Tesla Follow-Up Study of In Vivo Breast Cancer Cell Invasion by MRI Four Dimensional MR Microscopy of Respiratory Mechanics in Transgenic Mice with Emphysema: Lung Motion Quantification Via a Non-Rigid Registration Algorithm Four Weeks of Close Proximity to the 4.7T Magnet Does Not Stimulate Heat Shock Protein Expression in the Rat Brain Four-Dimensional Volumetric Analysis of the Lung Over the Respiratory Cycle in Ventilated Mice with Emphysema Fractal Properties of Tumours in Dynamic Contrast Enhanced Magnetic Resonance Imaging Fractionated Manganese-Enhanced MRI FRED-GMC: Filtering of Raw EPI Data for Gradient Map Calculations Free Breathing 3D Lung Imaging Free-Breathing and High B-Value Diffusion-Weighted MR Images of Malignant Urinary Tract Obstruction Free-Breathing Combined Functional and Viability MR Imaging of the Heart Free-Breathing Coronary Angiography Using Alternating-TR Balanced SSFP and a 3D Cones Trajectory Freely Diffusible Contrast Agents for Hyperpolarized 13C Perfusion Imaging Frequency Dependent Mechanical Contrast : An Analytical Perspective of the High Frequency Mode Conversion Magnetic Resonance Elastography Frequency-Dependent Changes in Lactate Concentration During Activation of Human Visual Cortex Frequency-Dependent Correlation Between Estimated LFPs and BOLD Responses in Human From Technical Innovations to Clinical Routine From Tractography to Graph Tracking Frontal Lobe Function: Association Between Neuropsychological Test Scores and N-Acetyl Aspartate Full Brain Coverage Perfusion Measurements at 3T Using Pulsed Arterial Spin Labelling (PASL) and Parallel Imaging Full Signal Intensity for Short Echo Time Localized Spectroscopy on a Clinical Scanner Full-Brain Coverage and High-Resolution Imaging Capabilities of Passband SSFP fMRI at 3 T Full-Wave Evaluations of Loading Factors of Small Animal RF Receive Coils Fully Autocalibrated Parallel Imaging for Arbitrary Trajectories Using a Combination of GRAPPA-Operator Gridding and Conjugate-Gradient Optimization Fully Automated Volume of Interest Segmentation in the Virtual Bone Biopsy Fully Automatic Segmentation of the Brain from T1-Weighted Images Using Bridge Burner Algorithm Fully Automatic Segmentation of the Left Ventricle in Cardiac Cine MR Images Fully Integrated Whole Body 3T MRI System for Parallel RF Transmission Functional 31P-{1H} EPSI with 6 S Temporal Resolution of the Human Brain Functional Brain Correlates of Response Time Variability in Children Functional Brain Mapping During Acute Stimulation Through Chronic Electrode Implants in Rat Functional CBV Contrast Revealed by Diffusion Weighted Stimulated-Echo Imaging Functional Changes in CSF Volume Estimated Using Spectroscopic Water T2 Decay Measurement Functional CMRO2 Study in Cat Visual Cortex: Findings and Implications Functional Connectivity During the Resting State in the Default-Mode Network: A Major Role for the Cerebellum? Functional Connectivity Measured with Mutual Information at 7 Tesla Functional Contrast Based on iDQC - Influence of the Correlation Distance Functional Evaluation of Object Analysis in Children with Autistic Disorder Functional Hierarchy of the Visual System as Revealed by Resting-State Connectivity Functional Hippocampal Connectivity Identifies AD Risks in Mild Cognitive Impairment Subjects Functional Imaging Capabilities of a Combined Animal PET/MR System Functional Imaging of Olfactory Neural Network In Vivo Using Manganese Enhanced MRI: A Comparative In Vivo Study Between Normal and Anosmia Rat Models Functional Imaging of the Prostate: Quantitative DCE-MRI and Its Repeatability Functional Imaging Using Nitroxides - A Feasibility Study at 11.7T Functional Liver Imaging Using Inter-Pixel Cross Correlation (IPCC): A Brute Force Univariate Approach Functional Magnetic Resonance Imaging (fMRI)-A Useful Tool for the Assessment of Hypothalamus Function? Functional Magnetic Resonance Imaging Based on an Inversion Recovery Method for Grey Matter Signal Suppression Functional Magnetic Resonance Imaging of Cortical Tissue Slices by Means of Signal Enhancement by Extravascular Water Protons (SEEP) Contrast Functional Magnetic Resonance Imaging with Undersampled Projection-Reconstruction Functional Mapping of Rat Barrel Activation Following Whisker Stimulation Using Activity-Induced Manganese-Dependent Contrast Functional MRI at 3T Using Spin Echo and Gradient Echo Intermolecular Double Quantum Coherence Acquisitions Functional MRI in a Zebra Finch Model of Dysfluency Shows Altered BOLD Responses to Familiar Birdsong Stimuli Functional MRI of Spontaneous Absence Seizures in a Genetic Rat Model Functional MRI of the Brainstem and Cervical Spinal Cord of Children Based on SEEP Contrast Functional Mri of the Spinal Cord in Patients with Relapsing-Remitting Multiple Sclerosis Functional MRI of Unilateral Vocal Cord Paralysis Before and After Thyroplasty: Comparison to Healthy Subjects Functional MRI Reveals Strong Hemodynamic Impairment in arcAß Mice Modeling Vascular Pathology of Alzheimer’s Disease Functional MRI Study of Negative Priming Implications for Frontal Disinhibition Functional Neuroimaging of Inner Field-Of-Views Using FLASH with 2D-Selective RF Excitations Functional, Biochemcial, and Morphological Changes with Age Further Investigation on the SNR and De-Blurring Effect of the Weighting Window on PROPELLER EPI Reconstruction Fusion of FDG-PET and Proton-MRI of the Lung in Patients with Lung Cancer: Initial Results in Differentiating Tumor from Atelectasis GABA Changes Acutely in Human Brain After Nicotine Administration GABA Detection with MEGA-PRESS at 3 Tesla; Improved Sensitivity Using Inner Volume Saturation Gadofluorine M Uptake in Stem Cells as a New Tracking Method at 1.5T MRI Gadolinium and the Development of Nephrogenic Fibrosing Dermopathy Gadolinium Based Steady-State Technique for Longitudinal Fractional Cerebral Blood Volume Mapping Gadolinium Contrast Agents as a Possible Trigger for the Development of Nephrogenic Fibrosing Dermopathy (NFD) Gadolinium Mixed Micelles Containing Apolipoprotein E Derived Peptide for Atherosclerotic Plaque Detection Through Interaction with Macrophages Gadolinium-Enhanced Excretory MR Urography for Upper Tract Urothelial Carcinoma in High Risk Population Gadolinium-Enhanced Off Resonance Contrast Angiography GAG Content Via Chemical Exchange Saturation Transfer: Assessing OA Gated 31P MRS Acquisition During Steady State Electrical Stimulation of Mouse Skeletal Muscle Enables Determination of Contractile ATP Cost and Phosphocreatine Recovery Time Gaussian Process Modeling for EPI Distortion Correction Gender Differences in Brain Iron Level Gender Differences in Water Diffusion of the Corpus Callosum: A Diffusion Tensor Imaging Study Gene Based Production of Magnetic Nanoparticles for MRI General Method for Acoustic Noise Reduction by Avoiding Resonance Peaks Generating 1H- And 13C-Hyperpolarized Molecular Probes of Variable Size from Parahydrogen to Explore the Lung Via MRI Generation of an Accurate 3D Computational Model of the Mouse Heart from MR Images Generation of MR Myocardial Perfusion Maps Without User Interaction Geographically Weighted GRAPPA Reconstruction and Its Evaluation with Perceptual Difference Model (Case-PDM) Geometric Reconstruction of Brain Vasculature from Small Rodents; a Comparison of Different Imaging Methods Global 2D Polynomial Fit Method for Efficient Filling of Coil Sensitivity Profile Gaps Global Vs Local Arterial Input Function Glycogen Utilization During Hypoglycemia in the Human Brain Gold Nanoparticles for MRI Golden Angle PROPELLER MRI Gradient Coil Array for the Super-Parallel MRI: Experimental Evaluation Gradient Coil Array for the Super-Parallel MRI: Theory and Design Gradient Coils for the Focused RF Ablation with Magnetic Fluids Gradient Driver with Digital Control Gradient Echo Plural Contrast Imaging for Evaluating Multiple Sclerosis Gradient Moment Nulling in MR Elastography of the Liver GRAPPA Estimations Using Undersampled Propeller Trajectories Gray Matter Prefrontal Changes in Type 2 Diabetes Detected Using MRI Group Analysis of ASL Perfusion fMRI Data Based on Permutation Testing in Individual Subjects Group Independent Component Analysis Reveals Consistent Resting-State Networks Across Multiple Sessions Guiding Off-Resonance Interventional MR with Dephased Fast Low-Angle Positive-Contrast Steady-State Free Precession Imaging Habituation and Dishabituation of the Auditory Cortex Haircut: A Method to Reduce the Dragging Effect Due to Smoothing in Voxel-Based Morphometry HASTE Sequence with Parallel Acquisition and T2 Decay Compensation: Application to Carotid Artery Imaging Heating of Metallic Implants and Instruments Induced by Gradient Switching Hemodynamic Characteristics in Various Arteriolar Segments Upon Physiological Changes Hemodynamic Effects of Vacuum-Assisted Closure Therapy in Cardiac Surgery, Assessment Using Real Time Magnetic Resonance Flow Quantification Hemodynamic Responses to Transient Brain Deactivations: Modifications to the Balloon Model to Account for Non-Linear Effects Hemorrhage Detection in the Carotid Atherosclerotic Lesion – Initial Results at 3T Hepatic Glycogen Signal Detection in Rats Using Gaussian-Weighted Phase Encoding C-13 MR Spectroscopic Imaging Hepatic Steatosis and Perfusion Parameters in the Progression of Liver Fibrosis: Findings in Carbon Tetrachloride (CCl4)-Treated Rats Using Three-Point Dixon and Dynamic Contrast-Enhanced MRI Heroin Cue-Induced Neural Activation in Heroin Addicts: An fMRI Study Heterogeneity of DTI Diffusion Anisotropy in the Myocardium High Accordance of Diffusion Weighted MRI and 18-FDG PET/CT in Cervical Cancer High B-Value Diffusion-Weighted MR Images of Biliary Tumors and Tumor-Like Lesions High Contrast Imaging at High Field Strengths with Low SAR High Contrast Susceptibility Weighted Imaging: Reliable Unwrapping Susceptibility Technique (RUST SWI) Improved Visualization of Midbrain Nuclei for Deep Brain Stimulation High Dose of Mn2+ Injected Intracerebrally Causes Neuronal Losses in the Ventral Tegmental Area of Rat High End Clinical Applications of Parallel Imaging High Field (7 T) and Spatial Resolution (0.05 Ml Voxels) 3D MRSI in the Rhesus Macaque Brain High Field 3 Tesla MRI and Positron Emission Tomography Detection of Malformations of Cortical Development in Refractory Focal Epilepsy High Field fMRI of the Parahippocampal Region High Field Imaging of Non-Human Primates: Anatomical Imaging and Relaxation Rates High Field MR Imaging of Experimental Mouse Colitis High Flip Angle Slice Selective Parallel RF Excitation on an 8-Channel System at 3T High Frame-Rate Simultaneous Bilateral DCE-MR Breast Imaging High Performance Computation of Spatially Selective Excitation Pulses Regarding Realistic Experimental Conditions High Power, High Efficiency On-Coil Current-Mode Amplifier for Parallel Transmission Arrays High Resolution 2D and 3D EPR Imaging of Melanin in Biological Samples High Resolution 3D MR Plaque Detection in the Thoracic Aorta in 45 Acute Stroke Patients at 3Tesla High Resolution 3D MRI of Cortical Lesions in Multiple Sclerosis High Resolution Cardiac Imaging in Small Laboratory Animals Using a Standard Clinical 3.0T Gradient Set High Resolution Diffusion Tensor Image Using Segmented FOV High Resolution fMRI in the Human Ventral Visual Pathway Using a 32-Channel Phased Array Receive Coil High Resolution Functional MR Imaging of Material-Specific Encoding High Resolution MRA, Imaging M4 and Beyond High Resolution MR-Elastography of In-Vivo Rat Brain – Understanding the Scaling Behaviour of the Structures High Resolution MR-Elastography to Diagnose Liver Fibrosis and Hepatic Steatosis in Rats High Resolution MRSI and DTI of Prostate Cancer at 3T High Resolution Myelin Water Measurements in Rat Spinal Cord High Resolution Myocardial Perfusion Imaging at 3T: Comparison to Standard 1.5T Perfusion Studies and Diagnostic Accuracy in Patients with Suspected CAD High Resolution NMR Spectroscopy on Rat Brain In Vivo Through Indirect Zero-Quantum-Coherence Detection High Resolution pHe Imaging of Tumors High Resolution PWI of the Brain; Comparison with SWI, MRA, and T1-CBV Images High Resolution Radial Diffusion-Weighted Imaging at 7T High Resolution SE-fMRI in Humans at 3 and 7 T Using a Motor Task High Resolution Sodium Imaging of Isolated Neurons High Resolution Steady State Imaging of Peripheral Arteries with a Blood Pool Agent Compared with Standard First Pass Imaging and DSA: Assessing the Clinical Benefit High Resolution T2 Mapping of Abdominal Organs at 1.5 Tesla: Normal Statistical Variations High Spatial and Temporal Resolution MRA (TWIST) in Acute Aortic Dissection High Spatial Resolution Diffusion Imaging with Inner Volume Acquisition at 7T High Spatial Resolution Multispectral Quantitative MRI of the Human Knee: Mixed-TSE Pulse Sequence High Spatial Resolution Myocardial Perfusion MR Imaging in Patients with Coronary Artery Disease Using K-T SENSE High Spatial Resolution Optimization of SSFP TruFISP Myocardial Perfusion MRI and Comparison with Spoiled Gradient Echo High Temporal Resolution Diffusion MR Imaging of the Mouse Spinal Cord Using Echo Planar Imaging High Temporal Resolution Measurements of Metabolic Water Production from 17-Oxygen Bolus Gas Delivery in a Large Animal High Temporal Resolution Tissue Phase Mapping Detects Age-Related Segmental Changes of Myocardial Velocities in Healthy Volunteers High Time Resolution DWI of Muscle Contraction During Electrical Simulation High-Energy Phosphate (HEP) Metabolism During Exhaustive Calf Exercise in Patients with Bilateral Symptomatic Peripheral Arterial Disease (PAD) High-Field Actively Detuneable Transverse Electromagnetic (TEM) Coil with Low Bias Voltage for High Power RF Transmission High-Field Double-Tuned TEM/Birdcage Hybrid Volume Coil for Human Brain Imaging. High-Field MR Microscopy as a Tool for Comparative Morphological Studies: Soft Tissue Discrimination in Sea Urchins High-Field MRI of Brain Cortical Substructure Based on Signal Phase Highfield Proton MRSI in Adult Patients with X-Linked Adrenoleukodystrophy Highly Accelerated k-T SENSE Cardiac Perfusion Imaging Highly Accelerated Contrast-Enhanced, Time-Resolved Peripheral Three-Dimensional Magnetic Resonance Angiography with Submillimeter Spatial Resolution at 3.0 Tesla Highly Accelerated IDEAL Vs Fat Sat Acquisition: A Comparison for Volumteric Liver Imaging Highly Accelerated, Millimeter In-Plane Resolution Myocardial Perfusion MRI Using a 32-Channel 3.0 T System Highly Constrained Back Projection (HYPR) Processing for Phase Contrast MRI Highly Efficient Accelerated Acquisition of Perfusion Inflow Series by Cycled Arterial Spin Labeling Highly K-T-Space Accelerated Tissue Phase Mapping Highly Localized Alterations of White Matter in Fixation-Off Sensitivity: A Study Using DTI Highly Parallel Volumetric Echo-Planar Spectroscopic Imaging with 2D Acceleration Highly Time-Resolved Lower Extremity MRA with TWIST, a Novel Data-Sharing 3D Gradient Echo Sequence with Spiral K-Space Filling Highly-Automated 3D Segmentation of Femoral Bone from Hip MRI High-Quality Non-Water Suppressed MR Spectra with Correction for Motion Induced Signal Reduction High-Resolution 3D Breath-Hold Coronary Artery Imaging at 3T Using Wideband SSFP High-Resolution 3D MRI Mapping of Tumor Angiogenesis Using a5ß1-Targeted Perfluorocarbon Nanoparticles High-Resolution Contrast-Enhanced, Susceptibility-Weighted Magnetic Resonance Imaging at 3 in Patients with Brain Tumors High-Resolution Dynamic Imaging with Spiral Scanning and Spatiotemporal Modeling High-Resolution Human Functional MRI: Feasibility and Specificity at High (3T) and Ultra-High (7T) Fields High-Resolution Imaging of Normal Human Hippocampus at 7 Tesla High-Resolution In-Vivo Imaging of Multiple Sclerosis at 7T High-Resolution LASER-Localized Chemical Shift Imaging in the Rat Brain at 9.4 T High-Resolution MRI of Internal Field Diffusion-Weighting in Trabecular Bone High-Resolution MRI of the Triangular Fibrocartilage Complex (TFCC) at 3T: Comparison of Surface Coil and Volume Coil High-Resolution MRS in Inhomogeneous Fields Via Double-Quantum-Filtered Intermolecular Zero-Quantum Coherences High-Resolution Spectroscopic Imaging with Statistical Reconstruction High-Resolution T1 Mapping with Incorporated Transmit Radio Frequency Field Inhomogeneity Correction High-Spatial-Resolution Bilateral Contrast-Enhanced Breast MRI at 3.0T: Preoperative Staging of Patients Diagnosed with Invasive Lobular Cancer Hilbert-Sampling in K-Space Hippocampal Atrophy is the Critical Brain Change in Patients with Memory Disorder Resulting from Anoxic Episode Hippocampal EEG Signal Complexity Correlates with NAA/Cr Hippocampal Sclerosis: Evaluation with High-Spatial-Resolution T2-Weighted Images at 3T Histogram Analysis of Cerebral Dynamic Susceptibility Contrast-Enhanced Perfusion MRI Data in Moyamoya Arteriopathy and Correlation with MRA Findings Histogram Based Water and Fat Identification in a Symmetrically Sampled Dual Echo Dixon Technique Homogeneity and Shimming Requirements for a Field-Cycled MRI/PET Scanner Homogeneity Improvement Using a 2 Port Birdcage Coil Host Tissue Dependence on the Tracer Relaxation Effect in Spin Echo How Long Does It Take Before ADC Reduction Becomes Irreversible? How Low Can We Go? Limits of Detection in PASADENA 13C Hyperpolarization How Many Compartments are Needed to Analyze Pulmonary Perfusion Data? How Many Shells? - Investigating a Long Held Tradition in DT-MRI How Much Confidence Do We Have in a MRI Tractography Experiment? How Much of the Reported Myelin Water Component in T2 Decays Is Actually a Reconstruction Artefact of the Main Water Peak? How to Make It Happen - Practical and Strategic Issues of Interventional MRI How to Tackle AIF Clipping for Myocardial Perfusion Modelling with Bayesian P-Splines How to Unwind in the Low Field Limit HR-MAS Spectroscopy of Oral Cancer Tissues and Their Assessment with Histopathological Examination HR-MAS Spectroscopy of Post-Radiation Prostate Biopsy Tissues HTS Surface Coil for MRI of the Patella Human Brain-Structure Resolved T2 Relaxation Times of Proton Metabolites at 3 Tesla Human Lung Imaging in Supine Versus Upright Positions with a 6.5 mT Open-Access 3He MRI System: Initial Results Human Pulmonary Diffusion Weighted Imaging at 0.2T with Hyperpolarized 129Xe Human Regional Pulmonary Gas Exchange with Xenon Polarization Transfer (XTC) Hybrid Diffusion Imaging in a Brain Model of Dysmyelination Hybrid MR - Optical Imaging Hybrid MR and X-Ray Fluoroscopy Hybrid Radial-Cartesian MRI HydRA: Highly Constrained Regridded Angiography Hypercapnia-Induced Vasoreactivity as Evaluated by Vascular-Space-Occupancy (VASO) Dependent fMRI Hyperpolarized 13C-DNP-NMR Allow Metabolic in Vitro Studies Over Minutes Hyperpolarized 3He Magnetic Resonance Imaging of Ventilation Defect Volume Variability in COPD Hyperpolarized 3He MRI at 3.0 Telsa: Anatomic Bias of Apparent Diffusion Coefficients in Chronic Obstructive Pulmonary Disease Hyperpolarized C-13 MRSI Data of Dog Prostate at 3T Hyperpolarized Helium3 Phase-Contrast Velocimetry on Human Paranasal Sinus Ostial Patency Hyperpolarized Helium-3 Spiral Ventilation Imaging: Implementation and Validation of a Free-Breathing Protocol on a Clinical MR Scanner Hyperpolarized N-15 of Choline - Potential for Observing Phospholipid Metabolism in Cancer Hyperpolarized Xe-129 as a Non-Invasive Biosensor to Characterize Atherosclerotic Plaques Hyperpolarizing and Exploring the Function of Drugs Used to Combat Epilepsy Via Parahydrogen-Enhanced MRI Hyperpolarizing Drugs to Determine Their Role in Suppressing Epileptic Seizures and Migraine Headaches Via MRI Hypothalamic Functional MRI Response After Glucose Ingestion Is Diminished in Patients with Type 2 Diabetes Mellitus HYPR MR Fluoroscopy HYPR Myocardial Perfusion MR Imaging HYPR Reconstruction with Automatic Detection of Contrast Arrival Ice Ball Imaging During Cryoablation of Canine Prostates: Contrast-Enhanced MRI Provides Most Accurate Delineation of the Acute Necrotic Zone IDEA Simulator Extension: A Sequence Analyzer Identification and Prevention of Common Artefacts in 1H-MR Spectra of Intramyocellular Lipids (IMCL) Identification of a Multivariate Biomarker of Alzheimer's Disease with ASL Identification of Breast Carcinoma in Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE MRI) by Independent Component Analysis (ICA) - Initial Results Identification of Diaschisis Post Stroke with Rest-Stress Quantitative CASL MRI iDQC Anisotropy Map Imaging for Tumor Tissue Characterization In Vivo IIn Vivo Cell Tracking 19F MRI using Perfluorocrown Ether Nanoparticles Image Based Ghost Correction for Oblique Imaging Image Entropy of Undersampled Data: A Useful Measure of Aliasing Severity Image Reconstruction from Randomly Undersampled Cine MRI Data - A Comparison with the k-T BLAST Method Image-Based Coronary Tracking and Beat-To-Beat Motion Compensation for Robust Coronary MR Angiography Image-Based Tracking of Heart Valves for Improved Motion Compensation Imaging 3D Respiratory Dynamics Using Hyperpolarized He-3 Multi-Echo HYPR VIPR Imaging Characteristics of an MRI-Compatible Stent Delivery System Imaging Concentration and Temperature in Cryopreservation Solutions from -80C to Room Temperature Imaging Corticospinal Tract Connectivity in Injured Rat spinal Cord Using Manganese-Enhanced MRI Imaging Immune Response In Vivo: Cytolytic Action of Genetically Altered T-Cells Directed to Glioblastoma Multiforme Imaging Lung Aveolar Fluid Clearance with MRI Imaging of Submillisecond T2 Species with 2D and 3D Radial Imaging Sequences Imaging of the Deep Radial and Calcified Layers of the Cartilage Using Ultrashort TE (UTE) Sequence at 3T Imaging Oxygenation, Blood Volume, and Blood Flow Changes in the Retina Imaging Stroke with Hyperpolarized 129Xe MRI Imaging the Progression of Iron-Loaded Glioma Tumours with FIESTA at 3T Imaging Water Content in the Lungs – Measuring and Correcting the Influence of Breathing Imaging Water, Fat, and Silicone with Regional Iterative Phasor Extraction (RIPE) Imaging Weak Currents by Means of Balanced SSFP IMCL Is Increased in Adolescent Type 1 Diabetics - Comparison with Both Age Matched and Adult Controls Impact of Altered Head Shape on Talairach Parcellations of Neonate Brain Images Impact of ASL and BOLD Noise Thresholds and Duration of CO2 Calibration on the Estimates of Calibrated BOLD Impact of Bias-Correction and Skull-Stripping Pipelines on Spatial Normalisation Using SPM5 in a Phantom Model Impact of Diffuse Peripheral Arterial Disease (PAD) on High-Energy Phosphate Metabolism in the Exercising Calf Muscle Impact of Geometric Distortions on 3T fMRI Retinotopic Maps Implementation of a Fast Inversion Recovery Sequence to Assess Delayed Enhancement of Myocardial Infarction in Mice Implementation of Localized Two-Dimensional Homonuclear Correlated MR Spectroscopy (L-COSY) Sequence for Prostate Study at 7T Implementation of MR Breast Imaging in Supine Position Implementing Cerebral 13C MRS Using Low RF Power for Proton Decoupling on a 3 Tesla Clinical Scanner Implications of Heterogeneous Variance of Tensor-Derived Quantities for Group Comparisons Implications of Testosterone Treatment on Trabecular Bone Elastic Constants Assessed by Micro-Finite Element Analysis of In Vivo Images Implicit Intonation Mudoulation of Priming in Auditory Related Brain Areas - An fMRI Study Importance of K-Space Trajectory for Accurate Quantification of AIF and High CNR of Myocardial Wall Enhancement in First-Pass Myocardial Perfusion MRI Improved Artifact Correction for Combined EEG/fMRI Improved B0 Field Mapping with an Interleaved SE/ASE Acquisition and a Multi-Channel Receive Coil Improved Background Suppression for Intracranial 3D TOF MRA Using Robust Fat Suppression with IDEAL at 3T Improved Body Phase Contrast Imaging Using a Prospectively Gated VIPR Acquisition Improved Cardiac Manganese-Enhanced MRI (MEMRI) with T1 Mapping in Rodent Improved Correction for TR Variation in Cardiac Gated fMRI Using Unscented Kalman Filter Improved Coverage of Brain Tumors with 1H MRSI Using Cosine Modulated Very Selective Suppression Pulses at 3T Improved DCE-MRI Quantification of Pharmacokinetics Based on an Accurate Approach for Individually Measured Arterial Input Functions Improved DENSE MRI Using Balanced Multi-Point Displacement Encoding Improved Detection and Diagnosis of Sturge-Weber Syndrome Using MR Susceptibility Weighted Imaging (SWI) Improved Detection of Glycosaminoglycan Content in Cartilage Using PARACEST MRI Contrast Agents Improved Diffusion Measurement in Heterogeneous Systems Using the New Magic Asymmetric Gradient Stimulated Echo (MAGSTE) Technique Improved Distortion Correction in Cerebral and Spinal DTI Using Interleaved Reversed Gradients Improved Fourier Based Method for Calculating Field Inhomogeniety from Known Susceptibility Distribution Improved High-Resolution MRS in Inhomogeneous Fields Via Intermolecular Zero-Quantum Coherences Improved Inversion Efficiency in Arterial Spin Labeling Using Adiabatic Null Pulses Improved K-T BLAST Using FOCUSS Improved MR Image Magnification by Generalized Interpolation of Complex Data Improved MR Spectral Analysis for a PFC-Filled Endorectal Prostate Surface Coil Compared to an Air-Filled Coil Improved Myocardial T2* Normal Values at 1.5T and 3T Improved Outer Volume Suppression for Prostate MR Spectroscopic Imaging Improved Phase Processing in Susceptibility Weighted Imaging Improved Physiological Noise Modelling Reveals Expected Pattern of Pain-Related Spinal Cord Activation Improved Preoperative Evaluation of Cerebral Cavernomas by High-Field, High-Resolution Susceptibility-Weighted Magnetic Resonance Imaging at 3 Tesla Improved Procedure for Automatic Alignment of Strongly Overlapping Peak-Regions in High-Resolution 1H NMR Spectra Improved Proton NMR Thermometry by Field Inhomogeneity Correction Post-Processing Improved Sensitivity to BOLD Contrast with Multi-Echo Gradient Echo Imaging Improved Separation of Vascular Territories in Vessel Encoded Pseudo-Continuous Arterial Spin Labeling Improved Stent Visualisation with High Flip Angle Magentic Resonance Angiogram During XMR Procedures Improved Temporal Resolution in Time-Series ASL Perfusion Imaging with Single-Shot 3D GRASE Using Variable Shared Control Phases Improved Tissue Metabolite Quantification in 1H HR-MAS Spectroscopy Using the ERETIC Method Improved Unsupervised Assessment of Abdominal Fat in MRI by Automatic Correction of Intensity Inhomogeneities Improved Vessel Localization in Magnetic Resonance Venography at 3T Using Multiple-Echo Image Combination and Asymmetric Triangular Filter Improved Visualization of Intra-Axial Gliomas on Enhanced MR Imaging with Gadobenate Dimeglumine Compared to Gadopentetate Dimeglumine: Implications for Therapeutic Intervention Improvement of DTI Measurement Accuracy Using Real-Time Navigated Data Acquisition Improvement of MR Visualization of Prosthetic Heart Valves Improvement of Perfusion Imaging of the Human Lung Using Retrospective Gating Improvement of the Specificity of DCE-MRI Using a Dynamic Optical Imaging System Improving Computation of Cardiovascular Relative Pressure Fields from Velocity MRI Improving Diffusion Tensor Fiber Tracking by Acquiring Additional FLAIR EPI Data to Eliminate CSF Contamination Improving High-Field Transmit B1 Field Homogeneity Using Coupled Inner Elements Improving Image Quality for Single Echo Acquisitions (SEA): Introducing Two Novel Approaches Improving Myocardial Perfusion Imaging with B0- And B1-Insensitive Saturation RF Pulse at 3T Improving Quantitative Analysis of Gray and White Matters in Brain Magnetic Resonance Imaging Based on Coupling Independent Component Analysis with Support Vector Machines Improving Super-Resolution by Adopting Phase-Scrambling Fourier Imaging Improving the Diagnostic Accuracy of 3D Breast DCEMRI Data Using an Empirical Mathematical Model Improving the SNR of Stimulated Echo Acquisition Mode (STEAM) Cardiac Cines In Utero Fetal Brain Diffusion Weighted Imaging In Vitro and In Vivo Relaxation Times of N-Acetylaspartate, Creatine and Choline at 4.7T and 7T In Vivo 13C MRS Using Very Low RF Power for Proton Decoupling In Vivo 1H CSI in the Abdomen with Free-Breath Prospective Acquisition Correction In Vivo 1H MRS and Ex Vivo HR-MAS Metabolic Profile in Diffuse Liver Pathologies In Vivo and In Vitro 7T MR Elastography with Parallel Imaging In Vivo Application of Quantitative Mapping of Myelin Water Fraction Using T2* Decay In Vivo Assessment of Axonal Transport in Diabetic Mice Using Manganese-Enhanced MRI (MEMRI) In Vivo Assessment of Optic Nerve Degeneration in Glaucoma Rat Model Using Diffusion Tensor Imaging In Vivo Assessment of Renal Blood Flow and Volume in Rat Kidney by Using a Macromolecular MRI Contrast Agent In Vivo Brain 1H-MRS of Sodium Pentobarbital: A Potential Index Reflecting Anesthesia Depth and States of Brain Energy Metabolism and Activity In Vivo Brain 1H-MRS of Sodium Pentobarbital: Potential Contaminations to the Cerebral Metabolites Quantification In Vivo Brain Connectivity: Optimization of Manganese Enhanced MRI for Neuronal Tract Tracing In Vivo Cell Tracking Using Micron-Sized Iron Oxide Particle (MPIO) Labeling in Rat Model of Liver Tumor Metastasis In Vivo Cell Transfer Labeling of Dendritic Cells Using Feridex–labeled GM-CSF Tumor Vaccines for Evaluation of Immune Adjuvants In Vivo Characterization of Brain Phenotypes Associated with Two-Pore Domain K+ Channel (K2P) Gene Disruption In Vivo Characterization of the Pharmacokinetics of Perfluorocarbon Nanoparticles in a Mouse Model Using 19F MRS In Vivo Conductivity Measurement Using MRI Based Noise Tomography at 3T In Vivo Co-Registered Proton T1? and Sodium MRI of the Human Knee In Vivo Coronary Artery Imaging in Mice In Vivo Detection, Tracking and Quantitation of SPIO-Labeled Dendritic Cells in the Mouse Lymphatic System In Vivo Determination of Electric Conductivity and Permittivity Using "Electric Properties Tomography" (EPT) In Vivo Determination of the Rate of Cerebral Carbonic Anhydrase Reaction In Vivo Diffusion Kurtosis Imaging of Rat Brain In Vivo Diffusion Measurements of Hyperpolarized Helium-3 in Rat Lungs at Low Field: Time Dependence with a Fast Sequence In Vivo DNP-Enhanced 13C Labeled Acetate Brain Studies in a 9.4T Animal Scanner In Vivo DTI Study of Developmental Rat Brain In Vivo Editing of Glutathione Using Doubly Selective Hartmann-Hahn Match at High Magnetic Field In Vivo High Resolution Imaging of the Knee at 7T-Potential for MRI of Osteoarthritis In Vivo Identification of Iron-Marked Cells in the Heart by Gadolinium-Enhanced MRI in a Single Breath-Hold In Vivo Imaging of Myelin Development in Young Males Using T2 Relaxation In Vivo Imaging of Nicotine-Exposed Adult Male Zebra Finches In Vivo Labeling of Adult Neural Progenitors with Micron Sized Particles of Iron Oxide: Quantitation of Labeled Cell Type In Vivo Lipid Quantitation in Mouse Liver Using the Gradient Reversal Water-Fat Imaging Method In Vivo Localized Sensitivity Enhanced 13C MRS of [1,6-13C2]-Glucose Metabolism of an Intracerebral Glioma in Mice In Vivo Lung Morphometry with Hyperpolarized 3He MRI in a Mild COPD Population In Vivo Mapping of Functional Connectivity in Active Neurotransmitter Systems Using Pharmacological MRI In Vivo Measurement of Intramyocellular Lipids in Pre-Diabetic and Diabetic Female Zucker Diabetic Fatty Rats Using Magnetic Resonance Spectroscopy In Vivo Measurement of Iron Deficiency in Restless Legs Syndrome (RLS) with Voxel-Based R2 Relaxometry In Vivo Measurements of Brain Serine with 1H-MRS In Vivo Measurements of Tissue Transglutaminase Activity Using New Contrast Material for Magnetic Resonance Imaging In Vivo Metabolite Compartmentalization Probed Using Intracellular GdDTPA In Vivo Metabolite Differences Between the Basal Ganglia and Cerebellum of the Rat Brain Detected with Proton MRS at 3 T In Vivo Mitochondrial Function in Type 2 Diabetes Mellitus Patients Before and After Treatment with a PPARgamma Agonist In Vivo Molecular MRI of Mouse Embryonic Stem Cell Viability In Vivo Monitoring Therapeutic Response of NHL Xenograft by MRS and MRI In Vivo MR Diffusion Tensor Study of Bacteria Infiltration in Murine Tumor In Vivo MR Elastography of Liver and Brain Using Multi Frequent Shear Wave Excitation In Vivo MR Imaging of Human Glioblastoma Cell Derived Tumor by Using Anti MT1-MMP Antibody Conjugated Ultrasmall Superparamagnetic Iron Oxides (USPIOs) In Vivo MR Imaging of Mouse Lung Structure In Vivo MR Imaging of the Evolution of the Immune Response in Type 1 Diabetes Progression In Vivo MR Quantification of the Lipid-Rich Necrotic Core In Vivo MR T1? Relaxation Time in Bone Marrow Edema Overlying Cartilage in Knees with ACL Injuries In Vivo MR Velocimetry in Intracranial Aneurysms: Computational Fluid Dynamics Specification and Validation In Vivo MRI Investigation of Decreased Neuronal Transport with Aging and in Brains Expressing Alzheimer’s Pathology In Vivo MRI of Axonal Damage with Subtle Myelin Defects in PLP-Null Mice In Vivo MRI Quantification of Circumferential Wall Shear Stress Distribution at Atherosclerotic-Prone Sites in Mouse Abdominal Aorta In Vivo MRI Studies of Cardiac Morphology and Function in Transgenic Mice Overexpressing the Exon 22 Isoform of the Human Cav1.2a1C Channel In Vivo MRI Using Positive Contrast Techniques for Tracking of SPIO Labeled Cells In Vivo MRI/MRS of PTEN-Null Mice - An Animal Model of Hypermyelination In Vivo MR-Monitoring of Kidney and Renal Cyst Volume in Preclinical Mouse Model Under Therapy In Vivo MRS Markers of Response to Chemotherapy in a Relapsed Non-Hodgkin's Lymphoma Xenograft In Vivo Parallel RF Excitation with B0 Correction In Vivo pH Measurements by 31P MRS in Subcutaneous Melanoma Tumors in SCID Mice: Effect of Proton Pump Inhibitors In Vivo Proton Magnetic Resonance Spectroscopy of Human Adipose Tissue Fatty Acids: A Feasibility Study In Vivo Quantification of Lumbar Intervertebral Disc Degeneration Using Axial T2 Mapping In Vivo Single Voxel 1H MR Spectroscopy with Segmented 2D-Selective RF Excitations In Vivo Sodium Imaging of Rat Kidney at High Temporal and Spatial Resolutions In Vivo Sodium MRI Relaxometry of Normal and Pathological Mouse Liver at 4.7 T In Vivo T1? Mapping in Cartilage Using 3D Magnetization-Prepared Angle-Modulated Partitioned-K-Space Spoiled Gradient Echo Snapshots (3D MAPSS) In Vivo Tracking of Solitary Cells as a Tool for Comparing the Behaviour of Two Metastatically-Distinct Cell Lines in a Mouse Model of Breast Cancer Metastasis to the Brain In Vivo Visualization of Spinal Cord Injury in Experimental Mouse Model: A Feasibility Study on a Clinical 3.0 Tesla MR System Incidental Findings on Brain MRI in the General Middle-Aged and Elderly Population Incorporation of a Vascular Term Into a Reference Region Model for the Analysis of DCE-MRI Data Increased Brain Diffusion in the Genu of HIV Patients at One-Year Follow-Up Increased Brain Perfusion Following an Acute Dose of Alcohol Increased Cortical Anisotropy in Neonatal Meningitis-An Indicator of Meningeal Inflammation Increased Cortical Fractional Anisotropy Is a Marker of Infection in Meningitis Patients Associated with Brain Abscess Increased Detectability of Alpha Glutamate/Glutamine on Brain 1H-MRS in Neonatal Seizures Caused by Hypoxic-Ischemic Encephalopathy Increased Fractional Anisotropy in Cortical Lesions in Multiple Sclerosis Increased Interneuron Activity Is Associated with Ipsilateral fMRI Activation Following Forepaw Denervation Increased Sensitivity of 19F MR of Perfluoro-Emulsions Using Lanthanide Chelates for T1 Shortening Increased Splenic Stiffness: A Potential Indicator of Portal Hypertension Increasing Efficiency of Parallel Imaging by Using Information from Spatially Adjacent Slices Increasing the Sensitivity to BOLD Contrast in High Resolution fMRI Studies by Using 3D Spiral Technique Independent Component Analysis of fMRI Data - Assessing Reliability Independent Phase Modulation for Dual-Slab 3D Imaging Indication for Reduced Neuro-Functional Reserve and Connectivity in Patients with Subcortical Vascular Encephalopathy Indirect Detection of Phosphorus-31 Signals in Cells by 2D-Heteronuclear Methods Infarct Resorption and Functional Recovery After Reperfused First-Time Myocardial Infarction Infection with Plasmodium Berghei ANKA Leads to Brain Damage in Mice Resistant to Cerebral Malaria Inferring Evoked and Baseline Cerebral Blood Flow, Volume, and Oxygen Metabolism from Dynamic BOLD and ASL Measurements Inferring on Connections: A Bayesian Framework for Global Diffusion Tractography Influence of Anisotropic Conductivity Measured Using DTI on the EEG Forward Solution: A Whole Human Head Sensitivity Analysis Influence of Linear Steady Background Gradients on the Accuracy of Molecular Diffusion Anisotropy Evaluation Using MRI Influence of Microscopic Background Gradients on the Diffusion Parameters Observed in a Fiber Model System Influence of Mn2+ Concentration on Transport Rates Influence of Oxygen Administration on Pulmonary Vascular Resistance in Patients with Emphysema: Evaluation with Cine Phase Contrast MR Imaging Influence of Pulmonary Regurgitation Inequality on Differential Perfusion of the Lungs in Tetralogy of Fallot Post-Repair: A Phase-Contrast MRI and Perfusion Scintigraphy Study Influence of the Background-Handling Strategy on the Metabolite Concentration Estimates Influence of the Noise Floor: Paradoxical Effects on DTI Information Extraction from Ischemic Stroke MR Images Using Independent Component Analysis Technique Ingested Lipid Modulates Hypothalamic and Brainstem Neuronal Activity in Man: A phMRI Study Ingestion Versus Infusion: Contribution of Preabsorptive Mechanisms to the Hypothalamic Response to Glucose Inherent Smoothing in Accelerated Parallel Imaging Reconstruction Techniques Inhibition of ASK1 Enzymatic Activity Does Not Protect Heart from Angiotensin-II Induced Hypertrophy Inhomogeneous Magnetization Transfer Imaging of Myelin Concentration in Multiple Sclerosis Initial Analysis of Biventricular Cardiac Function in Preterm Neonates Using MR Imaging at 3.0T Initial Evaluation of Patients with Suspected Intracranial Aneurysms: Comparison of 3.0 Tesla Contrast-Enhanced MR Angiography and Multi-Slice CT Angiography Initial Experience with Isotropic 3D-FSE-XETA (eXtended Echo Train Acquisition) Imaging of the Cervical Spine Initial Measurements with an Ambulatory Static and Gradient Magnetic Field Dosimeter for Workers in MR Environments Initial Results from Diameter Dependence of Thoracic Aortic Hemodynamics Acquired by 4D Flow-Sensitive MRI at 3T Initial Testing of a Two Region Gradient Coil Injury to Corpus Callosum Development with Hypoxia: A Behavioral DTI Study on C57B/L6 Mice Insights Into the Dynamics of Hemodynamic Response to Millisecond Stimulus Duration: A fMRI and VEP Combination Study Instant Magnetic Labeling of Stem Cells Using Magnetosonoporation (MSP) Integrated Cluster Analysis of DTI and MRSI for Brain Tumors Integrated Environment for High-Throughput MR Histology of the Developing Mouse Integrated Local Correlation: A New Measure of Local Coherence in fMRI Data Integrated Low Noise Amplifier and Balun for MRI Receiver-On-Coils Integrated MRS and Neuropathological Analysis of Alzheimer Mouse Brain in Response to Anti-Inflammatory Treatment Integrated Parallel Imaging and rFOV Without Temporal Filtering Integrated RF Birdcage Head Coil* for 7T MRI Integrating PET or SPECT with MRI: How, Where, and Why? Integration of Magnetoencephalography and Q-Ball Tractography in the Visual Function Intensity Correction Using Eigen Modes of Channels Interactive MR Imaging Using Parallel Acquisition and Parallel Reconstruction Interactive One-Shot Spatially Resolved Real-Time Velocity Imaging Inter-Centre Agreement of Brain Atrophy Measurement in Multiple Sclerosis Patients Using Manually Edited SIENAX and SIENA Interclass Correlation Coefficient as a Measure of Drug Intervention in FMRI Interdependencies Among Resting-State Networks in Schizophrenia Using Independent Component Analysis Interest of a Contrast-Enhanced Imaging Sequence at 3 Minute Delay in 3T MRI for Acute Myocardial Infarct Evaluation Interhemispheric Transmission in Adults Prenatally Exposed to Alcohol Interleaved T1- And T2-Weighted Imaging Interleaved Narrow-Band Adiabatic Spatial-Spectral Pulse Sequence for 1H MRSI at 7T Internal Motions of Manduca Sexta Pupae Studied Using Magnetic Resonance Microscopy Interpatient Analysis of T2 and Thickness of the Human Patellar Cartilage with Hierarchical Clustering Intersubject Differences in the Effect of Acidosis on Phosphocreatine Recovery Kinetics After Exercise Are Due to Differences in Proton Efflux Rates Interventricular Mechanical Asynchrony in Pulmonary Arterial Hypertension: Right-To-Left Delay in Peak Shortening is Due to Right Ventricular Overload and Impairs Left Ventricular Filling Intra- And Inter-Observer Reproducibility of Meniscal Damage Scores at 3.0T: Using WORMS Intraarterial Perfusion to Monitor Endovascular Procedures in MR Intracellular Diffusion in Normal and Ischemic Rat Tissues via 133Cs MR at 12 T Intracellular pH After Perinatal Cerebral Hypoxia-Ischaemia Estimated from Nucleotide Triphosphate, Phosphoethanolamine, and Inorganic Phosphate Chemical Shifts Intracerebral Metastases Showing Restricted Diffusion: Correlation with Histologic Findings Intracoronary MR Imaging Using a Novel 0.014-Inch MRIG: Toward MRI-Guided Coronary Interventions Intracranial Time-Of-Flight MR Angiography at 7T with Comparison to 3T Intracranial Vascular Malformations: Tractography Reveals Motor Pathway Anatomy and Integrity Intra-Procedural Monitoring of Perfusion Changes in Targeted Fibroids and Surrounding Uterine Wall During Uterine Artery Embolization Intravascular Imaging of the Carotid Artery Using a Combined Stent and Imaging Catheter in a Porcine Model Intrinsic Accuracy of Myocardial T1 Quantification with Modified Look-Locker Inversion Recovery (MOLLI) Intrinsic Signal Amplification in 2D SENSE Elliptical Centric 3D Contrast-Enhanced MRA Introducing Auto-Calibrated Parallel Imaging GRAPPA to 3D Axial Continuously Moving Table Whole-Body MRI In-Utero 3D High Resolution Fetal Brain Diffusion Tensor Imaging Inversion Recovery Echo Planar and Spin Echo MR Imaging in Assessment of the Kinetics of a New MR Contrast Medium (P846) in Ischemically Injured Myocardium Inversion Recovery-Prepared SSFP for Cardiac-Phase-Resolved Delayed Enhancement Imaging Inverted Double Half RF Pulse for Long T2 Suppression in Ultrashort Echo-Time Imaging Investigating Absolute Quantification in MR Perfusion Studies Investigating Binocular Rivalry Using Quantitative fMRI Investigating fMRI and fNIRS Signal with Balloon Model During Breath Hold Task Investigating GSD Type III Patients with Multi-Parametric Functional NMR Imaging and Spectroscopy Investigating Structural Abnormalities in Adolescent-Onset Schizophrenic Patients: A Combined T1-Weighted and Diffusion-Weighted Study Investigating the Influence of Anesthesia on Resting State Connectivity in Rats Using Multiple Analysis Techniques Investigating the Structural Integrity of Brain Tissue in Intermittent Explosive Disorder: A Turboprop-DTI and Voxel-Based Morphometry Study Investigating the Subendocardial Dark Rim Artefact in First-Pass Myocardial Perfusion Investigating Water Exchange Across the BBB as a Mechanism for the Slow Time Constant of Blood Volume Investigating White Matter Changes in Amyotrophic Lateral Sclerosis Using High-Dimensional Deformable Diffusion-Tensor Image Registration Investigating Williams Syndrome with Diffusion Tensor Imaging Investigation by Means of Absolute Quantification of Proton MR Spectroscopy in Adolescent with Attention-Deficit/Hyperactive Disorder Investigation of a Carcinoma-Specific SPIO-Antibody Conjugate for MR Visualisation of Epithelial Tumours Investigation of a Dual Thresholding Scheme in fMRI Using ROC Methods with Real Data Investigation of an Aerobic Exercise Effect on the Peripheral Blood Flow in the Visualization of Nonenhanced Fresh Blood Imaging (FBI) Investigation of BOLD Adaptation to Hand Tapping in Healthy Controls and Patients with MS Investigation of Distortion-Correction Procedures for a Double Inversion-Recovery Sequence with an Echo-Planar Imaging Readout Investigation of Dynamic Range Requirement for MRI Signal Transmission by Optical Fiber Link Investigation of Efficacy of Depicting Deep Vein Thrombus (DVT) Using Diffusion-Weighted Imaging (DWI) and Fresh Blood Imaging (FBI) Venography Investigation of Long-Term Neurotoxicity of Irradiation and Chemotherapy by Diffusion Tensor Imaging and H-1 MR Spectroscopy in Children with Medulloblastoma and Pilocytic Astrocytoma Investigation of Metabolite Changes in Neonatal Rat Brain After Cerebral Hypoxia-Ischemia Using 1H-Spectroscopy at 9.4T Investigation of Partial Volume Effects in fMRI Using Artificial 3D Time Series Investigation of SNR for DTI with Human Articular Cartilage at 17.6 Tesla Investigation of Temperature Dependent Phase Shift in Frozen Tissues During Cryoablation Investigation of the Impact of Noise on Standard Fibre Tracking Algorithms Investigation on RF Heating of Standard Implants in a Gel Phantom During MRI with a 1.5 T MR System (GE Medical Systems) Investigations of a DTI-Phantom with Properties Similar to In Vivo Neuronal Tissue In-Vivo Classification of Trabecular Bone Rods and Plates Via Local Inertial Anisotropy (LIA) In-Vivo Dental Impression Using MRI In-Vivo Detection of Human Brain GABA* in Frontal Cortex, Thalamus and Hippocampus by J-Difference Spectroscopy at 3T In-Vivo Evaluation of Cartilage Repair Using Steady-State Diffusion Weighted Imaging In-Vivo Proton HRMAS Detects Effects of Trauma in Drosophila Melanogaster In-Vivo Quantification of Turbulent Velocity Fluctuations In-Vivo Serial Assessment of Aortic Aneurysm Formation in Mouse In-Vivo Trabecular Bone Imaging at 7 Tesla In-Vivo, Human Diffusion Tensor Imaging at 7T: First Results Iron in Basal Ganglia Causes Weak Reproducibility of T2-Weighted Images at 3.0 Tesla Iron Oxide Enhancing Atherosclerotic Plaque: Feasibility of White Marker Imaging Techniques Iron Oxide Incorporation for Cell Tracking Does Not Prevent Osteogenic, Chondrogenic or Adipogenic Differentiation of Mesenchymal Stem Cells But Does Affect Extracellular Matrix Patterns and Gene Expression Iron Oxide Labeling of Primary Rat Monocytes Using Magneto Electroporation Iron-Labeled Neural Stem Cell Homing After Neonatal Hypoxia-Ischemia Is a Progressive Increase in the Number of Microhemorrhages in the Aged an Earlier Sign of Alzheimer’s Disease? Is Cognitive Decline Associated with Progression of White Matter Hyperintensities in Normal Ageing? A Longitudinal Brain MRI Study in the 1921 Aberdeen Birth Cohort Is Diffusion-Weighted Imaging Helpful for Detection of Small Hepatocelluar Carcinoma in Cirrhosis or Chronic Hepatitis: Preliminary Quantitative Study at 3-T Is Glutamate or Glutamine Elevated Following Traumatic Brain Injury? Is HYPR Compatible with a Cartesian Acquisition? Is Pre-Optimization of DTI Data Necessary for Correct Interpretation of Group Differences of Regional Fractional Anisotropy? Is PWI-DWI Mismatch Region Equal to Ischemic Penumbra: Experimental Study in Monkey Middle Cerebral Artery Occlusion (MCAO) Model Is Spending Extra Scan Time on Measuring a `Macromolecules-Only' Signal Worthwhile? Is Sub-Pixel Registration Necessary for Continuously Moving Table MRI? Is the Diffusion Biexponential in Brain Grey Matter? Is the Ventouse Responsible for Subdural and Extra Cranial Neonatal Hemorrhages? Isotropic MRI of the Knee at 1.5T with 3D-FSE-XETA (Extended Echo Train Acquisition) It Is Not Possible to Design a Rotationally Invariant Sampling Scheme for DT-MRI Iterative Back-Projection Reconstruction for Radial SENSE Iterative Fourier Transform Magnetic Resonance Current Density Imaging (FT-MR-CDI) Iterative GRAPPA (iGRAPPA) for Improved Parallel Imaging Reconstruction Iterative GRAPPA: A General Solution for the GRAPPA Reconstruction from Arbitrary K-Space Sampling Iterative Highly Constrained Back Projection (HYPR) Reconstruction of Undersampled Diffusion Weighted Data in Hyperpolarized Helium-3 MRI Iterative Reconstruction for SMART Imaging Iterative Reconstruction of Time-Resolved Projection Images Using Highly Constrained Back Projection Iterative Segmentation Optimization for Model-Based Detection of fMRI Activation J Coupling Effects on Signal Modulation at Very High Fields Joint Activation of the SMA and Pre-SMA During Simultaneous Motor and Language Tasks: A Functional MRI Study Joint Design of Trajectory and RF Pulses for Parallel Excitation Joint Image Reconstruction and Sensitivity Estimation in Spiral SENSE Karhunen-Loeve Transform Filter to Improve Signal to Noise Ratio in Dynamic Cardiac Imaging Kidney and Renal Cysts Volume Calculation Based on MR Data: A Reproducibility Study with ADPKD Patients Kinematic MR Imaging Using 3D FIESTA and Diffusion Tensor Imaging on an Open-Type MR Scanner Kinetic Data from Cellular Assay Using Hyperpolarized 13C-DNP-NMR Kinetic Modeling of Hyperpolarized 13C1-Pyruvate Metabolism Using Dynamic Magnetic Resonance Spectroscopy Kinetic Parameter Estimation of Independent Components Derived from Simulated Dynamic Contrast Enhanced Breast MRI Data Kissing or Crossing: Validation of DTI Tractography in Ground Truth Hardware Phantoms k-Space Based Multicoil Phase Correction and Reconstruction for Multishot Diffusion Weighted Imaging k-Space Sample Density Compensation Via Basis Function Cross-Correlations, with Application to the Design of 2D RF Excitations K-Space Trajectory Estimation in Spiral Imaging Lactate and Alanine as Metabolic Biomarkers for Prostate Cancer in TRUS- Guided Biopsies Measured by 1H HR-MAS Spectroscopy Lactate Detection for Gliomas Patients Using Lactate-Edited 3D 1H MR Spectroscopic Imaging with Flyback Echo-Planar Readout Gradient at 3T Lactate/Creatine Ratio Tracks with HIF-1 Alpha Accumulation in High-Grade Astrocytoma Cells Laminar Analysis of the BOLD Effect in Human Visual Cortex: Effect of Extracortical Veins Laminar Specific MEMRI Enhancement of the Rat Spinal Cord In Vivo Lamina-Specific Anatomical and Functional Imaging of Retinal Degeneration Landmark-Based Assessment of Human Lung Motion Analysis Via Registration of Sagittal 2-D MR Images Late Enhancement in Non-Ischemic Myocardial Disease – Specific Patterns of Late Enhancement in Contrast-Enhanced Cardiac MRI Help to Characterize Different Etiologies Late Enhancement of the Left Ventricular Myocardium in Patients with Aortic Valve Stenosis and Left Ventricular Hypertrophy LAVA Dual Echo with Water Reconstruction: Preliminary Experience with a Novel Pulse Sequence for Gadolinium-Enhanced Abdominal MR Imaging Lead Exposed Encephalopathy: Evaluation by 1H Spectroscopy of a 3T MR Scanner Learning Effects of Neurofeedback-fMRI on Neural Substrates Involved in Motor Imagery Left Temporal White Matter Integrity Predicts Verbal Memory in Older Children Left Ventricular Shape, Myocardial and Intracavitary Volume Alteration After Surgical Ventricular Restoration: Effect on Left Ventricular Contractility Left-Right Differences in 1H2O T1 Values of Multiple Sclerosis Normal Appearing Brain Tissue Lesion Characterization in Breast Imaging: VIPR-SSFP Versus FSE Less Wiggle Room at High-Field: A Segmented Birdcage-Like Example with Excellent Planar Uniformity Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated White Matter Lactate (LBSL). Serial Proton MRS and DTI of a Child Over a Period of 6 Years Limbic Morphometry Correlates of Mood Disoders in Traumatic Brain Injury Limited Default Network in Bipolar Disorder by BOLD-Based fMRI Limits on Measuring Axon Diameters In Vivo Using Diffusion MRI Linear Off-Resonance Correction for Partial-K-Space 3D Spiral Imaging Linear Predictive Modeling of Patient Motion Using External Sensors Linearity of the BOLD Response: A Comparison Between fMRI and MEG Liver Diseases Diagnosis: The Role of Contrast-Enhanced MR Venoportography Liver Imaging Using T2-Weighted BLADE with Parallel Imaging and Through-Plane Motion Correction at 3T Local B1 Shimming for Imaging the Prostate at 7 Tesla Local Arterial Input Function in Bolus Tracking Using Data Defined Vascular Territories Local Volumetric Analysis of the Brain Ventricles in Alzheimer's Disease Using MRI Localization of Perfusion Water Signal in ASL and VASO Techniques Localized Constant-Time Correlated Spectroscopy (LCT-COSY) of Human Muscle Using a Clinical 3T MRI Scanner Localized Exchange Spectroscopy of Muscle at 3T Localized H1-MRS of the Human Frontal White Matter at 3 T: Metabolite Concentrations and Relaxation Times Localized Inter-Subject Comparison of Knee Cartilage Thickness, T2 and T1?: Generating an Atlas of the Knee Localized Parallel Echo Volume Imaging at 1.5 T: A First Extensive fMRI Study Localized Quantification of Geometry, Hemodynamics, and Histology in a Rat Model of Abdominal Aortic Aneurysm Long Diffusion Time Improves DTI Tractography Longitudinal 2D Stresses in Carotid Plaques Using MRI-Based Fluid Structure Interaction Models Longitudinal and Cross-Sectional Measurements of Intra-Hepatic Lipid Levels in Mouse Via Localized 1H MRS Longitudinal Changes in Amyotrophic Lateral Sclerosis Detected by Diffusion Tensor Imaging and MR Spectroscopy Longitudinal Changes in the Heterogeneity of Cartilage T2 in Osteoarthritis Subjects Longitudinal Detection of Neuronal Stem Cells Labeled with Two Types of Iron Oxide Particles Longitudinal Diffusion-Weighted MRI Study of the Tumor Tissue Destruction Process Induced by Novel Attenuated Salmonella Typhimurium Expressing Protein Drugs Longitudinal fMRI and DTI Study of Brain Development in Preterm Newborns Longitudinal Helium-3 and Proton Imaging of Magnetite Biodistribution in a Rat Model of Instilled Nanoparticles Longitudinal Lactate 2D-MR Spectroscopic Imaging and DCE-MRI Studies in Prostate Tumors to Assess Tumor Hypoxia and Vasculature Longitudinal Monitoring of Brain Changes in Canines Immunized with Fibrillar or Oligomeric Beta-Amyloid Longitudinal Monitoring of Vascular Normalization with MRI Perfusion Imaging of 9L Gliosarcoma Tumor Longitudinal MRI Evaluations of Lung Inflammation within Cystic Fibrosis Mouse Models Longitudinal MRI of Spinal Cord Injury in Mouse: Changes in Signal Patterns Associated with the Inflammatory Response Longitudinal Short Echo Time Proton Magnetic Resonance Spectroscopy as a Biomarker in Patients with Inherited Prion Diseases Longitudinal T2 Relaxation Times Following Treatment for Juvenile Idiopathic Arthritis Longitudinal Tracking of Recipient Macrophages in Chronic Cardiac Rejection with Non-Invasive In Vivo MRI Using Micrometer-Sized Paramagnetic Iron Oxide (MPIO) Particles Looking for T/R Coils with Long Field of View for 7T Head Imaging Lorazepam Effects on Brain Activity Pattern Related to Cholecystokinin Tetrapeptide (CCK-4)-Induced Panic Attack Lorentz Effect Imaging of Ionic Currents in Solution Low B-Value Diffusion-Weighted Imaging and Echo Planar T2-Weighted Imaging in Assessment of Hepatic Metastases from Neuroendocrine Tumors Low Latency Interventional MRI Visualization Using a GPU Cluster Low Noise Preamplifier with Integrated Cable Trap Lower Glutamate Levels in the Anterior Cingulate Cortex of Chronic Cocaine Users: A Proton MRS Study Using TE-Averaged PRESS at 3T with a Modified Glutamate Quantification Strategy Low-Frequency Fluctuations in the Cardiac Rate Contribute to Variance in the Resting-State fMRI BOLD Signal Low-Frequency RF Coil Loading Measurements to Guide Field-Cycled MRI System Design LOW-TIDE: Linear Filter Based Optimal Window Transition to Driven Equilibrium for B-SSFP Sequences L-Tetrahydropalmatine Administration Induces Region-Specific BOLD Responses in the Mesocortical Limbic Network of the Human Brain MADNESS: Magic Angle Diffusion Employing the Steady State Magic Angle Spinning MRS to Evaluate Cardiac Preservation Prior to Transplantation Magnesium (Mg) and ATP Abnormalities Correlate with Weakness in Chronic Alcoholic Myopathy Magnetic and MR Relaxation Properties of Avidin-Biotin Conjugated Superparamagnetic Nanoparticles Magnetic Field Distribution and Signal Decay in fMRI Using the Dipole Model and Monte Carlo Diffusion Modeling Magnetic Field Strength Dependence of S-PRESS Signal Modulation in Glutathione Magnetic Resonance Acoustic Radiation Force Imaging (MR-ARFI) Magnetic Resonance Angiography (MRA) of the Lower Extremities with Parallel Imaging (PI): Comparison of Different PI Acceleration Factors and Different Coils at 3.0 Tesla Magnetic Resonance Diffusion Tensor Imaging and 1H Magnetic Resonance Spectroscopy in Ischemic Penumbra Magnetic Resonance Electrical Impedance Tomography Using Biologically Safe Injected Current Levels Magnetic Resonance Image Classification Via Over-Complete Independent Component Analysis and Active Support Vector Machines Magnetic Resonance Imaging and Spectroscopy for Measuring Hepatic Steatosis Magnetic Resonance Imaging Characteristics of Hepatocellular Carcinoma After High-Intensity Focused Ultrasound Ablation Magnetic Resonance Imaging Comparison of Arthroscopic and Open Repair of Triangular Fibrocartilage Complex Tears of the Wrist Magnetic Resonance Imaging of Delivery Multifunctional Liposomes with Novel Peptide Ligand Targeted to Breast Cancer Vasculature Magnetic Resonance Imaging of Fractures of the Tibia Using Ultrashort TE Pulse Sequences: A Feasibility Study Magnetic Resonance Imaging of Pancreatic Inflammation in Type 1 Diabetes Magnetic Resonance Imaging of the Post Mortem Fetus - An Important Adjunct to the Autopsy Magnetic Resonance Imaging of the Progression of Systolic and Diastolic Dysfunction in Transgenic Tgaq*44 Mice In Vivo Magnetic Resonance Imaging to Optimize Boron-Neutron Capture Therapy: In Vivo Studies on a Murine Tumor Model Magnetic Resonance Microimaging of Adult Zebrafish Brain Using Cryoprobe Technology Magnetic Resonance Microscopy of Discreet Microstructures in 5µm-Isotropic Images of the Excised Rat Striatum Magnetic Resonance Microscopy of Ex Vivo Mouse Brains: Contrast and Structure Magnetic Resonance Spectoroscopic (MRS) Analysis of the Osteonecrotic Intercalated Bone Magnetic Resonance Spectroscopy on Cardiac Tissue in a Canine Heart Transplant Model Magnetically Labeled Sensitized Splenocytes to Identify Glioma by MRI Magnetically Labeled Transgenic Endothelial Progenitor and Dendritic Cells as Probes for Cellular MRI and Gene Delivery Vehicles Magnetisation Transfer Ratio (MTR) of Basal Ganglia in Primary Biliary Cirrhosis (PBC) Patients: Correlation with Fatigue Impact Score and Age Magnetization Exchange (MEX) MRI: A Clinically Viable Protein-Based Imaging Method Magnetization Transfer and T2 Measurements of Isolated Muscle: Effect of pH Magnetization Transfer Based Contrast for Human Atherosclerotic Plaque Characterization Magnetization Transfer Contrast in Mri as a Diagnostic and Monitoring Tool for Muscular Dystrophy Magnetization-Prepared Imaging Using a Concentric Rings Trajectory Magnetofection Accelerates the Loading of SPIO Nanoparticles for MRI Cell Tracking Magnitude-Weighted Complex-Sum SSFP Major Speed-Up of Nyquist Ghost Correction in Ramp-Sampled EPI Manganese Enhanced MP-RAGE Abdominal MRI Manganese Enhanced MRI Enables Identification of Individual Glomeruli in the Olfactory Bulb Manganese Enhanced MRI of Olfactory Pathway in Developing Rats Manganese Guided Cellular MRI of Human Embryonic Stem Cell Viability Manganese Oxide (MnO) Nanoparticles as a New T1 Contrast Agent for MRI Manganese-Enhanced and Diffusion Spectrum MRI of Hippocampal Cytoarchitecture in Epileptic Rats Manganese-Enhanced MRI (MEMRI) and Diffusion-Weighted MRI Mismatch in the Absence of a Specific Neuronal Stimulus Manganese-Enhanced MRI Detects Distinct Patterns of Neuronal Activation Following Anorexigenic Gut Hormone Administration Manganese-Enhanced MRI of Acute Cardiac Ischemia and Chronic Infarction in Pig Hearts Manganese-Enhanced MRI of Axon Regeneration by Peptide Nanofiber Scaffold Induction Manganese-Enhanced MRI of Severe Hypoxic-Ischemic Injuries in Neonatal Rat Model Manganese-Enhanced MRI Reveals Multiple Cellular and Vascular Layers in Normal and Degenerated Retinas Mapping 2D Strain in the Wall of the Carotid Artery Using Displacement-Encoded MRI Mapping BOLD Sensitivity to CO2 in the Human Brainstem Mapping Concentration and Pressure Dependent Transfer Constants in Tumors by Slow Infusion DCE-MRI Mapping Functional Brain Plasticity Following Spinal Cord Injury in Rats: A Combined fMRI and MEMRI Study Mapping Human Pulmonary Oxygen Partial Pressure in Supine and Vertical Orientations: Initial Results Mapping Mossy Fiber Sprouting in Epileptic Rat Hippocampus with Diffusion Spectrum Magnetic Resonance Imaging Mapping of Task-Relevant Activation in Human Posterior Parietal Cortex for Processing Spatial and Non-Spatial Stimulus Characteristics Mapping Relative Fiber Density with Composite Q-Ball and Diffusion Tensor Imaging Mapping Single Digit Cortical Representation in the Rat Using Systematic Nerve Transection and fMRI at 9.4T Mapping T2 Relaxation Time of Cerebral Metabolites Using Proton-Echo Planar Spectroscopic Imaging (PEPSI) Mapping the Plasticity of the Striatonigral Pathway in a Transgenic Mice Model Using MEMRI Maximum Likelihood Estimation of Diffusion Parameters with a Rician Noise Model Maximum Likelihood Estimation of T1 Relaxation Parameters Using VARPRO MDT Based Fiber Tracking in Complex Crossing Regions by Using a Spatial Point Process Measurement of Breast Prosthesis Contour Irregularities Measurement of Cerebral Blood Volume Using Hyperoxic Contrast Measurement of Citrate Chemical Shift Changes in HR-MAS NMR Spectra of Prostate Biopsies Measurement of Deep Gray Matter Perfusion Using a Segmented True FISP ASL Method at 3T Measurement of Filtration Fraction Using 2D Look-Locker Technique in Humans at 3.0T Measurement of Hyperpolarized Gas Diffusion at Very Short Time Scales Measurement of Intrinsic Fiber Diffusivity Using Spherical Deconvolution of High Angular Resolution Diffusion Data Measurement of Pulse Wave Velocity in the Aortic Arch by Tracking the Velocity Peak Measurement of Skeletal Muscle Perfusion at Rest and Its Change After Exercise Using Arterial Spin-Labelling Measurement of T1 and T2 in the Cervical Spinal Cord at 3 Tesla Measurement of the Diffusion of Hyperpolarized 3He in Human Lungs Over Short and Long Time Scales During One Breath Hold Measurement of the GABA/Glutamine Cycling Rate in the Human Brain Using 13C MRS Measurement of Visual Evoked Potential During and Following Exposure to Switched Magnetic Fields Measurements of Diastolic Function in Rats Using High Resolution Cine-MRI Measurements of Hyperpolarized He-3 T2* and ADC in the Lungs Using Multi-Echo VIPR Measurements of Relaxation Times of Human Fetus Fixed Tissues at 1.0 T Measurements of T2 Relaxation of J-Coupled Metabolites in the Human Brain at 4 Tesla Measuring Epilepsy Networks: Combining Simultaneous fMRI/EEG and Functional Connectivity Measuring Human Gastrocnemius Pennation Angle Utlizing Most Likely Pathway Distributions in Diffusion Tensor Imaging Measuring Intra- And Extra- Cellular ADC in Edematous Skeletal Muscle Measuring Medium- And Long-Time-Scale Regional 3He Diffusion Using Stimulated Echoes Measuring the Glutamate-Glutamine Cycle Rate in the Brain: Simulated Comparison Between [1-13C]glucose and [2-13C]acetate Measuring the System Noise Figure (Coil Inclusive) of an MRI System Measuring Through Plane Strain in Brain Using Strain-Encoding (SENC) MRI Measuring Variability in the BOLD Response to Interictal Epileptiform Discharges: An EEG/fMRI Study MEDUSA: A Scalable MR Console for Parallel Imaging MEMRI for In Vivo Imaging of the Embryonic Mouse Nervous System MEMRI Provides Morphological Correlate of Functional Deficits Observed by fMRI in Experimental Stroke MEMRI Reveals Functional Alterations in the Auditory Midbrain of Fgf17 Knockout Mice MEMRI Reveals Plasticity Changes in the Auditory Midbrains of Mice After Two-Tone Rearing Meta-Analysis of fMRI Activation Associated with Response Inhibition During Performance of Go/Nogo Tasks Metabolic Abnormality in Early Multiple Sclerosis Observed by Proton MRS Metabolic Alteration of the Dorsolateral Prefrontal Cortex in Depressed Sprague-Dawley Rats by In Vivo Proton MR Spectroscopy Metabolic Alterations in Exercising Muscle of Patients with Becker Muscular Dystophy Assessed by 31P MRS Metabolic and Bioenergetic Changes in the Livers of Living Mice During Acute Anti-Fas Induced Apoptosis Metabolic Changes Detected by Proton Magnetic Resonance Spectroscopy In Vivo and In Vitro in a Murin Model of Parkinson’S Disease, the MPTP-Intoxicated Mouse Metabolic Characterization of Muscular Dystrophy, Inflammatory and Mitochondrial Myopathy Using in Vitro MRS Metabolic Characterization of Patients with Alcohol and Non-Alcoholic Steatohepatitis Metabolic Fingerprints of Altered Brain Growth in a Rett Syndrome Mouse Model : A 31P and 1H MRS Study of Tissue Extracts Metabolic Magnetic Resonance Progression Markers of Neurodegeneration in the Transgenic G93A-SOD1 Mouse Model of Amyotrophic Lateral Sclerosis Metabolic Networks in Temporal Lobe Epilepsy Metabolism of Glutathione in Tumour Cells Before and After Irradiation as Evidenced by 1H MR Spectra Metabolite Analysis of Preinvasive and Invasive Cervical Cancer Tissues Using 1H and 31P HR-MAS Spectroscopy Metabolite Profile Analysis of Childhood Brain Tumours Using Quantitative In Vivo 1H Magnetic Resonance Spectroscopy Metabolite Profiling Using 1H-HRMAS NMR Spectroscopy of the Response to Methionine Stress in a Malignant Melanoma Model Metabolomic Analysis of Ex-Vivo 1H MRS Profiles from Experimental Tumours Metabolomic Imaging Metabolomic Study of AKT Activation Method for Cardiac Localization in Multiple Mouse MRI Method for Electronically Setting Transmit Gain for Non-1H Imaging and Spectroscopy Methodology for Optimal Quantitative Flow Analysis by Planar Analysis of CINE Phase Contrast 2D or 3D MR Data Methodology for Rapid Cardiac Axis Generation from Non Gated Cardiac MR Images Methodology for Sub-Millimeter Resolution fMRI in Awake Monkeys at 7T Methods for Robust Quantification of Trabecular Bone Parameters from Highly Accelerated In Vivo MR Images Obtained by GRAPPA Based Techniques at 3 Tesla and 7 Tesla Microcapsules Used in Cell Based Therapy Were Designed for Post Implantation Tracking Microstructural Analysis of Foam-Like Structures by Use of R2 Dispersion Microstructure in Subcortical White Matter in Individual Cortical Regions: Age-Related Changes After Adolescence Migration of SPIO Labled EPCs and Angiogenic Factors Mild Fetal Cerebral Ventriculomegaly:association with Corpus Callosum Miniature Optical Signal Transmission System for an Active Intravascular Device Minimize the Power of Variable-Rate Gradient Pulse Using Conjugated Gradient Algorithm Minimizing BOLD Contamination in VASO fMRI with SE-EPI Minimum Norm Parallel Transmit Pulse Design Mitigation of Physiological Noise in the fMRI Time-Series by CSF Nulling Mixed-CPMG Radial-FSE for Diffusion Imaging at 3T Mixed-TSE with Reduced Flip Angle TSE Readouts: Quantitative MRI Accuracy and SNR Vs. Specific Absorption Rate (SAR) M-Mode Echocardiography Over-Estimates Left Ventricular Mass Compared with Magnetic Resonance Imaging Model Comparison and Reproducibility Test of DCE-MRI in Glioblastoma Patients Model Independent Correction of Complex Intensity Inhomogeneities Model-Based Bootstrap Resampling Methods for HARDI: Quantitation of ODF Uncertainty Without Multiple Acquisitions Model-Free Arterial Spin Labelling CBF Quantification Using Regional Arterial Input Functions Identified by Factor Analysis Modeling and Evaluation of Resistive Magnet Thermal Performance in Field-Cycled MRI Modeling Dopamine Dynamics Using Combined Microdialysis and MRI Measurements. Modeling Loaded RF Coils Using the Method of Moments Modeling Pulsed Magnetization Transfer Modelling BOLD Response in Auditory Cortex with Baloon Hemodynamic Model Modelling Diffusion Data Using a Stretched-Exponential Model : Pitfalls in Estimation Methodology Modelling Large Head Motion Events in fMRI Studies of Patients with Epilepsy Modelling Regulatory Compliance of Occupationally Exposed MRI Workers During Gradient Pulsing Modelling the Bolus Dispersion from DSC-MRI Data Modulation of Pi Flux by Short Term Exercise Modulation of the Functional Cerebral Blood Flow Response by Reductions in Baseline Blood Flow Modulation of the Inverse Functional Relation of Resting and Working Memory Networks Molecular Imaging of Collagenous Scar Tissue in Chronic Myocardial Infarction Using a Targeted MR Contrast Agent Molecular Imaging of Endothelial Activation in Acute Stroke Using a Targeted Iron Oxide Nanoparticle Contrast Agent Molecular Imaging of Lentiviral-Mediated Silencing of Choline Kinase as Gene Therapy in a Human Breast Cancer Xenograft Molecular Imaging of Macrophages in Atherosclerotic Plaques Using Bimodal PEG-Micelles Molecular Magnetic Resonance Imaging (MRI) of Surface-Epithelial-Derived Protein CA125 in Human Ovarian Carcinoma Cells Using Superparamagnetic Immunomicelles Molecular Markers and DCEMRI of Breast Cancer: Relationship with Kinetics in Invasive Ductal Carcinoma Molecular MRI of Myeloperoxidase Activity in Experimental Atherosclerosis Using a Novel Paramagnetic “Smart” Contrast Agent Molecular MRI of Thrombosis Using Novel Fibrin-Specific Contrast Agent: Initial Results in Humans at 3.0 T Molecular Signatures of Disease Treatment Efficacy: The Potential of Molecular Imaging in Assessing Therapeutic Interventions Monitoring Brain Dimpling and Intracortical Micro-Electrode Arrays with High Resolution MRI in Rats Monitoring of Glycogen Synthesis in Liver of Diabetic Patients Using 13C-MR Spectroscopy Monitoring of Liver Tumor Response to Treatment by MRI Monitoring of the Consistency of Brain Activation by Using a Dynamic Analysis of T-Statistics - An Application to Conventional Mapping of the Motor Areas Monitoring of Therapeutic Response of Tumor in Locally Advanced Breast Cancer by Diffusion Weighted MRI Monitoring Prostate Cancer Progression in a Transgenic Murine Model Using 3T Hyperpolarized 13C MRSI Monitoring Prostate Thermal Therapy with Diffusion-Weighted MRI Monitoring Stem Cell Therapies of Spinal Cord Injury Using Quantitative T2 Relaxation Monitoring the Fate of Iron-Labeled Metastatic Melanoma Cells within the Mouse Lymphatic System Monitoring the Role and Metabolism of 13C-Hyperpolarized Steroids and Nonsteroidal Anti-Inflammatory Drugs Via Parahydrogen-Enhanced MRI Monitoring Treatment Effects in Transgenic Mouse Model of Alzheimer’s Disease Using MRMI Monitoring Tumor Microvasculature Development in a Rodent Model of Human GBM Using DCE-MRI More Optimal HYPR Reconstructions Using a Combination of HYPR and Conjugate-Gradient Minimization Morphing-SSFP: A New Method for Fast Detection of Strong Magnetic Field Inhomogeneities and Its Application for Tracking Ferromagnetic Devices Morphological Difference Between In Vivo and Ex Vivo Adult C57BL/6J Mouse Brain by Magnetic Resonance Microscopy Morphological Differences in the Grey Matters of Mathematicians: A Voxel-Based Morphometry Study Morphometry of the Retrobulbar Human Optic Nerve: Comparison of 3T MRI with Conventional Sonography Motility of the Small Bowel: Comparison of Spasmolysis with Hyoscine Versus Glucagon Motion Artifact Correction in Cardiac MRI as an Irregularly Sampled Parallel Imaging Reconstruction Motion Artifact Removal in J-Difference Editing -- Is Phase Correction of Individual Acquisitions Enough? Motion Artifacts for Diffusion Spectrum Imaging Motion Compensated Catheter Tracking Motion Correction for 19F Radial MRI Based on a Simultaneous Proton Signal Motion Correction Technique for Segmented Acquisition Using Parallel Imaging Reconstruction and Image Based Correlation Motion Estimation for PROPELLER MRI Using Image-Based Registration Motion Insensitive 3D Imaging Using a Novel Real-Time Image-Based 3D PROspective MOtion Correction Method (3D PROMO) Motion-Tracked Imaging of the Aortic Valve with Super-Resolution Enhancement Motor Plasticity: An Investigation Using Functional MRI and Structural Equation Modeling Motor Representations of Well-Practiced Handwriting Versus Novel Motor Sequences of Graphomoto Output: An fMRI Study MP-RAGE Techniques for Imaging the Mouse Abdomen at 9.4T MR Angiography Detects Cerebral Amyloid Angiopathy (CAA) Associated with Alterations of Cerebral Blood Flow in Thalamic Vessels of APP23 Mice Modelling Alzheimer’s Disease MR Angiography in Rabbits: Comparison of a New Blood Pool Contrast Agent with Dotarem® MR Angiography of the Supraaortic Arteries: A Methodical Update MR Arthrography in Patients with Shoulder Instability: Cartilage Loss Associated with Labral Tears and Bone Marrow Edema MR Assessment of Arterial Distribution Territories Prior to and Following Embolization of Meningiomas MR Assessment of Multi-Modal Targeted Contrast Agent MR Based Radiation Therapy Treatment Planning on an Avanto/TIM System MR Bone Atlases for Shape Characterization MR Characterization of an Experimental Invasive GBM Model MR Cholangiopancreatography at 3.0 T: Intraindividual Comparative Study with MR Cholangiopancreatography at 1.5 T MR Colonography at 3T Using 1D- And 2D- Accelerated Autocalibrated Parallel Imaging MR Contrast Agent Coupled to an Antisense Peptide Nucleic Acid - Cell Penetrating Peptide Conjugate MR Detection of Spinal Axonal Degeneration in a Mouse Model of Amyotrophic Lateral Sclerosis MR Determination of Flow Fields in Patient-Specific Models of Intracranial Aneurysms Using 7D PC-MRI MR Determined Metabolic Phenotype - A Possible Tool for Prediction of Long Term Survival in Breast Cancer Patients? MR Diffusion Microscopy of the Mouse Pup Heart: Visualization of Myocardial Fiber Reorganization in Congenital Heart Disease Models MR Doppler of High-Speed Jets MR Elastography in the Liver at 3T Using a 2nd Harmonic Approach MR Elastography of the Eye: Initial Feasibility MR Feature Analysis and Classification of Renal Masses with Pathologic Correlation MR Findings of Acute Gangrenous Cholecystitis MR Fluoroscopy Employing Interactive Pulse Sequence Switching MR Fluoroscopy Guidance for Liver Biopsies in a Short, Wide-Bore 1.5T Scanner – Preliminary Results MR Guided Angioplasty of Peripheral Arteries: Delivery of Substances Into the Vessel Wall MR Imaging Assists in Diagnosis of Stress Urinary Incontinence in Women: Results from a Pilot Prospective Trial MR Imaging Features of Ovarian Fibromas: Emphasis on the Detection of a Separate Ipsilateral Ovary MR Imaging for the Determination of Lumenal and Outer Wall Boundaries in Intracranial Aneurysms MR Imaging Guided Biopsy of the Prostate Using a 32-Channel Phased-Array Coil at 3 Tesla MR Imaging of a Postmortem Formalin-Fixed Human Brain of a Multiple Sclerosis Patient at 3T and 7T MR Imaging of Adventitial Vasa Vasorum in Carotid Atherosclerotic Plaque MR Imaging of Fibrocystic Changes of the Breast MR Imaging of Pathological Complete Response Following Neoadjuvant Chemotherapy MR Imaging of Pulmonary Perfusion and Gas Exchange by Intravenous Injection of Hyperpolarized 129Xe MR Imaging of Sodium Using a 3D Cones Acquisition MR Imaging of the Chest: Pulmonary Lesion Detection in Comparison to MDCT Mr Lymphangiography of the Axilla with Spio, in Patients with Breast Cancer MR Manifestations of Decidualized Endometrial Cysts During Pregnancy MR Manifestations of Endometrial Cysts at 3T Compared to 1.5T MR Measurements of Diffusion, Perfusion and T2 with Proteomic Analysis in the Hippocampus Following Status Epilepticus in the Rat Lithium-Pilocapine Model MR Microscopic Imaging of Rodent Brain Using Contrast 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MRI of Upper Airway and Lung in Rats: Routine Reversal of Neuromuscular Blockade with Neostigmine Predisposes to Upper Airway Collapse MRI Quantification of USPIO-Labeled Cell Density and Number MRI Study of Cerebral Asymmetry in Patients with First-Episode Treatment Naive Schizophrenia MRI Study of the Cortical Folding Process in the Premature Newborn Brain MRI Tagging of In Vivo Ventricular Function Reflects Changes in Myocyte Contractility and Calcium Handling in a-Dystrobrevin Knockout Mice MRI Thermometry Calibration Concept for the Qualification of HIFU Tumor Ablation Real-Time Thermometry Protocols MRI Tracking of Iron-Labeled Radioembolization TheraSpheres: Phantom and Animal Model Feasibility Studies MRI/3D-MRSI of Prostate to Direct TRUS-Guided Biopsy in Patients with Prior Negative Biopsy MRI/PET Insert: Investigations of Eddy Currents on Copper Shields in the Bore MRI-Based Attenuation Correction for PET Reconstruction MRI-Based Investigation on the Outflow Segment of Human Brain Bridging Veins MRI-Based Pulmonary Function Test Using Forced Breathing Maneuvers MRI-Based Pulse Wave Velocity Measurement Using a 4D Aorta Model MRI-Detected Breast Lesions Less Than 5mm in Size: Variables That Influence the Likelihood of Malignancy MRI-Monitoring of Hyperthermia Induced Gadodiamide Release from Long-Circulating Thermosensitive Liposomes in Tumors MRM of Perfused Alzheimer’s Mice Hippocampal Slices MRS Pharmacodynamic Markers of a Novel Histone Deacetylase Inhibitor, LAQ824, in a Human Colon Carcinoma Model MRS Studies of Spermine: Factors Affecting Detectability MR-Safety and Compatibility of Intrauterine Devices at 3T and 7T MRSI Localization at 7T Based on Frequency Modulated RF Pulses MR-Visible and RF-Safe Low Profile Transmission Line for Active Devices MS Repair Potential and Disease Progression from Short-Term T2 Change MTR Abnormalities in Relapse Onset MS Patients 20 Years After the Onset of Disease Multi Tuned Coupled Microstrip Resonator for High Field Magnetic Resonance Imaging at 9.4T Human System Multichannel High Power Single-Pole Double-Throw (SPDT) Microstrip T/R Switch for 470 MHz Arrays Multi-Colored Nano-CEST MRI Contrast Particles for Cell Imaging Multidimensional Arbitrary-Flip-Angle Parallel Transmit Pulse Design Using an Optimal Control Approach Multidimensional Displacement Analysis of the Triceps Surae Muscle Tendon Complex During Isometric Contraction - A Velocity-Encoded MRI Study at 3T Multidisciplinary Approaches to MR Engineering Multi-Echo 3D Hybrid Radial SSFP Cardiac CINE Imaging for Whole Heart Coverage in a Single Breathhold Multi-Echo IDEAL/T2*-IDEAL Liver Imaging: Simultaneous Assessment of Fatty Infiltration and Iron Overload in a Single Breath-Hold Multi-Echo IDEAL-GRE Water-Fat Separation for Rapid Assessment of Cartilage Morphology Multiexponential Diffusion Properties of Human High Grade Gliomas Multifunctional Plasmonic Nanoparticles for Photothermal Therapy of Cancer with MRI Monitoring Multi-Institutional Analysis of rCBV Measurements from DSC MRI of Low-Grade Gliomas Predicts Patient Outcome Better Than Histopathology Multi-Layers Structure of Mouse Retina Detected Using T2 and ADC In Vivo Multimodal Approaches Multimodal Characterisation of Substantia Nigra Pathology in Parkinson Disease Brains: A Pilot MRI Study at 3 and 7 Tesla Multimodal Image-Guided Enzyme/Prodrug Cancer Therapy Multimodality Imaging: Development of Nude Rat Model of Metastatic Breast Cancer to the Brain Multimodality Voxel-Based MRI Study: Possible Tool for Disease Diagnosis and Monitoring in ALS Multiparametric Analysis for Differentiating Tumor Recurrence from Radiation Effect Multiparametric Analysis of Advanced MR Imaging Changes Following Concurrent Radiation Chemotherapy Multiparametric and Ex-Vivo MR Imaging in Diagnosis of Prostate Cancer: Preliminary Results from a Prospective Trial in Patients Undergoing Prostatectomy Multiparametric MR Studies for Monitoring Treatment Response of Human Head and Neck Cancer Multiple Narrow-Band Excitations Spiral Imaging Multiple Overlapping K-Space Junctions for Investigating Translating Objects (MOJITO) Multiple Regression Method for Optimizing Scan Parameters in Pulmonary Partial Pressure Oxygen Measurement by Hyperpolarized 3He MRI Multiple Streamline Tractography Approach with High Angular Resolution Diffusion Imaging Data Multiple-Quantum 23Na Signals Without Slow Motion Multi-Resolution Dynamic Contrast Enhanced MRI for Improved Kinetic Modeling Multi-Resolution Non-Iterative Field Map Estimation for Water and Fat Separation Multiresolution Strategy to Estimate Arterial Transit Time and Cerebral Blood Flow Maps in Rhesus Monkeys Multisensory Recruitment Associated with REM Sleep Eye Movements: An fMRI Study Multi-Shot Diffusion-Weighted Split-Echo PROPELLER MRI of the Abdomen Multislice 2D Spin-Echo Imaging Using Frequency-Swept Pulses Multi-Slice Body Diffusion Weighted Imaging with Peripheral Pulse Unit (PPU) Gating Multi-Slice Compressed Sensing Imaging Multi-Tensor Tractography Enables Better Depiction of Motor Pathways Multivariate Analysis of MRI Datasets of the Liver: Enhancing Definition of Disease Severity by Combination of Parameters Multivariate Granger Causality Analysis of Brain Networks Multivariate Hypothesis Testing for Tissue Clustering and Classification: A DTI Study of Excised Rat Spinal Cord Multivariate Linear Discriminant Analysis of DTI Data Improves the Detection of Microstructural Damage in Young Professional Boxers Multivariate Linear Modeling of Quantitative MR Features for Prognosis in Patients with Glioblastoma Multiforme Multivariate Methods for Discrimination in the Analysis of fMRI Data Multivariate-Defined Spatial Networks of Age-Associated Atrophy Muscle Atrophy Observed in Burns Due to Reduced Rate of ATP Synthesis by 31P NMR Musculoskeletal Imaging Using 3D Ultrashort TE Scanning at 7.0 T Mutation of the Mecp2 Gene Causes Perturbations of Osmolyte and Neurotransmitter Metabolism in Mouse Brain. A 1H MRS Study of Tissue Extracts Mutual Information Based MREIT Reconstruction Using MR Anatomical Data Myelin Water Imaging of Multiple Sclerosis at 7T: Correlations with Histopathology Myocardial Blood Oxygenation Level Dependent MRI at 3T for Detection of Significant Coronary Disease Myocardial Ca2+ Influx Deficits in a Mouse Model of Sandhoff’s Disease Utilizing MEMRI Myocardial Ca2+ Influx Increases in Response to Hyperglycemia Myocardial Contour Propagation in Cine Cardiac MRI Myocardial Contrast Concentration Estimated in First-Pass MR Perfusion Imaging Does Not Increase Proportionately with the Dose of Gadolinium-DTPA Myocardial Motion Tracking with MRI SPOTs Myocardial Perfusion Measurement with Arterial Spin Labeling at 3 T: A Comparison with 1.5 T Myocardial Perfusion Reserve by CMR: Dual or Single Bolus Approach? Myocardial T1 Mapping Using Inversion Recovery SSFP Cine Myocardial T2 Imaging - Comparison of Free-Breathing T2-Prepared Transient-State TrueFISP to Breath-Hold T2-Prepared Segmented True FISP at 1.5T and 3T Myocardial T2* Measurement in Iron Overloaded Thalassemia: An Ex Vivo Study Myocardial Tissue Tracking Using Volumetric Cine DENSE with Three-Dimensional Displacement Encoding: Development and Preliminary Results Myocardial Viability Assessment During Continuous Infusion of Gd(DTPA): Comparing R1-Map-Based and Signal-Intensity-Based Percent-Infarct-Mapping Myo-Inositol - A Marker for Reactive Astrogliosis in Glial Tumors? Near-Infrared Light Penetration in Rat Brain Modeled Using MRI Structural Information Necessary and Sufficient Conditions for the Admissibility of DTI Gradient Vectors Negative and Positive Contrast Strategies to Track Cell Encapsulation Devices Post Implantation Negative BOLD Signal Response to Inhaled Carbon Dioxide Correlates with Decreased Cerebral Blood Flow on Arterial Spin Labeling Negligible Dehydroascorbate and GSSG Signal Contributions to Human Brain 1H NMR Spectra In Vivo Neonatal MRI Brain Tissue Segmentation and Morphological Analysis Networks of Correlated Activity in the phMRI Response to Amphetamine Resolved by Cluster Analysis Neural Bases of Dyslexia in Italian: Does a History of Language Delay Matter? Neural Correlates of Attentional Control of Conflict Processing: fMRI Evidence from a Stroop Match-To-Sample Task Neural Correlates of Cross Script Repetition Priming: An fMRI Study Neural Stem Cells Tracking by MRI in Wobbler Mouse, a Model of Motoneuron Disease Neural Substrates of the Orexigenic Hormone Ghrelin: A Pharmacological MRI Study in the Rat Neuroabnormality of Thalamus in Secondarily Generalized Seizure: A Diffusion Tensor Study at 3T Neuroanatomical Correlates of Visual Field Bias Neurochemical Alterations in the Cortex and Cerebellum of MECP2 Knockout Mice Neurochemical Changes in the Early Stage of Huntington’s Disease Progression Studied in Transgenic Mice Using 1H and 31P NMR Spectroscopy Neurochemical Changes in the Rat Brain with STZ-Induced Diabetes Using In Vivo 1H MR Spectroscopy at 9.4 T Neurochemical Modulation in a Rat Model of Birth Asphyxia Detected by In Vivo Proton MRS Neuromagnetic Correlates of the 7T BOLD Response in Visual Cortex Neuroprotective Composition Effective for Ameliorating Mental Decline: Volume MR Image In Vivo Neuroprotective Effects of Modafinil in a Nonhuman Primate Parkinson Model Neurovascular Metabolism Coupling in the Human Visual Cortex: A Biophysical BOLD fMRI Model Comparison New Devices for Safety and Usability to Introduce Robot Assistance Into Clinical MR Guided Microwave Ablation of Liver Tumors New Diffusion Phantoms Dedicated to Study and Validation of HARDI Diffusion Models New Frontiers in Use of MR as a Biomarker in Therapeutics New Sequence for a Fast and Accurate Measurement of Hyperpolarized Helium-3 Diffusion New Slice-Selective Pulse Cascades Producing Uniform Tipping in Inhomogeneous RF Fields New Strategy for Detection of Glycine in Human Brain In Vivo New Synthetic Reference Signal Injection Method for Absolute Quantitation of Metabolite Concentration NMDA Receptors Participate in Control of Manganese-Enhanced MRI (MEMRI) NMR Lipid Profiles of Hepatic Bile Collected from the Patients Undergoing Liver Transplantation (OLTx) NMR Microscopy with Isotropic Resolution Down to 3.0 µm Using Dedicated Hardware NMR Molecular Diffusion in the Presence of Distant Dipolar Field Interactions NMR Signal Intensity and Receive Sensitivity Noise Analysis and Filtering for Diffusion Tensor Imaging Noise Analysis of Accelerated 3D-EPI fMRI Noise Characteristics in MRI with Multi-Channel Arrays, Parallel Imaging, and Reconstruction Filters Noise Characterization in Cine DENSE MRI Noise Dependence of T2* Maps on Echo Times and Number of Echoes Noise Reduction in Combined EEG/fMRI Using a Vector Beamformer Noise Suppression in Black-Blood STEAM Cardiac Imaging Noise-Induced Bias in Low-Direction Diffusion Tensor MRI: Replication of Monte-Carlo Simulation with In-Vivo Scans Non Parametric Approach for Axon Diameter Distribution Estimation from Diffusion Measurements Non-Cartesian Parallel Reconstruction Based on BOSCO with Simultaneous Off-Resonance Correction Non-Contrast-Enhanced MR Angiography of the Pulmonary Veins Using a Whole Chest 3D Steady-State with Free-Precession Technique Non-Contrast-Enhanced MR Angiography of the Thoracic Aorta Using a Whole-Chest 3D Steady-State with Free-Precession Technique Non-Contrast-Enhanced Renal MRA Using Time-Spatial Labeling Pulse (T-SLIP) with 3D Balanced SSFP Nondiffuse Fatty Infiltration of the Liver: Does the Uptake of Iron-Oxide Increase or Decrease at SPIO-Enhanced MR Imaging? Non-Invasive Absolute Temperature Imaging with TmDOTMA Non-Invasive Generation and Monitoring of Ultrasound-Induced Blood-Brain Barrier Opening in the Murine Hippocampus Non-Invasive Imaging of Oxidized LDL Using MDA2-Labeled Gadolinium Immunomicelles Non-Invasive In Vivo MRI Angiogenesis Assays Noninvasive Quantitation of Liver Triglycerides in Steatosis Patients Using MR Methods Non-Invasive Spatial Control of Gene Activation by Local Heating with Focused Ultrasound Under MRI Temperature Guidance Nonischemic Applications of First Pass Cardiac Imaging Non-Iterative Decomposition of Fat and Water Using Chemical Shift Nonlinear Image Registration with Voxel Adaptive Regularization to Correct for EPI-Induced Geometric Distortions Nonlinear Magnitude-Constrained Estimation of Image Phase for Accelerated Flow Imaging Nonlinear Modelling of Dynamic Contrast Enhanced Gd Imaging Data in Rheumatoid Arthritis: Extraction of Ktrans Normal In Vivo Skeletal Muscle Mitochondrial Function in Subjects with Impaired Glycemic Control and in Long-Standing, Insulin Treated Type 2 Diabetes Patients Normal' Controls for Intracranial MRI? Normal Regional Fractional Anisotropy and Apparent Diffusion Coefficient of the Brain on 3T Normal Right-To-Left Asymmetry in Fractional Anisotropy of Superior Occipitofrontal Fasciculus Disappears in Schizophrenia Novel Design for Notched RF Saturation Pulses Using the SLR Transform Novel MR Imaging Contrast Agents for Detection of HT29/219 Cells in Mice Novel MRI Contrast in Nervous Tissue Based on the Observation of Anomalous Diffusion Novel Multi-Mode Probe for MR-Guided Therapeutic Endovascular Interventions Novel Numerical Modelling of Lumped Circuit Elements in RF Coils for Identifying Resonant Frequencies Novel Radiopaque and MR-Visible Intracellular Contrast Agents for Cell-Tracking and Viability Enhancement of Human Pancreatic ß-Islets Novel Solubility Switch Contrast Agents: In Vivo Detection of MMP-7 Activity Novel Urokinase Plasminogen Activator Receptor (uPAR) Targeted Probe and Its In Vivo MRI of 4T1 Xenograft Breast Cancer Model Now That’s a Hippo! a Clinical Imaging Protocol for the Human Hippocampus at 7T Null Point Imaging Numeric Simulations for Optimization of Wild Bootstrap Technique as a Robust Estimator of DTI Measurement Uncertainty Numerical Modeling of CSF Flow in Patient - Specific Anatomical Models Numerical Simulation of Magnetic Fields and Spin Velocity for Unsaturated Ferrofluid Driven by External Static and Rotating Magnetic Fields Numerical Study of Currents in Occupational Workers Induced by Body-Motion Around High-Ultrahigh Field MRI Magnets Observation of Two Distinct Spatial-Temporal BOLD Clusters During Sensory Stimulation in Rats Observer Preference of Magnetic Resonance Images at Fixed Imaging Time Obtaining a New Frame from Each Excitation in Real-Time Acquisitions Off Resonance Contrast Angiography Using Frequency-Shifting Catheter Coatings Off-Resonance Behaviour of RARE and TrueFISP in Imaging of Hyperpolarized 13C Off-Resonance Dependent Slice Profile Effects in Balanced SSFP Imaging Off-Resonance Saturation Method to Enhance SPIO Contrast in Molecular Imaging of Cancer On Bursting Balloons and Collapsing Endothelia: What Does Cause the Post-Stimulus Undershoot? On Magnetization Transfer and Balanced SSFP On Optimal Filter Sizes for Measuring Cardiac Motion Using HARP-MRI On Optimality of Parallel MRI in K-Space On the Effect of Vascular Tree Parameters on 3D Texture of Its Images On the Effects of Random Subject Rotation on Icosahedral Diffusion Sampling Schemes in DT-MRI On the Feasibility of White Matter Arterial Spin Labeling Measurements On the Influence of Respiratory Motion in Quantitative Myocardial Perfusion MRI On the Limits of Image Noise Suppression in High-Speed Cardiac MR Parallel Acquisition On the SSFP Signal One Third of the Anterior Portion of the Optic Nerve Is Susceptible to Motion of Different Eye Direction One-Shot Fourier Velocity Encoding with Higher Spatial Resolution On-Line Brain Mapping Using fMRI and a Magnetic Resonance Compatible Hand-Induced Robotic Device (MR_CHIROD) Optic Neuritis Pathology Detected with Directional Water Diffusivities by MRI in a Murine EAE Model Optimal Design of Pulsed ASL Sampling Schedules Optimal Properties of Chemical Exchange Saturation Transfer (CEST) Contrast Agents Optimal Z-Encoding Frequency for zHARP: In-Vivo Validation and Comparison with SF-CSPAMM Optimisation of 3D Inversion Recovery Fast Spin Echo for Lesion Detection in Multiple Sclerosis Brain Optimisation of Functional Signal Changes for SSFP Optimization and Application of Simultaneous Triple Contrast, T1, Arterial TOF and BOLD Venography at 7T Optimization and Validation of Small Bowel Water Content Estimation Using MRI Optimization of 3D-PRESTO (Principles of Echo Shifting with a Train of Observations) Sequence forT2* Sensitized High-Resolution MR-Venography Optimization of Acquisition and Post-Processing Strategies for Na-23 Imaging of the Human Kidney Optimization of Arterial Input Function Selection for Cerebral Perfusion Imaging with Quantitative Blood Volume Correction Optimization of Coronary Wall Imaging Optimization of Extravascular Contrast Injection Parameters to Prolong Data Acquisition Window for Coronary MRA at 3T Optimization of Hybrid 2-Dimensional Navigator Correction to Suppress Respiratory-Induced Physiological Noise Optimization of In Vivo Diffusion Tensor Imaging of Muscles of the Human Lower Leg: Application to Fiber Tracking Under Plantarflexed Conditions of the Foot Optimization of In-Phase and Opposed Phase Imaging at 3T for Abdominal MRI Optimization of Intracellular Delivery of PARACEST Contrast Agents by Combining Liposomes and Cell Penetrating Peptides Optimization of Multi-Compartment Analysis of T2* Decay in Myelin Water Fraction Mapping with Fixed Brains Optimization of PRESS-Localized Metabolite Measurements in the Frontal Lobes In Vivo at 3T Optimization of Steady State Free Precession Sequences for Hyperpolarized 3He Lung MRI Optimization of the SNR/resolution Tradeoff for Registration in Magnetic Resonance Images Optimized “All-In-One” Liver MRI Featuring Gd-EOB-DTPA Administration in the Evaluation of Potential Living Liver Donors: Preliminary Results of a Comparison with “All-In-One” Contrast-Enhanced Multislice-CT Optimized Asymmetric Quadrature Split Birdcage Coil for Hyperpolarized 3He Lung MRI at 1.5T Optimized Data Compression and Denoising with PCA Using a Kurtosis Based Selection Criterion Optimized Detection of Glutathione in the Human Brain at 3T Using MEGA-PRESS Optimized DTI for Fibre Bundles of Known Predominant Orientation Optimized fMRI of Hand-Squeezing at 3T Optimized fMRI Protocol for Fear Conditioning Experiments at 3 Tesla Using Parallel Acquisition Technique Optimized High-Resolution Mapping of Magnetisation Transfer at 3 Tesla Reveals Substructures in the Human Thalamus in Clinically Feasible Measurement Time Optimized MRI Parameters for Positive Contrast Detection of Iron-Oxide Labeled Cells Using Double-Echo Ultra-Short Echo Time (D-UTE) Sequences Optimized Nonlinear Normalization for Voxel-Based Analyses: A Comparison of the Free-Form Deformation in VTK to the Discrete Cosine Function in SPM2 Optimized Pre-Processing of Time-Resolved 2D and 3D Phase Contrast MRI Data Optimized Quadrature Surface Coils Incorporating Circular, Figure-8 Loops, and Strips Optimum b-Value Vs. SNR for Apparent Diffusion Coefficient Measurements Optimum Ventilation Mixture Ratio for Maximizing Hyperpolarized 129Xe MR Brain Signal Organ-Specific Effects of Oxygen and Carbogen Gas Inhalation on Tissue Longitudinal Relaxation Times Oxygen Effects in Tissue Preparation Neuronal Current MRI Oxygenation and Hematocrit Dependence of Blood T2 and T2* at 3T Oxygenation of Mouse Hearts In Vivo at 17.6 Tesla Oxygen-Enhanced Lung Imaging Using Rapid Acquisition of T1-Maps During Free Breathing p38 MAPK Inhibition Reduces Aortic Ultrasmall Superparamagnetic Iron Oxide Contrast Agent Uptake as Assessed by MRI in an Atherosclerotic Mouse Model P846 and Gd-DOTA in Characterizing Occlusive and Reperfused (Reversible, Irreversible) Myocardial Infarcts Paint and Track: Surface-Based ROI Selection in DTI Fiber Tracking Paired Studies of Glycogen Storage Using 13C MRS: The Second Meal Effect Pancreatic Islet Graft Monitoring by Magnetic Resonance Imaging in Non-Human Primates PARADISE: Patient-Adaptive Reconstruction and Acquisition in Dynamic Imaging with Sensitivity Encoding Parahydrogen Induced Polarization of Drug Compounds for MRI Parahydrogen-Induced Hyperpolarization of 15N Parallel Diffusion-Weighted Single-Shot STEAM - Less Is More Parallel Excitation Experiments Using a Novel Direct Calibration Technique for RF-Pulse Determination Parallel Excitation on a 3T Human MRI Scanner Using Current Source Amplifiers and Iterative RF Pulse Design Parallel Imaging and 2 R-R Acquisition for Tagged Imaging of 100% or More of the Cardiac Cycle with Improved CNR Parallel Imaging as a Non-Linear Inversion Problem - Improved Reconstructions Parallel Imaging at 7T Facilitates High-Resolution Whole-Brain BOLD fMRI in Humans Parallel Imaging Based on Successive Convolution Operations (BOSCO) Parallel Imaging for Diffusion-Weighted MR Imaging in Gastric Cancer: A Comparative Study Parallel Imaging of Knee Cartilage at 3 Tesla Parallel Imaging of Mice on a Clinical 3-Tesla MRI System with a Dedicated 8-Channel Small-Animal Coil Array Parallel Imaging Reconstruction for Arbitrary Trajectories Using K-Space Sparse Matrices (kSPA) Parallel Imaging with Concomitant Motion Compensation of the Carotid Vessel Wall at 3T Parallel Intravital Microscopy, MR Imaging, and Fluorescence Imaging of Tumor Angiogenesis Using Paramagnetic Quantum Dots Parallel MRI with Extended and Averaged Grappa Kernels (PEAK-Grappa): SNR Optimized Fast Dynamic Imaging with High Acceleration Factors Parallel Transmission Parallel Transmission with an 8 Channel Whole Body System at 3 T Paramagnetic and Diamagnetic Cerebral Lesions in Susceptibility Weighted Phase Imaging (SWI) Paramagnetic Dy(III)-Loaded Liposomes as T2 Susceptibility MRI Agents Parametric Spherical Deconvolution: Inferring Multiple Fiber Bundles Using Diffusion MR Imaging Parsimonious Model Selection for DTI Tissue Segmentation and Classification: Study on Simulated and Experimental Data Partial Volume Compensation for Improved Reliability of BBB Permeability Partial Volume Effects in DTI Partial Voxel Segmentation of the Left Ventricle: Interpolating Blood Content of Voxels PASADENA: A Novel Tool to Image Atherosclerotic Plaque Passive Catheter Tracking/Visualization Using Frequency Demodulation and IDEAL Passive Tobacco Smoke Exposure Assessed by Long-Time-Scale 3He Diffusion MRI Pathological Change in Nigrostriatal Pathway in MPTP Induced Parkinson's Disease Animal Model Using DTI and MRS Pathophysiologically Relevant Perivascular Processes in Multiple Sclerosis – Can We Detect Them In Vivo by MRI? Patients with Acromegaly Exhibit Altered Mitochondrial Function Despite Successful Treatment Patient-Specific Wall Shear Stress Determination in the Coronary Arteries Using Phase Contrast Magnetic Resonance PatLoc: Imaging in Non-Bijective, Curvilinear Magnetic Field Gradients Pattern and Model Based Analysis of Dynamic Contrast Enhanced Prostate MRI Data PCA-Based Image Registration for On-Line MR Temperature Monitoring of Moving Tissues Penile Arterial Blood Supply: Gadolinium-Enhanced, Dynamic 3D-Liver Acquisition with Volume Acceleration (LAVA) MR Evaluation at 3T with 8-Channel Phased Array (PA) Coil Prior to Radical Retropubic Prostatectomy Perceptual Difference Model (Case-PDM) for Evaluation of MR Images Performance Comparison of Direct Fourier Sum and Regridding Reconstructions of Sodium TPI Performance Comparison of Two Signal Decay Models in Assessment of T2-Star (T2*) for Diagnosis of Myocardial Iron Overload by Multiecho Cardiovascular Magnetic Resonance Performance of a 200 MHz Cryogenic RF Probe Designed for Small Animal MRI/MRS Performance of Inductively Coupled RF Coils as Reference Markers Under Various Conditions at 1.5 T Performance of the ASTM-Phantom at 3T Perfusion and Water Exchange Effects on T1-Based Measurements of Blood Volume Perfusion Imaging of Brain Tumor Using Pulsed Arterial Spin Labeling: Correlation with Histopathological Blood Vessel Proliferation Perfusion Imaging of Glioma Using Continuous Arterial Spin Labeling (CASL): Comparison with Histopathological Features Pericardial Enhancement in Pericarditis and Pericardial Constriction: Evaluation with Myocardial Delayed Enhancement Sequences Peripheral Contrast-Enhanced MR Angiography at 3.0T Using a Dedicated 36-Element Peripheral Phase Array Coil Persistent Distal White Matter Microstructural Changes Caused by New Lesions at the Earliest Stage of Multiple Sclerosis Perturbation of Mouse Glioma MRS Pattern In Vivo at 7.0 Tesla by Induced Acute Hyperglycemia pH Measurement with a MRI-PARACEST Contrast Agent: Nd-DOTAM-Gly-Lys Phantom Experiments with a Novel MR-Guided Transrectal Prostate Interventional System Pharmacokinetic Modeling of DCE-MRI Data with Arterial Input Function Phase Constraint Relaxation in Parallel Excitation Pulse Design Phase Contrast Imaging of Flow Dynamics in the Lungs Using Hyperpolarized Helium Phase Contrast Imaging of Vortex Rings During Diastolic Filling of the Left Ventricle Phase Contrast MRA Measurements of Total Cerebral Blood Flow in Newborns. Phase Encoding Without Gradients Using TRASE-FSE MRI Phase fMRI at 7 Tesla Phase Imaging of Brain Tumor Patients at 7T Phase Imaging of the Human Brain at 7T Phase Information in Transition-Band SSFP fMRI (BOSS fMRI) Phase Preparation in Balanced Steady State MR Elastography Phase Refocusing for Improved Visualization of Interventional Guidewires Phase Sensitive Fat Suppression SSFP with Phase Correction Phase Velocity Imaging of Portal Pressure Gradients for Assessing Liver Fibrosis/Cirrhosis Phased Array MR Spectroscopic Imaging of the Brain at 7T Phased Array Optimized for Simultaneous Reception with a Transmit Volume Coil for SNR Improvement of the Spectroscopic Imaging of the Hippocampus. Phenotypic Severity of Primary Distorsion Dystonia Is Uncovered with Diffusion Tensor Imaging in Brains of Mouse Models Phenotyping the APP/PS2 Mouse Model for Alzheimer's Disease: Cerebral Perfusion, Blood Volume, and Vessel Density Physical Model of Weiskoff EPI Temporal Stability Test Physical Models of Cerebrospinal Fluid Flow in Patients with Chiari I Malformation Physiologic Changes of the Normal Ovaries on T2-Weighted Images and Diffusion-Weighted Images During the Menstrual Cycle Physiological Modulations in Arterial Spin Labeling Physiologically Improved NCAT Phantom (PINCAT) Enables In-Silico Study of the Effects of Beat-To-Beat Variability on Cardiac MR PI3K Inhibition Using a Novel Inhibitor Deregulates Choline Kinase Resulting in PC Depletion Detected by MRS Pitfalls and Advantages of Different T2 Correction Strategies for the Absolute Quantification of Choline, Creatine, N-Acetil Aspartate in Human Grey Matter by 1H-MRS PLACE + SPHERE: A Robust Approach for Correction of Susceptibility Artifacts in EPI Plaques in the Descending Aorta – a New Risk Factor for Stroke? Visualization of Embolization Pathways in the Thoracic Aorta by 4D MRI at 3T Plasticity of the Optic Radiation Following Unilatoccipital Lobe Resection: A Diffusion Tensor Imaging Study.Eral Plate-Like Structures in the Endometrial Canal: Characterization with Dynamic Contrast-Enhanced 3D MR Imaging Point Spread Functions in K-Space and Image-Based Parallel Image Reconstructions Polydisulfide-Based Biodegradable Macromolecular Contrast Agents for Dynamic Contrast Enhanced MRI: First Experience with Human Prostate Cancer Xenograft Polymorphic Deletion in DCDC2 Affects Brain Morphology - A Voxel Based Morphometric Study Portal Vein Suppression with Centric K-Space Ordering on Three-Dimensional Segmented True Fast Imaging with Steady-State Precession Magnetic Resonance Imaging Position Dependent Shear Wave Group Velocities in In Vivo Human Biceps Muscle Positional Variations of the Breast in Supine Position Between Two MR Scans Positive Contrast Imaging of Micron-Sized Iron Oxide Particles Positive Contrast MRI Demonstrates Retention of Mesenchymal Stem Cell Therapy Administered Intramuscularly in Ischemic Skeletal Muscle Positive Contrast MRI of Magnetically Labeled Human Cervical Carcinoma Cells and Tumor Monitoring Positive Default-Mode Activation in Epilepsy Using 2dTCA Possible Evidence for Multiple Vascular Pathways in Cerebral ASL Perfusion Measurements Postnatal Neural Development of the Brain: In Vivo Diffusion Tensor Imaging Postoperative Evaluation of Cruciate Ligament Reconstruction Involving Metallic Implants Using 3D Ultrashort TE Imaging Potential of Gd-EOB-DTPA for Differential Diagnosis of Nonalcoholic Steatohepatitis and Fatty Liver in Rats Using Magnetic Resonance Imaging Potential Value of Diffusion Weighted Imaging as an Indicator of Tumor Aggressiveness in Prostate Cancer Power Calculation for fMRI Data Analysis with Non-Central Random Field Theory Power Scavenging Circuit for Wireless DC Power Practical Iterative MR Image Reconstruction from Very Sparse Radial Samples Pre- And Post- Gadolinium Enhanced Susceptibility-Weighted Imaging at 1.5T for Intracranial Neoplasms: Contrast of Pathologic Lesions Pre- And Postoperative MR Brain Imaging with Automatic Planning and Scanning Software in Tumor Patients: An Intraindividual Comparative Study at 3 Tesla Preattentive Auditory Processing in Professional Musicians Versus Non-Musicians - An fMRI Study Precise Flip Angle Calibration for Hyperpolarized 13C Scans Precision of Metabolite Concentrations Obtained by LCModel as a Function of the Signal-To-Noise Ratio in Rodent Brain Preclinical Evaluation of P846, a New High-Relaxivity Low Diffusible Gadolinium-Based Contrast Agent, for Contrast-Enhanced MR Angiography in Rabbits at 1.5T Predicting Final Infract Size and Pattern of 3-Month Lesion in MRI for Patients with Ischemic Stroke: Using Artificial Neural Network Technique Predicting the Energy of Finite Time RF Pulses Predicting Tissue Outcome Using Multiparametric Algorithms and the Four Ps of Acute Stroke Imaging: Parenchyma, Pipes, Perfusion and Penumbra Prediction and Prevention of Encephalopathy in Mouse Model of Glutaric Acidemia Prediction of Response to AC Chemotherapy Based on Early Changes in Size and Pharmacokinetic Parameters After 1 Cycle Treatment Predictors of Success in MRI-Guided Focused Ultrasound Therapy of Uterine Leiomyomas Preliminary Clinical Experience with Liver and Bone Biopsies Guided by a Robotic Assistance System in a Closed-Bore 1.5T MR Scanner Preliminary Cross-Sectional MRI-Derived ROI-Based Analysis of PET Data from the Alzheimer’s Disease Neuroimaging Initiative Preliminary Cross-Sectional Structural MRI Analysis of Data from the Alzheimer’s Disease Neuroimaging Initiative Preliminary Evaluation of the Effects of Blood Flow on PET Detection of 64Cu-ATSM by Dynamic Gadolinium Enhanced MRI in a Rat Tumour Model. Preliminary Experience with Liver MRI and 1H MRS at 7 Tesla Preliminary Study of Olfactory on Alzheimer's Disease Using BOLD-fMRI at 3.0T Preliminary Study of Whole Body Short T1 Inversion Recovery Diffusion Weighted Imaging in Staging of Prostate Cancers Prenatal Cocaine Exposure Alters the Attention Regulation Between Emotion and Working Memory Processing: An fMRI Study Prenatal Magnetic Resonance Imaging of Normal Pituitary Stalk Preoperative Mapping of Language with fMRI: Frequency Maps and Comparison of Three Tasks in Healthy Subjects Prescan Optimization for Whole Body Diffusion Weighted Imaging Preservation of Manganese Induced Contrast in Fixed Rat Brain Preserving Phase Information in Propeller Imaging Pre-Treatment by Lamotrigine Attenuates the Ketamine-Induced BOLD Response in Healthy Volunteers: A phMRI Study PRF Shift Thermometry Using Multiple-Acquisition Phase-Cycled Balanced SSFP PRF Thermometry Using Iterative Decomposition of Water and Fat Probabilistic Atlas of Human Brainstem and Application to Quantitative Analysis of Anatomical Abnormalities in Stroke Patients Probabilistic Connectivity Using Kullback-Leibler Distance Probabilistic Diffusion Tensor Tractography of Human Spinal Cord and Spinal Nerves at 3T Probabilistic Diffusion Tractography of the Spinal Cord to Assess Disability in Multiple Sclerosis Probabilistic Gray and White Matter MRI Atlas of Human Brain Probability Maps of Optic Radiation in Patients Wtih Hippocampal Sclerosis Probing Fast Neuronal Interaction Based on Fundamental Hemodynamic Signals Probing Into Specificity of Neuronal Circuits Through fMRI Refractory Response Probing Intracellular Compartments in Normal Brain and Brain Tumor Using Short Diffusion Times Probing Intracellular Structure by Diffusion-Weighted Imaging with Oscillating Gradients Probing Lung Geometry: Measurement of Time-Dependent Diffusion of Hyperpolarized 129Xe in Healthy Mice Probing Microvascularity and Heterogeneity of Human Glioma Using Improved T1 Weighted Dynamic Contrast Enhanced MRI Probing Short Diffusion Time Behavior by Oscillating Gradient Spin Echo Sequences Probing T1- And Off-Resonance-Based Signal Enhancements with Gd-DTPA Using Fast Low Angle Positive Contrast Steady-State Free Precession Imaging Probing the Blood/Brain Barrier in Neonates: 1H-MR Spectroscopy Shows Low Protection Against High Phenylalanine Programmable Flow Simulator with Simultaneous Physiology and MR Event Acquisition Progress in Multimodality Imaging: Truly Simultaneous Ultrasound and Magnetic Resonance Imaging Progress in Rapid and Short Acquisition Delay Imaging with SWIFT Progression of Emphysema Evaluated by Hyperpolarized 3He ADC Measurements Progression of Magnetization Transfer Ratio Changes Following Cerebral Hypoxia-Ischemia in Neonatal Rats: Comparison of Mild and Moderate Injury Models Progressive White Matter Microstructural Changes Following Mild Traumatic Brain Injury Revealed by Bootstrap Analysis of Serial 3T Diffusion Tensor MRI Projection Reconstruction MR Imaging Using FOCUSS PROPELLER EPI: Application to ASL Perfusion Imaging Using FAIR PROPELLER Image Reconstruction Using the Non-Uniform Fast Fourier Transform PROPELLER MRI at 7T PROPELLER Reconstruction Using Discrete Fourier Interpolation Prospective Brain T2 Relaxometry and Diffusion Tensor Imaging in a Rat Model of Early-Life Febrile Convulsions Prospective Correction of Large Simple Through-Plane Motion Prospective Head Movement Correction for High Resolution MRI Using an In-Bore Optical Tracking System Prospective Motion Compensation with Floating Navigators Prospective Motion Correction Using Nonlinear Predictive Filtering Prospects of Resolution and Senstivity Enhancement Using In Vivo iZQC MR Spectroscopy Prostate Cancer Detection in Patients with Intermediate Prostate Specific Antigen Levels Using High-Resolution Diffusion Tensor Imaging Prior to Transrectal Ultrasound-Guided Biopsy Prostate Cancer: Added Value of Subtraction Dynamic Imaging in 3T Magnetic Resonance Imaging with a Phased-Array Body Coil Prostate Segmentation on MR Images Without Endorectal Coil Prostate Spectroscopy Analysis with LCModel: Development of 3T Scoring Criteria Protected Carotid Artery Stenting: High Frequency of Silent Cerebral Embolic Lesions Detected by DWI Protection of Skeletal Muscle Against Ischemia by Inactivation of the Oxygen Sensor Phd1: An In Vivo 31P and in Vitro 1H Mrs Study Protein Cage Nanoparticles as Cellular MRI Contrast Agents for Detecting Inflammation in Atherosclerosis Proton MR Spectroscopic Definintion of Glioma Location: Relationship to Survival and Tumor Grade Proton MR Spectroscopic Imaging in Border Zone of Gliomas: Correlation of Metabolic and Histological Changes at Low Tumor Infiltration Proton MR Spectroscopy of the Hippocampus at 3 Tesla in Patients with Major Depression Under Pharmacological Treatment Proton MRI as a Non-Invasive Tool to Characterize a Murine Model of Allergic Pulmonary Inflammation Proton NMR Detection of Glycine in Rat Brain at 9.4 T Proton Single Voxel Magnetic Resonance Spectroscopy in Liver Fat Evaluation of Patients with Planned Liver Resection – Methods and First Experiences Proton Spectroscopy of Humans Skeletal Muscle at 7T Proton Spectroscopy Without Water Suppression Using a High Dynamic Range A/D Converter Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI) on the Human Brain Using a 32-Channel Coil Array and GRAPPA Reconstructions at 3T Providing 1H- And 13C-Hyperpolarized Gamma-Aminobutyric Acid (GABA) for Parahydrogen-Enhanced MRI and MRS Pulmonary Perfusion Imaging in the Rodent Lung Using Dynamic Contrast Enhanced MRI Pulse Design Methods for Reduction of Specific Absorption Rate in Parallel RF Excitation Pulse Sequence for Comprehensive Evaluation of Renal Artery Stenosis Pulse-Acquire 31P MRS Allows to Measure Brain ATP Synthesis in Humans at 3 Tesla Pyramidal Tract Tracking Based on Presegmentation of Superior Longitudinal Fasciculus and Tensor Field Interpolation QABox: Automatic Real-Time MR Image Quality Assurance System for Clinical Trials QMT Estimated Pool Size Ratio and DTI Derived Radial Diffusivity Reflect the Integrity of Myelin Sheath in Mice QMT Is Specifically Sensitive to Myelin and Not Axonal Injury in Optic Nerve from Mice Undergoing Transient Retinal Ischemia q-Space Diffusion Weighted MRI of the Human Spinal Cord In Vivo: Application to Multiple Sclerosis Quadrant Radial K-Space (Quark) – A New Trajectory in Between Radial and Cartesian. Quadrature Strip-Line Surface Coil for Ultra-High Field Imaging (7T) Quadrature TV+L1 Regularization for MR Image Denoising Quality Analysis of DTI Images Quality Control for 1HMRS Longitudinal Studies Quality of Single-Trial Discrimination in Simulataneous EEG/fMRI Quantification and Spatial Analysis of Intra-Tumoural Perfusion Heterogeneity in Cervix Cancer Using DCE-MRI Quantification of 3D Pulmonary Perfusion in Pigs Using a Prebolus Technique and Singular Value Decomposition with a Block-Circulant Deconvolution Matrix Quantification of Arterial-Phase Perfusion Kinetics in the Liver Quantification of Bone-Water Concentration in the Human Tibia In Vivo by 3T Solid-State Radial Imaging Quantification of Cerebral Blood Flow and Vascular Territories in Normotensive and Hypertensive Rats Quantification of Cerebral Vascular Volume After Stroke in a Rat Model Using an Intravascular Contrast Agent and Steady State MRI Quantification of Choline and Ethanolamine Containing Phospholipids in Healthy and Malignant Prostate Tissues Quantification of Co-Edited Macromolecules in GABA J-Editing Quantification of Components of Bile Acids in Human Bile and Proton HR-MAS Spectroscopy of Gall Bladder Tissue: A Route for Diagnosis of Gall Bladder Malignancy Quantification of Delayed Enhancement Image Contrast at 3T Using Serial T1 Measurements Quantification of Diffuse White Matter Abnormalities Using T2 Relaxometry in Preterm Infants at Term Equivalent Age Quantification of Ferritin Iron in Presence of Hemosiderin Quantification of Hepatic Steatosis with IDEAL-SPGR: Correlation with PRESS Spectroscopy and Biopsy Quantification of Intramyocellular Lipids (IMCL) in Mouse Models of Insulin Resistance Quantification of Lipid-Rich Necrotic Core Size in Carotid Atherosclerotic Plaque of Symptomatic and Asymptomatic Patients Quantification of Liver Tumor Necrotic Fraction Using Diffusion-Weighted PROPELLER MRI Quantification of Liver Volume, Liver Fat Fraction and Subcutaneous-Visceral Fat Changes with 3T MRI After Hypocaloric Diet in Morbidly Obese Patients Quantification of Mixed Perfusion Using Vessel Encoded Pseudo-Continuous Arterial Spin Labeling Quantification of Multicomponent T2 in Brain After Reversible Ischemia Quantification of Myocardial Perfusion Using Free-Breathing MRI and Prospective Slice-Tracking Quantification of No-Reflow Zone Using Semi Automated Approach Quantification of Perfusion and Endothelial Permeability in Inflammatory Joint Diseases Quantification of Prostate Spectra at 3T Using LCModel with a Simulated Basis Set Quantification of Regional Functional Improvement of Infarcted Myocardium After Primary-PTCA by Contrast-Enhanced Magnetic Resonance Imaging Quantification of Release of Thermosensitive Liposome-Encapsulated Gadodiamide Quantification of Renal Perfusion on a Voxel-By-Voxel Basis: Comparison of Perfusion Values in Different Age Groups Quantification of Resting State CMRO2 Using Low-Frequency Hemodynamic Oscillations in Rat Brains Quantification of Restricted Diffusion Via Kurtosis and Q-Space Imaging Quantification of Rodent Cerebral Blood Flow (CBF) in Normal and High Flow States Using Pulsed Arterial Spin Labeling Magnetic Resonance Imaging Quantification of SPIO Iron: Comparison of Three Methods Quantification of the Association Between the Apparent Diffusion Coefficient and Age in Normal Pediatric Hips Quantification of the Effect of Induced Graded Ischemia in the Popliteal Artery and Vein by MR Oximetry Quantification of the Regional Myocardial Function After Dobutamine in Rat Using Cine and Tagged MRI Quantification of the Spinal Cord Axon Diameter Using an Extension of the PGSE Sequence Quantifying Brain Tissue Deformation in Patients with Cerebral Hematoma Through an Iterative B-Spline Image Registration Approach Quantifying Hepatic Lipid Content and T2* Decay Using a Single Breath-Hold Multiecho Sequence at 3 Tesla Quantifying Therapy Effects on Diffusional Permeability in Human Bruch’s Membrane Explants by MRI Quantitation and Classification of HR-MAS Brain Biopsy Tissue Spectra Quantitation of Brain Tissue Swelling Using MRI Quantitation of Glutamate and GABA in the Human Brain In Vivo Using Localized 2D Constant Time COSY at 4.7 T Quantitative in-Vivo Brain Water Contents Measurements at 3.0T Quantitative 3.0 T Carotid Plaque Imaging Quantitative Analysis of Brain Functional Hemodynamics with Time-Series T1 Mapping Quantitative Analysis of Brain Morphology in a Mouse Model of the Huntington’s Disease Quantitative Analysis of Human White Matter Brain Curvature: Perspectives on Folding from Neonate to Adult Quantitative Analysis of MCh Induced Ventilation Changes in Mouse Lungs Quantitative Analysis of MR-Defined White Matter Hyperintensities in Late-Life Depression. Quantitative Analysis of MRI Tumor Characteristics for Neoadjuvant Chemotherapy Response Prediction in Breast Cancer to the First-Line Doxorubicin-Cyclophosphamide Regimen and the AC Followed by Taxane Regimen Quantitative Analysis of Myocardial Perfusion Reserve with Correction for R-R Interval Variability Quantitative Arterial Spin Labelling (ASL) at Ultra-High Field Quantitative Assessment for Delayed Gadolinium Enhancement of Myocardium: Detection of Abnormal Enhancement in Apparently Non-Enhanced Myocardium of Cardiac Amyloidosis Quantitative Assessment of Anemic Patient's Bone Marrow Using Apparent Diffusion Coefficient with GRAPPA Quantitative Assessment of Axonal Transport Integrity in the Mouse Brain In Vivo Using MEMRI at 9.4 T Quantitative Assessment of Compression Fracture Using Apparent Diffusion Coefficient with GRAPPA: Acute, Chronic, and Pathological Compression Fractures Quantitative Assessment of Reperfusion Six Months After Acute Myocardial Infarction Using Gd-DTPA DCE-MRI Under Adenosine Induced Stress Quantitative Assessment of Sensitivity Enhancement in Short Echo Time 1H MRSI of the Human Brain at 3T Using a Spin Locking Pulse Sequence Quantitative Assessment of Vascular Maturation and Function Using Contrast Referenced BOLD MRI Quantitative Assessment of Ventricular Volume from 3D Dual Phase Single Breath–Hold Scan Quantitative Bone Matrix Density Measured by Water and Fat Suppressed Proton Projection MRI (WASPI) Using a Polymer Phantom Quantitative Bone Quality Assessment Using Digital Topological Analysis and FDT on 7T MRI Quantitative Brain Anatomy in a Sample (N=93) of Healthy Elderly People Quantitative Brain Tissue Mapping Using Fast Spin Echo Imaging Quantitative CBF Measurement by T1 Weighted MRI Is Possible at 3 Tesla Quantitative Cerebral Blood Flow Measurement in a Canine Stroke Model : Validation with Regional Blood Flow Measurement Using Fluorescent Microspheres Quantitative Cervical Proton Magnetic Resonance Spectroscopy of Multiple Sclerosis Quantitative Cervical Proton Magnetic Resonance Spectroscopy of Relapsing-Remitting Multiple Sclerosis Quantitative Comparison of Minimum Inductance and Minimum Power Algorithms for the Design of Small Animal Shim Coils Quantitative Comparison of Registration-Based Lung Motion Estimates from Whole-Lung MR Images and Corresponding Two-Dimensional Slices Quantitative Comparison of Two Biophysical Models for the BOLD fMRI Signal: A Theoretical Study Quantitative Comparisons of Measurement Uncertainty in Human Brain Data with Different DTI Protocols Using a Wild Bootstrap Method Quantitative DCE 1H2O R1 Measurements Suggest Increased Fractional Blood Water in MS Normal Appearing Brain Tissue Quantitative Description of Magnetization Transfer (MT) Asymmetry in Experimental Brain Tumors Quantitative Determination of Mn Content in Rat Brain by Fast T1 Mapping Quantitative Diffusion Tensor Imaging in a Murine Model of Parkinson’s Disease Quantitative Diffusion Tensor Imaging Shows Remodelling of the Infarct Area and Fiber Tratcs Plasticity in Patients Recovering from Small Ischemic Mca Stroke. Quantitative Diffusion Weighted Imaging of Nonpalpable Breast Lesions at 3T Quantitative Dynamic Contrast-Enhanced MRI of Angiogenesis in VEGF-Enhanced Tissue-Engineered Bladder Constructs Using Contrast Agents of Different Molecular Weights Quantitative Dynamic Contrast-Enhanced MRI: A Potential Tool for Guiding Treatment Decisions in Acute Ischemic Stroke Quantitative Evaluation of BBB Blocking Property of BB1101 Using MRI Quantitative Evaluation of Blood-Brain Barrier (BBB) Permeability Using Patlak Plots Methodology in a Model of Transient Focal Ischemia in Rats Quantitative Evaluation of Cerebral Venous Oxygenation Using T2-Relaxation-Under-Spin-Tagging (TRUST) MRI Quantitative Evaluation of Signal Elimination in Gastrointestinal Tract by Oral Negative Contrast Agent in MRCP Using 3T Apparatus in Comparison with 1.5T Quantitative Evaluation of the Effect of Propylene Glycol on BBB Permeability Quantitative Ex Vivo MR Histology in Experimental Dog Osteoarthritis Quantitative Fiber Tracking Analysis of the Optic Radiations in Premature Newborns Quantitative Flow Sensitive 4D MRI: Detailed Flow and 3D Wall Shear Stress Analysis in the Entire Normal Thoracic Aorta Quantitative Global and Regional Cardiac Wall Motion Analysis with a 3-Dimensional Reconstruction Cardiac Image Modeling (CIM) Tool Quantitative J-Resolved Prostate Spectroscopy Using Two-Dimensional Prior-Knowledge Fitting Quantitative Magnetic Resonance Imaging of Tomato Fruit Quantitative Magnetisation Transfer Parameters Show Dramatic Changes in Low Grade Gliomas Quantitative Magnetization Transfer Imaging of Focal EAE Lesions Quantitative Mapping of Susceptibility Gradients from Regular Gradient Echo Images and First Application at 7T Quantitative Measurement of Cerebral Metastatic Tumor Burden of Breast Cancer Cells in a Nude Rat Model Using T2* Map Histograms with Bioluminescence Imaging Correlation Quantitative Measurement of Neurotransmitters in Rat Brain Tissue Using HR MAS 13C NMR Spectroscopy and the ERETIC Method Quantitative MR Spectroscopy of Diffuse Intrinsic Brain Stem Glioma Quantitative MR Spectroscopy to Monitor Treatment Response of Breast Cancer to Neoadjuvant Chemotherapy Quantitative MR Tracking of Magnetically Labeled Mesenchymal Stem Cells in a Mouse Glioma Model at 3T Quantitative MRI Analysis of Skeletal Muscle Injury and Regeneration in a Rat Hindlimb Model Quantitative MRI and MRS at Five to Eleven Months After Traumatic Brain Injury in Rat Quantitative MRI of a Radiation Sensitive Gel Foam for Absorbed Dose Verification of Conformal Radiotherapy in Lung-Equivalent Tissue Quantitative MRI of Parallel Changes of Articular Cartilage and Trabecular Bone Quantitative MT (qMT) Characteristics of the Human Spinal Cord In Vivo Quantitative Myocardial Perfusion Imaging Using Parallel Acquisition Techniques Quantitative Prediction of Ischemic Tissue Fates: Incorporating Spatial Information to Improve Prediction Accuracy Quantitative Relationships Between Brain-Water T2 and ADC at Term in Infants Born Prematurely Quantitative Relationships of Metabolic and Vascular Parameters in Brain Activation: A Multi-Modal fMRI Study Quantitative Study of Motion Detection Performance of Center-Of-Kspace Measurements Quantitative SWI in Differentiation of MSA and Parkinson's Disease Quantitative T1 and T2 Relaxation in Apoptotic Cells in the Presence of Gd-DTPA Quantitative T2 Mapping of Matrix-Associated Autologous Chondrocyte Transplantation at 3 Tesla: An In Vivo Cross-Sectional Study Quantitative T2 Relaxation of White Matter Hyperintensities in Probable Alzheimer Patients Quantitative Time-Domain Analysis of Intermolecular Multiple-Quantum Coherences (iMQC) and Effects of Radiation Damping Quantitative Tissue Analysis in MRS Using Many Element Coils. Quantization Noise in MRI Acquisition R2* Quantitation Reveals That Serum Ferritin Is an Unreliable Surrogate for Tissue Iron Concentration in Myocardium and Liver Rabbit’s Intervertebral Disc In Vivo Imaging at 9.4 T Radial K-T FOCUSS: K-T Space Focal Underdetermined System Solver Using Radial Trajectory Radial Off Resonance Contrast Angiography Radial Single-Shot STEAM MRI Radial Undersampling That Is Variable in Kz Radiation Gel Dosimetry Using an Earth Field NMR Relaxometer Radiation Induced Changes in Perfusion Metrics in Low Grade Glioma Using Dynamic Contrast Enhanced MRI Radiofrequency Ablation of Porcine Adrenal Glands: Interactive Guidance on a High-Field Interventional MR Scanner Ranking and Averaging Independent Component Analysis by Reproducibility (RAICAR) Rapid 3D fMRI Using an Echo-Volumar Imaging Trajectory Rapid 3D Mapping of the B1 Field Using a Low-Flip-Angle, Phase-Based Method with Improved Sensitivity Rapid 3D-T1 Mapping of Cartilage Using Variable-Flip-Angle (VFA) and Parallel Imaging at 3.0T Rapid Cardiac MRI Using Local Planar Gradients Rapid DCE Breast MRI Using TSENSE Accelerated 3D Spiral Imaging Rapid Dynamic 3D T1-Mapping of the Abdomen Rapid Imaging Using Undersampled Radial Trajectories and L1 Reconstruction Rapid In-Vivo MRI Measurement of Fluorinated Gas Concentration in Lungs Using T1- Mapping Rapid Isotropic Diffusion Weighted Imaging Using PROPELLER Rapid Measurement of Transit Time, CBF, M0 and T1 with Turbo-CASL Rapid M-Mode MRI Using Undersampled 2D Excitation and Parallel Reconstruction Rapid MR Microscopy of the Mouse Inner Ear Structures in Vitro Using True-FISP at 7.0T Rapid Prospective Motion Correction Using Principal Axes Computations Rapid Quantitative Magnetic Resonance Microscopy of Excised Anatomy in the Transgenic Mouse at 3.0 Tesla Rapid RF-Mapping Using TurboSTEAM Rapid Simultaneous Data Acquisition of T1 and T2 Mapping, Using Multishot EPI and Automated Variations of TR and TE at 3T Rapid Simultaneous Measurement of Stimulus Related Signal Changes in Visual and Motor Cortex with MR-Encephalography RASER: A New Ultra Fast Magnetic Resonance Imaging Method Rat BOLD fMRI Using Domitor for Anesthesia: Investigation of Stimulus Dependence and Negative BOLD Response in Somatosensory Network rCBV Estimates in Tumor and Normal Brain Depend on Choice of Data Acquisition and Analysis Methods Real Time Kinemtaic Imaging of the Ocular Movement Using FIESTA with Tagging Method Realistic Model of Partial Volume Effect on the AIF in Dynamic Susceptibility Contrast Perfusion MRI Realistic Simulations of Neuronal Activity: Contribution to the Debate on Direct Detection of Neuronal-Currents by MRI Real-Time Adaptation of TI and Flip Angles in Inversion Prepared Coronary Angiography Real-Time Balanced Steady State Free Precession Imaging with Through-Plane Flow Real-Time Measurement of Substrate Uptake and Metabolism in Heart Using Dynamic Nuclear Polarization-Magnetic Resonance (DNP-MR) Real-Time MR Imaging of Myocardial Regional Function with Tissue Through-Plane Motion Tracking Real-Time Navigation of an Untethered Ferromagnetic Device Using an MRI System in a Human Carotid Phantom Based on Pre-Acquired Waypoints Real-Time Prospective Shim Correction Using Self-Referencing Navigators Real-Time Quantitative Treated Volume Estimation in MR Guided FUS Uterine Fibroids Surgery Real-Time Registration by Contour Tracking for Interventional Guidance Using Cardiac MRI Real-Time SAR Monitoring to Ensure Patient Safety for Parallel Transmission Systems Real-Time Temperature Monitoring Using Line-Scan Phase Measurement Real-Time Tracking and Visualization of Regional Lung Motion with Dual Gradient Echo Acquisition Real-Time Ultrasound Imaging in MRI Scanner for Guidance of Cardiac MR Reciprocity and Gyrotropism in Magnetic Resonance Transduction Reconstructing Metabolic Images from Hyperpolarized 13C 3T MRSI Data Using AMARES for Reduced FID Sampling Reconstructing Topologically Correct Cerebral Surfaces - A Method Based on Simple Points Reconstruction in Image Space Using Basis Functions (RIB): Eigenmode Analysis Method Reconstruction of Arbitrary Non-Cartesian Trajectories Using Pseudo-Cartesian GRAPPA in Conjunction with GRAPPA Operator Gridding (GROG) Reconstruction of Dynamic Contrast-Enhanced Lung MR Imaging Using K-T BLAST Reconstruction of the Optic Radiation by Means of Combined DTI and fMRI Reconstruction of Variable-Density Data in Fourier Velocity Encoding Recovery Kinetics Throughout Successive Bouts of Various Exercises in Professional Road Cyclists Recruitment of Spinal Muscles in Static Postures Rectal Cancer at 3.0T: Correlation of DCE-MRI Findings with Tumor Angiogenesis Recurrence Quantification Analysis: A Model-Free Analytical Method for Cerebral fMRI Data Reduced Mid Parietal NAA and Creatine Marks Conversion from Mild Cognitive Impairment to Alzheimers's Disease Reduced-Voltage RF Shimming for Adiabatic Pulse Design in Parallel Transmission Reducing Artefacts by Inverting the Effects of Non-Rigid Motion During a Free-Breathing Liver Scan Reducing B1 Inhomogeneity Using Optimized Parallel Transmit Pulses Reducing Correlated Noise in fMRI Data Reducing Data Handling Issues in Large Coil Arrays by ‘If’ Undersampling Reducing Effects of Drift in fMRI Data Using Joint Reconstruction of R2* and Field Maps Reducing Measurement Error of DCE-MRI by Altering Arterial Input Functions Does Not Improve the Prediction of Outcomes for Breast Cancers Patients Treated with Chemotherapy Reducing Side Lobes and SAR in Parallel Transmission Using Variable Density Spirals Reducing the TR in SSFP Imaging with Ramp-Sampled FIESTA Reduction in Blood Volume and Vascular Permeability Induced by Anti-PDGF-R Therapy as Detected by DCE-MRI Reduction of False Positive Valued Area by Combining Probability Maps Reduction of Functional Connectivity in Cocaine Users Revealed by Resting-State Functional MRI Reduction of In-Flow Enhancement in 3D Balanced SSFP Cine Sequences Reduction of Lipid Contamination in MR Spectroscopic Imaging Using Signal Space Projection Reduction of Magnetic Susceptibility Artifacts in Olfactory fMRI with SENSE-GESEPI-EPI Method Reduction of Partial Volume Artifacts in DTI Tractography by Post-Processing Reduction of Random and Systematic Errors in ASL Quantitative Perfusion Maps Using Image Denoising Reduction of the Transient Oscillations in Alternating-TR SSFP Reduction of Vascular Artefacts in Arterial Spin Labeling Using Principal Component Analysis of Vessel Timeseries Reference Surface Constrained Navigation Controller for 3D Image Data & Real-Time MRI Reference-Less EPI Ghost Correction in Real-Time Cardiac MRI Regeneration and Carcinogenesis in a Model of Chronic Inflamed Liver Monitored by MRI Regional Analysis of Cartilage T2 Changes in the Knee After Running Regional and Developmental Variation in Vitamin C Concentration in the Rat Brain Quantified In Vivo Using Short Echo-Time 1H MRS Regional and Global Apparent Diffusion Coefficient in Inherited Prion Diseases: Correlation with Disease Severity Regional Differences in Cerebral Perfusion Parameters in Non-Human Primates: Comparison Between DSC and ASL Perfusion Imaging Regional Hippocampal Connectivity Index: Evaluation of an fMRI Marker for Alzheimer’s Disease Regional Metabolic Abnormalities as a Function of Age in Familial Amyotrophic Lateral Sclerosis (FALS) Mice Assessed Using 1H Magnetic Resonance Spectroscopy (1H MRS) Regional Pattern of Age-Related Water Diffusion Changes in Human Brain by Concordance and Dissociation Analysis of High-Field DTI Regional Perfusion Imaging Using Arterial Spin Labeling in the Assessment of Collateral Circulation – a Comparison with Digital Subtraction Angiography Regional Pulmonary Blood Flow: Comparison of Phase Contrast MR and Dynamic Contrast-Enhanced MR Perfusion Regional Quantification of Pulmonary Biomechanics Using Dynamic MRI of Grid-Tagged Hyperpolarized 3He Regionally-Specific Atrophy Following Traumatic Brain Injury Revealed by Deformation Morphometry of Serial 3 Tesla Volumetric MRI Registered 1H/23Na In Vivo Imaging of Human Articular Cartilage with 3D Cones Trajectory at 7T Registration of Anatomical MRI and Histological Sections for Rat Brain Registration of Dynamic Contrast-Enhanced MRI Using a Progressive Principal Component Registration (PPCR) Registration of High Order Diffusion Tensor Imaging Based on Apparent Diffusion Coefficients Relating Longitudinal and Cross-Sectional Analyses of Atrophy in Alzheimer's: BSI, SIENA and SIENAX Relating Yourself to Visual Scenes Incongruous with Body Posture: An fMRI Study Relation Between Axonal Damage and Inflammation by 1H-MRSI and T2-Weighted Lesion Volume in Early Relapsing Remitting Multiple Sclerosis. The Effect of Subcutaneously Interferon Beta-1a Relation Between Changes in Microvasculature Detected by MRI and Evolutions of the Expression of the Main Angiogenic Factors on Two Different Rat Brain Tumors Relationship Between 3He Gas ADCs and Lung Microstructure. Computer Simulations Relationship Between Body Fat Composition and Concentrations of Brain N-Acetyl-Aspartate and Choline Compounds in Middle-Aged Adults Relationship Between dGEMRIC and Other Histochemical Markers for Cartilage Proteoglycan Content Relationship of BOLD Response in SI of Primate Cortex to Intensity of Tactile Stimulation Relationship of Fatty Liver MR Spectroscopy to 7-Point Gradient-Echo Imaging Relaxation Properties of Cavitation Induced Tissue Lesions Relaxation Time Mapping in Skeletal Muscle During Reactive Hyperemia Relaxation Times Obtained by Dipolar Echo Techniques – a New Diagnostic Tool for Osteoarthritis Relaxivity of Cobalt Nanoparticles, a Novel MR Contrast Agent Relaxometry Study of Baboon Fetal Brains at 3T Relayed Carbon-13 Magnetization Transfer. Detection of Malate Dehydrogenase Reaction In Vivo Reliability of Deconvolution Methods and Parameter Formulas for DSC-MRI Brain-Perfusion Maps Reliability of Mismatch Measurement Methods Removal of Artifacts Arising from Stimulated Echoes in Proton Two-Dimensional Double-Quantum Magnetic Resonance Spectroscopy Removal of Lipid Nuisance Signals in MRSI Using Spatial-Spectral Constraints Removing Gradient Non-Linearity Effects in Deformation Morphometry of High Field Serial MRI Renal Cortical Volume Measured by MRI: A Feasibility Study Towards Estimation of Total Number of Glomerular in the Kidney Renal MRA at 3.0T with 0.1mmol/kg Gadolinium - Interindividual Comparision to Renal MRA at 1.5T with Full Dose of Gadolinium Renal R2 Changes and Dynamic Kidney Size Variations in Response to Vasoactive Substances in the Rat Reperfusion-Based Hemorrhagic Transformation in Spontaneously Hypertensive Rats: A Model for Translational Research Representative Colour Schemes for Visualisation of Diffusion Tensor Tractography Data Reproducibility and Convergence of CASL Perfusion MRI at 3.0 Tesla Reproducibility and Quality Assurance in Hyperpolarized 13C MRI and MRS Reproducibility of Bone Microstructure Parameters Measured with a Compact MRI for a Finger Reproducibility of DTI-Based Muscle Fiber Tracking Reproducibility of In Vivo GABA Quantification in Anterior Cingulate at 3 Tesla Reproducibility of In Vivo Localized MRI and MRS Measurements in Human Liver Reproducibility of Partial Pressure of Oxygen and Oxygen Depletion Rate in Animal Model Reproducibility of Pseudo-Continuous ASL at 1.5T and 3T Reproducibility of Quantitative Cerebral Blood Flow Measurement Using Contrast Agent Reproducibility of Quantitative Cerebral T2 Relaxometry, Diffusion Tensor Imaging, and 1H Magnetic Resonance Spectroscopy at 3.0 Tesla Reproducibility of Quantitative Magnetization Transfer Imaging Parameters Reproducibility of Quantitative Parameters Derived from Dynamic Hyperpolarized 3He MRI Reproducibility of Segmented Brain Volumes Using SPM5: Effects of Changes in Signal-To-Noise Ratio and Scanner Software Reproducibility of Shear Modulus Estimates in Clinical Steady State MR Elastography Reproducibility of Short Echo Time MRSI of the Human Brain at 3T Using a Semi-LASER Approach Resampling Strategies to Estimate Mean Concentrations from Low SNR In Vivo MR Spectra Residual Magnetism in an MR Suite After Field-Rampdown of an 8T Superconducting Magnet Resolution Enhanced TOSSI (T-One Insensitive Steady State Imaging) Resolution-Dependent Differences in Fiber Tracking and Quantification Resolving and Identifying an Unexpected MRS Peak – Arising from a PUFA – in the “Citrate Region” of Intact Human Prostate Cancer Tissue Using 1D and 2D 1H-HRMAS NMR Resolving Crossing Fibres Using Constrained Spherical Deconvolution: Validation Using DWI Phantom Data Resolving White Matter Fiber Crossings with Diffusional Kurtosis Imaging Respiratory Gated Body Diffusion Weighted Imaging Avoiding Prolongation of Scan Time: Tracking Only Navigator Echo (TRON) Technique Respiratory Motion Estimation Using Real-Time 3D Imaging for Improving Roadmaps in Image Guided Interventions Respiratory Variation of the Extrahepatic Bile Duct: Evaluation with Deep Inspiratory and Expiratory MRCP Response to Deep Inspirations in Reactive and Non-Reactive Asthmatic Subjects Using Hyperpolarized 3He MRI Resting Connectivity Elucidates the Effect of Daily Priming Stimulation on the Motor Cortex Resting in Peace, Noise or with Instructions: The Influence of Scanner Background Noise on the Default Mode of Brain Functions Resting State fMRI of the Thalamus Resting-State Functional Connectivity and Stimulation-Induced Neural Activity in the Cortex and Sub-Cortical Structures of Rat Brain Retrograde Wallerian Degeneration of Cranial Corticospinal Tracts in Cervical Spinal Cord Injury Patients Using Diffusion Tensor Imaging Retrospective Adaptive K-Space Filtering for Improved Image Quality in Hyperpolarized Gas MRI Retrospective Gating for Whole Body Mouse MRI Retrospective Quality Assessment of fMRI Data Reversible Axonal Injury Detected by DTI and Immnohistochemistry Reversible Loss of N-Acetyl Aspartate After Transient Middle Cerebral Artery Occlusion in Rats: A Longitudinal Study by Proton Magnetic Resonance Spectroscopy RF Heating Model of Active Implants During MRI Examinations RF Non-Uniformity Over the Whole Heart at 3T RF Pulse Design for Adiabatic Spin Decoupling RF Pulse Design for High-Resolution Imaging with FLASE RF Pulse Design Methods for Reduction of Image Artifacts in Parallel RF Excitation: Comparison of 3 Techniques on a 3T Parallel Excitation System with 8 Channels RF Safety Aspects for Hip Implants During MRI: A Comparison Between Numerical Calculations and Experimental Measurements RF Safety at 9.4T - Porcine In Vivo Results RF Shimming and SAR Considerations with an Eight-Element 3T Body Coil RF Shimming Considering Both Excitation Homogeneity and SAR RF Shimming Using a Multi-Element Transmit System in Phantom and In Vivo Studies RF Shimming with a Conventional 3T Body Coil RF-Induced Electromagnetic Fields and Implant Heating in MRI RF-Safe Intravascular Imaging Using a Self-Visualizing Transformer Line Rician Noise and the T2 Distribution: Fitting Complex Decays Rician Noise Reduction in MR Images Via Non-Local Maximum Likelihood Estimation Right Ventricular Late Enhancement – A Rare Correlate of Different Pathologies in Contrast-Enhanced Cardiac MRI Rigid Head Motion Correction for DTI Using Non-Linear Conjugate Gradient Ring Structured RF Coils for Ultra-High Field MRI Robust Carotid Atherosclerotic Plaque Imaging at 3.0T with Black Blood Single Shot EPI Robust Detection of Contrast Bolus Arrival in Time-Resolved Magnetic Resonance Angiography Robust DSC-MR Perfusion Using a Patient Motion Correction Scheme Robust Kinetic Model Fitting for Motion Corrupted DCE-MRI Data Robust Lung Morphology Assessment in Children with Cystic Fibrosis (CF) Using Ultra-Short TR/TE 2D Steady State Free Precession (SSFP) Robust MR Thermography with iZQCs Robust Water and Lipid Suppression Using Multiple Dualband Frequency-Selective RF Pulses for 1H Spectroscopic Imaging at 3T ROC Analysis Improves CMRO2 Estimation for Rehabilitation Subjects Rodent Cardiac MRI on 3T Clinical Scanner: Comparison with 4.7T ROI Based Analysis of Diffusion Tensor Imaging in Traumatic Brain Injury Role of 3D 1H MR Spectroscopy for Prospective Detection of Prostate Cancer in Men with Prior Negative Biopsies Role of Diffusion-Weighted MR Imaging in Comparison with PET/CT Imaging for Lymph Node Detection of the Abdomen and Pelvis Role of Functional MR Imaging Is Assessing Treatment Response to Transarterial Chemoembolization (TACE) in Patients with Hepatic Metastatses Role of Glutamate Release in Ketamine-Induced Blood-Oxygenation Level Dependent (BOLD) Responses: An fMRI Study in Rats. Role of Magnetic ‘Structure’ in Determining In Vivo Relaxivity-Iron Behavior: Size Does Matter Roughness: A Reshuffling-Variant Differential Geometric Index for DWI Safety and Feasibility of Using Implanted Depth Electrodes for Intracranial EEG-fMRI at 3 Tesla Safety of Human MRI at Static Fields Above the FDA 8T Guideline: Exposure to a 9.4T Static Magnetic Field Does Not Change Vital Signs and Cognitive Ability Safety of Localising Intracranial EEG Electrodes Using MRI SAR Analysis for Transmit SENSE at 7T with a Human Head Model SAR and B1 Field in a Human Head Model for Birdcage, TEM and Microstrip Coils at 7T SAR and Temperature Rise Evaluation for Pregnant Woman Models During MRI SAR and Temperature Rise Within Tissues Near a Medical Implant SAR Reduction for Parallel Transmission Using VERSE and K-Space Filtering SAR Reduction in Transmit SENSE Using Adapted Excitation K-Space Trajectories SAR Simulations and Experiments for Parallel Transmission SAR-Reduced TrueFISP Using Variable Flip Angels: Influence on In-Plane Resolution and SNR Properties Saturated T2 /sub> Curves for Relaxometry-Based Compartmental Analysis in Localized 1H MRS Scaling Up 129Xe Hyperpolarization - A Diagnostic Tools System Scaling-Up 129Xe Hyperpolarization - Theoretical Modeling Scan Time Reduction and Selective Maximization of Three Metabolites of Interest with 31P LFA-MRS in Human Brain at 3T Schizophrenia Patients Showed Impaired Hippocampal and Prefrontal Responses During Associative Learning: fMRI Evidence of Hypoactivation and Dysplasticity Secondarily Generalized Seizures Induce a Functional Reorganization of Working Memory, as Demonstrated by fMRI Segmentation of Abdominal Fat in MR Images Segmentation of Gd-DTPA Enhancing Lesion of Brain Using Time to Peak of Concentration Time Curve and Its Pharmacokinetic Analysis in Dynamic Contrast Enhanced (DCE) MRI Segmentation of Subtraction Images Yields Improvement in Reproducibility and Sensitivity of Lesion Change Measurements in MS Segmentation of Tumor Necrosis by Mapping Fractional Plasma Volume (fPV) from Dynamic Albumin-(Gd-DTPA)30 Enhanced MRI for Evaluation of Therapeutic Response to Gefitinib in Breast Cancer Model Selective Cell Kill of Breast Cancer Cells through Choline Kinase Downregulation as an Adjunct Therapy Selective Damage of the Visual Pathways in Patients with Migraine: A MR Tractography Study at 3 T Selective Homonuclear Hartmann-Hahn for 13C-13C Polarization Transfer in Solution State NMR Selective Involvement of the Amygdala in Systemic Lupus Erythematosus Selective Modulation of Functional Connectivity in the Brain’s Reward Pathway by D3 Receptor Antagonism Selective Passive Shielding Selective Rotation Pulses Calculated with an Inverse Scattering Algorithm Selective Visualization of Hypokinetic Small Bowel Loop Using Low B Value EPI Selectively Dissolvable Manganese/Alginate Microcapsules for Novel Drug Delivery Strategies and Positive Contrast Imaging at 3T Self Calibrated Spiral-In/Out for fMRI Self Rewinding Trajectories for Spectroscopic Imaging Self-Calibrated GRAPPA Operator Gridder (SC-GROG) Self-Calibrated Multi-Echo Sequences: Use of Conjugate Gradient Method with Radial Trajectories to Remove Phase Cancellation Self-Calibrating Cartesian Parallel MRI Using Continuous Sampling Sequences Self-Gated Multi-Animal Cardiac Cine Imaging Self-Gated PROPELLER Cine Cardiac Imaging: Simultaneously Tracking the Cardiac Pulsation and the Respiratory Motion Semi-Automated Carotid Arterial Morphometry from Sub-Millimeter Isotropic Spatial Resolution Diffusion-Prepared SSFP Data: A Feasibilty Study Semiautomatic 3D Segmentation and Quantification of Stenotic Carotid Arteries from CE-MRA by Means of a B-Spline Tubular Surface Model Semiconductive Coated Transverse Gradient Board Increases Partial Discharge Inception Voltage Semi-Quantitatively Assessed Non-Contrast-Enhanced MRI for Lung Cancer Screening: Detectability and Initial Outcome in 161 Cases SENSE EPI Water-Fat Imaging SENSE Factor Optimization for Diffusion Tensor Imaging of the Human Brain at 7T SENSE Factors for Reliable Cortical Thickness Measurement Sensitive and Automated Detection of Iron-Oxide Labeled Cells Using Phase Image Cross-Correlation Analysis Sensitive J-Coupled Metabolite Mapping Using Sel-MQC with Selective Multi Spin Echo Readout Sensitive Positive Contrast Imaging of Paramagnetic Contrast Agent Distributions by Visualizing Phase Gradients Sensitivity Analysis of Cross-Relaxation Imaging Sensitivity of DCE-MRI to Fractional Volumetric Changes in Tumor Delineation: A Semi-Automated Study Sensitivity of Feedback-Enhanced Contrast to Sub-Voxel Microscopic Field Variations Sensitivity of Low Flip Angle SSFSE of the Abdomen to Cardiac Motion Sensitivity of Random Effects Analyses to Group Size and Individual Outliers: A Jackknife Study Sensitivity Study of MR–Based Temperature Mapping at 7T Separate Detection of NAA and NAAG Using MEGA-PRESS at 3 Tesla Sequential Cerebral Hemodynamics and Oxygen Metabolism MRI Study in Rats Before, During and After Middle Cerebral Artery Occlusion Sequential Imaging of Tissue pO2 by Electron Paramagnetic Resonance Imaging and Anatomy by MRI at 300 MHz Serial Cellular Changes After TACE as Detected by Perfusion and Diffusion-Weighted MR Imaging in Patients with Unresectable HCC Serial Dynamic Contrast Enhanced MR Imaging to Quantify Treatment Induced Temporal Changes in Brain Tuberculomas Serial MR Spectroscopic Imaging of NAA and Lactate Levels After Ischaemic Stroke Serial Proton MRS Evaluation of Neurometabolism in a Mouse Model of Systemic Lupus Erythematosus (SLE) Serial Sodium MRI During Non-Human Primate Focal Brain Ischemia Severely Reduced Creatine Levels in Skeletal Muscle and Brain of Mice Lacking Arginine: Glycine Amidinotransferase Assessed by Multinuclear MRS Sex Difference and Age Dependence of the Human Brain Structure Delineated at the High Magnetic Field of 4.7T Sex Differences in the Mid-Sagittal Area of Corpus Callosum in the Human Brain Image Obtained at 4.7T Sharpening Improves Clinically Feasible Q-Ball Imaging Reconstructions Shim Requirements for High-Order Localised Shimming of the Human Brain Short Echo Time Proton Spectroscopy of the Human Brain at 3 Tesla Using an Optimized PRESS Sequence Without Water Suppression Short-Echo-Time 1H MRS of the Mouse Lacking Brain-Specific Glutamate-Dehydrogenase Short-TE Proton Spectroscopic Imaging of the Neurochemical Profile in the Rat Brain at 1 µl Resolution Short-Term Metabolic Changes in Rat Brain After Intravenous CDP-Choline Administration Studied by Means of Localised 31P and 1H MR Spectroscopy In Vivo Short-Time-Scale and Long-Time-Scale 3He Diffusion MRI in Emphysema: Which Is More Sensitive? Shutter-Speed DCE-MRI Pharmacokinetic Analyses Facilitate the Discrimination of Malignant and Benign Breast Disease Signal and Contrast Properties of Very-Long Spin-Echo Trains for 3D T2-Weighted Turbo-Spin-Echo Imaging Signal and Shape of Subthalamic Nucleus on Susceptibility-Weighted Image (SWI). -Comparison with STIR Image- Signal Changes of the Brain in Susceptibility-Weighted Imaging Under Low Cerebral Blood Flow Signal Dropouts in EPI Caused by Susceptibility-Induced Gradients in the Readout Direction: Modeling and Compensation Signal Intensity of the Motor Cortex on Phase-Weighted Images at 3T Signal Processing and Image Reconstruction for SWIFT Signal Vector Decoupling for Transmit Arrays Signal-To-Noise Analysis of T1-Based Fluid Oxygen Partial Pressure Measurements Signal-To-Noise Ratio of IDEAL-Separated Water and Fat Images from Accelerated Acquisitions Significance of Interictal Water Diffusion Changes in Frontal Lobe Epilepsy. Correlations with Stereo-Electro-EncephaloGraphy (SEEG) Simple and Robust Design for Susceptibility-Matched NMR Magnetic Field Monitoring Probes Simple Digital Tuning System for Large Arrays of Coils Simplified Perfusion Quantification for Arterial Spin Labeling in Case of Whole Brain Coverage Simulating the Tagging Process in Velocity-Selective ASL Simulation and Experimental Verification of the Diffusion in the Interstitial Space Simulation of Relative Temporal Resolution of Time-Resolved MRA Sequences Simulation of the Effect of Mode Coupling on SAR for a Birdcage Resonator Simulation Study for Suppression of Myo-Inositol for Glycine Measurement by PRESS at Various Field Strengths Simulations of In Vivo 3D Structural MRI of Trabecular Bone Using High Resolution µCT Simulations of a 3D-Segmented Asymmetric Body Coil for Parallel Transmission Simultaneous 19F/1H Imaging for Quantification : Calibration and Sensitivity Assessment Simultaneous Acquisition of Morphological Images and Functional T2 Values: A Feasibility Study in Patients After Cartilage Repair in the Knee Using a Double Echo Steady State (DESS) Approach at 3 Tesla Simultaneous Acquisition of Short and Long Echo Time Spectra of the Mouse Brain Using Proton Magnetic Resonance Spectroscopic Imaging at 11.75 T Simultaneous and Quantitative Investigation of the Cerebral Arterial and Venous Vasomotor Reactivity Using Phase-Contrast Magnetic Resonance Imaging Technique: A Multi-Fractional CO2 Inhalation Approach Simultaneous and Ultrafast Monitoring of CMRO2, CBF and pO2 Changes in Response to Acute Global Ischemia in Rat Brain Simultaneous Bilateral Imaging of the Femoral Arteries in Peripheral Arterial Disease Patients Simultaneous Dynamic R1 and R2* Measurement for AIF Assessment Combined with DCE MRI in a Mouse Tumor Model Simultaneous EEG and fMRI of Centro-Temporal Spikes in Benign Focal Epilepsy of Childhood Simultaneous Estimation and Correction of Main Field Inhomogeneity Simultaneous Image Acquisition of Human Extremities Using a Super-Parallel MRI Simultaneous Measurement of Cerebral Blood Volume, Cerebral Blood Flow, and Cerebral Blood Oxygenation After Hypercapnia Challenge: A Preliminary Result Simultaneous Measurements of Ascorbic Acid and NAA in the Rat Brain In Vivo Using a Single-Shot, Two-Echo Selective Multiple Quantum Spectroscopy Simultaneous Monitoring of Temperature and Magnetization Transfer During HIFU Transmission: ex Vivo Experiments Simultaneous Off-Resonance Correction and Fat/Water Separation for Non-Cartesian Trajectories Using a Multi-Frequency Least-Squares Approach Simultaneous Optical and MR Imaging of Window Chambers Simultaneous PET-MR: Toward a Combined microPET®-MR System Simultaneous Quantification of Myocardial Deformation and T1-Relaxation Simultaneous Recording of Auditory-Evoked Brain Potentials and Continuous, High-Field Functional Magnetic Resonance Imaging in Humans Simultaneous T1, T2 and Spin Density Quantification in 5 Seconds Using Inversion Recovery SSFP Simultaneous T1, T2, PD, and B1 Mapping with Dual Angle IR-bSSFP (DAIRy-bSSFP) Simultaneous T2 and T2* Dynamic Susceptibility Contrast Perfusion Imaging Using a Multi-Echo Parallel Imaging Approach Simultaneous Temperature and Motion Tracking Using HARP MRI [T-HARP] Single Breathhold CINE T1 Mapping of the Heart Single Breath-Hold MR Imaging of the Bowel Employing a 32-Channel Coil Single Session Whole Body T2-Weighted and T1-Weighted MRI (Both with and without Fat Suppression) Single Subject Voxel-Based Analysis in Mesial Temporal Lobe Epilepsy Single Voxel In Vivo Proton Spectroscopy of Gynaecology Lesions: Initial Experiences of Choline Quantification at 1.5T and 3.0T Single Voxel Proton Resonance Spectroscopy as a Method for the Classification of Brain Tumors Using Artificial Neural Networks Single Voxel Spectroscopy of the Pons: Shimming, Quantitation, and Reproducibility Issues at 3T Single-Shot 3D GRASE with Cylindrical K-Space Using Circular and Fly-Back K-Space Trajectories Single-Shot ADC Imaging for fMRI Single-Shot MR Spectroscopic Imaging with Partial Parallel Imaging Single-Shot Z-Shimmed Sensitivity-Encoded Spiral-In/Out Imaging for fMRI Single-Voxel 1H MRS of the Rat Brain: Effect of Anesthesia Single-Voxel Proton MRS at 1.5 Tesla Significantly Correlates with Hypofrontality in Schizophrenia Six-Fold 2D-SENSE Accelerated Intracranial Contrast-Enhanced MR Venography - A Comparison Between 1.5T and 3T Size-Dependent Chemical Exchange Saturation Transfer (CEST) in Liposomes Skeletal Muscle Mitochondrial Function and Intramyocellular Lipids in the Diabetic ZDF Rat: A Longitudinal Study Using In Vivo 31P and 1H MRS Skeletal Muscle Oxidative Capacity in Children: A 31P-MRS Study Slice Dispersed Linear Combination SSFP - A New Tool for Banding Reduction Slice Profile Effects in Variable Flip Angle Hyperpolarized 3He MRI Slice Selective Parallel Excitation in the Presence of Off-Resonance Sliding Phase Encoding in Table Motion Direction for 3D Continuously Moving Table Imaging SLIPS - A Novel Method for Rapid Three-Dimensional Spin-Locked Imaging Small Hypervascular Hepatocellular Carcinoma: Diagnostic Value of Portal and Equilibrium Phase on Dynamic MR Imaging in the Cirrhotic Liver Smart Algorithm for the Acquisition of the Optimal Set of Projections for Functional MRI Smoking: A TBSS and VBM-Style Investigation of White Matter Integrity and Grey Matter Volume Smoothelin-B Deficiency in Mice Results in Increased Thoracic Aorta Circumferential Stretch and Mild Cardiac Hypertrophy Snap-Shot ASL Snapshot MRI with Volume Reconstruction of the Fetal Brain SNR and G-Factor Optimized 16-Channel Anterior Cardiac Array for 3T SNR Enhancement of Real-Time Cardiac Imaging by Respiratory Motion Corrected Averaging SNR Estimation in Fast Dynamic Imaging Using Bootstrapped Statistics SNR Performance of Q-Space Formalism and Multi-Exponential Modelling for Hyperpolarized 3He Gas Diffusion Spectroscopy in Human Lungs SNR Variation with Regularization Term for Non-Cartesian SENSE Reconstruction Social Network Analysis of Functional Connectivity Sodium Chemical Shift Imaging of Induced Diuresis in a Mouse Renal Model Sodium MRI Clocks Pre-Necrotic Alterations in Rat Glioma Model Without Changes in Tumor Diffusion Solid Hypervascular Liver Lesions: Accurate Identification of True Benign Lesions on Delayed Hepatobiliary Phase MR Imaging After Gadobenate Dimeglumine Soluble Telencephalin is a Marker for Frontotemporal Dysfunction in Epilepsy as Revealed by fMRI Source of the Myocardial “Bite” Artifact in High Field Cardiac MRI Sources of Quantitative Error in T2 Mapping of Articular Cartilage Sparse Spokes Slice Selective Design for B1 Inhomogeneity Correction at 7T Spatial and Temporal Accuracy of MR Thermometry During MRI-Guided Prostate Thermal Therapy Spatial Fuzzy Clustering of fMRI SPMs Using MRF's Spatial Interference in Localized J-Difference GABA Editing Spatial Localization with Pulsed Second-Order Shims Spatial Mapping of Mineralization with Manganese-Enhanced Magnetic Resonance Microscopy Spatial Normalization of fMRI Results Using Study-Based EPI and T1-Weighted Brain Templates Spatial Segmentation Based on the Signal Time Activity of Dynamic Cardiac Images During Intracoronary Infusion of Gd Contrast Agent Spatial Specificity of CBV and BOLD fMRI in Monkey Striate Cortex at 4.7T and 7T Spatially Resolved Measurement of Bone Marrow Fat Content and Unsaturation Index Via Spectroscopic MR Imaging Spatio-Spectral Non-Linear Filtering of Spectroscopic Imaging: Increasing Signal-To-Noise Ratio While Preserving Spatial and Spectral Structures Spatio-Temporal Fuzzy Clustering of fMRI Timeseries Spectroscopic Imaging of Cryopreservative Concentration and Diffusion in Cartilage Spectroscopic Imaging of the Knee Using an Interleaved Ultrashort TE (UTE) Sequence Spectrum Optimized Parallel Excitation Pulse Design Sphere Model to Study SENSE Imaging Performance Spin Echoes Underestimate Functional Changes in Microvascular Cerebral Blood Volume Spinal Cord Blood Flow (SCBF) Measurement by Arterial Spin Labeling (ASL) Spinal Cord fMRI: Functional Response and Linear Model Assessment Spin-Echo fMRI of the Temporal Lobe in Awake, Behaving Monkeys at 7T Spin-Echo Micro-MRI of Trabecular Bone Using an Improved 3D FLASE Sequence SPIO Enhanced MR Imaging Permits Accurate Differentiation of Benign from Malignant Focal Hepatic Arterial Phase Gd-Enhancing Lesions in End Stage Liver Disease SPIO Labeling Promotes Cardiac Differentiation of Embryonic Stem Cells in Vitro But Does Not Prevent Their Uncontrolled Proliferation In Vivo SPIO-Loaded Nano Test Tubes as Ultra-Sensitive MRI Contrast Agents Spiral Diffusion Tensor Imaging at 7T - Fiber Tracking on a Rat Model of Brain Trauma SQUID-EPR and Magnetization of the DNP-MRI Trityl Radical SSFP fMRI at 0.37 Mm3 Voxel Volume: Effects of Spatial Resolution on SNR and Functional Sensitivity SSFP fMRI with Parallel Interleaved Multiple Frequency Acquisition SSFP in the Steady-State Can Detect Myocardial Edema in Canines Stability Evaluation of Geometric Distortion Correction in Multi-Station Whole-Body MR Imaging Stand-Alone GUI of Analyzing and Displaying Proton 2D/3D MRSI Data Sets with LCModel Standardization Decreases Interpatient Differences in rCBV Measurements as a Function of Brain Tumor Grade Standardized Threshold Approach Using 3D Proton MR Spectroscopic Imaging in Prostate Cancer Localization of the Entire Prostate Statistical Analysis of Metabolites of Histologically Confirmed Preinvasive and Invasive Cervical Cancer Tissue Using 1H HR MAS Statistical Shape Analysis on 3D MRI of the Ventricular System of the Cyln2/Rsn Double Knock-Out Mice Statistical Shape and Position Analysis on 3D Structural MRI Data of a Motor Region Involved in Vocal Behavior of Songbirds Steady-State Free Precession Diffusion Tensor Imaging in Human Brain Fixed and In Vivo Tissue Stimulated Echo Prepared Balanced SSFP with Variable T2* and T1 Contrast Stimulus Induced Rotary Saturation (SIRS); A New Method for the Direct Detection of Neuronal Currents with MRI Strain-Encoded Magnetic Resonance Imaging Provides Reproducible Assessment of Right Ventricular Regional Function Strategies for Improved Temporal and Spatial Resolution: In Vivo Oxymetric Imaging Using Time-Domain EPR Strategies to Improve Temporal Resolution of PARACEST MRI Strategy and Validation of Large-Scale MRI Registration Framework Streak Artifact Suppression in Multi-Coil MRI with Radial Sampling Stretchable Coil Arrays Stripline/TEM Transceiver Array for 7T Body Imaging Stroke Volume and Cardiac Output Measured on a Beat-To-Beat Basis Stroma Fibroblasts are Recruited Systemically to Contribute to the Tumor Angiogenic Rim: Cell Tracking by MRI and Two Photon Microscopy Structural Abnormalities of Adolescent Males with Attention-Deficit/Hyperactivity Disorder: A DTI Study Structural Asymmetry of the White Matter Language Pathway in Relation to Functional Hemispheric Language Lateralization in Both Right and Left-Handed Healthy Subjects: A Combined Functional MRI and DT-Tractography Study. Structural Brain Deficits in Smokers Measured by MR Volumetry at 3 T Structural Correlates of Implicit Memory Learning Deficits in Developmental Dyslexia Structural Equation Modeling of Resting-State Temporal Lobe Functional Connectivity Structure Effect of Biodegradable Macromolecular MRI Contrast Agents on Tumor MR Imaging in an Animal Tumor Model Study of Brain Metabolite Change in Amyotrophic Lateral Sclerosis Using TE-Averaged PRESS Study of Magnetization Behavior of MR Tagging with Steady State Free Precession Study of MR Interference in a Combined Small Animal PET/MR Scanner and In Vivo Simultaneous Imaging Subclinical Carotid Atherosclerosis by MRI Is Associated with Coronary Atherosclerosis Measured by CT and MRI: Initial Results Subcortical Physiological Abnormalities in Type 2 Diabetes Detected Using Magnetization Transfer Subdivisions of Mid-Sagittal Corpus Callosum by Cortico-Cortical Connectivity with QBI Tractography Subjective Symptoms During MRI of the Upper Abdomen and Pelvis at 3T Sub-Millimolar PARACEST Detection Using EPI-CEST Sub-Pixel Image Registration Using Ferrite-Containing Micro-Beads Subregional Analysis of Tibial Cartilage Changes in Persons with Knee Osteoarthritis and Malalignment Subtraction Errors in Regional Perfusion Imaging Using a Single Control Aquisition Suitability of T1(Gd) as the "dGEMRIC Index" at 1.5T and 3.0T Super-Resolution for Whole Body Diffusion-Weighted MRI Suppression of Large Scale Susceptibility Artifacts in Positive Contrast Images Suppression of Noise in Dynamic Magnetic Resonance Inverse Imaging Using Signal-Space Projection Suppression of Residual Transverse Magnetisation in SPI Sequences Using Phase Cycling Filter Surface Coil Intensity Correction for Phase Sensitive Inversion Recovery Delayed Enhancement of Myocardial Infarction Improves Image Appearance Surpassing Square-Root of Imaging Time Accuracy Gain in T1 Estimation Using SPGR Sequence Susceptibility Weighted Imaging (SWI) of Cerebral Blood Oxygenation During Voluntary Hyperventilation and Apnea Susceptibility Weighted Imaging at 1.5T, 3T and 7T Susceptibility Weighted Imaging Reveals Unique Information in Multiple-Sclerosis Lesions Using High-Field MRI Susceptibility Weighted MRI for Assessment of Ferritin Content in Liver and Spleen in People at High Risk for Type 2 Diabetes and Detection of Changes After Phlebotomy Susceptibility-Matched Multiwell Plates for High-Throughput Screening by MR Imaging and Spectroscopy Susceptibility-Weighted Imaging of Brain Tumor Patients at 7T Using an Autocalibrating Parallel Technique Susceptibiliy Matching the Head Fixing Implant for Alert Animal High Field fMRI Symmetric Echo Acquisition of Hyperpolarized C-13 MRSI Data in the TRAMP Mouse at 3T Synthetic Vs. Directly-Acquired MRI of Identical-Slice Brain Images: Large Scale and Multi-Contrast (PD, T1, and T2-Weighted) Image Quality Comparison System Characterization for VP-PROPELLER MRA Systematic Evaluation of Linear and Nonlinear DTI Estimation Methods: An Open Framework Systemic Sclerosis: Detection of Myocardial Fibrosis by Magnetic Resonance Imaging T1? MRI of Patients with Alzheimer’s Disease T1? MRI of the Human Brain Using a Spin-Locked SSFP Pulse Sequence T1 and T2 Relaxation Times of Human Median Nerve at 3 Tesla T1 Mapping in Childhood Abdominal Tumours T1 Mapping to Identify Changes in Cortical Structure T1 Measurement of Brain Metabolites at 3T with a Saturated-Inversion Recovery Method T1 Relaxivity of Liposomal-Encapsulated Gadolinium Contrast Agents: Effect of Particle Size and Gadolinium Concentration T1? and T2 of Fat and Water as Surrogate Markers for Trabecular Bone Structure T1(Gd) of Meniscus in dGEMRIC Scans: An Index of Meniscal Tissue Degeneration? T1-Contrast Enhanced Single-Point Dixon with Integrated PSIR Based on Orthogonal Phase T1-Mapped Acute Cocaine-Induced Brain Activation with Systemic Administrated Manganese-Enhanced MRI T1-Optimized Single-Slab 3D Turbo Spin Echo Imaging with Long Echo Trains T1rho Imaging of Cartilage in High-Field Scanner: Effects of Field Inhomogeneity T1-Weighted PROPELLER GRE Using Inversion Recovery (IR) T2 and T2* Mapping of the Human Femoral-Tibial Cartilage at 1.5 and 3 Tesla T2 Relaxation Illustrates Correlation Between Myelin Development and Verbal IQ Scores in Young Males T2 Relaxation of Coupled Spin Resonances of Cerebral Metabolites in Rat Brain at 9.4 T T2 Weighted fMRI with Whole Brain Coverage at Ultra-High Fields T2* Quantification Can Differentiate Alzheimer’s Plaques Burden Following Anti-Amyloid Therapy T2* Relaxometry for Quantitative 3.0 T MR Imaging of Iron Deposits in Alzheimer’s Disease Brain T2* Sensitized High Resolution MR Venography Using 3D-PRESTO ( Principles of Echo Shifting with a Train of Observations) T2* Value Correlates with Iron Concentration in Atherosclerotic Rabbit Aorta T2*-Weighted Cardiovascular Magnetic Resonance Imaging Detects Reperfusion Hemorrhage in a Dog Model of Myocardial Infarction T2-Prepared SSFP Improves Diagnostic Confidence in Edema Imaging in Acute Myocardial Infarction Compared with Turbo-SpinEcho T2-Star Relaxation as a Means to Diffrentiatie Cartilage Repair Tissue After Microfracturing Therapy T2-Weighted MR Imaging in the Female Pelvis with PROPELLER (BLADE) Data Acquisition; Comparison with Conventional T2-Weighted MR Images T2-Weighted MR Imaging of the Pelvis at 3.0 Tesla: Optimum Routine Fast Spin-Echo Sequences T2-Weighted Volumetric Acquisition with Water-Fat Separation in a Clinically Feasible Scan Time Tapered Head Gradient Coil Design Using the Wave Equation Method Targeted Imaging of Breast Cancer Brain Metastasis Using Antibody Labeled Manganese Oxide (MnO) Nanoparticles Targeted Treatment of Localized Regions Within the Prostate Gland Using MRI-Guided Transurethral Ultrasound Therapy Targeting Tumor Cells with Gd(III) Chelates by Means of the Glutamine Transporting System Tau Hyperphosphorylation in the Hippocampus of Alzheimer-Like Rat Is Associated with Reduction of Total Choline TBLADE-Spatiotemporal PROPELLER MRI Teasing Apart the Paced Auditory Serial Addition Task (PASAT): An fMRI Study Temperature and Oxygenation Dependence of Haemoglobin and Hemocyanin Relaxation Times at 9.4T Temperature Imaging with a MRI-PARACEST Contrast Agent: Eu-DOTAM-Gly-Phe Temperature Mapping Considerations in the Breast with Spectroscopic Imaging: Internal Referencing Significantly Improves Temperature Change Stability In Vivo Temperature Mapping in Human Brain Postmortem by MR Spectroscopic Imaging Template-Based Automatic DTI Fiber Bundle Labeling Temporal and Regional Evolution of Aquaporin 4 Expression and Magnetic Resonance Imaging in a Rat Pup Model of Neonatal Stroke Temporal and Spatial Evolution of Wallerian Degeneration in Central Nervous System Detected Using DTI Temporal Assessment of Rat Brain Vasculature After Transient Focal Cerebral Ischemia Temporal Changes in Moderate-To-Severe Traumatic Brain Injury: A Tract-Based Spatial Statistical Analysis Temporal Profiles of the Infarct Frequency in Acute Stroke Temporal-Spatial Analysis of Acupuncture Effect: A Functional Connectivity Study Tensor Estimation for DTI Using Non-Linear Conjugate Gradient Tensor-Based Morphometry and Classifier Algorithms for the Identification of Structural Brain Changes in Geriatric Depression Test-Retest Reliability of Functional MRI Using Smart Phantom: Analysis II Test-Retest Reproducibility of Cerebral and Subjective Responses to Painful and Non-Painful Contact-Heat Evoked Potential Stimulation (CHEPS) Texture Analysis Parameters and the Point Spread Function Texture Based Computer Aided Malignant Lesion Segmentation of MR Mammography Images Compared with Majority of Manual Segmentations TGRAPPA on Rat Hearts In Vivo Using a 4-Channel Receive Array at 9.4 T Thalamic Involment in Painful and Painless Diabetic Neuropathy on H-MRS Thalamic Metabolic Characterization of Human Mild Traumatic Brain Injury Thalamo-Cortical Abnormalities Correlate with Thalamic Atrophy in CIS Patients at Presentation THE "Mirror-Neuron" and Cortical Adaptation in MS: A 3 Tesla fMRI Study The "Rung Pair" Birdcage Coil That Has the Transmission Line Resonance Mode The “Whirlpool” Sign - A Turning Point in the Diagnosis of Pelvi-Ureteric Junction Obstruction The 3T Loopless Antenna: SNR Triples Compared to 1.5T, Heating Suppressed The 5 Minutes MR Examination Using Rapid Quantification of T1, T2 and Proton Density The ADC Value in Hormone Refractory Prostate Cancers on Diffusion-Weighted MR Images for Predicting Effect of Chemotherapy The Added Value of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) in Predicting Depth of Myometrial Invasion and Overall Staging in Patients with Endometrial Carcinoma The ADNI Phantom and Analysis Algorithm: A New and Accurate Tool to Measure Scanner Performance The Advantage of MRI in Detecting Congenital Anomalies of Fetal Spine Comparing with Ultrasonography The Age and Gender Dependence of Total Transverse Relaxation Rate in Normal Human Brain at 3 T The Apparent Diffusion Coefficient Response During Brain Activation: A Gradient-Echo EPI Study at 9.4 T The Application of Acceleration Techniques for High Spatial and High Temporal Resolution Extra- And Intracranial Contrast-Enhanced MRA The Application of Consistency Constraint in Sliding Window Functional MRI Analysis The Application of Diffusion Weighted Whole Body Imaging with Background Body Signal Suppression (DWIBS) in Lung Malignancies Pre- And Post-Treatment with CT-Guided Ar-He Cryoablation The Applications of Nanoshells and Nanocapsules in Magnetic Resonance Molecular Imaging The Assessment of Tumor Angiogenesis and Hypoxia Using Multi-Parametric and Multi-Modal Imaging The Benefit of Reduced FOV Diffusion Imaging with and without SENSE The BOLD FMRI Response to Spontaneous Fluctuations in CO2, Evaluated in the Human Brainstem The Bold Signal Response Differences Between Encoding and Recognition Memory of Face-Name Associations The Cg25 Resting State Network The Characterization of MRI Artifacts Surrounding Brachytherapy Seeds for Use in Localization The Clinical Value of ADC Maps in the Detection of Prostate Cancer The Clinical Value of Veno-BOLD on Vascular Malformations at 3.0T The Combined Application of MRI and 3D Contrast Enhanced Time-Resolved MRA in Detecting Spinal Cord Vascular Diseases The Cone of Uncertainty Is Elliptical: Implications for DTI Tractography The Developing Canine Brain: Characterization by MRS and DTI The Dissolving Aspirin Sign: An Aid in Differentiating Benign and Malignant Lesions Detected During Gadolinium-Enhanced Breast MRI The Distribution of Pulmonary Perfusion as Measured by FAIR MRI The Effect of Age on the SNR of CBF and BOLD Measures of Functional Activity The Effect of Cerebrovascular Risk Factors on Regional Cerebral Blood Flow: A Population Study with Arterial Spin Labeling MRI The Effect of Charge on the Uptake Kinetics and Distribution of Gadolinium Chelates in dGEMRIC Cartilage MRI The Effect of Feature Extraction on MRS Brain Tumour Classification The Effect of Gd-DTPA Dose on Renal Function in a Rat Cisplatin-Induced Chronic Renal Failure Model The Effect of Linear and Micro-Circular Shear Flow on Diffusion MR Measurements The Effect of Myelin on the Q-Space and Conventional DTI Indices in Excised Myelin-Deficient Rat Brains The Effect of Navigator Resolution on Registration Accuracy in Rigid Head Motion Correction The Effect of Of Meal Calorie Content on Water Secretion and Absorption in the GI Tract Using MRI The Effect of Oligodendroglial -1p/-19q Genotypes on Glioma Grading from MR Perfusion Imaging The Effect of Pioglitazone on Muscle and Liver Triglyceride Content and Total Body Fat in Patients with Familial Combined Hyperlipidaemia The Effect of Radiation on Normal Appearing Gray and White Matter After Treatment for Low Grade Gliomas Using Dynamic Contrast Enhanced MRI The Effect of Shield Proximity on the Mode Distribution of a Birdcage Resonator The Effect of Training in Left Hand Mirror Writing on Brain Activation - A Simultaneous fMRI and Kinematics Study The Effective Connectivity Between the MTL and PCC Is Significantly Reduced in aMCI Subjects When Using Structural Equation Modeling The Effects of Hemicholinium-3 on Phenylbutyrate Induced Changes in Lipid Metabolism The Effects of Slice-Timing and the Use of Registration Parameters as Covariates in the Analysis of fMRI Experiments Exhibiting Either Task-Correlated Motion or Residual Motion from Image-Based Motion Tracking. The Efficiency of 3T Body Transmit Array Coils The Employment and Validation of Keyhole Imaging Technique in MR Spin-Echo Diffusion Tensor Imaging The fMRI Study of Visual Spatial Working Memory in Subcortical Vascular Dementia The Functional Neuroanatomy of Perisylvian Language Networks in Schizophrenia The Impact of Different Arterial Input Function Models on Vascular Parameter Estimates Using DCE-MRI. The Impact of Imperfect Saturation and Inflow on Perfusion Input Function The Impact of Magnetisation Transfer Effects on Inversion-Recovery Sequences Using a Fast Spin-Echo Readout The Influence of Imaging Parameters on SSFP-Based Microcirculatory Blood-Oxygen-Level Dependent (BOLD) Contrast: Theory and Experiment The Influence of RF Inhomogeneity on the Metabolite Signals Measured by Volume Pre-Selected Spectroscopic Imaging Sequences The Influence of Temporal Lobe Epilepsy on Thalamocortical Connectivity The Influence of Temporal Resolution and Phase-Encoding Order on Shape-Based Classification of Dynamic Contrast Enhanced (DCE) MRI Uptake Curves in the Breast The Integrity of Corpus Callosum and Cingulum in Schizophrenia Assessed by Diffusion Tensor Tractography The Liver Response to Hemorrhagic Shock and Subsequent Resuscitation – fMRI Analysis The Magnetic Shielding Effect of Polymer Coated Nano-Sized Iron Oxide The Median of Modelling Parameters Ktrans and Ve in a Tumour ROI Best Characterises Breast Cancer Response to Treatment The Neural Correlates of Interpreting Speech-In-Noise in Children with Unilateral Sensorineural Hearing Loss Investigated Using a Functional MRI Paradigm with Silent Gradient Intervals The Novel 12 Channel Octahedral Transmit/receive Array for Parallel Imaging of Human Head at 3 T. The Organic-Mineral Interface in Bone is Stabilized by Polysaccharides: {31P} – 13C REDOR Solid State NMR Evidence The Pattern of Brain Iron Accumulation During Normal Aging The Potential Sensitivity of Cerebral Blood Flow to Cross-Calibration The Pulmonary Blood Volume Variation Decreases After Experimentally Induced Myocardial Infarction in Pigs – A Novel Quantitative MRI-Based Measure of Preload? The Regional Pattern of Diffusion Anisotropy in the Preterm Primate Cerebral Cortex The Respiration Response Function: Modeling the Temporal Dynamics of Respiration-Volume Induced Changes in the Brain The Role of 19F Diffusion Weighted Spectroscopy for Specific and Sensitive Detection of Molecularly Targeted Perfluorocarbon Nanoparticles The Role of Mitochondrial Superoxide in Alzheimer's Pathology The Role of Prefrontal Lobe in FEP: Evidence from PPI Analysis The SAR Measurement Phase Transition Method The Silent Carotid Plaque Rupture -- A 70-Month Serial Follow-Up Case by In Vivo High Resolution MRI The Similarity of the Brain in Healthy Monozygotic Twins: A Voxel Based Analysis of Volume, T2 and DTI The Study of Temporal Behavior and Image Quality of HYPR Using Computer Simulations The Use of 1H NMR Metabolic Profiling in the Differentiation of Clinical and Environmental Isolates of Acanthamoeba The Use of K-T BLAST for Measuring Velocities in Stenotic Vessels with Phase-Contrast MRI The Use of Magnetic Resonance Angiography (MRA) in the Assessment of Synovial Disease in Patients with Early Rheumatoid Arthritis The Use of Simultaenous EEG and fMRI to Investigate the Correlation of BOLD Responses and the P300 The Usefulness of Diffusion MR Imaging in the Detection of PancreaticCancer: Pathological Correlation with ADC Values The Usefulness of Proton MRS in Monitoring Ketogenic Diet Therapy in Mitochondrial Encephalopathy The Utility of Diffusion-Weighted MR Imaging for Differentiating Uterine Sarcomas from Benign Leiomyomas The Utility of In-Phase and Opposed-Phase Gradient Recalled Echo Magnetic Resonance Imaging for Detection of Susceptibility in Abdominal Imaging The Utility of PROPELLER Technique Applying for T2-Weighted Thoracic MR Imaging with PACE Technique The Value of 1H MRS Positive Voxels Percentage in the Detection and Localization of Prostate Cancer The Value of Delayed Hypointensity of Arterially-Enhancing Nodules in the Cirrhotic Liver for the Diagnosis of Hepatocellular Carcinoma The Value of Diffusion and Perfusion MRI of the Brain in Comatose Patients Treated with Mild Hypothermia After Cardiac Arrest Therapeutic Effect of Intensive Sensory Motor Integration Training in Children with ADHD: A Multimodal Approach Using fMRI and VBM Three Dimensional Atlas of Developing Mouse Brains Based on Diffusion Tensor Imaging Three Dimensional Carotid Wall Imaging at 3T Using a New Muti-Channel Surface Coil Three Dimensional Probabilistic Atlas of the Human Striatal Territories Based on Diffusion Imaging Three Dimensional Spatial and Temporal Temperature Control with MR-Thermometry Guided Focused Ultrasound Three-Compartment Modeling of the Arterial-Spin-Labeling Data at Different Post-Labeling Delays with and Without Flow-Attenuating Gradient Three-Dimensional 1H-Magnetic Resonance Spectroscopic Imaging of the Prostate Peripheral Zone in Clinical Practice Three-Dimensional Delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) for In Vivo Evaluation of Reparative Cartilage After Matrix-Associated Autologous Chondrocyte Transplantation at 3.0 Tesla – Preliminary Results Three-Dimensional Overlapping "Rod" Acquisition (TORQ): A Novel K-Space Trajectory for 3D Extension of PROPELLER Three-Dimensional Visualization of the Cardiac Veins by Means of Intravascular Contrast Agent Enhanced MRI. Three-Dimensional, J-Resolved H-1 MRSI of Volunteers and Patients with Brain Tumors at 3 T Thyroid Status Is a Key Modulator of Tumor Response to Irradiation: Determination of the Underlying Metabolic Causes Tikhonov Regularization Optimisation for PreLearn: Effects on the Detection of Activations in Functional MRI Time Course Analysis of Paediatric fMRI Data with ICA Time Course of ADC and FA in Brainstem Infarcts Time Course of PPARa Agonist Effects on Plasma Lipid Level, Liver Size and Hepatic Lipid Content in Fat Red Rats: an In-Vivo MR Imaging and Spectroscopy Study Time Resolved Contrast-Enhanced Breast MR with 0.6 Isotropic Spatial Resolution Time Resolved Lung Ventilation Volume Measurement with Multislice EPI Using Hyperpolarized 3He Time Resolved MRA of Intracranial AVM Patients at 3.0 Tesla: Assessment of Circulation and Transit Times Time Resolved TWIST MR Angiography of the Head and Neck: Time-Course Characterization by DCE-MRI of Kidney Dysfunction in Rats Over-Expressing the Human Renin and Angiotensinogen Genes Time-Intensity Curve (TIC) of Rectal Lesions on Dynamic Contrast-Enhanced MRI at 3T Time-Of-Flight Imaging of Hyperpolarized Gas Flows in the Human Airways at True Temporal Resolution Lower Than 10 Ms Time-Related Flow-Metabolism Relationship in Activated Human Visual Cortex: fMRI Vs. PET Time-Resolved 3D Quantitative Flow MRI of the Major Intracranial Arteries Time-Resolved Contrast-Enhanced Imaging Using 3D HYPR VIPR Reconstruction with Adaptive Composite Window Time-Resolved Contrast-Enhanced MR Angiography of Intracranial Lesions Time-Resolved MR Angiography for the Detection of Stenoses and Occlusions of Central Veins Time-Resolved MR Angiography with Limited Projections Time-Resolved MR-Angiography (TWIST) of the Hand in Comparison to Digital Substraction Angiography (DSA) Time-Resolved, Three-Dimensional Brain Motion Measurements Using 3D-DENSE Time-Segmented Spin Domain Method for Fast Large-Tip-Angle RF Pulse Design in Parallel Excitation Time-Variable Filtering of Spiral Acquisitions for Outer Volume Suppression Tissue Perfusion Changes and Neuropsychological Impairment in Multiple Sclerosis Tissue Specificity of DCE-MRI Pharmacokinetic and Semi-Quantitative Parameters in Human Liver Metastasis Tissue-Specific, Smoothing-Compensated Voxel-Based Analysis of DTI Data To TOF or Not to TOF; Nonenhanced MRA at 7T Too Many Peanuts Makes You Fat: Sensitivity of Diffusion Weighted Steady State Free Precession to Anisotropic Diffusion in Ex Vivo Brain Tissue Topographic Variation of T2 Value in Hip Articular Cartilage at 3T Topographical Variation of T2 Relaxation Time in Adult Knee Cartilage at 1.5T Topography of the Corpus Callosum – A Comparative DTI Study of Human and Rhesus Monkey Total Removal of Unwanted Echoes in Harmonic Phase MRI (TRUE-HARP) Total Variation Denoised Dynamic Reconstruction Applied to Pulmonary Perfusion Imaging in the Rat Toward Clinically Practical T2-Mapping for Neurodegenerative Diseases Toward Quantitation of Whole-Brain Tractography Group Comparisons with Application to Alzheimer Disease Towards a 10 Minute Clinical Alzheimer MR Imaging Protocol Towards a Clinically Feasible Measurement of TCA Cycle Rates: A Novel Approach for Mathematical Modeling Towards a Complete Coil Array Towards a Diffusion Biomarker of Autism Towards Accurate In Vivo Diffusion Measurement in Human Optic Nerve Towards an In Vivo Model of Complicated Atherosclerosis Towards an Automatic Identification of Cancer Regions in In Vivo MR Spectroscopy Data from the Prostate Towards Automatically Assessment of Kidney Volume from 3D DCE-MRI Time Courses Using Active Contours Towards Detection of Sub-Micromolar Contrast Agent Concentration with Hyperpolarized 6-Lithium Towards Functional MRI in Blood Free Rats Towards Hyperpolarized 13C Succinate Imaging of Brain Cancer Towards MRSI of the Prostate at 7T Using Adiabatic RF Pulses and a Transmit and Receive Endorectal Coil Towards Optical and MR Imaging of Vulnerable Atherosclerotic Plaques Using Bimodal Quantum Dots Towards ParaCEST MRI Contrast Agents Without Coordinated Water: Lanthanide Complexes of Novel Acetamido-Substituted Diethylenetriamine- And Triethylenetetramine Ligands Towards Quantitative Dynamic Vessel Size Imaging in Humans Towards Quantitative Magnetic Resonance "Angstromscopy" Towards the Detection of Hepatocellular Carcinoma with a pH-Responsive Dendritic MRI Contrast Agent Towards Whole Brain Myelin Imaging Trabecular Bone Analysis: Correlation of 3D Structural Features with 3D Texture Analysis Trabecular Structure Measured with the MRI-Based Virtual Bone Biopsy at a Surrogate Site Contributes to Vertebral Fracture Load Independently of Spinal BMD Tracing Olfactory Neural Circuits In Vivo Using 3D Manganese Enhanced MRI Track Brain Tumor Growth by MRI and Planar Bioluminescence Imaging Track Ribbons - Visualising Structural Information in Diffusion Tensor Axial Asymmetry Tracking MEP-Labeled Mesenchymal Stem Cells Relative to New Vessel Formation Using MRI in a Rabbit Model of Peripheral Arterial Disease Tracking the Left Ventricle from Under-Sampled MR Images Tracking Trial to Trial Changes in Brain Activity Related to Cognitive Automatization Tract Based Spatial Statistics of Diffusion Tensor Imaging in Neuropsychiatric Systemic Lupus Erythematodus Reveals Diffuse Involvement of White Matter Tracts Tract-Based Spatial Statistics: Application to the Study of Multiple Sclerosis Tract-Specific Analysis of the Superior Occipitofrontal Fasciculus in Schizophrenia Tract-Specific Effects of Schizophrenia Demonstrated with Quantitative MR Diffusion Tractography Tract-Specific Effects of Sex and Age on Human White Matter Demonstrated with Quantitative MR Diffusion Tractography Tradeoffs Between Tensor Orientation and Anisotropy in DTI: Impact of Diffusion Weighting Scheme Trajectory-Corrected Dual-Echo PC VIPR Imaging at 3T Transcatheter Intraarterial First-Pass Perfusion (TRIP) - MRI Monitoring of Liver Tumor Embolization in VX2 Rabbits Transcatheter Intraarterial First-Pass Perfusion (TRIP)-MRI Monitoring of Chemoembolization Transceive Field Probes for Magnetic Field Monitoring at 7T Transient Steady-State Free Precession Coronary Vein MRI Translational Motion Self-Navigation in Center Out Radial Micro-MRI of Trabecular Bone Transport in the Preterm Infant Brain: Quantitative Analysis of the Relative Roles of Pulsatile Flow and Diffusion Transportation of Mn2+ in the Brain of Rats with Exclusive Caudoputaminal Lesions After Transient Focal Cerebral Ischmeia Transversal Relaxation Effects on Arterial Spin Labeling Investigated by Dual Echo Pseudo Continuous ASL Transverse Relaxation Time (T2) and Susceptibility Measurement with Phase-Cycled Steady-State Free Precession Treatment with the Novel PI3K Inhibitor PX-866 Results in 1H MRS Detectable Changes in a Glioma Model In Vivo TRELLIS Motion Correction: Initial Results In Vivo Triple Arterial Phase Dynamic MR Imaging of the Whole Liver for Detection of Small Hypervascular Hepatocellular Carcinoma: Preliminary Study Using LAVA at 3-T Triple Spiral with Asymmetric Spin Echo: A New Method for Improved BOLD fMRI in Regions of Magnetic Susceptibility Induced Field Inhomogeneity Tripping Over Ourselves to Image the Cerebellum True Intraoperative Functional MRI: A Feasible Technology for Intraoperative Brain-Mapping Truly Non-Invasive NMR Determination of Peripheral Vascular Resistance by Combining Dynamic Angiography and Arterial Spin Labeling Techniques Tumor Detection by Diffusion Weighted MRI and ADC-Mapping – Initial Clinical Experiences in Comparison to PET-CT Tumor Surveillance Prior to Liver Transplantation Using Gadolinium Enhanced MRI Tumour Cells Irradiated with Gamma Rays and Proton Beams: A 1H MRS Study on Lipid Signals Tunable Microstrip Loop Arrays for 3T and 7T MRI Turbo PROPELLER with Asymmetric Blade Turbo-FLASH Imaging of Swallowing Function at 3T Turbo-Segmented Z-Shim EPI for Reduced Susceptibility-Induced Effects and Improved Temporal Resolution in fMRI Two Dimensional Parallel Imaging Acceleration with Autocalibrating Reconstruction for Cartesian Sampling (ARC) in Contrast Enhanced MRA Two fMRI Indices as Markers for Alzheimer's Disease Two-Dimensional Spiral Cine DENSE Twofold Improvement in Single-Shot EPI Efficiency Using Echo Shifting and Parallel Imaging Ultimate Intrinsic SNR of Regularized Parallel Imaging and Inverse Imaging Ultimate Spatial Resolution Accessible with a Miniature HTS Coil and a New-Generation 1.5 T Body Scanner Ultra High-Order Global Shimming of the Mouse Brain Using Diamagnetic and Paramagnetic Passive Shims Ultra Rapid Comprehensive Abdominal Imaging with 3D T1 and T2 Weighted IDEAL Ultradense Sampling of FID and SE Signals Using an Interleaved Multiple Gradient Echo Sequence for Improved T2* Mapping Ultra-Efficient Shielded Dome Gradient Coils Ultra-High Resolution Peripheral MRA with K-Space Segmentation Featuring a Blood-Pool Contrast Agent and Venous Suppression Ultra-High Resolution Vessel Imaging at 1.5T: Peripheral Vein Bypass Graft Wall Imaging Via Non-Selective Refocusing Inner Volume 3D Fast Spin Echo Ultra-Low Output Impedance RF Power Amplifier Array Ultra-Sensitive Micron-Cantilever Detection for MRI Ultrashort Echo Time Imaging of the Shoulder Ultrashort TE (UTE) Imaging and T2 Quantification of Short T2 Components in Brain White Matter Ultrashort TE (UTE) Imaging of the Cortical Bone at 3T Ultrashort TE (UTE) Spectroscopic Imaging of Cortical Bone Using a Variable TE Acquisition and Sliding Window Reconstruction Ultrastructural Organization of Bone and Tendon – Novel Method for Musculoskeletal Imaging of Extremely Fast Relaxing Spins UMMRIS - Particle-Based MR Simulation Framework Uncertainties of DTI Parameter Estimation Depend on the Fitting Algorithm: Monte Carlo Simulations and in-Vivo Data in Human Brain Under-Sampled Dynamic Reconstruction Using Motion Model of the Tissues and Multiple Coils Undersampled Radial MRI with Multiple Coils. Iterative Image Reconstruction Using a Total Variation Constraint Understanding Cognitive Disorder Not Otherwise Specified: Evidence for Neurochemical Subtypes of Mild Cognitive Impairment Understanding Risk of Cardiac Stimulation When Pacemaker Patients Undergo MRI Scanning Unexpected Magnetisation Transfer to Aliphatic Resonances in Z-Spectroscopy in Model Systems and In Vivo Unified Mathematical Model of Q-Space and Diffusion Tensor Imaging Uniform Virtual Coil Reconstruction for Autocalibrating Parallel Imaging Unilateral Diffusion and Bilateral Volumetric Differences of the Thalamus in Temporal Lobe Epilepsy Unique Structural Patterns in Rat Brain Tumors Revealed by High-Resolution Diffusion Tensor MRI Universal Approach to Quantification of SNR and G-Factor for Parallel MRI Unshielded Dual Tuned Birdcage for High Field MRI/MRS Unspoiled Gradient Recalled-Echo Acquired in the Steady-State (GRASS) with IDEAL Fat-Suppression for High Resolution Cartilage Imaging at 3T Use of 4D-TRAK for Contrast-Enhanced Dynamic MR Venography of the Head Use of a Cine-IR (Multi TI Inversion Recovery) Sequence in Diagnosis of Cardiac Amyloid: Comparison with Echocardiography Use of Highly Sensitive Dual Probes Gd-Liposome and Gd-Loaded Apoferritin for Targeting Tumor Angiogenesis for MR-Visualization and Drug Delivery Use of MRI in the Analysis of Corporal Fibrosis in the Rat Use of Simulated Weight-Bearing for MR Evaluation of Ankle and Hindfoot Mechanics: A Feasibility Study Use of White Matter as Reference Region to Quantify Dynamic-Susceptibility-Contrast MRI Images Usefulness of Magnetic Resonance Imaging to Compare the Influence of Stentless Versus Stented Valves on Left Ventricular Remodelling and Coronary Reserve in Patients with Severe Aortic Stenosis User-Independent Optimization of Spherical Deconvolution User-Independent Perfusion Post-Processing Using Gradient Echo and Spin Echo EPI at 1.5 T and 3.0 T Using In Vivo High Resolution Finger MRI to Study Scleroderma – A Feasibility Study and Preliminary Results Using Diffusion Tensor Imaging to Assess White Matter Integrity in Subjects with Math Difficulties Using Direct Water Saturation for Sensitive Detection of Iron in the Human Brain Using Genetic Algorithm (GA) to Improve Gradient-Reversal Method for Susceptibility Distortion Correction Using Hyperpolarized 3He MRI for Assessment of Radiation Treatment for NSCLC Using Independent Component Analysis to Measure Language Laterality Using Principal Component Analysis and Generalized Linear Models to Predict Final Outcome in Acute Stroke Using Q-Space Diffusion MRI for Structural Studies of a Biological Phantom at 3T Clinical Scanner Using Registration to Quantify the Consistency of Whole Liver Position During Patient Breath-Hold in Dynamic Contrast-Enhanced MRI Using Relaxation, Magnetization Transfer and Diffusion to Characterise Multiple Sclerosis Lesion Pathology Using the Wild Bootstrap to Quantify Uncertainty in Fibre Orientations from Q-Ball Analysis USPIO Dynamics in an Animal Model of Multiple Sclerosis USPIO-Enhanced Cellular Imaging in MS UTE Acquisitions of Rat Knee at 9.4T Uterine Peristalsis and Infertility: Evaluation with Cine MR Uterine Subserosal Leiomyomas Located in the Retroperitoneal Space: MRI Evaluation Utility of Magnetic Resonance Imaging and Spectroscopy in Prediction of Insignificant Prostate Cancer: Initial Analysis Validation of 3He-MRI to CT Image Registration and the Impact on NSCLC IMRT Planning Validation of 2D Ultrasound-Based Strain Estimates with MR Tagging Validation of Automatic Fibrous Cap Measurement with In Vivo MRI and FCPL Lesion Index Evalution Validation of Automatic Segmentation Algorithms for Short-Axis Cine Cardiac Magnetic Resonance Validation of Clinically Useful Fast, Multi Slice, Multi Echo T2 Quantification Sequence Validation of Diffusion Tensor MRI in the Central Nervous System Using Light Microscopy Validation of EPSI Angiography by Image Co-Registration Validation of Phase-Contras MR Velocimetry of Hyperpolarized Rare Gases Via Particle Image Velocimetry Validation of Quantitative Contrast-Enhanced Pulmonary Perfusion MRI Using H215O-PET Validation of Rat Muscle Volume Measurement by MRI as a Frailty Biomarker Validation of Surgical Strategies for Coronary Artery Bypass Grafting to Reduce Ischemic Brain Lesions Using Diffusion-Weighted Magnetic Resonance Imaging Validation of Voxel-Based Relaxometry Using Manual Region-Of-Interest Measurements Value of Automated Retrospective Correction of Contrast-Enhanced Dynamic Liver MRI – Initial Clinical Experiences Value of Online Frequency Correction for Total Choline Containing Compounds Peak Detection of Breast Tumors During Single-Voxel Proton MR Spectroscopy at 1.5 T Variable Detection Rate of the Hippocampal Lesion in Transient Global Amnesia According to Different Diffusion-Weighted Imaging Protocol Variable Echo Time Imaging and Signal Characteristics of 1-M Gadobutrol Contrast Agent at 1.5 and 3T Variable Field Strength MR System for Hyperpolarized Noble Gas Imaging of Rodent Lungs Variable Field-Of-View Three-Dimensional Projection-Reconstruction Imaging Variable Flip Angle MR Imaging of 3He Spin Lattice Relaxation Times for Measurement of Alveolar Oxygen Partial Pressure Variable Flip Angle MR Imaging of Regional Ventilation Using Hyperpolarized Helium in Rodent Lungs Variable Slew Rate Spiral Design for Local SAR Reduction in 2D RF Pulse Design Variable-Density Parallel Image Acquisition and Reconstruction with Partially Localized Coil Sensitivities Variation in T2 Values Related to Method of Calculation: Implications for Correlative and Longitudinal Studies Variational Framework for the Separation of Partially Volumed Tensor Compartments in the Human Brain Varying Kernel Extent Gridding Reconstruction Vascular Space Occupancy (VASO) MRI Demonstrates Changes in Cerebral Blood Volume in Internal Carotid Artery Stenosis Patients After Carotid Revascularization Vascular Tumor Response to Synchrotron Microbeam Radiation Therapy. A Short Term In Vivo Study Vasculature Characterization of Angiogenic Melanoma Metastases in Mouse Brain by Gd-DTPA and USPIO Contrast-Enhanced MRI Vasoconstriction Increases the Linearity of the BOLD Response VCAM-1-Targeted Contrast Agent Delineates Acutely Activated Cerebral Vasculature in Neuropathology VD K-T Acquisition for Accelerating Temperature Imaging Ventilation and Perfusion Ratio Obtained by Polarized Carbon-13 and Polarized Gas MRI Ventricular Shape Biomarkers for Alzheimer's Disease in Clinical MR Images Verification of CSF-Based HARM in Acute Stroke Patients with Early Blood-Brain Barrier Disruption Verification of Susceptibility Difference and Volume Fraction for the Calculation of Oxygenation Extraction Fraction Using Measurements of a Single Capillary and Network Phantom Verifying Visual Fixation to Improve fMRI with Predictive Eye Estimation Regression (PEER) Vertebral Perfusion in Disc Degeneration Patients Using Dynamic Contrast-Enhancement MR Imaging Very Fast 2D Proton MR Spectroscopic Imaging of the In Vivo Human Brain at 3 Tesla with High Spatial Resolution Using the SSFP Based Sequence "Spectroscopic FAST" Very High SNR Superconducting Receive-Only 7 Tesla Coil for Rat Brain Imaging Very Low Field 15 mT System for Hyperpolarized Noble Gas MRI Vessel Size Imaging of Brain Tumors Vessel Size Index MRI to Monitor the Effect of Antivascular Treatment in a Rodent Tumour Model Vibration Safety Limits for Magnetic Resonance Elastography Viscoelastic Properties of the Brain in High Field MR Elastography - In-Vivo Application to an Alzheimer's Mouse Model Visualization of a Passive Intra-Myocardial Needle with Off-Resonance Positive Contrast FLAPS Imaging for Regenerative Myocardial Therapy Visualization of Laminar and Columnar Organization in Rat Olfactory Bulb Using Diffusion Tensor MRI Visualization of Mouse Corticospinal Tract by Manganese-Enhanced Magnetic Resonance Imaging Visualization of the Paramagnetic Markers in Interventional MRI Using Spatial-Spectral Pulses Visualization of Venous Vessels by Phase Weighted Image Visualizing Diffusion Tensor Imaging Data with Stereoscopic Vision Visualizing Slow-Flow Endoleak After Endovascular Abdominal Aortic Aneurysm Repair with the New Blood Pool Agent Vasovist Volume Preserving Coregistration of Longitudinal Breast MRI During Chemotherapy for Accurate Localization of Tumor Volume-Interleaved SENSE for Bilateral Breast Imaging Volumetric Analysis of the Corpus Callosum in Early-Onset Bipolar Disorder Volumetric Dynamic Magnetic Resonance Inverse Imaging in the Human Brain Volumetric Mri Predicts Structural Changes in Preterm Infant Hippocampi Due to White Matter Injury and Steroid Exposure Volumetric Q-Space Map by Fast 3D DWI Voxel Based Morphometry and Statistical Parametric Mapping of Positron Emission Tomography (SPM-PET) in Patients with Frontal Lobe Epilepsy Compared to Normal Controls Voxel Based Morphometry Shows Hippocampal White Matter Reductions and a Correlation with Glycerophosphocholine Levels in Patients with Major Depression Voxel-Based Analysis of Global and Neocortical Progression of Brain Atrophy in RR MS Voxel-Based Measurment of Flow and Volume Using Regional Motion-Tracking in the Lung with Hyperpolarized 3He MRI Voxel-Based Morphometry with Z-Score Images for Evaluation of Fractional Anisotropy Alterations in Major Depressive Illness Voxelwise Analysis of MR Diffusion Data from Recovering Alcoholics Using Tract-Based Spatial Statistics Water Lineshape Analysis Identifies Regions of WMH Water Population Changes in Glioma Gene Therapy as Measured by T1? and T2? Wavelet Thresholding of Diffusion Tensor Images Wavelet-Based Denoising of Images Acquired with Parallel-MRI Techniques Wavelet-Based Filtering of Arterial Spin Labeling (ASL) fMRI Data Using a Wiener-Like Filter Wavelet-Based Mode-Scanning Excitation (MSE) for Selective Excitation at High Field What Happens When Nine Different Groups Analyze the Same DT-MRI Data Set Using Voxel-Based Methods? Where Will the Future Take Us? Which DCE-MRI Analysis Method, Pharmacokinetic or Empirical, Most Accurately Predicts Eventual Response During Neoadjuvant Chemotherapy? White Matter Changes in Chronic Cocaine Users Revealed by Voxelwise Group Analysis of Diffusion Tensor Imaging White Matter Damage in Nijmegen Breakage Syndrome by Diffusion and T2 MRI White Matter Hyperintensities and Balance Control in Elderly People with Diabetes and Hypertension White Matter Impairments as an Endophenotype of Bipolar Disorder – A Diffusion Imaging Study of Patients with Bipolar 1 Disorder and Their Unaffected Relatives White Matter Integrity Alterations in Disruptive Behavioral Disorder White Matter Integrity in First-Episode Schizophrenia: Gender Difference Revealed by Diffusion Tensor Imaging White Matter Microstructural Abnormalities in Late-Life Depression: A Diffusion Tensor Imaging Study White Matter Reorganization After Stroke Measured by Gaussian DTI, Q-Ball, and PAS MRI Whole Blade Method for Robust PROPELLER DWI Whole Body Diffusion Weighted Imaging and ADC Mapping for Detecting Metastatic Cancer Whole Body Fresh Blood Imaging (FBI): Non-Contrast MRA from Head to Feet Whole Brain Atrophy Rate in Relation to Cognitive Decline in Alzheimer’s Disease and Mild Cognitive Impairment Whole Heart Cine MRI Using Real-Time Respiratory Self-Gating Whole Mount Histological Registration and Validation of Hierarchical Clustering for Segmentation of Tumor and Normal Prostate Using Multi-Parametric MRI Whole-Body Diffusion-Weighted Imaging: Usefulness for Assessment of M-Stage in Lung Cancer Patients as Compared with Standard Whole-Body MR Imaging and FDG-PET Whole-Body STIR Imaging Versus MDCT in Patients with Renal Cell Carcinoma Whole-Brain Tractography Incorporating ICA Based Crossing-Fiber Orientations Whole-Heart Coronary MR Angiography for the Detection of Coronary Artery Stenosis in Patients with Coronary Calcification: Preliminary Comparison to 64-Slice CT Angiography Whole-Heart Magnetic Resonance Coronary Angiography with Visual Feedback Working Memory as a Function of Cognitive Decline in Old Age: An fMRI Study Working Memory in Major Depression – An fMRI-Study at 3 T Working Memory Related Differences in Brain Activation Measured with Functional Magnetic Resonance Imaging (fMRI) in Patients 1 Month After Minor Head Injury Compared to Healthy Controls. Z-Gradient Coil Optimisation in Presence of Time-Varying Eddy Currents Ababneh, Riad S. Abaei, Alireza Abarca, Jorge Abbott, David F. Abd-Elmoniem, Khaled Z. Abdelsalam, Emad Abduljalil, Amir Abduljalil, Amir M. Abdulkarim, Fadi Abdullah, Osama M. Abe, Hiroyuki Abe, Osamu Abe, Takayuki Abegunewardene, Nico Abela, John Abernethy, Darrell R. Abou-Khalil, Bassel Aboussouan, Eric Abraham, Roney Abraham, Roselle Abraham, Rpselle Abramovitch, Rinat Absil, Julie Abugharbieh, Rafeef Acebrón-Fabregat, Javier Acernese, Fausto Acevedo-Bolton, Gabriel Acharya, Suchitra S. Achenbach, Stephan Achten, Eric Achtnichts, Lutz Acion, Laura Ackerman, Jerome L. Ackerman, Joseph J.H. Ackerman, Joseph John Henry Acosta, Rodolfo Hector Acosta-Cabronero, Julio Adachi, Johnathan D. Adali, Tulay Adalsteinsson, Elfar Adam, Gerhard Adams, William Addadi, Yoseph Adhya, Sumita Adler, Andy L. Adler, Ronald S. Adluru, Ganesh Admiraal-Behloul, F Admiraal-Behloul, Faiza Adólfsdottir, Steinunn Adriaensen, Miraude E. Adriany, Gregor Adusumilli, Saroja Advani, Kamakshi Afacan, Onur Agarwal, Atul Kumar Agarwal, Harsh K. Agarwal, Rajid Agati, Raffaele Agayev, Ayaz Aggarwal, Nitin Aghayev, Emin Agner, Shannon Agni, Rashmi Agosta, F Agosta, Federica Agrawal, Garima Aguila, Francisco Aguilar, Brenda Aguilera, Carles Aguinaldo, Juan Gilbert Aguinaldo, Juan Gilberto S. Aguirre, Geoffrey K. Ah-See, Mei-Lin W. Aherne, Wynne Ahlström, Håkan Ahmad, Munir Ahn, Chul W. Ahn, Sinyeob Ahobila, Pallavi Ahrens, Eric T. Ailiani, Amit C. Aime, Silvio Ainala, Srilatha Aizenstein, Howard Aizenstein, Howard J. Ajilore, Olusola Akalin, Taner Akao, James Akao, James H. Akazawa, Kentaro Akella, Narasimha Shastry Akgun, Can Akgun, Can Eyup Akhtar, Syed Naved Akin, Ata Aksel, Bluent Aksel, Bulent Aksoy, Murat Al-Saffar, Nada M.S. Alagappan, Vijay Alagappan, Vijay Anand Alagappan, Vijayanand Alam, Rajibul Albarracin, Dolores Albensi, Benedict C. Albers, Greg Albers, Gregory W. Albers, Mark Albers, Mark J. Albers, Mark Julius Albert, Juliane Albert, Mitchell Albert, Mitchell S. Albert, Mitchell Scott Alberti, Diego Alberts, Jay L. Albiin, Nils Albrecht, Frank Albrecht, Karin Aldenkamp, Albert P. Aleman, A. Alenezy, Mohammed D. Aletras, Anthony H. Aletras, Anthony Homer Alexander, Andrew L. Alexander, Andy L. Alexander, Daniel C. Alexander, H L. Alexander, Murray E. Alfano, Bruno Ali, Azmat Ali, Md. Meser Ali, Osman Ali, S.M. Raashid Ali, Saad Alia, A. Alia, Alia Aliu, Sheye Aljaroudi, Wael Allaart, C. P. Allard, Mathieu Allen, Aaron Allen, John S. Allen, Monica S. Allen, Paul Allen, Peter S. Allen, Philip Daniel Allen, Philip J. Alley, Marcus Alley, Marcus T. Allison, Jerry D. Allsop, Joanna Allsop, Joanna M. Alonso, Juli Alonso-Galicia, Maggie Alonzi, Roberto Alrefae, Tareq Als, Heidelise Alsop, David Alsop, David C. Altaf, Nishath Altbach, Maria I. Altes, Talissa Altes, Talissa A. Altes, Tallisa A. Althaus, Matthias Altmann, Daniel R. Alway, Stephen E. Alyaev, Yury Amagami, Miho Amann, Kerstin V. Amann, Michael Amano, Akira Amano, Yasuo Amans, Matthew R. Amara, Catherine E. Amber, Vian Ambwani, Sonal Amir, Noam Amirkhanov, Nariman Amm, Bruce C. Ammann, Larry Amoh, Yoshiki Amrami, Kimberly K. An, Hongyu An, Jing An, K An, Kwangjin An, Li Anand, Praveen Anand, Vikram Anastasio, Mark Anastasovska, Jelena Ances, Beau M. Andersen, Anders H. Andersen, Linda B. Andersen, Peter Andersen, Richard A. Anderson, Adam Anderson, Adam W. Anderson, Douglas J. Anderson, Ian Anderson, Ian M. Anderson, Jeff Anderson, Kevan James Thompson Anderson, Meredith L. Anderson, Peter J. Anderson, Stasia A. Anderson, Stasia Ann Anderson, Stewart Anderson, Suzanne Anderson, Valeria Andersson, Jesper L.R. Andersson, Linda Anderwald, Christian Andino, Sara Gonzalez Ando, Koichi Ando, Ritsuko Andres, Pilar Andrés, Susana Andrew, David Andrews, David W. Andrey, Philippe Angelié, Emmanuelle Angelone, Leonardo Angelone, Leonardo M. Angenstein, Frank Anjari, Mustafa Annet, Laurence Anno, Izumi Ansiaux, Reginald Ansorge, Richard Antel, Samson B. Anthony, Daniel Anthony, Douglas C. Antill, Philip J. Antonakoudi, Anixi Antuono, Piero Anwander, Alfred Anzai, Yoshimi Anzalone, Nicoletta Aoki, Ichio Aoki, Masaaki Aoki, Shigeki Aoyama, Nobukazu Apidianakis, Yiorgos Appu, Sree Aprile, Taryn Aquino, Domenico Aquino, Theresa Aragones, Julian Arai, Andrew E. Arai, Andrew Ernest Araki, Tsutomu Arana, Estanislao Arap, Wadih Arat, Anil Aravindhan, Karpagam Arbab, Ali S. Arble, Jason B. Arceneaux, Billie Archer, John S. Ardekani, Siamak Arends, Mark Arepally, Aravind Arfanakis, Konstantinos Arheden, Hakan Arheden, Håkan Aribasala, Benjamin S. Arikan, Orhan Arimura, Hideaki Arimura, Hidetaka Aristizábal, Orlando Arkani, Sanaz Arkink, Enrico Arlinghaus, Lori Arlinghaus, Lori R. Arlinghaus, Lori Rose Armitage, Paul A. Arndt, Susan Arnelo, Urban Arnold, Doug L. Arnold, Douglas L. Arnold, Edith M. Arnold, Johannes F. Arnold, Johannes F.T. Arnold, Sheeba Arnts, Henk Arolt, Volker Arribas, César Arrigoni, Francesca Arsava, E Murat Artemov, Dmitri Arumana, Jain Mangalathu Arús, Carles Aruva, Mohan Arvanitis, Theo Arvanitis, Theo N. Arzouan, Yossi Asano, Kenji Asbach, Patrick Aschner, Michael Aschoff, Philip Asemu, Girma Ash, Susan Asher, Isaac M. Ashikaga, Ryuichiro Ashioti, Maria Ashtari, Manzar Ashton, Ed Ashton, Edward Ashwal, Stephan Asllani, Iris Aspden, Richard M. Assaf, Yaniv Assomull, Ravi Astrakas, Loukas G. Atadja, Peter Atalar, Ergin Atassi, Bassel Athanasopoulou, Maria D. Atherton, Duncan Atkinson, David Atkinson, Ian Atsumi, Hideki Atwood, Todd Atzori, Manfredo Au, Christopher Aubert, Michel L. Audoin, Bertrand Audrich, Jürgen Auer, Dorothee Auer, Dorothee P. Auerbach, Eddie Auerbach, Eddie J. Auerbach, Edward Auerbach, Edward J. Auerbach, Edward J.J. Aurich, Volker Austin, Vivienne Avallone, Francis A. Avants, Brian Avants, Brian B. Avdievich, Nikolai I. 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Fuentes, Miguel Angel Fujii, Hirotada Fujii, Shingo Fujii, Takuma Fujimoto, Koji Fujita, Hiroyuki Fujita, Takeshi Fujiwaka, Hideaki Fujiwara, Hideaki Fujiwara, Shunrou Fujiwara, Yasuhiro Fukatsu, Hiroshi Fukuda, Hiro Fukunaga, Masaki Fukushima, Hiroyuki Fukuyama, Hidenao Fulford, Jonathan Fung, Maggie Fung, Maggie M. Fung, Steve H. Fung, Steve Huntz Furber, Alain Furie, Karen Furman-Haran, Edna Furudate, Naoyuki Furuyama, Jon Fushimi, Yasutaka Futterer, Jurgen Fütterer, Jürgen J. Föger, Florian Föll, Daniela Förster, Alex Gaab, Nadine Gabellieri, Cristina Gach, H Michael Gach, H. Michael Gaddam, Santhosh R. Gaddipati, Ajeetkumar Gadian, David Gadian, David G. Gaertner, Jutta Gagoski, Borjan A. Gagoski, Borjan Aleksandar Gagoski, Borjan Alexsandar Gai, Neville Gai, Neville D. Gaidosh, Gabriel S. Gaige, Terry A. Gaillard, Sophie Gailloud, Philippe Galatsanos, Nikolas Galatsanos, Nikolas G. Galgano, Jessica Galiana, Gigi Galjart, Niels Gall, Peter Gallagher, Ferdia A. Gallez, Bernard Galli, Aurelio Gallichan, Daniel Gallinat, Jürgen Galloway, Graham J. Galloway, Graham John Galloway, Matthew P. Galons, Jean-Philippe Galron, Ronit Galun, Eithan Gambarota, Giulio Gamper, Urs Gamson, David Gan, C. T. Gan, Li-Ming Gandhi, Rajiv A. Gandy, Stephen J. Ganesan, Vijeya Ganguly, Arun Ganslandt, Oliver Gantois, Ilse Gao, Dingguo Gao, Fabao Gao, Jia-Hong Gao, Jiaping Gao, Jinming Gao, Li Gao, Wan-Yuo Gao, Wei Gao, Xiulai Gao, Y Gao, Yuangui Garbern, James Garces, Luis J. Garcia, Ana Isabel Garcia, Maria L. Garcia, Paloma Ballesteros Garcia, Raquel Garcia-Alvarez, Roberto Garcia-Armengol, Juan Garcia-Gomez, Juan Miguel Garcia-Martin, Maria L. Garcia-Martin, Maria Louisa Garcia-Martin, Maria Luisa García-Martín, Maria Luisa Gard, Catherine Diane Gardener, Alexander Graeme Gareis, Daniel Garg, Ankur Garland, Marrianne Garnero, Line Garreffa, Girolamo Garrett, Andrea L. Garrett, Robert W. Garrido, Lidia Nieto Garrood, Penny Gartenschlager, Soren Garwood, Michael Gasparetto, Emerson Leandro Gass, Aachim Gass, Achim Gasser, Thomas Gassert, Roger Gastaldelli, Amalia Gatehouse, Peter Gatehouse, Peter D. Gatehouse, Peter David Gatenby, Christopher J. Gatenby, J. Christopher Gatenby, Robert Gaudnek, Manuel Gaugh, Michelle Gaura, Véronique Gauss, Robert Gazdzinski, Stefan Ge, Yulin Gebetsroither, Simone Gee, James Gee, James C. Gefter, Gefter, Wa Gefter, Warren Gehl, James A. Geibel-Zehender, Annette Geier, Oliver Geier, Oliver Marcel Geiger, Bernard Geiner, Andreas Geisler, Sarah Geistert, Wolfgang Geitung, Jonn-Terje Gelernter, Joel Gelman, Neil Gelovani, Juri Gembris, Daniel Genadry, Rene R. Gendelman, Howard Gendelman, Howard E. Genega, Elizabeth Genega, Elizabeth M. Geninatti-Crich, Simonetta Gentry, Lindell R. George, Tony Georgiades, Christos S. Georgiadis, John G. Geppert, Christian Geraldes, Carlos Frederico De Gusmao Campos Gereige, Jessica Gereige, Jessica D. Gerig, Guido Gerigk, Lars Germain, Sean Germans, Tjeerd Gerrard, Phil Gerretsen, Suzanne C. Gerrish, Iona F. Gerritsen, Frans A. Gersbach, Joanne C. Gerson, Adam D. Gerus, Calvin L. Geschwind, Jean-Francois H. Geslin, Philippe Gessler, Manfred Geurts, Jeroen J. Geurts, Jeroen J.G. Ghadyani, Hamid Ghaghada, Ketan Ghajar, Jamshid Gharib, Ahmed M. Gharib, Morteza Ghatei, Mohammad A. Ghista, Dhanjoo Ghosh, Arko Ghugre, Nilesh Ghugre, Nilesh R. Giacomini, Eric Giallonardo, Anna Teresa Giannesini, Benoit Giannetta, Joan Gianolio, Eliana Giaquinto, Randy O. Gibbs, Jessica Gibbs, Peter Gibbs, Summer L. Gibson, Dan Giddens, Don P. Giedd, Jay N. Gierada, David S. Giercuszkiewicz, Dorota Gieseke, Juergen Gieseke, Jürgen Giesel, Frederik L. Giesel, Frederik Lars Gigandet, Xavier Gilad, Assaf A. Giladi, Nir Gilat, Yaron Gilbert, Fiona J. Gilbert, Fiona Jane Gilbert, Guillaume Gilbert, Kyle Michael Gilbert, Richard Gilderdale, David Giles, Anoja Gill, Andrew B. Gill, Andrew Brian Gill, David Gill, Edward Gillard, Jonathan Gillen, Joseph S. Gillet, Brigitte Gillies, Robert J. Gilmore, John H. Gilson, Wesley D. Gimi, Barjor Ginefri, Jean-Christophe Giorgio, Antonio Giori, Nicholas J. Giovannetti, Giulio Giovannini, Claudio Giove, Federico Giovenzana, Giovan Battista Girard, Olivier Girard, Séverine G. Gireesh, Elakkat Dharmaraj Gisselsson, Anna Giuliani, Alessandro Giulietti, Giovanni Gizewski, Elke R. Gizewski, Elke Ruth Glabe, Charles Glaesel, Dennis Glaser, Christian Glaser, Kevin Glaser, Kevin J. Glass, Hannah C. Glass, John O. Glauche, Volkmar Glencross, Debra Glenn, Orit Glickson, Jerry D. Glielmi, Christopher Glielmi, Christopher B. Glimcher, Melvin J. Gliori, Gemma Glockner, James Glockner, James F. Glogowski, Miriam Glover, Gary Glover, Gary H. Glover, Paul Glover, Paul M. Glunde, Kristine Gmitro, Arthur F. Go, Alan S. Goa, Paal Erik Goa, Pål Erik Gobbi, Gianni Gobets, Sebastiaan Gochberg, Daniel F. Gochberg, Daniel Frank Godbole, Madan M. Goddu, Beth Goddue, Beth Goebbels, Sandra Goebel, Rainer Goelman, Gadi Goense, Jozien B.M. Goerke, Ute Goettsch, Sandra Goko, Yasuaki Golay, X Golay, Xavier Golby, Alexandra J. Gold, Brian Gold, Garry Gold, Garry A. Gold, Garry E. Gold, Garry Evan Gold, Joseph Goldenberg, Alec Goldenberg, Daniel Goldfarb, James William Goldfinger, Meidan Goldman, Jeffrey Goldman, Robin I. Goldring, Robert M. Goldring, Roberta Goldschmidt, Juergen Gollapalli, Lakshman Gomez, Ana Maria Gomez, Christopher M. Gomez, Rosane Gonçalves, Carla Gonen, Oded Gong, Gaolang Gong, Qi Yong Gong, Qi-Yong Gonsalez, Robyn Gontu, Krishna Gonzalez, Leonardo Gonzalez, R Gilberto Gonzalez, Ramon Gilberto Gonzalez-Fernandez, Guillermo Goode, Stephen David Goodlett, Casey Brett Goodman, James Andrew Goodrich, K. Craig Goodyear, Bradley Goodyear, Bradley G. Gopez, Angela Gopinath, Anand Gopinath, Kaundinya Gorbis, Eda Gorczewski, Kamil Gordon-Lipkin, Eliza Gore, John Gore, John C. Gorman, Joseph H., III Gorman, Robert C. Gorny, Krzysztof R. Gotberg, Matthias Goto, Takao Gotte, M. J. Gottliebson, William Gottschalk, Sven Goulden, Nia Gounarides, John Govidan, Rajkumar M. Govindan, Siddharth Gowda, Ashok Gowland, Penelope Gowland, Penny Gowland, Penny A. Gowland, Penny Ann Goyal, Amit Goyal, Vivek K. Gozubuyuk, Ark Gozzi, Alessandro Grabowski, Thomas Graces, Alexandra Gracias, David Gradkowski, Wojciech Grady, Michael S. Graesslin, Ingmar Graf, Hansjoerg Graf, Hansjörg Grafendorfer, Thomas Graff, Christian Graham, John J. Graham, Lila Graham, Simon Graham, Simon J. Graham, Steven Gram, Andreas Grande, Sveva Grange, Cristina Granlund, Kristin L. Granot, Dorit Grant, Aaron Grant, Aaron K. Grant, P. Ellen Grant, Patricia Ellen Grant, Samuel C. Grant, Samuel Colles Granziera, Cristina Grau, Georges E Graveron-Demilly, Danielle Graves, Martin J. Graves, Martin John Grayev, Allison Michele Grazioli, Luigi Green, Jordin D. Green, Jordin Daniel Green, Marjorie Greenberg, Steven Mark Greene, Nicholas Greenshields, Ian R. Greenspan, Joel D. Greenwood, John P. Gregoire, Vincent Gregory, Carrie S. Gregory, Lloyd J. Gregory, Sarah L. Greil, Gerald Greiner, Andreas Greiser, Andreas Grélot, Laurent Gretka, Voytek Greve, Douglas N. Greve, Joan M. Grewer, Rüdiger Gribbestad, Ingrid S. Gribbestad, Ingrid Susann Gribbestad, Ingrid Susanne Gribbestad, Ingrid Synnøve Grieb, Pawel Griebe, Martin Grieve, Joan Griffioen, Arjan W. Griffith, Andrew J. Griffiths, Beatrice Griffiths, John R. Griffiths, P D. Griffiths, Paul D. Griffiths, Paul David Grimm, Jan Grimm, Roger C. Grimson, Eric L. Grinevich, Vladimir Gringel, Tabea Grissom, William Grissom, William A. Grist, Thomas M. Griswold, Mark Griswold, Mark A. Gritsch, H Albin Grodd, Wolfgang Groden, Christoph Groen, Jan Groen, Jan P. Groenendaal, Floris Groenewold, Erik Gropler, Robert Gropman, Andrea L. Gross, D. Gross, Donald William Gross, Eitan Gross, Patrick Gross-Issarof, Ruth Grossman, Elan Grossman, March Grossman, Robert Grossman, Robert I. Grotz, Thimo Grover, Keshav Groves, Adrain Groves, Adrian Richard Groves, Alan M. Gruber, Michael Gruber, Stephan Gruen, Jeffrey R. Gruetter, Rolf Grundmann, Kathrin Grundy, Richard Grundy, Richard G. Grunfeld, Robert Gruwel, Marco Gruwel, Marco L.H. Grüll, Holger Gründer, Wilfried Grüner, Renate Grzelak, Ireneusz Grässlin, Ingmar Gräßel, David Gröhn, Heidi Gröhn, Olli Gröhn, Olli H.J. Grönemeyer, Dietrich H.W. Gu, Gina J. Gu, Hong Gu, Meng Gu, Tianliang Gu, Yu-Gui Guan, Xin Guan, Zhen Guarini, Marcelo Guarini, Marcelo W. Guarise, Alessandro Guasch, Antonio Guccione, Julius M. Gudinchet, François Guehring, Jens Guénin, Samuel Guenther, Matthias Guenther, Rolf W. Guer, Okan Guerra, Pedro Guerrini, Chiara Guhde, Renee Gui, Minzhi Guidone, Elizabeth Guidoni, Laura Guillemain, Isabelle Guillermier, Martine Guillot, Geneviève Guimaraes, Alex Guimond, Alexandre Guimond, Paul Guion, Peter Gulani, Vikas Gulati, Mittul Gulcur, Halil Ozcan Guleria, Saurabh Gulian, Jean-Marc Gullapalli, Rao Gullapalli, Rao P. Gulsen, Gultekin Gundelfinger, Eckart D. Gundersen, Hilde Gunn, Roger Gunny, Rox Gunter, Jeffrey L. Gunther, Rolf W. Guo, D-B Guo, Edward X. Guo, Hua Guo, Junyu Guo, X E. Guo, X. Edward Guo, Xiaodong Guo, Xing-Gao Gupta, Amit Gupta, Arun Kumar Gupta, Ashish Gupta, Himanshu Gupta, N P. Gupta, R.K. Gupta, Rakesh K. Gupta, Rakesh Kumar Gupta, Rk Gupta, Sandeep Gupta, Sandeep N. Gupta, Sandeep S. Gupta, Twinkle Gupta, Vivek Gur, Raquel E. Gur, Ruben C. Gurachevsky, Andrey Gurney, Paul K. Gurney, Paul T. Gurney, Paul Thomas Gurol, M. Edip Gustafsson, Lotta Gustavsson, Helen Guthmann, Stefanie Guthrie, Ashley Guttman, Michael A. Guttmann, Charles R.G. Guy, Nicolas Guye, Maxime Guyer, Richard Guze, Barry Guzel, Elif Güldner, Manuela Güllmar, Daniel Günther, Albrecht Günther, Matthias Günther, Rolf W. Günther, Ulrich L. Göricke, Sophia L. Götte, Marco Jw Haack, Soren Haacke, E Mark Haacke, E. Mark Haacke, Ewalt Mark Haacke, Ewart Mark Haacke, Mark Haacke, Mark E. Haag, Michael A. Haage, Patrick Haaker, Paul Haakstad, Michael J. Haans, Paul Haap, Michael Haase, Axel Habara, Hideta Habbel, Anne Habeck, Christian Habermeyer, Benedikt Habets, Jo W. Habib, Dayane Hackenbroch, Mathias Hackeng, Tilman M. Hackett, Neil R. Hackney, David B. Haddidin, Ihab S. Hadjidekov, Georges Hadley, J R. Hadley, J. Rock Haeberlin, Maximilian Haertle, Mareile Haffner, Rebecca Hagberg, Gisela Hagberg, Gisela E. Hagberg, Gisela Elisabeth Hagberg, Gisela Elizabeth Hagen, Karl Hager, Gregory D. Haghihi, Parvez Hagler, Donald J., Jr. Hagmann, Cornelia Franziska Hagmann, Patric Hagspiel, Klaus Hagspiel, Klaus D. Hagstedt, Therese Hahn, Christopher Hahn, Dietbert Hahn, Horst Hahn, Horst K. Hahn, Horst Karl Hahn, Jooyoung Hahn, Klaus Rudolf Hahn, Theresa Haider, Clifton R. Haider, Masoom A. Haishi, Tomoyuki Hajek, Milan Hajitou, Amin Hajnal, Jo Hajnal, Jo V. Hajnal, Joe Hajnal, Joesph V. Hajnal, Joseph V. Haker, Steve Haker, Steven J. Hakkarainen, Antti Halbach, Van Hald, John K. Haldar, Justin Haldar, Justin P. Haldorsen, Anita Gjeilen Haley, Andreana Petrova Haley, Robert Halgunset, Jostein Hall, Daeana L. Hall, Matt G. Hall, Nathan Hall, Timothy L. Hallak, Jaime Eduardo Hallenbeck, John M. Haller, Sven Hallett, William Halliday, Jane Hallock, Kevin Hallock, Kevin J. Halpern, Howard J. Halsted, Philip Hamada, Yusuke Hamalainen, Matti S. Hamamci, Andac Hamamura, Mark J. Hamamura, Mark Jason Hamandi, Khalid Hamann, Stephan Hamans, Bob C. Hambrock, Thomas Hamdorf, Mareike Hamhaber, Uwe Hamilton, Amanda Marie Hamilton, Gavin Hamilton, James Hamilton, James A. Hamilton, Scott Hamm, Bernd Hamm, Michael Hammen, Thilo Hammond, Kathryn E. Hammond, Kathryn Ellen Hamprecht, Fred A. Han, Bingue Han, Byung Hee Han, Eric Han, Eric T. Han, Jay Han, Jing Han, Misung Han, Steve Han, Yeji Han, Yuchi Han, Zhaohui Hanamiya, Mai Hanaoka, Syouhei Hancu, Ileana Handa, Shinya Handler, William B. Handler, William Bradfield Haney, Chad R. Hanks, Robin Hanley, Daniel F. Hann, Byron Hann, Byron C. Hanna, Magdi Hannila, Ilkka Hansen, Adam Espe Hansen, Brian Hansen, Michael S. Hanson, Christian G. Hanson, Lars G. Hanson, Tim Hansson, Georg Hantraye, Philippe Hao, Nan-Xin Haque, Hasnine Haque, Hasnine A. Haque, Hasnine Akter Haque, Muhammad E. Har-El, Yahel Hara, Masaki Hara, Shinji Harada, Masafumi Haradome, Hiroki Haraldseth, Olav Hardies, Jean Harding, Sally Harding, Sally G. Hardung, Hendrik Hardy, Christopher Hardy, Christopher J. Hardy, Christopher Judson Hardy, Micael J. Hardy, Peter Harel, Noam Hargrave, Darren Hargreaves, Brain A. Hargreaves, Brian Hargreaves, Brian A. Hargreaves, Brian Andrew Hargreaves, Richard J. Hariharan, Hari Haris, Mohammad Harisinghani, Mukesh Harkins, Kevin Harloff, Andreas Harmatz, Paul Harmelin, Alon Haroon, Ebrahim Haroon, Hamied A. Harris, Andrew B. Harris, Ashley D. Harris, James C. Harris, Kathleen R. Harris, Kent Harris, Kent C. Harris, Kent Christopher Harris, Lisa Maria Harris, Lisa Marie Harshbarger, Todd Brenson Hart, Lori Harter, Ray Hartke, James Hartley, Michael R. Hartman, Robert P. Hartmann, Michael Hartmann, Tina Hartwig, Valentina Harvey, Harvey, A. Simon Harvey, Alfred Harvey, Ann K. Harvey, Paul Harvey, Paul R. Hasan, Khader Hasan, Khader M. Hasboun, Dominique Hashiguchi, Yuji Hashmi, Ali T. Hasnine, Haque Hassan, Diana M. Gomez Hassanein, Tarek I. Hassanipour, Mohammad Hasselbalch, Steen G. Hassid, Yaron Hata, Nobuhiko Hatabu, Hiroto Hatakeyama, Hideo Hatayama, Hiroshi Hatsukami, Thomas Hatsukami, Thomas S. Hatsukami, Tom Hattingen, Elke Hatton, Matthew Q. Hattori, Mineyuki Hattori, Noriaki Hauber, Sandra Haude, Michael Haueisen, Jens Haueisen, Ralf Haughton, Victor Haughton, Victor M. Hauksson, Jón Hautle, Patrick Hautvast, Gilion Hauwell, Mathieu Havrdova, Eva Hawkes, David Hawkes, David J. Hawkes, Rob Hawley, Catherine Hawryluk, Greg Hayasaka, Satoru Hayashi, Naoto Hayashi, Shigenori Hayashida, Yoshiko Hayden, Michael E. Hayes, Carmel Hayes, Cecil Hayes, Cecil E. Haynor, David R. Hazeltine, Eliot Hazle, John D. He, Bin He, G He, Gaunglong He, Guanglong He, Hongjian He, Huamei He, Lili He, Qiuhong He, Renjie He, Taigang He, Xiang He, Yi He, Yong-Yue Head, Elizabeth Head, Kay Head, Kay E. Head, Kevin Heberlein, Keith Hebrank, Franz Hebrank, Franz Xaver Hecht, Elizabeth Hecht, Elizabeth M. Hedlund, Laurence W. Hedström, Erik Heemskerk, Anneriet M. Heemskerk, Anneriet Marie Heemskerk, Johan W. Heeneman, Sylvia Heerschap, A. Heerschap, Arend Heethaar, Rob M. Heffron, Thomas Hegde, Sanjeet R. Hegde, Sanjjet Hegele, Robert Hegge, Julia Heiberg, Einar Heid, Oliver Heidbreder, Christian Heidbreder, Christian A. Heidemann, Robin M. Heidenreich, Jens O. Heidenreich, Jens Olaf Heier, Linda A. Heijden, Jan Vd. Heijman, Edwin Heijmink, Stijn Heijmink, Stijn W. Heijnen, Cobi Heil, Werner Heiler, Patrick Michael Heilman, Jeremiah Aaron Heilmann, Melanie Hein, Patrick A. Heindel, Walter Heinze-Paluchowska, Sylwia Heisen, Marieke Heishman, Stephen J. Heiss, Wolf-Dieter Hekmatyar, S K. Hekmatyar, Sk K. Helekar, Santosh A. Heller, Martin Helm, Emma Helm, Katharina Helm, Patrick Helm, Patrick A. Helmecke, Sven Helms, Gunther Helpern, Joseph A. Hemal, A.K. Hemmings, Brian A. Henderson, David Hendler, Talma Hendrikse, Jeroen Henerici, M.G. Hengerer, Arne Henkelman, Mark Henkelman, R M. Henkelman, R Mark Henkelman, R. Mark Henn, Fritz A. Hennemuth, Anja Brigitte Ziva Hennerici, Michael G. Hennig, Juergen Hennig, Jürgen Hennig, M E. Henning, Anke Henning, Erica C. Henninger, Nils Henry, Mike E. Henry, P-G. Henry, Pierre-Gilles Henry, Roland G. Henry, Thomas Reid Henze, Günter Henze, Marcus Herard, Anne Sophie Hérard, Anne-Sophie Herberg, Ben Herbert, Joseph Herbik, Magdalena Herborn, Christoph Herdener, Marcus Herfkens, Robert J. Hergt, Martin L. Herlihy, Amy Herlihy, Amy H. Herlihy, David Hermann, Bruce P. Hermann, Christiane Hermann, Simon Hermans, Robert Hermesh, Haggai Hermier, Marc Hernaiz-Driever, Pablo Hernandez, Andrea Hernández, Ricardo M. Hernandez-Garcia, Luis Hernando, Diego Herrmann, Karl-Heinz Hersman, Elizabeth Hersman, F W. Hersman, F William Hersman, F. W. Hersman, F. William Hersman, William Herzka, Daniel A. Heshiki, Atsuko Hess, Andreas Hess, Christopher P. Hesselink, Matthijs Hesser, Jürgen Hetherington, Hoby P. Hetherington, Hoby Patrick Hetzel, Andreas Hetzer, Roland Hetzer, Stefan Heufelder, Jens Heumann, Thomas Heurteaux, Catherine Heusch, Gerd Heußel, Claus Peter Heverhagen, Johannes T. 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Hoff, Michael Nicholas Hoffman, Eric Hoffman, Robert D. Hoffmann, Karl Titus Hoffmann, Kerstin Hoffmann, Stefanie Hoffmann, Ulrich Hofman, Albert Hofman, Mark B.M. Hofman, Paul Am Hofmann, Lawrence V. Hoge, Richard D. Hoge, W. Scott Hoge, William Scott Hogers, Bianca Hoggard, Nigel Hoh, Carl K. Hohl, Christian Hohnholt, Michaela Hoisie, Daniel J. Holbrook, Andrew Bruce Holder, Chad Holdsworth, David W. Holdsworth, Samantha J. Hole, Knut Håkon Holik, Alexander Holland, Christopher M. Holland, Christopher Michael Holland, Scott K. Holland, Scott Kerry Holle, Eerke Holley, André Hollingsworth, Kieren Grant Hollmann, Maurice Holloway, Claire Holm, David Alberg Holmes, James Holmes, Jim Holmvang, Gotfried F. Holodny, Andrei Holodny, Andrei I. Holthuizen, Ronald Holtzheimer, Paul E., III Holtås, Stig Holvoet, Paul Holwell, Joshua J. 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Radjenovic, Aleksandra Radjenovic, Sasha Radtke, Arnold Radue, Ernst-Wilhelm Radzwill, Nicole Ines Rae, Caroline Raffaele, Luigi Raghunand, Natarajan Ragin, Ann Ragin, Ann B. Ragnehed, Mattias Rahme, Laurence Rahme, Laurence G. Rahmer, Juergen Rahmer, Jürgen Rai, Vijan Raikin, Steven M. Raince, Avtar Rainey, Timothy Raith, Johann Raj, Ashish Raj, M Karthick Rajaei, Sheeva Rajagopal, Akila Rajagopalan, Amrita Rajakumar, Nagalingam Rajakumar, Nagarajan Rajan, Pauline Rajapakse, Chamith S. Rajeevan, Nallakandi Rakestraw, Pamela A. Ralph, Matt A. Lambon Ralston, Sarah Ramadan, Soha Said Ramadan, Usama Abo Ramamurthy, Senthil Raman, Steven Raman, Steven S. Raman, Subha V. Raman, Venu Ramanan, Venkat Ramani, A. Ramani, Anita Ramani, Ramachandran Ramanna, Sudhir Ramazzotti, Anna Rambaldelli, Gianluca Ramirez, Manfred Ramirez, Manfred Junemann Ramirez, Marc S. Rammohan, Kottil W. Ramones, Darlene Ramos, Marco A. Ramos, Pedro Rampin, Olivier Ramu, Jaivijay Ramus, Gabrielle Rand, Scott D. Randell, Chris Rane, Swati D. Ranefall, Petter Ranganath, Vanishree Ranjeva, Jean-Philippe Rao, Anil Rao, Hengyi Rao, Jyothi P. Rao, Raghavendra Rao, Stephen M. Rapezzi, Claudio Rasche, Volker Rashid, Shams Rasi, Mana Rastogi, Leena Rastogi, Shishir Ratai, Eva Ratai, Eva-Maria Ratcliffe, Mark B. Ratel, Sébastien Ratering, David Rathore, Chaturbhuj Rathore, Divya Ks Rathore, Divya Singh Rathore, Ram Ks Rathore, Rks Ratiney, Hélène Ratnikov, Vyacheslav Raubitschek, Andrew Rauch, Astrid Veronika Rausch, Martin Rauschenberg, Jaane Rauscher, Alexander Rauvala, Erkki Raval, Amish N. Raya, José G. Rayens, William S. Raylman, Raymond R. Raymond, Gerald V. Raynaud, Florence Rayner, Tammy Rayz, Vitaliy Rayz, Vitaliy L. Razavi, Reza Razavi, Reza S. Razoux*, Florence Rea, Marc Rea, Marc A. Read, Elizabeth J. Read, Paul Read, Paul W. Readhead, Carol Realmuto, Jennifer Reddick, Wilburn E. Reddy, Leila Reddy, Ravinder Reddy, Vivek Y. Redpath, Thomas W. Ree, Anne Hansen Reeder, Scott Reeder, Scott B. Rees, Jeremy Rees, Jeremy H. Reese, Timothy G. Reese, Torsten Reeves, Michael James Regan, Fiona Regatte, Ravinder R. Regino, Celeste Regli, L Rehwald, Wolfgang G. Reiber, J H. Reiber, Johan H.C. Reich, Daniel S. Reichardt, Wilfried Reichek, Nathaniel Reichenbach, Alexandra Reichenbach, Jürgen Reichenbach, Jürgen R. Reichert, Ines L. Reid, David G. Reid, Jean Reijs, Rianne P. Reinhardt, Michael Reinl, Herbert M. Reintke, Frank Reischauer, Carolin Reischmann, Bettina Reiser, M Reiser, Maximilian Reiser, Maximilian F. Reiser, Maximilian Ferdinand Reishofer, Gernot Relwald, Wolfgang Remme, Heike Remmert, Gregor Remonda, Luca Rémy, Chantal Remy, Chantal Remy, Philippe Ren, Christine Ren, Jia Q. Ren, Jimin Ren, Xiao Jun Rendell, John Renema, W Klaasjan Rengle, Adrian Renken, R.J. Renou, Jean-Pierre Renshaw, Perry F. Renteria, Laura Renz, Wolfgang Requardt, Martin Resnick, Scott A. Ressler, Kerry Restom, Khaled Rettmann, Dan Wade Rettmann, Daniel Reutelingsperger, Chris Pm Reuter, Françoise Rexilius, Jan Reyes, Carolina Reyes, Denise A. Reyes, Diane K. Reykowski, Arne Reynolds, Ashley Reynolds, Charles Reynolds, Glenn Reynolds, Steven Reyt, Sébastien Reza, Shahed Rha, Sung Eun Rhee, Thomas Rhee, Thomas K. Rhode, Kawal Ri, Hyeong-Cheol Rialland, Amandine Ribeiro, Luciana Torres Ribés, Alejandro Ribic, Jasna Ricci, Alessandro Riccioli, Luca Albini Richardson, Paul C. Riches, Sophie Riches, Sophie F. Richmond, Josh Richter, Ernst-Juergen Richter, Marlene C. Richter, Wolfgang Richter-Spahn, Bernhard Rick, Jochen Ricketts, Janette Ricks, Jerry L. Riddehough, Andrew Riddle, William R. Ridgway, John P. Rieckmann, Peter Riederer, Stephen J. Riegler, Jörg Rieke, Viola Riemer, Thomas Ries, Mario Riess, Olaf Rietema, H. Rieul, Bernard Riffe, Matthew J. Riffe, Matthew Joseph Righini, Andrea Riklund, Katrine Ringe, Wendy K. Ringel, Israel Ringer, Steven A. Ringer, Thomas Ringgaard, Steffen Rioux, James A. Risa, Øystein Risse, Frank Risse, Wolfgang Ritter, Johannes Ritter, Rogers Rius, Maria Riutcel, Terri L. Rizi, Rahim Rizzo, Giovanna Rizzo, Giovanni Rizzo, Joseph F. Robbins, Peter A. Robbins, Robert Robbins, Robert C. Robert, Benjamin Robert, Philippe Roberts, C Roberts, Caleb Roberts, John A. Roberts, Katherine Roberts, Timothy Robertson, Nicola J. Robertson, Nicola Jayne Robertson, Richard L., Jr. Robidel, Franck Robinson, Ian Robinson, Melissa Robinson, Philip Robinson, Robert G. Robinson, Simon P. Robison, Ryan G. Robison, Ryan K. Robison, Ryan Keith Robson, Matthew Robson, Matthew D. Robson, Matthew David Robson, Phil Robson, Philip Robson, Philip M. Rocca, Cathy Rocca, Maria Assunta Roccatagliata, Luca Roche, Aidan Rockel, Conrad Roddey, Cooper Roddey, Copper Roden, Michael Rodenacker, Karsten Rodionov, Roman Rodrigo, Jose Rodrigues, Loreta M. Rodriguez, Alfredo O. Rodriguez, Genevieve Rodríguez, Ignacio Rodriguez, Juan Carlos Roe, Anna Roe, Anna Wang Roebroeck, Alard Roebuck, Joseph R. Roell, Stefan Roeschmann, Peter Rofsky, N. M. Rofsky, Neil M. Rogers, Baxter P. Rogers, Kem Rogers, Kem A. Rogers, Richard Rohling, Kenneth W. Rohrbaugh, Scott Rohrer, Lisa Rohrer, Susan Roig, Jose Vicente Roland, Joerg Roldan, Alejandro Roldán, Alejandro Rolf, Marijn P. Rollet, Simona Rollins, Nancy K. Roman, Brian B. Romani, Gian Luca Romano, Anthony J. Romano, Rocco Romanzetti, Sandro Rome, Claire Romeny, Bart M.Ter Haar Romeo, Maria Antonietta Romijn, Johannes Rommel, Dennis Ron, Maria Ronald, John Ronca, April Ronen, Itamar Ronen, Sabrina M. Ronen, Sabrina M.M. Rooney, William D. Roosendaal, Stefan Dirk Ropele, Stefan Rosa-Neto, Pedro Rose, Chris Rose, Chris J. Roselli, Antonella Rosen, Bruce Rosen, Bruce R. Rosen, Mark Rosen, Mark A. Rosen, Matthew Scott Rosen, Yael Rosenbaum, David H. Rosenberg, Gary Rosenberg, Jens T. Rosenblum, Rachel Rosenfeld, Michael E. Rosenfeld, Myrna R. Rosenzweig, Anthony Rosi, Antonella Rosquist, Hannah Ross, Brian D. Ross, Brian David Ross, James Ross, Thomas J. Rossetti, Luciano Rossi, Charles J. Rossi, Cristina Rossman, Phillip Rossman, Phillip J. Rostrup, Egill Roth, Marguerite Rothman, Douglas Rothman, Douglas L. Rottner, Kurt Rougon, Geneviève Rourke, David Edward Roux, Stéphane Rovaris, Marco Rovet, Joanne Rovira, Alex Rowe, Daniel B. Rowland, Ian John Rowley, Howard Rowley, Howard A. Roy, R Jack Roy, Raja Roys, Steve Rozera, Carmela Rozie, Sitske Rubin, Geoffrey D. Rudd, Brent W. Rudd, James Hf Rudersdorf, Daniel Rudin, Markus Rueckert, Daniel Rueckriegel, Stefan Rueger, Maria Adele Ruehm, Stefan Ruehm, Stefan G. Ruehm, Stephan G. Ruel, Martin Ruf, Daniel M. Ruf, Katharina Ruf, Matthias Ruff, Jan Ruggieri, Michael Ruhl, Karl M. 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Saebo, Karen Saeed, Maythem Saft, Carsten Saga, Tsuneo Sah, Pannalal Saha, Punam K. Sahajwani, Mitali Sahara, Tomohiro Sahinbas, Hüseyin Sahn, David J. Said, Adnan Said, Hasan Al Saiki, Shutaro Saint-Jalmes, Hervé Saito, Naoko Sajda, Paul Sajja, Balasrinivasa Rao Sakahara, Harumi Sakai, Koji Sakai, Osamu Sakai, Shuji Sakai, Toyohiko Sakaie, Ken Earl Sakamoto, Masahiko Sakata, Motomichi Sakata, Tomotaka Sakoglu, Unal Saksena, Sona Sakuma, Hajime Sakurada, Aine Sala, Evis Sala, Stefania Salameh, Najat Salarirad, Sima Salat, David Salat, David H. Saleh, Roya Saleh, Roya S. Salek-Haddadi, Afraim Salem, Riad Salerno, Michael Salgado-Commissariat, Delanthi Salgin, Burak Salhotra, Amandeep Salibi, Nouha Salizzoni, Eugenio Salluzzi, Marina Salman, Khalil Salman, Khalil N. Salmeron, Betty Jo Salo, Ruth Salomon, Noriko Salomonowitz, Erich Saloner, David Saluste, Erik Salvado, Olivier Salvatore, Marco Samber, Daniel D. 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Saraswathy, Suja Sardanelli, Francesco Sari-Sarraf, Farid Sarin, Hemant Sarin, Ritu Saritas, Emine Ulku Sarkar, Chitra Sarkar, Ranjeeta Sarkar, Subhendra Sarkari, Shirin Sarlls, Joelle E. Sarma, Manoj K. Sartorius, Alexander Sasai, Hideko Sasaki, Hidenao Sasaki, Makoto Sasaki, Takahiro Sasaki, Tomio Sasportas, Laura Sarah Sasso, Giuseppe Sasson, Efrat Sathyanarayana, Shashank Satkunasingham, Janakan Sato, Kent Sato, Kimihiko Sato, Toru Saukkonen, Tero Saunders, Michele Saunders, Michele I. Saur, Ralf Savadjiev, Peter Savage, Cary Roger Savic, Ivanka Sawamoto, Nobukatsu Sawamura, Chigusa Sawiak, Stephen John Saxena, Sanjaya Saxena, Vipin Sayed, Christopher Sayed, Imran Saylor, Charles Saylor, Charles Albert Sayre, James Saywell, Véronique Scadeng, Miriam Scaff, Kristen M. Scaglione, Cesa Scardino, Peter Scardino, Peter T. Scarmeas, Nikolaos Scattini, Barbara Schaal, Benoist Schabel, Matthias Christian Schacht-Hansen, Michael Schad, Lothar R. Schad, Lothar Rudi Schade, Heinz Schaefer, Andreas Schaefer, Pamela W. Schaefers, Gregor Schaeffter, Tobias Schar, Michael Schar, Mike Scharfetter, Hermann Scheef, Lukas Scheenen, Tom Scheenen, Tom W. Scheenen, Tom W.J. Scheenstra, Alize E.H. Scheffler, Klaus Scheich, Henning Scheidegger, Rachel Scheie, David Schellenberg, Angela Schellenberg, Angela E. Schelp, Marie Scheltens, Philip Schenck, John Schenck, John F. Schengel, Max Schenkel, Michael Schepkin, Victor D. Schernthaner, Guntram Scheunders, Paul Schiavina, Riccardo Schibur, Daniel Schick, Fritz Schiff, David Schiffbauer, Hagen Schifitto, Giovanni Schijns, Olaf E. Schild, Hans H. Schild, Hans Heinz Schillak, Scott M. Schilli, Elly Schilling, Harry Schiltz, Kolja Schindera, Sebastian Tobias Schipper, M Schirda, Claudiu Schirf, Brian E. Schirmer, Timo Schirra, Carsten Oliver Schizas, Demetrios Schlemmer, Heinz-Peter Schlemmer, Heinz-Peter W. Schlentz, Bob Schloss, Robert Schlosser, Thomas Schlumbohm, Cristina Schlüter, Mathias Schmainda, Kathleen Schmainda, Kathleen M. Schmainda, Kathleen Marie Schmalbrock, Petra Schmid, Albrecht I. Schmid, Albrecht Ingo Schmid, Florian Schmid, Jean-Paul Schmid, Volker J. Schmidig, Daniel Schmidt, C M. Schmidt, Ehud Schmidt, Ehud J. Schmidt, Gerwin P. Schmidt, Joachim Schmidt, Melanie Schmidt, Michaela Schmidt, Robert Schmidt, Robert E. Schmidt, Sein Schmidtz, Nicole Schmieder, Anne H. Schmiedeskamp, Heiko Schmiedeskamp, Jorg Schmiedeskamp, Jörg Schmierer, Klaus Schmithorst, Vincent J. Schmithorst, Vincent Jerome Schmitt, Franz Schmitt, Melanie Schmitt, Peter Schmitter, Sebastian Schmitz, Annemarie Caroline Schmitz, Christoph Schmitz, Sebastian Schmitz, Stephan Schmitz, Stephan A. Schmuecking, Ingo Schnack, Christoph Schnackenburg, Bernhard Schnall, Mitchell D. Schnall, Mitchelle Schneider, Erika Schneider, Frank Schneider, Gerald E. Schneider, Guenther Schneider, Jurgen Schneider, Jurgen E. Schneider, Martin Schneider, Peter Schnell, Susanne Schnell, Wilfried Schnitker, Ralph Schnitzer, T Schnoebelen, Sarah Schnorr, Joerg Schnorr, Jörg Schocke, Michael Schoder, Heiko Schoenberg, Stefan Schoenberg, Stefan O. Schoenberg, Stefan Oswald Scholl, Clara A. Scholl, Timothy J. Scholl, Timothy James Schollmayer, Curd Scholnick, Joshua Scholtzova, Henrieta Scholz, Alexander Scholz, Alexander W. Scholz, Thomas D. Schomig, Albert Schonberg, Tom Schor, Stefan Schoth, Felix Schott, Jonathan M. Schrader, Jürgen Schraml, Christina Schrauwen, Patrick Schrauwen-Hinderling, Vera B. Schreiber, Wolfgang Schreiber, Wolfgang G. Schreiber, Wolfgang Guenther Schreiber, Wolfgang Günther Schreiber, Wolgang G. Schreibmann, Eduard Schroeder, Marie A. Schroeder, Marie Allen Schroth, Gerhard Schröder, Johannes Schröder, Tobias Schubart, Anna Schubert, Florian Schubert, Mirjam I. Schubert, Rolf Schuchard, Ronald A. Schuff, Norbert Schulam, Peter Schulte, Marie L. Schulte, Michael Schulte, Rolf Schulte, Rolf F. Schulte, Rolf Feodor Schulte, Tilman Schultze-Haakh, Helmuth Schulz-Menger, Jeanette Schulz-Schaeffer, Walter Schulz-Wendtland, Rüdiger Schulze, Almut Schulze, Katja Schumacher, Martin Schuman, Melissa Lynne Wagner Schunck, Therese Schurink, Geert Willem Schuster, Christian Schuster, David M. Schwab, Martin E. Schwaiger, Markus Schwartz, Daniel M. Schwartz, Eric D. Schwartz, Jon Schwartz, Kenneth A. Schwartz, Lawrence Schwartz, Michael L. Schwartz, Stephen Schwartzman, Armin Schwarz, Adam Schwarz, Adam James Schwarzbach, Jens Schweitzer, Mark E. Schweizer, Susanne Schwenzer, Nina F. Schwerdt, Alenka Schweser, Ferdinand Schwimmer, Jeffrey B. Schwitter, Juerg Schäfer, Andreas Schäfer, Oliver Schäfer, Sebastian Schönfeldt-Lecuona, Carlos Schöning, Sonja Scifo, Paola Scott, Greig Scott, Greig Cameron Scott, Kevin R. Scott, Rodney C. Scotti, Giuseppe Scotti, Roberta Scouten, Amy Margaret Jane Scurr, Erica Seabrook, Tim Seaquist, Elizabeth R. Sebolt-Leopold, J S. Secchi, Francesco Sedlacik, Jan Seeber, Derek A. Seed, Mary Seeger, Achim Seenu, V Seethamraju, Ravi Teja Seevinck, Peter Roland Segebarth, Chistoph Segebarth, Christoph Segers, Jerome Sehgal, Vivek Seiberlich, Nicole Seierstad, Therese Seifert, Frank Seifert, Terese R. Seifritz, Erich Seith, Ashu Sekino, Masaki Sela, Gal Sellers, Michael B. Selvan, Madeswaran Selvanayagam, Joseph Selvarajah, Dinesh Semmler, Wolfhard Semnic, Robert Semple, Scott I. Semple, Scott Ian Kay Senaj, Viliam Sénégas, Julien Senft, Stephen Sengupta, Saikat Senior, Emma L. Senseman, David M. Seo, Hidekazu Seo, Taro Seo, Won Seok Seppenwoolde, Jan-Henry Serai, Suraj Serduc, Raphael Serkova, Natalie Serkova, Natalie J. Serra, Laura Serrano, Faridis Serruys, Patrick W. Sestina, Lisbeth Setser, Randolph M. Setsompop, Kawin Seunarine, Kiran Kumar Sevick, Robert Seymour, Zachary A. Sgouros, George Sgouros, Spyros Shabat, Shay Shafa, Eiman Shah, Ashish Shah, Bijay K. Shah, Jon N. Shah, Manisha Shah, Maulin Shah, N. Jon Shah, Nadim Jon Shah, Niral Shah, Nirvish Shah, Rachana N. Shah, Saurabh Shah, Tariq Shah, Tejal Shah, Vipul Shah, Zarine Shahbazi-Gahrouei, Daryoush Shahram, Morteza Shaibani, Ali Shaikh, Abe Shan, Zhang Jin Shanbhag, Dattesh D. Shang, Hui Fang Shankaranarayanan, Ajit Shankland, Eric G. Shanmuganathan, Kathirkamanthan Shantanu, Sinha Shao, Yong-Cong Shapira, Itai Shapiro, Erik M. Sharan, Ashwini Sharif, Behzad Sharif, M. Reza Akhavan Sharma, Abhinav Sharma, Ajay Sharma, Leena Sharma, Puneet Sharma, Raju Sharma, Rakesh Sharma, Uma Sharp, Jonathan C. Sharpe, Lindsay Shaw, Ashley Shea, Steven M. Sheehan, John Sheehan, John Joseph Sheikh, Kazim A. Shen, Gary X. Shen, Gary Xiong Shen, Hao Shen, Jun Shen, Ningyan Shen, Qiang Shen, Xiaolan Shen, Yimin Shen, Yuji Sheng, Jinhua Sheng, Ke Shenoy, Ravikiran Shepard, Timothy Shepherd, Timothy M. Shepherd, Timothy Michael Shepp, Larry Shera, David Sherbondy, Anthony Jacob Shergill, Suki Sherman, Yoav Sherry, A. Dean Sherry, Allen Dean Sherry, Dean Shestov, Alexander Shestov, Alexander A. Shet, Keerthi Sheth, Sujit Sheth, Vipul R. Shetty, Aarti Shetty, Anil Shetty, Anil M. Shetty, Sanjay Shetty, Sanjay K. Sheu, Hwo-Shuenn Shi, Jianrong Shi, Xianfeng Shi, Yundi Shibamoto, Yuta Shieh, Dar-Bin Shieh, Mason Shih, Chia-Ming Shih, George Shih, Yi-Yu Shiino, Akihiko Shiloff, Deborah Shiloh, Roni Shiloh, Yosef Shimada, Morio Shimada, Takeshi Shimakawa, Ann Shimauchi, Akiko Shimizu, Ayame Shimizu, Yu Shimono, Taro Shimony, Josh S. Shimony, Joshua S. Shin, David Shin, Dongsuk Shin, Jaemin Shin, Lewis K. Shin, Taehoon Shin, Wanyong Shinar, Hadassah Shinmoto, Hiroshi Shinoda, Kazunobu Shinohara, Katsuto Shirai, Toru Shirwan, Haval Shmueli, Karin Sho, Eiketsu Shokek, Ori Shono, Sadahisa Shore, Angela Shou, Zhiping Shrager, Joseph Shrivastava, Devashish Shroyer, Kenneth R. 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Simoes, Rui Vasco Simon, Tony Simon, Tony J. Simonetti, Arjan W. Simonetti, Arjan Willem Simonetti, Orlando P. Simor, Tamás Simpson, Helen J.Z. Simpson, John Simpson, Kenneth Simpson, Nicholas Edward Simpson, Peter J. Sindile, Adrian Singal, Ashish Singh, Anup Singh, Anurag Singh, Charan Singh, Gurmeet Singh, Jitesh K. Singh, Manbir Singh, Satinder Singh, Sujata Singh, Sumit Singh, Sunil Singhal, Aneesh Singhal, Aneesh B. Singhal, Udit Sinha, Neelam Sinha, Shantanu Sinha, Tuhin K. Sinha, Tuhin Kumar Sinha, Usha Sinitsyn, Valentin Sinkus, Ralph Siok, Wai-Ting Sipilä, Pekka Sira, Liat Ben Sirabella, Paolo Sirlin, Claude Sirlin, Claude B. Sironi, Annamaria Sirotin, Y.B. Sisney, Gale Sison, Shiloh Siston, Robert A. Sitaram, Ranganatha Sitaraman, Shanthi Sitoh, Yih Yian Sitoh, Yih-Yian Sitter, Beathe Siu, Hiu-Fai Sivaswamy, Lalitha Sizonenko, Stephane Sizonenko, Stéphane V. Sizonenko, Stephane V. Sjogren, Johan Sjøbakk, Torill E. 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Wang, Ping Wang, Qidong Wang, Qing Wang, Rui Wang, Ruopeng Wang, Shih-Chang Wang, Shu-Ming Wang, Shumin Wang, Si-Lun Wang, Sumei Wang, Tungte Wang, Wei Wang, Wen-Tung Wang, Wenchao Wang, Wenle P. Wang, Xiao Ying Wang, Xiao-Ying Wang, Xiaochuan Wang, Xiaoxia Wang, Xiaoying Wang, Xinjiang Wang, Xuxia Wang, Ya Wang, Yang Wang, Yanxin Wang, Yao Wang, Yi Wang, Yuenan Wang, Yun-Ming Wang, Ze Wang, Zhangwei Wang, Zhao-Qi Wang, Zhen J. Wang, Zhikang Wang, Zhiyue J. Wang, Zhiyue Jerry Wansapura, Janaka Warach, Steven Warach, Steven J. Ward, Barney D. Ward, Chadwick P. Ward, Erin Ward, Heidi Ward, Heidi A. Ward, Janice Wardlaw, Joanna M. Warfield, Simon K. Wargo, Christopher Joseph Warmuth, Carsten Warmuth, Marcus Warnking, Jan Warntjes, J Bm Warren, Jane E. Warren, Ruth Warren, Warren S. Warren, Warren Sloan Warrick, Nicholas Wary, Claire Washko, George Wassenaar, Peter A. Wasser, Martin Watanabe, Atsuya Watanabe, Hidehiro Watanabe, Takashi Watanabe, Tomoko Watanabe, Toshiyuki Watanabe, Yasuharu Watanabe, Yuji Watcha, Daena Sarah Waters, Emily Alex Waters, Emily Alexandria Waterton, John C. Watkins, Kate E. Watkins, Ronald Watkins, Ronald D. Watson, Terri Louise Watson, Yvonne Watters, Michael Watts, Richard Watzl, June Waugh, Shelley A. Weadock, William Weadock, William J. Weale, Peter Weatherall, Paul T. Weaver, John Webb, Andrew Webb, Andrew G. Webb, Douglas Webb, Tom Webber, Colin E. Weber, Christian Weber, Daniel Ludwig Weber, Ewald Weber, Jürgen Weber, Marc-André Weber, Michael Weber, Oliver Weber, Oliver M. Weber, Stefan Weber, Thomas Weber-Fahr, Wolfgang Webster, Nicole Weckbach, Sabine Wedeen, Van Wedeen, Van J. Wedeen, Van Jay Wegener, Susanne Wegh, René Wegh, René T. Wehling, Eike Wehner, Martin Wehrl, Hans F. Wehrli, Felix Wehrli, Felix W. Wehrli, Suzanne Wehrli, Suzanne L. 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Wentz, S Weon, Young-Cheol Werner, Beat Werp, Peter Wesarg, Stefan Wesolowski, Roman Wesseling, Pieter Westenberg, Jos J.M. Westesson, Per Lennart Westin, Carl-Fredrik Westphal, Christopher Wetzel, Stephan Wetzel, Stephan G. Wetzel, Timm Weyhermüller, Thomas Whalen, Stephen Whalley, Lawrence J. Wharam, Moody Wheeler, David Wheeler-Kingshott, Claudia A.M. Wheeler-Kingshott, Claudia M. While, Peter Thomas Whitaker, Kirstie Whitby, E H. Whitby, Elspeth Helen Whitcher, Brandon Whitcomb, Louis L. White, Keith White, Mark J. White, Nathan White, Nathan S. White, R. Allen Whiting, Eric Whitlock, Mark Whitman, Gary J. Whittingstall, Kevin Whitton, Polly Whyte, Douglas Wiberg, Maria Kristoffersen Wibral, Michael Wichmann, Tobias Wickline, Sam A. Wickline, Samuel A. Wicklow, Karsten Wickstrom, Eric Wideroe, Marius Widjaja, Elisa Widmaier, Stefan Widmark, Maria T. Wieben, Oliver Wiedemair, Wolfgang Wielopolski, Piotr A. 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Zwettler, Elisabeth Zwick, Stefan Zwingmann, Claudia Zwygart, Karin Zygmanski, Piotr Zylka, Waldemar Zänker, Paul Philipp Zöllei, Lilla Zöllner, Frank Gerrit Østergaard, Leif Abdominal MR: Cutting Edge Abdominal MRI: New Techniques Advanced Parallel Imaging Advances, Acquisitions & Artifacts in Diffusion MRI Alzheimer's Disease Imaging Alzheimer's Disease: From Animal Models to Man Animal Models Artifact Corrections for EPI Artifacts Artifacts and Correction Beyond BOLD: fMRI Contrast & Connecting Brain Neworks Biophysics, Histology & Validation of Diffusion MRI Body GI & Liver Body MR: Chest, Breast & Genitourinary Body MRI - Renal Body: Hepatobiliary, GI, and Women's Imaging Brain Degeneration: Ataxias & Dementias Brain Iron Imaging Brain Tumors: Diagnosis and Response to Therapy Breast & Female Pelvis Breast Cancer Breast Cancer Detection & Response Prediction & Assessment Cancer Detection & Diagnosis Cardiac Function Imaging in Animal Models Cardiac MRS Cardiac Perfusion & Mouse Cardiac Imaging Cardiac Viability and Contractility Cardiomyopathy Evaluation: Perfusion and Viability Cardiovascular Flow Quantification Cardiovascular Methods Cardiovascular: Other Cell Tracking and Biomarker Specific Imaging Cerebral Perfusion: Arterial Spin Labeling Methods Chemical Shift Imaging Clinical Applications in Head & Neck Cancer Clinical Brain Spectroscopy Clinical Science Focus: Breast MRI: Techniques & Lesion Characterization Clinical Science Focus: Clinical Applications of Cerebral Perfusion MRI Clinical Science Focus: Fetal and Female Pelvis Clinical Science Focus: fMRI - 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Already Clinical Reality? PLENARY LECTURES: Monitoring Treatment Response PLENARY LECTURES: Hybrid MR: Systems and Applications PLENARY LECURES: High Tech Approaches and Applications for MR Signal Transmission and Reception Pre-clinical Evaluation of Tumor Response Pre-clinical Imaging of Tumor Function and Structure PROPELLER MRI Prostate Cancer Prostate Cancer Detection & Diagnosis by Diffusion MRI Psychiatric Imaging Psychiatric MRI Q Space & Restricted Diffusion, etc. Rapid Acquisition Receive Coils and Arrays Regional Analysis of the Normal Human Brain by Diffusion Imaging Relaxation & Quantification Relaxation Time Mapping & Relaxometry Retroperitoneal and Gender Based Cancers RF & Gradient Systems RF and K-Space RF Coil Technology: Non-Array RF Coil: Non-Arrays RF Outside the Box RF Pulse Design Safety Regulations and Site Safety Procedure Concerns Safety: MRI and Contrast Agents Sequence Contrasts Sequences: Magnetization Preparation Sequences: RF Excitation Sequences: Sampling Strategies Sequences: Relaxation Spectroscopic Quantitation Spectroscopy Techniques Spine SSFP Stroke Animal Models Stroke: Clinical Applications Technical Developments and Applications of Perfusion in the Brain Technical Developments in Diffusion MR Analysis Term and Preterm Brain The Bright Future of MEMRI The Developing Brain Thermal Therapy Tractography & Tracts Tractography and Brain Disease Transmit Arrays and Amplifiers Tumor Assessment in the Body Tumor Perfusion & Permeability Tumor Therapy Response Uncertainty & Artifacts in Diffusion Vessel Imaging Above the Arch Vessel Wall & Clinical MRA Vessel Wall Imaging Vessel Wall Imaging: Technical Advances Displaying 1 - 4 of 4 Page: 1
Combining Voxel-Based Morphometry and Diffusion Tensor Imaging to Probe Neural Substrate of Schizophrenia on First Episode Treatment Naive Patients
Author: Xiao-Qi Huang Su Lui Wei Deng Luo Ouyang Chun-Xiao Li Tao Li Qi-Yong Gong
Session: Diffusion Analysis: Voxel Based Analysis & Tractography
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MRI Study of Cerebral Asymmetry in Patients with First-Episode Treatment Naive Schizophrenia
Author: Ling Zou Luo Ouyang Xiao-Qi Huang Wei Deng Qin Chen Yi Wei Su Lui Hua-Fu Chen Tao Li Qi-Yong Gong
Session: Psychiatric Imaging
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Neuroabnormality of Thalamus in Secondarily Generalized Seizure: A Diffusion Tensor Study at 3T
Author: Su Lui Luo Ouyang Qin Chen Xiao-Qi Huang Shu-Ying Zhang Wei Deng He-Han Tang Hua-Fu Chen Dong Zhou Qi-Yong Gong
Session: Epilepsy Imaging and Spectroscopy
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White Matter Integrity in First-Episode Schizophrenia: Gender Difference Revealed by Diffusion Tensor Imaging
Author: Xiao-Qi Huang Wei Deng Su Lui Luo Ouyang Chun-Xiao Li Tao Li Qi-Yong Gong
Session: Psychiatric MRI
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Displaying 1 - 4 of 4 Page: 1 | https://cds.ismrm.org/protected/07MProceedings/SearchResults.php?Author=Gong%2C%20Qi-Yong |
Appearance of the Tikhvin Icon of the Mother of God - Orthodox Church in America
According to ancient tradition, the wonderworking icon of Tikhvin is one of several painted by Saint Luke the Evangelist. The icon was taken from Jerusalem to Constantinople in the fifth century, where it was enshrined in the Church of Blachernae, which was built especially for this purpose. In…
Appearance of the Tikhvin Icon of the Mother of God
Troparion & Kontakion
According to ancient tradition, the wonderworking icon of Tikhvin is one of several painted by Saint Luke the Evangelist. The icon was taken from Jerusalem to Constantinople in the fifth century, where it was enshrined in the Church of Blachernae, which was built especially for this purpose.
Shortly after its miraculous appearance, the icon was discovered in several neighboring towns, including the village of Motchenitsy on the bank of the Tikhvinka River, before it finally appeared near the town of Tikhvin. A wooden church dedicated to the Dormition of the Theotokos was built on the site of the icon’s final resting place. Miraculously, the icon survived a number of fires.
In the early sixteenth century, through the zeal of Great Prince Basil Ivanovich, a stone church was built to replace the original wooden structure. In 1560, by order of Tsar Ivan the Terrible, a men’s monastery was established near the church and enclosed with a stone wall.
In 1613-1614, the Swedish army, having seized Novgorod, made several attempts to destroy the monastery. The countless prayers offered to the Theotokos before the icon were heard, and the monastery was spared. On one occasion, after monks had been alerted to the approaching Swedish army, they decided to flee and to take the icon with them. But the monks soon discovered that they could not remove the icon from its shrine. Seeing this as a sign of the Theotokos’ protection, the monks decided not to abandon the monastery, begging the Theotokos to spare them and their beloved spiritual home. To their amazement, a large Muscovite army appeared to defend the monastery.
When the Swedes encountered the army, they retreated immediately. Word of this miracle spread rapidly, and imperial emissaries soon visited the monastery. Accompanied by a copy of the wonderworking icon, they set off for the village of Stolbovo, 33 miles from Tikhvin, where they concluded a peace treaty with the Swedes on February 10, 1617. Afterwards, the copy of the icon was taken to Moscow and enshrined in the Kremlin’s Dormition Cathedral. Later, the same icon was placed in the Holy Wisdom (Hagia Sophia) cathedral in Novgorod at the request of the city’s faithful, who also found themselves under attack by the Swedes. Once again, through the intercession of the Theotokos, the city was spared.
Over the centuries, the icon’s fame spread far and wide. Copies of the wonderworking icon began to adorn churches throughout the land. Some of these copies also proved to be sources of miracles, and it was not uncommon to find the faithful praying before the icon to seek healing for children who were ill.
No fewer than 24 processions with the icon were celebrated each year at the Tikhvin Monastery, where the icon was enshrined. A decorative cover, or “riza,” adorned the icon, exposing only the faces and hands of the Holy Virgin and Christ child. Numerous precious stones studded the riza, and many of the faithful, desiring to express thanksgiving for prayers answered through the Theotokos’ intercession, affixed precious jewelry to the riza.
Most miraculous is the fact that the icon was preserved from destruction or sale after the Russian Revolution, which ushered in a 74-year persecution of the Church. During the 1920s, the communist government demanded that the Russian Orthodox Church turn over countless icons and other precious liturgical items, which through the nationalization of private property were considered the property of “the people.” Many of these sacred items were sold, allegedly to raise money to feed the Russian and Ukrainian population which was afflicted by famine.
During the World War II German occupation, the Nazis removed the icon from the Tikhvin Monastery, from where it was taken to Pskov and subsequently to Riga, Latvia. When the city was evacuated, Bishop John [Garklavs] of Riga, in whose care the icon was placed, took the icon to Bavaria, where it was venerated by Orthodox faithful who had been displaced because of the war. While Soviet agents had spotted the icon, Bishop John was permitted to take the icon to the United States in 1949, under the pretext that the icon in his care was a reproduction, the work of a simple monk, and that it was of little historic or monetary value. Shortly after his arrival in the United States, Bishop John, who was later elevated to the rank of Archbishop, was elected to oversee the Diocese of Chicago, and the icon was regularly displayed and venerated in Chicago’s Holy Trinity Cathedral.
Bishop John frequently took the icon on pilgrimage to various places throughout the United States and Canada. After his retirement in the late 1970s and death on Palm Sunday in 1982, Archpriest Sergei Garklavs, Bishop John’s adopted son, became the caretaker of the icon. In 2003, over a decade after the fall of communism and the resurrection of the Russian Orthodox Church, the decision was made to return the precious icon to its original home.
The icon began its year-long journey to Russia at the 99th annual Pilgrimage to Saint Tikhon Monastery, South Canaan, Pennsylvania, May 23-26, 2003. His Beatitude, Metropolitan Herman, Primate of the Orthodox Church in America, together with members of the Holy Synod of Bishops and guest hierarchs, greeted the icon, which was available for veneration by the faithful.
The icon follows the “Hodegetria” (Hodēgḗtria) model and is similar in style to the ancient Ivḗron icon of Our Lady. It differs in that the Christ child’s legs are crossed, while the sole of His foot is turned to the viewer. Several historic sources note that several other Hodēgḗtria icons of the Theotokos had been brought to Russia in the 1380s, during the rule of the saintly prince Demetrius Donskoy.
-- Archpriest John Matusiak
| https://www.oca.org/saints/lives/2016/06/26/101821-appearance-of-the-tikhvin-icon-of-the-mother-of-god |
GtR
The Gateway to Research: UKRI portal onto publically funded research
National Centre for Nuclear Robotics (NCNR)
Lead Research Organisation:
University of Birmingham
Department Name: Metallurgy and Materials
Overview
Organisations
People
Publications
Outcomes
Abstract
Nuclear facilities require a wide variety of robotics capabilities, engendering a variety of extreme RAI challenges. NCNR brings together a diverse consortium of experts in robotics, AI, sensors, radiation and resilient embedded systems, to address these complex problems.
In high gamma environments, human entries are not possible at all. In alpha-contaminated environments, air-fed suited human entries are possible, but engender significant secondary waste (contaminated suits), and reduced worker capability. We have a duty to eliminate the need for humans to enter such hazardous environments wherever technologically possible.
Hence, nuclear robots will typically be remote from human controllers, creating significant opportunities for advanced telepresence. However, limited bandwidth and situational awareness demand increased intelligence and autonomous control capabilities on the robot, especially for performing complex manipulations. Shared control, where both human and AI collaboratively control the robot, will be critical because i) safety-critical environments demand a human in the loop, however ii) complex remote actions are too difficult for a human to perform reliably and efficiently.
Before decommissioning can begin, and while it is progressing, characterization is needed. This can include 3D modelling of scenes, detection and recognition of objects and materials, as well as detection of contaminants, measurement of types and levels of radiation, and other sensing modalities such as thermal imaging. This will necessitate novel sensor design, advanced algorithms for robotic perception, and new kinds of robots to deploy sensors into hard-to-reach locations.
To carry out remote interventions, both situational awareness for the remote human operator, and also guidance of autonomous/semi-autonomous robotic actions, will need to be informed by real-time multi-modal vision and sensing, including: real-time 3D modelling and semantic understanding of objects and scenes; active vision in dynamic scenes and vision-guided navigation and manipulation.
The nuclear industry is high consequence, safety critical and conservative. It is therefore critically important to rigorously evaluate how well human operators can control remote technology to safely and efficiently perform the tasks that industry requires.
All NCNR research will be driven by a set of industry-defined use-cases, WP1. Each use-case is linked to industry-defined testing environments and acceptance criteria for performance evaluation in WP11. WP2-9 deliver a variety of fundamental RAI research, including radiation resilient hardware, novel design of both robotics and radiation sensors, advanced vision and perception algorithms, mobility and navigation, grasping and manipulation, multi-modal telepresence and shared control.
The project is based on modular design principles. WP10 develops standards for modularisation and module interfaces, which will be met by a diverse range of robotics, sensing and AI modules delivered by WPs2-9. WP10 will then integrate multiple modules onto a set of pre-commercial robot platforms, which will then be evaluated according to end-user acceptance criteria in WP11.
WP12 is devoted to technology transfer, in collaboration with numerous industry partners and the Shield Investment Fund who specialise in venture capital investment in RAI technologies, taking novel ideas through to fully fledged commercial deployments. Shield have ring-fenced £10million capital to run alongside all NCNR Hub research, to fund spin-out companies and industrialisation of Hub IP.
We have rich international involvement, including NASA Jet Propulsion Lab and Carnegie Melon National Robotics Engineering Center as collaborators in USA, and collaboration from Japan Atomic Energy Agency to help us carry out test-deployments of NCNR robots in the unique Fukushima mock-up testing facilities at the Naraha Remote Technology Development Center.
Planned Impact
The NCNR RAI Hub is uniquely equipped and resourced to achieve impactful engagement with the entire value chain. This is because the NCNR Pathways to Impact strategy has been co-created in partnership with key representatives of the entire value chain. NCNR has cemented key partnerships to ensure we deliver:
1) Education and career development of a large new nuclear robotics work-force.
2) Fundamental academic research which comprehensively spans the huge diversity of RAI technologies and related supporting technologies (sensors, resilient chips etc.) that are needed to meet the nuclear challenge.
3) Hand-in-hand partnership with nuclear end-users from the Hub's conception through to delivery - end-users specify the use-cases that drive all Hub research, and specify acceptance criteria used for evaluation.
4) Embedding research outputs directly into major industrial partners, both nuclear and robotics companies, large corporations and cutting-edge SMEs, via long-term embedding and secondments of our researchers.
5) £10million specialist RAI venture capital already committed, with specialist RAI investment and commercialisation experts forming full collaborating project participants from day 1, aimed at converting Hub research outputs into new spin-out companies and achieving commercial technology licensing to end-users.
6) Active participation of the national nuclear agencies of several countries, spanning three continents, to enable real deployments of Hub RAI technologies onto nuclear sites both nationally and internationally.
7) Outreach and public communication of science to engage the wider community with the Hub's contributions.
Our Work Plan supports industrial impact through successful transfer of technology out from the Hub and into partner organisations, including: new Hub spin-out companies; major nuclear end-user companies; large robotics companies and our network of cutting edge UK and European robotics SMEs; other extreme environment domains, e.g. bomb-disposal or firefighting robots; and manufacturing industry.
To ensure end-user exploitation, we will embed many of our PDRF and PhD researchers inside nuclear and robotics companies, and send others for extended collaborative research visits at the nuclear agencies of UK, France, Japan and South Korea. We will also collaborate with UK company partners on InnovateUK projects.
Additional specific pathways to industrialisation include:
1) Director Stolkin and Co-Director Scott are themselves directly embedded inside the nuclear industry (NNL Ltd, and AWE respectively) by Royal Society and RAEng fellowships respectively. This places them in a unique position, relative to any other academics in the country, to inject Hub research into building RAI capabilities in the UK nuclear industry. It also gives unique access to industry advice to help steer our Hub research towards industrial applications.
2) Project partner Shield Investment Management specialises in investing in robotics and AI, particularly in under-roboticised industries (of which nuclear is a prime example). Shield has committed £10million venture capital to NCNR, as well as expertise in taking RAI from conception through to industrialisation.
3) BRL (Melhuish, Pipe) have created the UK's first robotics incubator at the BRL site which has fostered numerous robotics start-up companies.
We will actively engage with the ongoing InnovateUK Demonstrator, Innovation and Nuclear SBRI Programmes. NCNR partners are already involved in four of the eight SBRI Integrated Nuclear Decommissioning projects which received Phase 1 awards. We will seek translation of NCNR technologies into the InnovateUK Innovation and Demonstrator ISCF Programmes, and we will collaborate with industry partners and investors to submit proposals to the regular 6-monthly InnovateUK calls.
Funded Value:
£12,256,861
Funded Period:
Oct 17
-
Mar 22
Funder:
EPSRC
Project Status:
Closed
Project Category:
Research Grant
Project Reference:
EP/R02572X/1
Principal Investigator:
Rustam Stolkin
Research Subject:
Electrical Engineering (55%)
Info. & commun. Technol. (20%)
Instrument. sensor & detectors (25%)
Research Topic:
Computer Graphics & Visual. (10%)
Human-Computer Interactions (10%)
Instrumentation Eng. & Dev. (25%)
Robotics & Autonomy (55%)
If populated the following is a graphic depicting where in the UK the given postcode is located.
Organisations
University of Birmingham, United Kingdom (Lead Research Organisation)
Jacobs Engineering UK Ltd. (Collaboration)
National Nuclear Laboratory (Collaboration)
Atomic Weapons Establishment (Collaboration)
Japan Atomic Energy Agency (JAEA) (Collaboration)
Australian Centre for Robotic Vision (Collaboration)
University of Bristol, United Kingdom (Collaboration)
Karlsruhe Institute of Technology (Collaboration)
University of the West of England, United Kingdom (Collaboration)
Sellafield Ltd (Collaboration)
Kyoto University Research Reactor Institute (Collaboration)
University of Essex, United Kingdom (Collaboration)
Cavendish Nuclear (Collaboration)
University of Lincoln, United Kingdom (Collaboration)
Organisation for Economic Co-operation and Development OECD (Collaboration)
Babcock International Group Plc (Collaboration)
Royal Institution of Great Britain, United Kingdom (Collaboration, Project Partner)
Korea Atomic Energy Research Institute (Collaboration)
KUKA Robotics UK Limited (Project Partner)
National Physical Laboratory NPL, United Kingdom (Project Partner)
Imitec Ltd (Project Partner)
Tohoku University (Japan), Japan (Project Partner)
Thales Research and Technology UK Ltd, United Kingdom (Project Partner)
Forth Engineering Ltd (Project Partner)
Haption (Project Partner)
Atkins Ltd (Project Partner)
Sellafield Ltd, United Kingdom (Project Partner)
James Fisher Nuclear Limited, Inverdurie, United Kingdom (Project Partner)
IHI Corporation (Project Partner)
Ionix Advanced Technologies Ltd, Leeds (Project Partner)
Bekiroglu Y
(2020) Benchmarking Protocol for Grasp Planning Algorithmsin Robotics and Automation Letters
Palermo F
(2020) Automatic Fracture Characterization Using Tactile and Proximity Optical Sensing.in Frontiers in Robotics and AI
Kunze L
(2018) Artificial Intelligence for Long-Term Robot Autonomy: A Surveyin IEEE Robotics and Automation Letters
Joshi P
(2021) Artificial Intelligence and Soft Computing - 20th International Conference, ICAISC 2021, Virtual Event, June 21-23, 2021, Proceedings, Part II
Del Duchetto F
(2020) Are You Still With Me? Continuous Engagement Assessment From a Robot's Point of View.in Frontiers in robotics and AI
Zaffar M
(2019) Are State-of-the-art Visual Place Recognition Techniques any Good for Aerial Robotics?
Joshi P
(2020) Are Current 3D Descriptors Ready for Real-time Object Recognition?
Smith J
(2021) ARDL - A Library for Adaptive Robotic Dynamics Learning
Kamrani M
(2020) Applying Markov decision process to understand driving decisions using basic safety messages datain Transportation Research Part C: Emerging Technologies
Connor DT
(2018) Application of airborne photogrammetry for the visualisation and assessment of contamination migration arising from a Fukushima waste storage facility.in Environmental pollution (Barking, Essex : 1987)
| https://gtr.ukri.org/projects?fetchSize=10&pn=34&ref=EP%2FR02572X%2F1&selectedSortOrder=DESC&selectedSortableField=title |
BCM-HGSC | Eric Boerwinkle, Ph.D. | page 4
Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information [email protected] Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the
Eric Boerwinkle, Ph.D.
Associate Director, Baylor College of Medicine Human Genome Sequencing Center
Contact information
[email protected] (link sends e-mail)
Other positions
Dean, UTHealth School of Public HealthM. David Low Chair in Public HealthKozmetsky Family Chair in Human GeneticsProfessor, Human Genetics Center and Dept. of Epidemiology
Research interests
The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes.
Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics.
Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information.
Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups.
Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype.
Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries.
Publications
2021
Lin BM , Grinde KE , Brody JA , Breeze CE , Raffield LM , Mychaleckyj JC , et al. . Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. EBioMedicine. 2021;63:103157. PubMed DOI Google Scholar Tagged
Wang P , Castellani CA , Yao J , Huan T , Bielak LF , Zhao W , et al. . Epigenome-wide association study of mitochondrial genome copy number. Hum Mol Genet. 2021;31(2):309-319. PubMed DOI Google Scholar Tagged
Bressler J , Davies G , Smith AV , Saba Y , Bis JC , Jian X , et al. . Association of low-frequency and rare coding variants with information processing speed. Transl Psychiatry. 2021;11(1):613. PubMed DOI Google Scholar Tagged
Murdock DR , Venner E , Muzny DM , Metcalf GA , Murugan M , Hadley TD , et al. . Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. Genet Med. 2021;23(12):2404-2414. PubMed DOI Google Scholar Tagged
Seplyarskiy VB , Soldatov RA , Koch E , McGinty RJ , Goldmann JM , Hernandez RD , et al. . Population sequencing data reveal a compendium of mutational processes in the human germ line. Science. 2021;373(6558):1030-1035. PubMed DOI Google Scholar Tagged
Cade BE , Lee J , Sofer T , Wang H , Zhang M , Chen H , et al. . Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. Genome Med. 2021;13(1):136. PubMed DOI Google Scholar Tagged
Wang H , Noordam R , Cade BE , Schwander K , Winkler TW , Lee J , et al. . Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. Mol Psychiatry. 2021;26(11):6293-6304. PubMed DOI Google Scholar Tagged
Li H , Sisoudiya SD , Martin-Giacalone BA , Khayat MM , Dugan-Perez S , Marquez-Do DA , et al. . Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Natl Cancer Inst. 2021;113(7):875-883. PubMed DOI Google Scholar Tagged
Fuentes Lde Las , Sung YJu , Noordam R , Winkler T , Feitosa MF , Schwander K , et al. . Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. Mol Psychiatry. 2021;26(6):2111-2125. PubMed DOI Google Scholar Tagged
Kwong AM , Blackwell TW , LeFaive J , de Andrade M , Barnard J , Barnes KC , et al. . Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries. Genetics. 2021;218(1). PubMed DOI Google Scholar Tagged
Schunk SJ , Kleber ME , Marz W , Pang S , Zewinger S , Triem S , et al. . Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J. 2021;42(18):1742-1756. PubMed DOI Google Scholar Tagged
Xu H , Schwander K , Brown MR , Wang W , Waken RJ , Boerwinkle E , et al. . Lifestyle Risk Score: handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions. Eur J Hum Genet. 2021;29(5):839-850. PubMed DOI Google Scholar Tagged
Ahluwalia TS , Prins BP , Abdollahi M , Armstrong NJ , Aslibekyan S , Bain L , et al. . Genome-wide association study of circulating interleukin 6 levels identifies novel loci. Hum Mol Genet. 2021;30(5):393-409. PubMed DOI Google Scholar Tagged
Natarajan P , Pampana A , Graham SE , Ruotsalainen SE , Perry JA , de Vries PS , et al. . Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. Nat Commun. 2021;12(1):2182. PubMed DOI Google Scholar Tagged
Yu Z , Grams ME , Ndumele CE , Wagenknecht L , Boerwinkle E , North KE , et al. . Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2021;77(3):376-385. PubMed DOI Google Scholar Tagged
Taliun D , Harris DN , Kessler MD , Carlson J , Szpiech ZA , Torres R , et al. . Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290-299. PubMed DOI Google Scholar Tagged
Jones G , Trajanoska K , Santanasto AJ , Stringa N , Kuo C-L , Atkins JL , et al. . Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nat Commun. 2021;12(1):654. PubMed DOI Google Scholar Tagged
Dyment DA , O'Donnell-Luria A , Agrawal PB , Akdemir ZCoban , Aleck KA , Antaki D , et al. . Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome. Am J Med Genet A. 2021;185(1):119-133. PubMed DOI Google Scholar Tagged
Xue D , Bush WS , Renton AE , Marcora EA , Bis JC , Kunkle BW , et al. . Large-scale sequencing studies expand the known genetic architecture of Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12255. PubMed DOI Google Scholar Tagged
2020
Chen S , Jain M , Jhangiani S , Akdemir ZC , Campeau PM , Klein RF , et al. . Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS). JBMR Plus. 2020;4(3):e10335. PubMed DOI Google Scholar Tagged
| https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=9219&page=3 |
Vetcommunique April 2014 AHC25 - edition 2014/2 - DAFF
Animal Health Committee 25 Face to Face, 25-26 March 2014 Welcome to the Animal Health Committee (AHC) newsletter for animal industry bodies. The aim of the Vetcommunique is to provide a communication link between AHC and industry bodies.
Vetcommunique April 2014 AHC25 - edition 2014/2
Animal Health Committee 25 Face to Face, 25-26 March 2014
Welcome to the Animal Health Committee (AHC) newsletter for animal industry bodies. The aim of the Vetcommunique is to provide a communication link between AHC and industry bodies.
AHC meetings are attended by the Chief Veterinary Officers (CVOs) of the Commonwealth, States and Territories, and representatives from New Zealand (NZ), Animal Health Australia (AHA), the Australian Animal Health Laboratory (AAHL), and Animal Division (Department of Agriculture). National industry association representatives and industry representatives from the host jurisdiction also attend an AHC industry session as part of the meeting.
AHC met on 25-26 March 2014 in Tasmania. Dr Rod Andrewartha is the Tasmanian Chief Veterinary Officer and AHC Chair for 2014.Further information on the structure of AHC can be found on the Department of Agriculture website at:daff.gov.au/animal-plant-health/animal/committees/ahc
Key issues discussed by AHC included:
Bovine Johne’s Disease (BJD) Management in Australia
AHC discussed the national approach to the future management of Bovine Johne’s Disease (BJD) in Australia. Discussion acknowledged the difficulties in implementing an effective regulatory BJD control program given technical limitations with surveillance and diagnostics, the lack of international guidance such as from the OIE Code, risks from cross species transmission with small ruminants and difficulties in achieving a nationally consistent approach. AHC has agreed to investigate the commissioning of a comprehensive, risk based, national cost benefit analysis for the management of BJD in Australia that recognises these technical limitations. This would provide a basis to further discussion with Industry on future options for BJD management. AHC will continue to explore how to better standardise surveillance and testing in BJD zones.
Ongoing Avian Influenza Risks
AHC received an update on the work of their Avian Influenza Working Group (AI WG) which is exploring how Australia might better manage ongoing risks from avian influenza outbreaks, including in the free range poultry sector. AHC requested that a broader range of options be further developed by the AI WG including; enhancing biosecurity on high risk farms via extension and/or audit-certification, enhancing surveillance, aligning levels of outbreak compensation with biosecurity status, reconsidering the treatment of avian influenza under the Emergency Animal Disease Response Agreement and considering the role of retailers given their push for free range production. When developed this options paper will be reconsidered by AHC and form the basis for industry consultation on the way forward.
National Enhanced General Surveillance Business Plan
AHC agreed that two national surveillance components were required for the animal health sector; a broader Animal Health Surveillance Strategy to be led by AHC incorporating the whole surveillance system; and an Enhanced General Surveillance Business Plan led by AHA which would be narrower, targeting the rapid implementation of activities to fill gaps in general surveillance of livestock such as via producer awareness campaigns and veterinary practitioner engagement. The Qld CVO was nominated as an additional AHC member on the Enhancing General Surveillance Steering Committee, while SA and WA were tasked with undertaking a review of previous AHC surveillance work and providing advice back to AHC on the development of the overarching Strategy.
Foot-and-Mouth Disease (FMD) Preparedness
AHC acknowledged the expectation from the National Biosecurity Committee for regular reporting on FMD preparedness, based on the FMD national action plan. AHC received reports on significant new programs within Qld and WA to enhance Emergency Animal Disease and FMD preparedness and their willingness to engage nationally and build on existing work. Specific areas identified for collaboration included FMD surveillance, response capacity and training, vaccination, carcase disposal and business continuity. Queensland requested that all AHC members provide contact points to better facilitate this national collaboration. It was noted that AHA would be initiating a swill feeding compliance program and that clearer information on timeframes would be provided.
World Organisation for Animal Health (OIE) Performance of Veterinary Services (PVS) Evaluation
The Australian CVO provided information to AHC on OIE PVS Evaluation which is a successful, well established OIE initiative to evaluate national veterinary services, based on internationally agreed OIE standards on the quality of veterinary services. To date 117 countries around the world have had their veterinary services evaluated through the PVS process. AHC agreed that an international expert(s) from OIE will be invited to present an information session at the next AHC face-to-face meeting in Adelaide. Industry leaders and the Australian Veterinary Association will also be invited to hear from the OIE expert(s) on OIE PVS evaluation as part of the AHC industry session.
Hendra Virus Policy
AHC received a detailed update from AAHL on Hendra virus research and policy implications. AHC noted research findings indicating that recovered sero-positive animals represented only a negligible infectious risk via recrudescence. Therefore the current policy on mandatory destruction for these animals could be revisited such as through case-by-case determination by the relevant CVO. Although agreeing in principle, AHC requested that separate policies be developed for acutely infected animals that may recover and those sero-positive animals already recovered and that endorsement by the relevant health authorities be sought as required and documented.
AHC’s Animal Health Research Priorities
AHC agreed to the concept of AHC collectively developing and formally documenting its national animal health and biosecurity research priorities. Documented AHC research priorities may be provided to relevant researchers and input into the implementation of the National Animal Biosecurity Research, Development and Extension Strategy 2013-2016 being managed by AHA as well as established processes via the Centre for Excellence in Biosecurity Risk Analysis (CEBRA).
Shifting of the Bluetongue Zones
AHC discussed the letter received from the Sheepmeat Council of Australia acknowledging the risks of a clinical case of bluetongue in sheep, given shifting bluetongue zones. Enhancing trade preparedness for this risk will be progressed with industry through the Live Export Protocol Committee managed within the Australian Government Department of Agriculture.
Use of Buparvaquone
AHC discussed the use of Buparvaquone as a successful treatment for Theileriosis in cattle balanced against the residue risks it may pose, as investigated through a report commissioned by Meat and Livestock Australia. NZ use Buparvaquone under very strict conditions but did acknowledge the risks. AHC agreed that it would only support Buparvaquone use if NSW advised that there was strong and widespread whole-chain industry support.
Key Contacts
Dr Rod Andrewartha (AHC Chair 2014), Tasmanian CVO, 03 6165 3261Dr Mark Schipp, Australian CVO, 02 6272 4644Dr Rick Symons, Queensland CVO, 07 3087 8014Dr Ian Roth, New South Wales CVO, 02 6391 3577Dr Cameron Bell, Acting Victorian CVO, 03 5430 4545Dr Malcolm Anderson, Northern Territory CVO, 08 8999 2130Dr Roger Paskin, South Australian CVO, 08 8207 7970Dr Michelle Rodan, Acting Western Australian CVO, 08 9368 3309Dr Will Andrew, Australian Capital Territory CVO, 02 6207 2357Dr Kurt Zuelke, Australian Animal Health Laboratories, 03 5227 5511Dr Eva-Maria Bernoth, Animal Health Australia, 02 6203 3944Dr Robyn Martin, Department of Agriculture, 02 6272 5364Ms Joanne Nathan, Department of the Environment, 02 6275 9252Dr John Stratton, Policy Coordinator, Animal Health Committee, 02 6272 5058Ms Adela Padurean, Secretary, Animal Health Committee, 02 6272 4549
| https://www.agriculture.gov.au/agriculture-land/animal/health/committees/communique/vetcommunique_april_2014_ahc25_-_edition_20142 |
GPP Web Portal - Transcript Details
Transcript: Human XM_006723104.3
PREDICTED: Homo sapiens caspase recruitment domain family member 8 (CARD8), transcript variant X23, mRNA.
Source:
NCBI, updated 2019-09-08
Taxon:
Homo sapiens (human)
Gene:
CARD8 ( 22900 )
Length:
5310
CDS:
432..1727
Additional Resources:
NCBI RefSeq record:
XM_006723104.3
NBCI Gene record:
CARD8 ( 22900 )
sgRNA constructs matching this transcript (CRISPRko, NGG PAM)
This list includes CRISPRko constructs with 100% (20mer + NGG) sequence match to
the coding regions of this transcript.
No results found.
shRNA constructs matching this transcript with 100% SDR
[?]
The SDR or "Specificity-Defining Region" encompasses the 19 bases within the shRNA stem region that are retained during siRNA processing/production. These are thus the bases that define the target specificity of the shRNA. Note that, while our shRNA designs nearly always extend the stem by two additional bases matching the intended target transcript (reported in the "Target Seq" column), these additional bases are not relevant to target specificity.
match
This list includes all shRNAs that have a perfect SDR
[?]
The SDR or "Specificity-Defining Region" encompasses the 19 bases within the shRNA stem region that are retained during siRNA processing/production. These are thus the bases that define the target specificity of the shRNA. Note that, while our shRNA designs nearly always extend the stem by two additional bases matching the intended target transcript (reported in the "Target Seq" column), these additional bases are not relevant to target specificity.
match to
Human XM_006723104.3,
regardless of what transcript they were originally designed to target.
For example, this list can include shRNAs that were originally designed to target:
(i) a different isoform or obsolete version of this transcript (as annotated by NCBI),
(ii) a transcript of an orthologous gene (in this collection, generally human-to-mouse or mouse-to-human), or
(iii) a transcript of a different gene (from the same or different taxon).
Clone ID Target Seq Vector Match Position Match Region [?] The region of the transcript where the match occurs (5UTR, CDS, 3UTR). NOTE: all matches to non-coding transcripts are labeled 3UTR. SDR Match % [?] Percent match of the "Specificity-Defining Region" of the hairpin target sequence to transcript RNA sequence. The SDR is defined as the initial 19 bases of the (21mer) target sequence. 84% = 16/19 89% = 17/19 95% = 18/19 100% = 19/19 Intrinsic Score [?] Also called "original score", this assesses the target sequence for predicted cloneability and knockdown performance. Adjusted Score [?] Also called "specificity score", this is a function of the intrinsic score and the specificity factor . Matches Other Human Gene? [?] Does this construct also match another Human gene an equal or better degree? Orig. Target Gene [?] The gene that this construct was originally designed to target Addgene [?] Link to this entity's page in the Addgene catalog, if available 1 TRCN0000425005 GATGTTGAGTTGATTGATAAG pLKO_005 621 CDS 100% 10.800 15.120 N CARD8 n/a 2 TRCN0000118330 GCCTTGCTAACAAAGGCGATA pLKO.1 1134 CDS 100% 0.405 0.567 N CARD8 n/a 3 TRCN0000421208 TCTGAAGAAGGTAGTAATATT pLKO_005 1923 3UTR 100% 15.000 10.500 N CARD8 n/a 4 TRCN0000433668 GGACATTCCCAGGAGACATTT pLKO_005 496 CDS 100% 13.200 9.240 N CARD8 n/a 5 TRCN0000413973 ACGTGCTCTTCAGAAGCATTA pLKO_005 1657 CDS 100% 10.800 7.560 N CARD8 n/a 6 TRCN0000424058 GTAACCTGGCATGTACCTATT pLKO_005 1870 3UTR 100% 10.800 7.560 N CARD8 n/a 7 TRCN0000118327 GCACACATATTTCCATCCTTT pLKO.1 2590 3UTR 100% 4.950 3.465 N CARD8 n/a 8 TRCN0000415828 GGACTTTGGTGTGGGATACTG pLKO_005 1384 CDS 100% 4.950 3.465 N CARD8 n/a 9 TRCN0000118329 GCACAAACAGATACAGCGTTT pLKO.1 643 CDS 100% 4.050 2.835 N CARD8 n/a 10 TRCN0000118331 CCTTTCTATGCTGTCCTGGAA pLKO.1 969 CDS 100% 2.640 1.848 N CARD8 n/a 11 TRCN0000118328 CCTATCTTAGACAGCAGAATT pLKO.1 1702 CDS 100% 0.000 0.000 N CARD8 n/a 12 TRCN0000413924 GTTTCCTCTTATGCTTCTAAA pLKO_005 537 CDS 100% 13.200 7.920 N CARD8 n/a 13 TRCN0000422111 TGAACTTTGGTTCCAGTTATA pLKO_005 1216 CDS 100% 13.200 7.920 N CARD8 n/a 14 TRCN0000162795 CTTCCAAAGTGCTGGGATTAT pLKO.1 4697 3UTR 100% 13.200 6.600 Y SLC48A1 n/a 15 TRCN0000155836 CCCAAAGTGCTGGGATTACAA pLKO.1 4382 3UTR 100% 5.625 2.813 Y KLHL30 n/a 16 TRCN0000105239 GATGATGAGGAAGATCGCTGT pLKO.1 1155 CDS 100% 2.160 1.512 N Crabp2 n/a 17 TRCN0000141025 CCCAAAGTGCTGGGATTACTT pLKO.1 4382 3UTR 100% 5.625 2.813 Y EID2B n/a
shRNA constructs with at least a near match to this transcript
This list includes shRNAs that have at least a >84% (16 of 19 bases)
SDR
[?]
The SDR or "Specificity-Defining Region" encompasses the 19 bases within the shRNA stem region that are retained during siRNA processing/production. These are thus the bases that define the target specificity of the shRNA. Note that, while our shRNA designs nearly always extend the stem by two additional bases matching the intended target transcript (reported in the "Target Seq" column), these additional bases are not relevant to target specificity.
match to the transcript
XM_006723104.3,
regardless of what transcript they were originally designed to target.
For example, this list can include shRNAs that were originally designed to target:
(i) a different isoform or obsolete version of this transcript (as annotated by NCBI),
(ii) a transcript of an orthologous gene (in this collection, generally human-to-mouse or mouse-to-human), or
(iii) a transcript of a different gene (from the same or different taxon).
NOTE: this download is a superset of the above result set.
All ORF constructs matching this transcript
Clone ID DNA Barcode Vector Sequenced % [?] Percentage of construct sequence that has been empirically verified through direct sequence data. Nuc. Match % [?] A simple nucleotide-based global alignment percentage, calculated as follows: total nt. matches ---------------------------------- aligned length (incl. gaps) Prot. Match % [?] A simple amino acid-based global alignment percentage, calculated as follows: total aa. matches ---------------------------------- aligned length (incl. gaps) Epitope Tag Match Diffs [?] This field may contain sequence annotations in HGVS format. For more information about HGVS annotations, please refer to the HGVS Quick Reference Guide . Addgene [?] Link to this entity's page in the Addgene catalog, if available 1 ccsbBroadEn_07813 pDONR223 100% 52.2% 48.6% None (many diffs) n/a 2 ccsbBroad304_07813 pLX_304 0% 52.2% 48.6% V5 (many diffs) n/a 3 TRCN0000468126 TTTACTGCCCTAACGTCACTTTAC pLX_317 30.3% 52.2% 48.6% V5 (many diffs) n/a
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Protein Global Alignment of TRCN0000468126 with XM_006723104.3 close
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Genomic and Transcriptomic Evidence for Descent from Plasmodium and Loss of Blood Schizogony in Hepatocystis Parasites from Naturally Infected Red Colobus Monkeys - DocsLib
bioRxiv preprint doi: this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Genomic and transcriptomic evidence for descent fromPlasmodiumand loss of blood schizogony in Hepatocystis parasites from naturally infected red colobus monkeys
1Parasite Genomics, Wellcome Sanger Institute, Hinxton, Cambridge, UnitedKingdom
2Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom
3Department of Anthropology and Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon
4Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin- Madison, Madison, WI 53706, USA
5Department of Anthropology, Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington DC, USA, 20037
6Shaanxi Key Laboratory for Animal Conservation, Northwest University, Xi’an, China
7School of Life Sciences, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, SouthAfrica,
8Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
ABSTRACT Hepatocystis is a genus of single-celled parasites infecting monkeys,batsandsquirrels. Although thought to descend frommalariaparasites (Plasmodium spp.), Hepatocystis spp. are thought not to undergo replication in the blood – the part of the Plasmodium life cycle which causes the symptoms of malaria. Furthermore, Hepatocystis is transmitted by midges, not mosquitoes. Comparative genomics of Hepatocystis and Plasmodiumspeciestherefore presents an opportunity to better understand some of the most important aspects of malaria parasite biology. We were able to generate a draftgenomefor Hepatocystis using DNA sequencing reads from the blood of a naturally infected red colobus monkey. We provide robust phylogenetic support for Hepatocystis as a sister group to Plasmodium parasites infectingrodents. We show transcriptomic support for a lack of replication in the blood and genomic support for a complete loss of a family ofgenesinvolved inred blood cellinvasion. Our analyses highlight the rapid evolution of genes involved in parasite vector stages, revealing genes that may be critical for interactions between malaria parasites and mosquitoes.
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Introduction Species of the genus Hepatocystis are single-celled eukaryotic parasites infecting Old World monkeys, fruit bats and squirrels (1). Phylogenetically, they are thought to reside within a clade containing Plasmodium species, including the parasites causing malaria in humans (2). They were originally considered distinct from Plasmodium and have remained in a different genus because they lack the defining feature of asexual development in the blood, known as erythrocytic schizogony (3). The presence of macroscopic exoerythrocytic schizonts (merocysts) in the liver of thevertebratehost is the most prominent feature of Hepatocystis (3). Similar to Plasmodium parasites, Hepatocystis merocysts yield many single-celled merozoites. However, unlike Plasmodium, Hepatocystis merocysts appear to be the only replication phase in the vertebrate host (4). First generation merozoites of Plasmodium spp. are released from liver cells and invade red blood cells, where they multiply asexually, before erupting from red cells as secondary merozoites. These merozoites invade further red blood cells before some develop into stages that can be transmitted to the vector. In contrast, liver merozoites of Hepatocystis spp. are thought to commit to the development of transmission stages directly upon invading red blood cells. They are then vectored not by mosquitoes, but by biting midges of the genusCulicoides(5). After fertilisation, Hepatocystis ookinetes encyst in the head and thorax of the midge between muscle fibres, whereas Plasmodium ookinetes encyst in the midgut wall of mosquitoes. After maturation, oocysts of both Plasmodium and Hepatocystis rupture and release sporozoites that migrate to the salivary glands (1). These discrete biological differences, in the face of phylogenetic similarity and many shared biological features, make Hepatocystis a potentially powerful comparator for understanding important aspects of malaria parasite biology, such as transmission and host specificity.
A population of red colobus monkeys (Piliocolobus tephrosceles), from Kibale National Park, Uganda were previously shown to host Hepatocystis based on morphological identification of infected red blood cells and DNA sequencing of the cytochrome bgene(6). In this work we use Hepatocystis genome and transcriptome sequences derived from P. tephrosceles whole blood samples to generate a draft genome sequence and gain insights into Hepatocystis evolution. We go on to use these insights to explore key aspects of malaria parasite biology such as red blood cell invasion, gametocytogenesis and parasite-vector interactions. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Results
Genome assembly and annotation To produce a genome assembly for Hepatocystis we took advantage of a published genomic sequence from a red colobus monkey (Piliocolobus tephrosceles) in Kibale National Park, Uganda (NCBI assembly ASM277652v1), where Hepatocystis had previously been reported (6). We examined AT-content and sequence similarity to Plasmodium spp. and macaque (Fig 1A). This revealed a subset of contigs with high AT content and similarity to Plasmodium spp. Phylogenetic analysis, using an orthologue of cytochrome b from these contigs, suggested that they represent the first substantial genomic sequence from the genus Hepatocystis (Fig 1B), which is known to infect similar types of Old World monkeys (6). At least four species of Hepatocystis are known to infect African monkeys – H. kochi, H. simiae, H. bouillezi and H. cercopitheci (6) – but with little sequence data currently linked to morphological identification, it was not possible to determine the species. We have thus classified the parasite as Hepatocystis sp. ex Piliocolobus tephrosceles (HexPt; NCBITaxonomyID: 2600580). The extraction of the Hepatocystis sequences from the P. tephrosceles assembly yielded a set of 11,877 scaffolds with a total size of 26.26 Mb and an N50 of 2.4 kb. Automated genome annotation with Companion (7) identified 2,967 genes and 1,432 pseudogenes in these scaffolds. To improve upon this assembly, we isolated putative Hepatocystis reads from the original short read DNA sequencing data. These were assembled into a draft quality nuclear genome assembly of 19.94 Mb, comprising 2,435 contigs with an N50 of 18.4 kb (Table 1). The GC content (22.05%) was identical to that of Plasmodium spp. infecting rodents, and slightly higher than P. falciparum (19.34%). We identified 5,340 genes, compared to 5,441 in P. falciparum and 5,049 in P. berghei, suggesting a largely complete sequence (Table 1; S1 Table). Despite the fragmented nature of the assembly, we were able to identify synteny with P. falciparum around centromeres (S1 Fig) and evidence of clustering of contingency gene families (S2 Fig), as seen in most Plasmodium species. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Table 1. Features of the Hepatocystis sp. ex. Piliocolobus tephrosceles assembly compared to P. falciparum 3D7, P. vivax P01 and P. berghei ANKA. Hepatocystis P. falciparum 3D7 P. vivax P01 P. berghei ANKA Nuclear genome Genome size (Mb) 19.94 23.3 29.0 18.7 G+C content (%) 22.05 19.34 39.8 22.05 Gaps within scaffolds 979 0 431 0 No. of scaffolds 2435 14 240 19 No. of chromosomes ND 14 14 14 No. of genes* 5,340 5,441 6,650 5,049 No. of pseudogenes 25 158 158 129 No. of partial genes 1,475 0 196 8 No. of ncRNA 19 103 35 47 No. of tRNAs 41 45 45 45 No. of telomeres 0** 26 1 12 No. of centromeres 5 13 14 14
Mitochondrial genome Genome size (bp) 6,595 5,967 5,989 5,957 G+C content (%) 30.99 31.6 30.5 30.9 No. of genes 3 3 3 3
Apicoplast genome Genome size (kp) 27.0 34.3 29.6 34.3 G+C content (%) 13.29 14.22 13.3 15.1 No. of genes 28 30 30 30
Completeness CEGMA - complete 63.31% 69.35% 68.15% 70.16% as least partial 69.35% 71.77% 71.77% 73.39%
* including pseudogenes, duplications and partial genes, excluding non-coding RNA genes
** two small contigs have telomeric repeats (scaffold 2410 (5 telomeric repeats, scaffold 2364, 9 telomeric repeats))
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
In vivo transcriptome data supports a lack of erythrocytic schizogony Transcriptome sequencing of blood samples from 29 individuals was performed as part of the red colobus monkey genome sequencing project (12). We found evidence that each of these individuals was infected with the same species of Hepatocystis as found in the genomic reads, consistent with high prevalence of this parasite in Kibale red colobus monkeys as previously reported (6). The extremely low SNP density suggested parasites between hosts were highly related (Fig 3A). We identified an average of 1.37 SNPs (standard deviation = 0.46) and 0.41 indels (standard deviation 0.17) per 10 kb of genome when calling variants using RNA-seq reads. Although it is believed that Hepatocystis spp. do not undergo erythrocytic schizogony (3), this has been challenged by limited microscopic evidence for asexual stages in the blood (13). To determine whether there was transcriptomic evidence for schizonts in the blood we deconvoluted the Hepatocystis transcriptomes bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
using transcriptome profiles representing different Plasmodium life stages. We found no such evidence, but observed varying proportions of cells identified as early blood stages (rings/trophozoites) and mature gametocytes (Fig 3B; S6 Fig; S2 Table). It is thought that chronic infections (of up to 15 months) may be maintained from continual development in the liver (3). The presence of early blood stages in these individuals may therefore reflect this continual production of new blood forms, rather than recent infection. Proportions of rings and trophozoites were positively correlated and both these forms correlated negatively with female gametocytes (Fig 3C). Interestingly, the inferred proportions of male and female gametocytes were not strongly correlated suggesting there might be variation in commitment rates of gametocytes to male or female development.
Expanded and novel gene families The largest gene family in Hepatocystis sp. was a novel family, which we have named Hepatocystis- specific family 1 (hep1; Table 2). These 12 single-exon genes (plus four pseudogenes) each encode proteins of ~250 amino acids, beginning with a predicted signal peptide (S7A Fig). We could find no significant sequence similarity to genes from any other sequenced genome (using HHblits (14)). However, they contain a repeat region with striking similarity to that in Plasmodium kahrp, a gene involved in presenting proteins on the red blood cell surface (15). Three members were highly expressed in in vivo blood stages, with one correlating well with the presence of early stages (S8A Fig; HEP_00211100, Pearson’s r=0.80 with rings). Another novel family, hep2, contained N-terminal PEXEL motifs, suggesting it is exported (S7B Fig). Distinct parts of its sequence showed similarity (albeit with low significance) to exported proteins from P. malariae (PmUG01_00051800; probability: 77.88% HHblits) and P. ovale curtisi (PocGH01_00025800; 78.47%) as well as a gene in P. gallinaceum (PGAL8A_00461100; 69.52%). Three or four members were highly expressed in blood stages in vivo, with one member highly correlated with predicted proportions of early blood stages (S8B Fig; HEP_00165500, Pearson’s r=0.83 with rings; HEP_00480100, Pearson’s r=0.77 with rings). bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Table 2. Frequencies of members of known and novel gene families in Hepatocystis Gene family Frequency
ApiAP2 transcription factors 27 Hepatocystis-specific family 1 (hep1) 16 (includes 4 pseudogenes) Hepatocystis-specifc family 2 (hep2) 10 (includes 4 pseudogenes) cpw-wpc 8 6-cysteine proteins 7 lccl 6 Thrombospondin-Related Anonymous Protein (trap) 6 pir 5 (includes 1 pseudogene) Serine repeat antigen (SERA) 5 (1 pseudogene) early transcribed membrane protein (etramp) 4 exported protein 1 (exp1) 4 (includes 2 pseudogenes) Tryptophan-rich antigen (trap) 4 Lysophospholipase 2-4 Phistdomain-containing 2 fam-a 1
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
The gene encoding Thrombospondin-Related Anonymous Protein (trap) is involved in infection of salivary glands and liver cells by Plasmodium sporozoites. It is found strictly in a single copy in all Plasmodium species sequenced to date. However, it is present in six copies in Hepatocystis, suggesting that trap-mediated aspect of sporozoite-host interactions may be more complex. None of these genes were highly expressed in blood stage transcriptomes, consistent with their known role in sporozoites. Exported protein 1 (e.g. PF3D7_1121600) is a single copy gene in all Plasmodium species. It encodes a Parasitophorous Vacuolar Membrane (PVM) protein and is important for host- parasite interactions in the liver (16). In Hepatocystis it is expanded to four copies.
Missing orthologues tend to be involved in erythrocytic schizogony The genomes of Plasmodium spp. each contain large families of genes known or thought to be involved in host parasite interactions (17). These include, amongst others the var, rif and stevor genes in the Laverania subgenus, SICAvar genes in P. knowlesi and the pir genes across the genus. We find only four intact pir genes and a single pir pseudogene in Hepatocystis, compared to ~200- 1000 in Plasmodium spp. infecting rodents. One was particularly highly expressed in the blood stages from most monkeys that were sampled (S8C Fig; HEP_00069900). All of these are most similar to the ancestral pir subfamily, present in single copy in Vinckeia species and in 19 copies in P. vivax P01 (Table 2; S9 Fig). The best described role for pir genes is in Vinckeia parasites, where they are involved in establishing chronic infections in mice (18). Given that asexual Hepatocystis are not thought to exist in the blood of monkeys or bats, there would be no need for this function of pir genes. However, in Vinckeia, pir genes are expressed in several other stages, including male gametocytes (19), which do feature in the Hepatocystis lifecycle. The function of the ancestral pir gene subfamily is unknown, although it is expressed at multiple stages of the lifecycle in P. berghei (20).
We wanted to determine, more generally, the types of genes that might have been lost in HexPt relative to Plasmodium spp. This is made difficult due to uncertainty in determining missingness in a draft genome. We overcame this problem using clusters of genes identified as having common expression patterns across the lifecycle of the close Hepatocystis relative P. berghei (20). Clusters 10 (late schizont expression; Fisher’s Exact test odds ratio = 0.12, FDR = 0.0003) and 4 (mixed stages; Fisher’s Exact test odds ratio = 1.95, FDR = 0.04) tended to contain orthologues shared by P. berghei, P. ovale wallikeri and P. vivax, but not HexPt (S3 Table; S10 Fig). When we considered an assembly of all HexPt RNA-seq reads, we found that the late schizont cluster was still significant (Fisher’s Exact test odds ratio = 0.09, FDR = 0.00014), but cluster 4 was not (S3 Table). Eleven out of 25 orthologues bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
missing in the late schizont cluster (including two pseudogenes) encoded Reticulocyte Binding Proteins (RBPs). In fact, we could not identify any RBPs in the Hepatocystis genome or Hepatocystis RNA-seq assemblies. Also missing from this cluster was Cdpk5, a kinase that regulates parasite egress from red cells (21). The other principal gene families involved in erythrocyte binding and invasion by Plasmodium are the erythrocyte binding ligands (eh)/duffy-binding protein (dbp) and the merozoite surface protein (msp) families (22). These are largely conserved relative to P. berghei. Thus, orthologues missing relative to Plasmodium spp. tend to be involved in erythrocytic schizogony, the part of the life cycle also absent.
The most rapidly evolving genes are often involved in vector biology and control of gene expression Our whole-genome phylogeny (Fig 2) suggested that some genes have changed extensively in Hepatocystis compared to Plasmodium spp. This might indicate functional changes important for the particular biology of Hepatocystis. We found previously that the ratio of synonymous mutations to synonymous sites (dS) saturates between Plasmodium clades (Böhme et al., 2018) and therefore considered the ratio of non-synonymous mutations (dN) rather than the more commonly used dN/dS. We first looked for enrichment of conserved protein domain families in genes with the highest 5% of dN values. There was an enrichment for the AP2 domain (Pfam:PF00847.20; Fisher test with BH correction; p-value = 0.0042). Most Plasmodium species possess 27 ApiAP2 transcription factors containing this domain, which are thought to be the key players in control of gene expression and parasite development across the life cycle. AP2-G plays an important role in exiting the cycle of schizogony and commitment to gametocytogenesis in Plasmodium spp. (23,24), whereas, as demonstrated, HexPt lacks erythrocytic schizogony. Hepatocystis spp. also form much larger cysts in the liver (giving the genus its name) and develop in different tissues within a differentinsectvector compared to Plasmodium spp. Our Hepatocystis assembly contained orthologues of all 27 ApiAP2 genes present in P. falciparum (Table 2). This suggests that life cycle differences between Plasmodium and Hepatocystis spp. are not reflected in gain or loss of these key transcription factors. However, the relatively high rate of non-synonymous mutations suggests there may have been significant adjustment in how these transcription factors act. To determine parts of the life cycle that were enriched for the most rapidly evolving genes, we looked at whether particular gene expression clusters from the Malaria Cell Atlas (19,20) were enriched for genes with high dN (top 5% of values; Table 3; S11 Fig; S4 Table). We found that three clusters (2, 4 and 6) had fewer genes with high dN than expected by chance (Fisher’s exact test with Holm multiple hypothesis testing correction, p- value < 0.05) and that these contained genes expressed across much of the life cycle, especially bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
growth phases and female gametocytes. These clusters also tended to contain essential genes that might be expected to be highly conserved in Hepatocystis. Although there was not a significant trend for gametocyte-associated genes having higher than average dN, the top 5% of genes ranked by dN contained several putative gametocyte genes (Table 3). Two of these encode putative 6-cysteine proteins P47 and P38, the first required for female gamete fertility (25). Additionally, Merozoite TRAP-like protein (MTRAP), essential for Plasmodium gamete egress from erythrocytes (26) and two genes (HEP_00254800 and HEP_00195400) with orthologues involved in osmiophilic body formation (27,28) had high dN values. Overall, clusters involved in ookinete (15) and generalmosquitostages (16) had significantly higher values than other clusters (Kolmogorov-Smirnov test: Cluster 15 vs all other clusters: D = 0.42, p-value = 1.08e-05. Cluster 16 vs all other clusters: D = 0.52, p-value = 4.68e- 12). This is also reflected in the Hepatocystis genes with the highest dN values, which include oocyst rupture protein 2 (orp2; dN = 1.08), ap2-o, ap2-sp2, secreted ookinete protein (psop7) and osmiophilic body protein (g377). These genes provide clues about changes in the parasite that might relate to its adaptation to transmission by biting midges, rather than mosquitoes. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Table 3. Top 15 genes with functional annotations ranked by Hepatocystis dN in comparison of Hepatocystis, P. berghei ANKA and P. ovale curtisi. Genes with completely unknown function and genes with very little information on their possible functions have been left out from this table. The rank column indicates the Hepatocystis dN rank of each gene in the complete table (with 4009 genes) that includes genes with unknown function (S4 Table) Hepato- P. P. cystis berghei ovale Gene id dN dN dN Annotations Rank Putative function HEP_00146800 PBANKA_1303400 Oocyst rupture Sporozoite egress from PocGH01_12075300 1.08 0.21 0.42 protein 2 (ORP2) 3 the oocyst (29) HEP_00446500 PBANKA_1003000 liver specific protein 2 Involved in liver stage PocGH01_03012800 0.71 0.19 0.34 (LISP2) 19 development (30) Essential for HEP_00295100 morphogenesis in PBANKA_0905900 ookinete stage in PocGH01_09049300 0.71 0.31 0.63 AP2-O 20 Plasmodium (31) P. berghei p38 is HEP_00035800 expressed in gametocytes PBANKA_1107600 6-cysteine protein and in asexual blood PocGH01_10033500 0.69 0.27 0.16 (p38) 24 stages (25) HEP_00213800 AP2 domain Required for sporozoite PBANKA_1001800 transcription factor production in Plasmodium PocGH01_03011500 0.67 0.45 0.63 AP2-SP2 28 (32) HEP_00337100 AP2 domain PBANKA_0112100 transcription factor Involved in blood stage PocGH01_11043100 0.62 0.36 0.42 ApiAP2 40 replication (32,33) HEP_00456700 Essential for gamete PBANKA_0512800 Merozoite TRAP-like egress from erythrocytes PocGH01_06021700 0.62 0.61 0.38 protein (MTRAP) 42 (26) Secreted ookinete HEP_00304800 proteins are necessary for PBANKA_1353400 Secreted ookinete invasion of the mosquito PocGH01_12023100 0.62 0.32 0.26 protein (PSOP7) 43 midgut (34) Plays a critical role in male HEP_00254800 gametocyte osmiophilic PBANKA_1449000 Microgamete surface body formation and PocGH01_14060000 0.59 0.26 0.26 protein MiGS 54 exflagellation (27) Merozoite surface HEP_00115700 proteins are involved in PBANKA_0304400 Merozoite surface red blood cell invasion PocGH01_04023000 0.55 0.41 0.15 protein 4 (MSP4) 62 (35) Localized to the apical end HEP_00166600 of merozoites, possibly PBANKA_0301000 Repetitive organellar involved in red blood cell PocGH01_04026800 0.54 0.36 0.2 protein (ROPE) 64 invasion (36) bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Female-specific protein, affects the size of the HEP_00195400 osmiophilic body and PBANKA_1463000 Osmiophilic body female gamete egress PocGH01_14074600 0.54 0.24 0.26 protein (G377) 67 efficiency (28) Part of a protein complex in parasitophorous vacuolar membrane, required for pathogenic protein secretion into host HEP_00130400 (37), important for PBANKA_1358000 maintaining normal blood- PocGH01_12018000 0.53 0.17 0.11 Thioredoxin 2 (TRX2) 75 stage growth (38) HEP_00391300 Predicted to be involved in PBANKA_0313400 Autophagy-related cargo selection in selective PocGH01_04013500 0.52 0.49 0.27 protein 11 (ATG11) 76 autophagy (39) HEP_00155500 PBANKA_1302300 Protease with caspase-like PocGH01_12076400 0.52 0.18 0.17 Metacaspase-2 80 activity (40)
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Discussion
We have assembled and annotated a draft quality genome sequence of Hepatocystis sp. ex Piliocolobus tephrosceles (HexPt). Our nuclear and apicoplast genome phylogenies confirm the recently proposed phylogenetic placement of this genus as an outgroup to therodent-infecting Vinckei subgenus of Plasmodium (2). However, a distinct branching pattern and low bootstrap support for many nodes in our mitochondrial genome phylogeny highlights why some previous analyses have come to different conclusions about the placement of Hepatocystis. Thus, the use of mitochondrial genes to infer phylogenetic relationships between species within the Hemosporidia should be approached with caution. We found a long branch leading to HexPt, suggesting a relatively deep split from the rodent-infecting species. In addition, we showed robustly that HexPt groups, as expected, with Hepatocystis epomophori, which infects bats. This finding supports the polyphyly of the Plasmodium parasites infecting apes, monkeys and rodents but the monophyly of Hepatocystis itself. A close relative of rodent-infecting P. berghei (P. cyclopsi) has been found in bats (10) and thus the Hepatocystis/Vinckeia group represents a relatively labile group with respect to host preference. Indeed, the possibility of cross-species transmission of HexPt was reported previously (6).
The paraphyly of Plasmodium with respect to Hepatocystis exists because Hepatocystis spp. lack a defining characteristic of the Plasmodium genus, namely erythrocytic schizogony - asexual development in the blood. Thus, the very part of the Plasmodium life cycle which causes the symptoms of malaria is thought to be absent in Hepatocystis. While multiple lines of enquiry have failed to identify these forms (Garnham, 1966) there has remained some doubt, with reports of cells with schizont-like morphology in the blood for some species (13,41). We were able to take advantage of bulk RNA-seq data collected from blood samples of a number of monkeys, all apparently infected with very closely related Hepatocystis parasites. By comparing to single-cell RNA-seq data from known cell types, we found no evidence for schizont stages in the blood. The apparent lack of schizonts could be due to sequestration of these stages away from the bloodstream. This is seen in some Plasmodium species, so we cannot rule out schizogony away from peripheral circulation. However, in its current state, this lack of evidence supports the idea that erythrocytic schizogony has been lost three times: in Hepatocystis,Polychromophilusand Nycteria (2). Ancestrally, gametocytogenesis must have been the default developmental pathway, being required for transmission. However, in Plasmodium, it seems that erythrocytic schizogony became the default developmental pathway with epigenetic control of the ApiAP2-G transcription factor, required for development into sexual stages (23,24). Perhaps the simplest possible explanation for a bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
loss of erythrocytic schizogony would be that ApiAP2-G is no longer under control, but is constitutively expressed in parasites leaving the liver. In line with this we find ApiAP2-G present and highly expressed in blood stage HexPt. Furthermore, all Plasmodium ApiAP2 transcription factors are conserved in HexPt, indicating that changes in its life cycle are not associated with their loss or gain.
The lack of erythrocytic schizogony is supported by a tendency for orthologues missing relative to Plasmodium spp. to be those expressed in blood schizonts. The most noticeable example being the complete absence of the Reticulocyte Binding Protein (RBP) family, found across all Plasmodium spp. examined so far, including those which infect birds (42). RBP proteins are known to function as essential red blood cell invasion ligands inPlasmodium falciparum(43) and multiple copies are thought to provide alternative invasion pathways (22). However, previous transcriptomic data have suggested that, while rbp genes in P. berghei are highly expressed in schizonts, they are less abundant or have a distinct repertoire in liver stages (20,44,45). This implies that RBPs are less important, or at least that distinct invasion pathways are used by first generation merozoites. Also missing were cdpk5 (involved in schizont egress) and msp9 (an invasion related gene enriched in blood vs. liver schizonts in Caldelari et al., 2019). Taken together, these results underscore the increasing realisation that first generation merozoites have distinct properties from merozoites that have developed in the blood and suggest the way in which first generation merozoites invade red blood cells may be distinct.
The genomes of Plasmodium spp. each contain large, rapidly evolving gene families that are known, or thought to be involved in host-parasite interactions, principally in asexual blood stages. The reason for their numbers may be due to a bet-hedging strategy, providing the diversity necessary for evading adaptive immune responses or dealing with unpredictable host variation. Although the Hepatocystis genome contains two novel multigene families, we identified only 10-15 copies of each. The largest gene families in the closely related rodent-infecting Plasmodium species (pir and fam-a) are present here only as their ancestral orthologues, also conserved in the monkey-infecting Plasmodium species. We should be cautious in noting a lack of expansion in such families in Hepatocystis, as previous draft Plasmodium genome sequences have been shown to under- represent these genes. However, it is perhaps not surprising that pir genes are poorly represented. They are thought to have a role in the maintenance of chronic infections mediated by asexual stages in the blood (18) and Hepatocystis infection does not involve this stage of development. Given that bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Hepatocystis can sustain long chronic infections (1), presumably from the liver, this parasite may help us to better understand how Plasmodium survives in the liver.
A striking feature of the Hepatocystis life cycle is its vector - a midge rather than a mosquito. We found evidence of rapid evolution amongst orthologues of Plasmodium genes involved in mosquito stages of development, suggesting that adaptation to a new insect vector was a major evolutionary force. The rapidly evolving genes provide clues to the players in parasite-vector interactions and may provide avenues for the development of interventions to prevent transmission of the malaria parasite.
We expect that high-quality genome sequences of additional Plasmodium relatives such as Nycteria,Haemoproteus, and Polychromophilus will provide more insights into the evolution and molecular biology of one of humanity's greatest enemies - the malaria parasite.
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Methods
Sample collection and data generation
The sequence data used in this study were part of different project originally designed to generate a reference genome for the red colobus monkey (genus Piliocolobus). Biomaterials used were from wild Ugandan (or Ashy) red colobus monkey (Piliocolobus tephrosceles) individuals from Kibale National Park, Uganda. These animals reside in a habituated group that has been a focus of long- term studies in health, ecology, and disease (12,46,47). Red colobus individuals were immobilized in the field as previously described (48). Whole blood was collected using a modified PreAnalytiX PAXgene Blood RNA System protocol as described in Simons et al. (12). Additionally, whole blood was collected into BD Vacutainer Plasma Preparation Tubes, blood plasma and cells were separated via centrifugation, and both were subsequently aliquoted into cryovials and stored in liquid nitrogen. Samples were transported to the United States in an IATA-approved liquid nitrogen dry shipper and then transferred to −80 °C for storage until further processing.
Methods for DNA extraction, library preparation, and whole genome sequencing are described in Simons (49). Briefly, high molecular weight DNA was extracted from the blood cells of one red colobus monkey individual and size selected for fragments larger than 50,000 base pairs. A 10X Genomics Chromium System library preparation was performed and subsequently sequenced on two lanes of a 150 bp paired-end Illumina HiSeqX run as well as two lanes of a 150 bp paired-end Illumina HiSeq 4000 run.
Methods for RNA extraction and library preparation are described in Simons et al. (2019). Briefly, RNA was extracted from 29 red colobus individuals using a modified protocol for the PreAnalytiX PAXgene Blood RNA Kit protocol. Total RNA extracts were concentrated, depleted of alpha and beta globin mRNA, and assessed for integrity (RIN mean: 8.1, range: 6.6–9.2). Sequencing libraries were prepared using the KAPA Biosystems Stranded mRNA-seq Kit and sequenced on four partial lanes of a 150 bp paired-end Illumina HiSeq 4000 run. These data were uploaded to NCBI as part of BioProject PRJNA413051.
Separation of Hepatocystis and Piliocolobus scaffolds The Piliocolobus tephrosceles genome assembly (ASM277652v1) was downloaded from the NCBI database. Scaffolds were first sorted by their GC% and Diamond 0.9.22 (50) BLASTX hits against a database of representative apicomplexan and Old World monkey proteomes. The sorting was improved by examining mapping scores of the scaffolds mapped to Plasmodium species and Macaca bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
mulatta genomes (Mmul_8.0.1, GenBank assembly accession GCA_000772875.3) using Minimap2 2.12 (51). The separation of scaffolds was further verified and refined by running NCBI BLAST of 960 bp fragments of all scaffolds against the NCBI nt database (Jul 18 2017 version) (52). To predict genes in the apicomplexan scaffolds, Companion automatic annotation software (7) was run with these scaffolds as input and the P. vivax P01 genome as the reference.
Identification of Hepatocystis sequences in Piliocolobus RNA-seq data Illumina HiSeq 4000 RNA-seq reads from the study PRJNA413051 were downloaded from the European Nucleotide Archive. In order to find out if the RNA-seq data contained apicomplexan sequences, mapping of these reads to apicomplexan scaffolds from Piliocolobus tephrosceles genome assembly (ASM277652v1) was done using HISAT2 2.1.0 (53).
Hepatocystis genome assembly
Filtering of reads for assembly Minimap2 (51) and Kraken 2.0.8-beta (54) were used to identify the best matching species for each 10x Chromium genomic DNA read (from Illumina HiSeq X and HiSeq4000 platforms). Our Kraken database contained 17 Old World monkey genomes and 19 Plasmodium genomes downloaded from NCBI FTP in June 2018 (52) . The Kraken database also included the contigs of the P. tephrosceles assembly ASM277652v1, separated into P. tephrosceles and Hepatocystis sp. Plasmodium malariae UG01 (from PlasmoDB (55) version 39) and Macaca mulatta (Mmul_8.0.1) assemblies were used as reference genomes for the assignment of reads based on Minimap2 mapping scores. Reads that were unambiguously identified as monkey sequences using Kraken and Minimap2 were excluded from subsequent assemblies. The Supernova assembler manual (56) warns against exceeding 56x coverage in assemblies. Reads selected for Supernova assemblies were therefore divided into 34 batches, with ~10 million reads in each batch. Reads were ordered by their barcodes so that those with the same barcode would preferentially occur in the same batch.
Supernova and SPAdes assemblies We generated 34 assemblies with Supernova v2.1.1 with default settings. In addition, two SPAdes v3.11.0 (57) assemblies with default settings were generated with Hepatocystis reads: one with HiSeq X reads and another with HiSeq 4000 reads. Chromium barcodes were removed from the reads before the SPAdes assemblies. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Deriving the mitochondrial sequence Hepatocystis Supernova and SPAdes assembly contigs were mapped to the P. malariae UG01 genome from PlasmoDB version 40 with Minimap2. The sequences of contigs that mapped to the P. malariae mitochondrion were extracted using SAMTools 0.1.19-44428cd (58) and BEDtools v2.17.0 (59). The contigs were oriented and then aligned using Clustal Omega 1.2.4 (60). Consensus sequence of aligned contigs was derived using Jalview 2.10.4b1 (61). The consensus sequence was circularised with Circlator minimus2 (62).
Canu assembly Scaffolds from the Supernova assemblies were broken into contigs. All contigs from the Supernova and SPAdes assemblies were pooled and used as the input for Canu assembler 1.6 (63) in place of long reads. Canu assembly was done without read correction and trimming stages. The settings for Canu were as follows: -assemble genomeSize=23000k minReadLength=300 minOverlapLength=250 corMaxEvidenceErate=0.15 correctedErrorRate=0.16 stopOnReadQuality=false -nanopore-raw.
Processing of Canu unassembled sequences file Selected contigs from the Canu unassembled sequences output file (*.unassembled.fasta) were recovered and pooled with assembled contigs (*.contigs.fasta). The first step in the filtering of the contigs of the unassembled sequences file was to exclude contigs that had a BLAST match in the assembled sequences output file (with E value cutoff 1e-10). Next, contigs where low complexity sequence content exceeded 50% (detected using Dustmasker 1.0.0 (64)) were removed. Contigs with GC content higher than 50% were also removed. Diamond BLASTX (against a database of Macaca mulatta, P. malariae UG01, P. ovale wallikeri, P. falciparum 3D7 and P. vivax P0 proteomes) and BLAST (using the nt database from Jul 18 2017 and nr database from Jul 19 2017) were then used to exclude all contigs where the top hits were not an apicomplexan species. In total, 0.34% of contigs from the unassembled sequences file were selected to be included in the assembly.
Deduplication of contigs Initial deduplication of contigs was done using BBTools dedupe (65) (Nov 20, 2017 version) and GAP5 v1.2.14-r3753M (66) autojoin. In addition, BUSCO 3.0.1 (67) was used to detect duplicated core genes with the protists dataset. Two contigs flagged by BUSCO as containing duplicated genes were removed. All vs all BLAST of contigs (with E-value cutoff 1e-20, minimum overlap length 100 bp, minimum identity 85%) was used to find possible cases of remaining duplicated contigs. Contigs yielding BLAST hits were aligned with MAFFT v7.205 (68) and the alignments were manually inspected. Contained contigs were deleted and contigs that had unique overlaps with high identity were merged into consensus sequences using Jalview. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Removal of contaminants after Canu assembly All Canu assembly contigs were checked with Diamond against a database of Macaca mulatta, P. malariae UG01, P. ovale wallikeri, P. falciparum 3D7 and P. vivax P01 proteomes. The Diamond search did not detect any contaminants. Contigs not identified by Diamond were checked with BLAST against the nt database (Jul 18 2017 version). Contigs where the top BLAST hit was a human or monkey sequence were removed from the assembly.
A subset of contigs in the assembly was observed to consist of short sequences with low complexity, high GC% and low frequency of stop codons. These contigs did not match any sequences by BLAST search against nt and nr databases (with E-value cutoff 1e-10). Due to their difference from the rest of the contigs in the assembly, it was assumed that these contigs were contaminants rather than Hepatocystis sequences. In order to programmatically find these contigs, GC%, tandem repeats percentage, percentage of low complexity content and frequency of stop codons were recorded for all contigs in the assembly. Tandem Repeats Finder 4.04 (69) was used to assess tandem repeats percentage and Dustmasker 1.0.0 (64) was used to find low complexity sequence content. PCA and k-means clustering (using R version 3.5.1) showed that the assembly contigs separated into two groups based on these parameters. The group of contigs with low complexity (189 contigs) was removed from the assembly.
Scaffolding and polishing of Canu assembly contigs Before scaffolding, contigs were filtered by size to remove sequences shorter than 200 bp. Hepatocystis RNA-seq reads were extracted from RNA-seq sample SAMN07757854 using Kraken 2. Canu assembly contigs were scaffolded with these reads using P_RNA_scaffolder (70). To correct scaffolding errors, the scaffolds were processed with REAPR 1.0.18 (71) using 197819014 unbarcoded Hepatocystis DNA read pairs. REAPR was run with the perfectmap option and -break b=1. Next, the assembly was scaffolded using Scaff10x (https://github.com/wtsi-hpag/Scaff10X) version 3.1, run for 4 iterations with the following settings: -matrix 4000 -edge 1000 -block 10000 - longread 0 -link 3 -reads 5. 197,819,014 Hepatocystis DNA read pairs were used for Scaff10x scaffolding. After this, P_RNA_scaffolder was run again as above. This was followed by running Tigmint 1.1.2 (72) with 419,652,376 Hepatocystis read pairs to correct misassemblies. fill_gaps_with_gapfiller (https://github.com/sanger- pathogens/assembly_improvement/blob/master/bin/fill_gaps_with_gapfiller) was used to fill gaps in scaffolds, using 197819014 unbarcoded Hepatocystis DNA read pairs. After this, ICORN v0.97 (73) was run for 5 iterations with 4608740 Hepatocystis read pairs. This was followed by polishing the assembly with Pilon 1.19 (74) using 21,794,613 Hepatocystis read pairs. Assembly completeness was assessed with BUSCO v3.0.1 (75) (run with the protists lineage and with -m geno -sp pfalciparum -- bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
long flags) and CEGMA v2.5 (76). P. berghei ANKA, P. ovale curtisi and P. falciparum 3D7 genomes from PlasmoDB release 45 were also assessed with BUSCO and CEGMA with the same settings in order to compare the Hepatocystis assembly with Plasmodium assemblies.
Curation and Annotation The assembly was annotated using Companion (7). The alignment of reference proteins to target sequence was enabled in the Companion run but all other parameters were left as default. A GTF file derived from mapping of Hepatocystis RNA-seq reads of three biological samples (SAMN07757854, SAMN07757861 and SAMN07757872) to the assembly was used as transcript evidence for Companion. To produce the GTF file, the RNA-seq reads were mapped to the assembly using 2-pass mapping with STAR RNA-seq aligner (77) (as described in the "Variant calling of RNA-seq samples" section) and the mapped reads were processed with Cufflinks (78). All Plasmodium genomes available in the web version of Companion were tested as the reference genome for annotating the Hepatocystis genome, in order to find out which reference genome yields the highest gene density. For the final Companion run the P. falciparum 3D7 reference genome (version from June 2015) was used. The Companion output was manually curated using Artemis (79) and ACT (80) version 18.0.2. Manual curation was carried out to correct the overprediction of coding sequences, add missing genes and correct exon-intron boundaries. Altogether 680 gene models were corrected, 546 genes added and 221 genes deleted. RNA-seq data was used as supporting evidence. Non-coding RNAs were predicted with Rfam (81).
All genes were analyzed for the presence of a PEXEL-motif using the updated HMM algorithm ExportPred v2.0 (82). Distant homology to hep1 and hep2 gene families was sought by using the HHblits webserver with default options (14).
The reference genomes used to produce statistics on features of Plasmodium genomes in Fig 2 and Table 1 were as follows: P. relictum SGS1, P. gallinaceum 8A (42), P. malariae UG01, P. ovale wallikeri, P. ovale curtisi GH01 (11), P knowlesi H (83), P. vivax P01 (84), P. cynomolgi M (85), P. chabaudi AS (18), P. berghei ANKA (86), P. reichenowi CDC (87), P. falciparum 3D7 (88).
For S1 Table, transmembrane domains of proteins were predicted using TMHMM 2.0 (89). Conserved domains were detected in proteins using HMMER i1.1rc3 (http://hmmer.org/) and Pfam-A database release 28.0 (90), with E-value cutoff 1e-5. Besides predicting exported proteins with ExportPred 2 (82), matches to PEXEL consensus sequence (RxLxE/Q/D) were counted in protein sequences using string search in Python. Signal peptides were detected using SignalP-5 (91). bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Phylogenetic trees Haemosporidian sequences were downloaded from NCBI FTP and PlasmoDB (release 43). The phylogenetic tree of cytochrome B and the tree that included 11 Hepatocystis epomophori genes were based on DNA alignments. The cytochrome B tree also included cytochrome B sequences from de novo assemblies of Hepatocystis RNA-seq reads derived from Piliocolobus tephrosceles blood. The trees of mitochondrial, apicoplast and nuclear proteomes were based on protein alignments. For apicoplast proteome and nuclear proteome trees, orthologous proteins were identified using OrthoMCL 1.4 (92). All vs all BLAST for OrthoMCL was done using blastall 2.2.25 with E-value cutoff 1e-5. OrthoMCL was run with mode 3. Proteins with single copy orthologs across all the selected species were used for the protein phylogenetic trees. Sequences were aligned with MAFFT 7.205 (93) (with --auto flag) and the alignments were processed using Gblocks 0.91b (94) with default settings. Individual Gblocks-processed alignments were concatenated into one alignment. The phylogenetic trees were generated using IQ-TREE multicore version 1.6.5 (95) with default settings and plotted using FigTree 1.4.4 (https://github.com/rambaut/figtree/releases). Inkscape (https://inkscape.org) version 0.92 was used to edit text labels of the phylogenetic trees generated with FigTree.
Clustering of pir proteins into subfamilies Sequences of Plasmodium pir family proteins (including bir, cyir, kir, vir and yir proteins) were downloaded from PlasmoDB (55) (release 39). The sequences were clustered using MCL (96), following the procedures described in the section "Clustering similarity graphs encoded in BLAST results" in clmprotocols (https://micans.org/mcl/man/clmprotocols.html). The BLAST E-value cutoff used for clustering was 0.01 and the MCL inflation value was 2. The pir protein counts per subfamily in each species were plotted as a heatmap using the heatmap.2 function in gplots package version 3.0.1.1 in R version 3.5.1.
RNA-seq mapping and assembly To separate Hepatocystis reads from Piliocolobus reads, RNA-seq data from the ENA (study PRJNA413051) were mapped to a FASTA file containing genome assemblies of Hepatocystis and M. mulatta (NCBI assembly Mmul_8.0.1), using HISAT2 version 2.1.0 (53), with "--rna-strandness RF". BED files were generated from the mapped reads using BEDTools 2.17.0 (59). Reads from each bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
technical replicate were merged, resulting in a single set of read counts for each individual monkey. The BED files were filtered to remove multimapping reads and reads with mapping quality score lower than 10. Names of reads that specifically mapped to the Hepatocystis assembly were extracted from the BED file. SeqTK 1.0-r31 (https://github.com/lh3/seqtk) was used to isolate Hepatocystis FASTQ reads based on the list of reads from the previous step. The Hepatocystis reads were then mapped to the Hepatocystis genome assembly using HISAT2 2.1.0 with "--rna-strandness RF" flag. The SAM files with mapped reads were converted to sorted BAM files with SamTools 0.1.19-44428cd (58). The EMBL file of Hepatocystis genome annotations was converted to GFF format using Artemis 18.0.1 (79). Htseq-count 0.7.1 (97) was used to count mapped reads per gene in the GFF file with "-t mRNA -a 0 -s reverse". Htseq-count files of individual RNA-seq runs were merged into a single file.
In order to extract Hepatocystis cytochrome b sequences of each RNA-seq sample, Hepatocystis RNA-seq reads of each sample were isolated from Piliocolobus reads as described above and then assembled with the SPAdes assembler v3.11.0 (98) with the "--rna" flag. Hepatocystis cytochrome b contigs were identified in each of the 29 RNA-seq assemblies using BLAST against Hepatocystis cytochrome b from the DNA assembly (E-value cutoff 1e-10).
In addition to assemblies of individual RNA-seq samples, an assembly of all RNA-seq samples pooled was done. The reads for this assembly were sorted by competitive mapping to P. ovale curtisi GH01 (from PlasmoDB release 45) and Macaca mulatta (Mmul_8.0.1, GenBank assembly accession GCA_000772875.3) genomes with minimap2 (with the "-ax sr" flag). Reads mapping to the Macaca mulatta genome with minimum mapping score 20 were removed and the rest of the reads were assembled with the SPAdes assembler v3.13.1 (98) with the "--rna" flag. Hepatocystis contigs were identified by comparison of sequences with Plasmodium and Macaca mulatta reference genomes using Diamond, minimap2 and BLAST, similarly to what is described in the section "Separation of Hepatocystis and Piliocolobus scaffolds". Further decontamination was done using Diamond and BLAST searches against 19747 sequences from Ascomycota and 165860 bacterial sequences downloaded from UniProt (release 2019_10) (99) and 3Babesiaproteomes from PiroplasmaDB (release 46) (100). Selected contigs were also checked with BLAST against the NCBI nt database. The assembly was deduplicated using BBTools dedupe (Nov 20, 2017 version) and GAP5 v1.2.14-r3753M. Assembly completeness was assessed using CEGMA 2.5. In order to reduce the number of contigs so that they could be used as input for Companion, the assembly was scaffolded with RaGOO Version 1.1 (101), using the Hepatocystis DNA assembly as the reference. The assembly was then processed by the Companion annotation software (Glasgow server, November 2019 version, with P. falciparum 3D7 reference genome, with protein evidence enabled and the rest of the settings left as default). In bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
order to detect proteins missed by Companion, EMBOSS Transeq (version 6.3.1) was used to translate the transcriptome assembly in all 6 reading frames. The output of Transeq was then filtered to keep sequences between stop codons with minimum length of 240 amino acids. Protein BLAST with E-value cutoff 1e-20 was used to detect sequences in Transeq output that were not present in the proteins annotated by Companion. These selected Transeq output sequences were checked for contaminants with BLAST similarly to what was described before. The sequences that passed the contaminant check were combined with the set of Hepatocystis RNA-seq assembly proteins that were detected by Companion. OrthoMCL was run with proteins from Hepatocystis RNA-seq assembly (Companion and selected Transeq sequences combined), Hepatocystis DNA assembly proteins, 20 Plasmodium proteomes from PlasmoDB release 43 and P. ovale wallikeri proteome (GenBank GCA_900090025.2). The settings for OrthoMCL were as described in the "Phylogenetic trees" section.
dN analysis P. berghei ANKA and P. ovale curtisi protein and transcript sequences were retrieved from PlasmoDB (55) (release 45). One-to-one orthologs between Hepatocystis, P. berghei ANKA and P. ovale curtisi were identified using OrthoMCL (92)and a Newick tree of the three species was generated with IQ- TREE (95). The settings for OrthoMCL and IQ-TREE were as described in the "Phylogenetic trees" section. Transcripts of one-to-one orthologs were aligned using command line version of TranslatorX (102) with "-p F -t T" flags, so that each alignment file contained sequences from three species. Gaps were removed from alignments while retaining the correct reading frame. Alignment regions where the nucleotide sequence surrounded by gaps was shorter than 42 bp were also removed. In addition, the script truncated alignments at the last whole codon if a sequence ended with a partial codon due to a contig break. The alignments and the Newick tree of the 3 species were then used as input for codeml (103) in order to determine the dN and dN/dS of each alignment. The codeml settings that differed from default settings were: seqtype = 1, model = 1. P. berghei RNA-seq cluster numbers from Malaria Cell Atlas (20) were assigned to each alignment based on the P. berghei gene in the alignment. Transcriptomics-based gametocyte specificity scores of Plasmodium genes were taken from an existing study on this topic (104) (transcripts table S2 of "Transcriptomics_all_studies" tab). The P. falciparum genes in the gametocyte specificity scores table were matched with equivalent Hepatocystis genes using OrthoMCL (run with the same settings as when used for phylogenetic trees). Statistical tests with the dN results (Kolmogorov Smirnov test, Fisher test and Spearman correlation) were performed using the stats library in R. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Variant calling of RNA-seq samples SNPs and indels were called in Hepatocystis RNA-seq reads that had been separated from Piliocolobus reads as described above. Four technical replicates of each RNA-seq sample were pooled. Variant calling followed the "Calling variants in RNAseq" workflow in GATK (105) user guide (https://gatkforums.broadinstitute.org/gatk/discussion/3891/calling-variants-in-rnaseq). First, the reads were mapped to the reference genome using 2-pass mapping with the STAR RNA-seq aligner (77) version 2.5.3a. 2-pass mapping consisted of indexing the genome with genomeGenerate command, aligning the reads with the genome, generating a new index based on splice junction information contained in the output of the first pass and then producing a final alignment using the new index. GATK (105) version 4.0.3.0 was used for the next steps. The mapped reads were processed with GATK MarkDuplicates and SplitNCigarReads commands. GATK HaplotypeCaller was then run with the following settings: --dont-use-soft-clipped-bases --emit-ref-confidence GVCF -- sample-ploidy 1 --standard-min-confidence-threshold-for-calling 20.0. Joint genotyping of the samples was then done using GATK CombineGVCFs and GenotypeGVCFs commands. This was followed by running VariantFiltration with these settings: -window 35 -cluster 3 --filter-name FS - filter 'FS > 30.0' --filter-name QD -filter 'QD < 2.0'. SNPs were separated from indels using GATK SelectVariants. Samples SAMN07757853, SAMN07757863 and SAMN07757870 were excluded from further analysis due to their low expression of Hepatocystis genes. The average filtered SNP counts per 10 kb of reference genome for each sample were calculated as the number of filtered SNPs divided by (genome size in kb * 10).
RNA-seq deconvolution Deconvolution of a bulk RNA-seq transcriptome sequence aims to determine the relative proportions of different cell types in the original sample. This requires a reference dataset of transcriptomes from “pure” cell types. To create this, we used single-cell P. berghei transcriptome sequences from the Malaria Cell Atlas (20). For each cell type, single-cell transcriptome sequences were combined by summing read counts per gene to generate a set of pseudobulk transcriptome sequences (see our GitHub repository). The aim of summing across cells is to reduce the number of dropouts which are common in individual single-cell transcriptome sequences. Bulk Hepatocystis RNA-seq transcriptome sequences, mapped and counted as above, were summed across replicates and filtered to exclude those with fewer than 100,000 reads. Hepatocystis and P. berghei pseudobulk read counts were converted to Counts Per Million (CPM) and Hepatocystis gene ids were bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
converted to those of P. berghei one-to-one orthologues. Genes without one-to-one orthologues (defined by orthoMCL analysis) were excluded. CIBERSORT v1.06 (106) was used to deconvolute the Hepatocystis transcriptomes with the MCA pseudobulk as the signature matrix file. To test the accuracy of this deconvolution process we generated mixtures of the pseudobulk resulting in e.g. equal representation of read counts from male gametocyte, female gametocyte, ring, trophozoite and schizont pseudobulk transcriptomes (see our GitHub repository). We also deconvoluted bulk RNA-seq transcriptomes from Otto et al. (86) processed as in Reid et al. (19).
Enrichment of missing genes in Malaria Cell Atlas gene clusters We wanted to determine whether there were functional patterns common to orthologues missing from the Hepatocystis genome relative to Plasmodium species. To do this we looked for orthologous groups (orthoMCL as above) containing genes from P. berghei, P. ovale wallikeri and P. vivax P01, but not Hepatocystis. Genes from P. berghei have previously been assigned to 20 clusters based on their gene expression patterns across the whole life cycle (20). We looked to see whether missing orthologues tended to fall into particular clusters more often than expected by chance (see our GitHub repository). We used Fisher’s exact test with Benjamini-Hochberg correction to control the false discovery rate. We reported clusters with FDR >= 0.05.
Data availability
The raw sequence data for Hepatocystis can be retrieved from the European Nucleotide Archive, project accession number ERP115621 and sample accession number ERS3649919. The assembly can be found under the study PRJEB32891. The individual accession numbers for the contigs are: CABPSV010000001-CABPSV010002439. Accession numbers for the apicoplast and the mitochondrion are LR699571-LR699572. Illumina HiSeq 4000 RNA-seq reads, containing a mix of Piliocolobus tephrosceles and Hepatocystis sp. sequences can be found in the European Nucleotide Archive under study accession PRJNA413051. Other data and code are available from our GitHub repository: https://github.com/adamjamesreid/hepatocystis-genome.
Acknowledgements We would like to thank Alan Tracey for advice on genome assembly and J. Byaruhanga, P. Katurama, A. Mbabazi, A. Nyamwija, J. Rusoke, D. Hyeroba and G. Weny and the staff of Makerere University Biological Field Station for assistance in the field. Manoj Duraisingh provided helpful comments on the manuscript. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Funding
This work was funded by National Institutes of Health (NIH), USA grant TW009237 as part of the joint NIH-NSF Ecology of Infectious Disease program and the UK Economic and Social Research Council (TLG, NT, CAC). National Science Foundation Grant BCS-1540459 (NT, NDS). The Wellcome Sanger Institute is funded by the Wellcome Trust (grant 206194/Z/17/Z) which supports EA, UB, MB, and AJR. AJR is also supported by funding from the UK Medical Research Council (MRC Programme grant #: MR/M003906/1). CIN is funded by a Wellcome Investigator Award (104792/Z/14/Z).
Author Contributions Conceptualization AJR, TS
Data Curation EA, UB
Formal Analysis AJR, EA
Investigation AJR, EA, NDS, UB
Project Administration CAC, NT, TLG
Resources CAC, NT, TLG
Software AJR, EA
Supervision AJR, MB, NT
Visualization AJR, EA, UB
Writing – Original Draft Preparation AJR, EA, TS, UB
Writing – Review & Editing AJR, CAC, CIN, EA, MB, NDS, NT, TS, TLG, UB
bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
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bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Figure Legends
Fig 1. An assembly of genomic sequencing reads from a red colobus monkey blood sample contained significant amounts of sequence from the parasite Hepatocystis spp. (A) Contigs from the Piliocolobus assembly had a bimodal distribution of AT-content and sequence similarity to Plasmodium spp. (B). A phylogenetic tree of cytochrome b indicated that the closest match for the apicomplexan parasite sequenced from Piliocolobus tephrosceles blood is a Hepatocystis isolate from a monkey host. Parasite cytochrome b sequences derived from RNA-seq assemblies from Piliocolobus tephrosceles blood samples are almost entirely identical to the cytochrome b sequence assembled from Hepatocystis DNA reads from a single monkey. Branches of the tree have been coloured by bootstrap support values from 15 (red) to 100 (green). Some of the bootstrap support values have also been added next to the nodes as text. Red arrows highlight the Hepatocystis samples from the current study.
Fig 2. Whole genome phylogeny and key features of the Hepatocystis genome. A whole-genome phylogenetic tree is combined with a graphical overview of key features of Hepatocystis and Plasmodium species (genome versions from August 2019). The maximum likelihood phylogenetic tree of Hepatocystis and Plasmodium species is based on 1112706 amino acid residues from 3271 single copy orthologs encoded by the nuclear genome. Bootstrap support values of all nodes were 100, except for one node where the value was 82. The rooting of the tree at P. gallinaceum is based on previously published Plasmodium phylogenetic trees (11,42). TRAP - thrombospondin-related anonymous protein. RBP protein - reticulocyte binding protein. For the phylogenetic tree P. cynomolgi B was used (107).
Fig 3. Deconvolution of Hepatocystis in vivo RNA-seq data supports a lack of erythrocytic schizogony and a variable sex ratio. (A) Distributions of SNPs per 100 kb in each Hepatocystis RNA-seq sample highlight low and consistent genetic diversity. (B) Deconvolution of RNA-seq samples to identify parasite stage composition shows no evidence for blood schizonts. Ring and trophozoite cells are assumed to relate to early stages of gametocyte development, which are not distinguishable from asexual rings and trophozoites. (C) Proportions of early blood stages (ring and trophozoite) are negatively correlated with mature female gametocytes, however male and female gameocyte ratios are poorly correlated, suggesting that sex ratios vary between samples.
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Figures
Fig 1
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Fig 2 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig 3
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Supporting information
S1 Fig. Conservation of synteny in the core regions of the assembly. ACT (Artemis Comparison Tool) screenshot showing a comparison of centromere-proximal regions of Hepatocystis scaffold 132, P. falciparum 3D7 (Pf3D7) chromosome 4 and P. vivax (PvP01) chromosome 5. The red blocks represent sequence similarity (tBLASTx). The centromere is shown in green. Coloured boxes represent genes. The graph shows the GC-content.
S2 Fig: Organization of putative subtelomeric regions of Hepatocystis scaffold 67, scaffold 211, P. knowlesi H chromosome 4 and P. falciparum 3D7 chromosome 9. Exons are shown in coloured boxes with introns as linking lines. ‘//’ represents a gap. The shaded/grey areas in P. knowlesi and P. falciparum mark the start of the conserved, syntenic regions to other Plasmodium species. The presence of genes that are subtelomeric in Plasmodium species, i.e. PHIST proteins, suggests that the Hepatocystis scaffolds are also subtelomeric. A complete subtelomere that includes telomeric repeats is missing in our Hepatocystis assembly. Thus, whether Hepatocystis chromosomes retain the organisation common to most Plasmodium species remains unclear.
S3 Fig. Phylogenetic tree of Haemosporidian mitochondrial proteins. Hepatocystis sp. ex. Piliocolobus tephrosceles (this work, marked with red arrow) appears next to a previously sequenced Hepatocystis sample from the flying fox Pteropus hypomelanus (NCBI accession FJ168565.1). Branches of the tree have been coloured by bootstrap support values from 45 (red) to 100 (green). Bootstrap values below 100 have also been added to the figure as text.
S4 Fig. Phylogenetic tree of 18 apicoplast protein sequences of Plasmodium spp. and Hepatocystis. Branches of the tree have been coloured by bootstrap support values from 66 (red) to 100 (green). Bootstrap values below 100 have also been added to the figure as text.
S5 Fig. Phylogenetic tree of 11 nuclear genes of Hepatocystis and Plasmodium species. Genes of Hepatocystis sp. ex Piliocolobus tephrosceles are highly similar to Hepatocystis epomophori genes sequenced in a different study (2). The tree is based on the following genes: splicing factor 3B subunit 1, tubulin gamma chain, DNA polymerase delta catalytic subunit, eukaryotic translation initiation factor 2 gamma subunit, T-complex protein 1 subunit alpha, pantothenate transporter, ribonucleoside-diphosphate reductase large subunit, aminophospholipid-transporting P-ATPase, GCN20, transport protein Sec24A and RuvB-like helicase 3. Branches of the tree have been coloured by bootstrap values from 73 (red) to 100 (green). Bootstrap values below 100 have also been added to the figure as text. The red arrow points to the Hepatocystis sample from the current study. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
S6 Fig. Deconvolution using CIBERSORT and the Malaria Cell Atlas accurately determines the presence and absence of different Plasmodium life stages in bulk RNA-seq data. (A) Pre-defined mixtures of pseudobulk RNA-seq data were deconvoluted with very high accuracy. (B) Real samples of P. berghei bulk RNA-seq from Otto et al (2014) were deconvoluted showing almost pure mixtures of gametocyte, ookinete or asexual stages as expected. The low proportions of expected parts of the IDC in each asexual sample may result from differences between what the MCA defines as a ring/trophozoite/schizont and what would microscopically be defined as such.
S7 Fig. Multiple sequence alignments of two Hepatocystis-specific gene families. (A) Alignment of Hepatocystis-specific gene family 1 (hep1). Pseudogenes (HEP_00099300, HEP_00250500, HEP_00323900) were not included in the alignment. HEP_00353700 is 476 amino acids long and was truncated here. (B). Alignment of Hepatocystis-specific gene family 2 (Hep2). This gene family contains a PEXEL motif (marked with a black box). Pseudogenes (HEP_00165000, HEP_00165200, HEP_00324000, HEP_00489100) were not included in the alignment.
S8 Fig. Heatmaps of Hepatocystis gene family expression in the blood of its mammalian host. (A) Expression levels (log vst-normalised) of hep1 genes across blood samples from multiple red colobus monkeys. The estimated proportions of early blood stages (rings/trophozoites) and mature gametocytes are highlighted above. (B) Expression levels of hep2 genes (C) Expression levels of pir genes.
S9 Fig. Heat map of pir protein subfamilies in Hepatocystis and Plasmodium species. Rows correspond to species and columns correspond to pir subfamilies. The columns have been ordered by the number of sequences in each subfamily and the order of rows is approximately based on phylogeny. Colours represent the numbers of proteins belonging to each subfamily for each species. All Hepatocystis pir proteins belong to the only subfamily conserved across all these species (108) (indicated with red arrow).
S10 Fig. Some orthologues missing in Hepatocystis sp. relative to Plasmodium species show common gene expression patterns across the Plasmodium life cycle. (A) Malaria Cell Atlas (MCA) gene cluster 10 represents genes highly expressed in late schizonts. 25 genes from this cluster were conserved in P. ovale wallikeri and P. vivax, but were missing from our Hepatocystis genome assembly. Genes were clustered here by expression pattern and single-cells were ordered by pseudotime as in (20). (B) MCA cluster 4 represents genes highly expressed across much of the life cycle - liver stages, trophozoites, female gametocytes and ookinetes/oocysts. 27 genes from this cluster were conserved in P. ovale wallikeri and P. vivax, but were missing from our Hepatocystis genome assembly. bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
S11 Fig. Distributions of Hepatocystis dN values in Malaria Cell Atlas (MCA) clusters. Hepatocystis dN was calculated in 3-way comparison between Hepatocystis, P. berghei ANKA and P. ovale curtisi using codeml. The Malaria Cell Atlas clusters have been described in Figure 2B in the article on Malaria Cell Atlas (20). (A) Hepatocystis genes with dN in the top 5%: observed versus expected ratios for Malaria Cell Atlas clusters. Hepatocystis genes that correspond to Malaria Cell Atlas clusters 2, 4 and 6 have less genes with dN rank in the top 5% than expected by chance (Fisher exact test p-value < 0.05). None of the MCA clusters contain significantly more genes ranked in the top 5% of dN than expected by chance, although there is a trend towards clusters clusters 15 and 16 having higher dN. (B) Boxplot of all Hepatocystis dN values per each Malaria Cell Atlas cluster. Distribution of values in clusters 15 and 16 differs from the rest of the clusters. Kolmogorov-Smirnov test statistics are the following. Cluster 15 vs all other clusters: D = 0.42, p-value = 1.08e-05. Cluster 16 vs all other clusters: D = 0.52, p-value = 4.68e-12. Clusters 15 and 16 combined vs all other clusters: D = 0.46, p = 2.33e-15.
S1 Table. Summary of gene properties. For each gene in the assembly, the following is listed: annotation, number of exons, gene length (bp), the presence or absence of start and stop codons (reflecting the completeness of the assembly of the gene) and RNA-seq expression level (mean FPKM with standard deviation) in sample SAMN07757854 (RC106R). For the proteins encoded by the genes, the table shows the number of transmembrane segments predicted by TMHMM, ExportPred 2 score, 1 to 1 orthologs in P. berghei ANKA and P. ovale curtisi GH01 (based on OrthoMCL), PFAM domains, the number of matches to PEXEL motif (RxLxE/Q/D) and SignalP-5 signal peptide prediction.
S2 Table. Raw and normalised Hepatocystis gene expression data.
S3 Table. Plasmodium orthologues missing in the Hepatocystis genome assembly. Plasmodium berghei genes, which have an orthologue in P. ovale curtisi or P. vivax, but not the HexPt DNA (A) or RNA-seq (B) assemblies and are enriched in Malaria Cell Atlas gene clusters.
S4 Table. Genes with Hepatocystis dN rank in the top 5% in codeml 3-way comparison between Hepatocystis, P. berghei ANKA and P. ovale curtisi GH01. The total number of genes in dN analysis was 4009, out of which 200 correspond to 5%. The table includes Malaria Cell Atlas cluster numbers for each gene.
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Fig S1
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Fig S2 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S3
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Fig S4 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S5
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Fig S6 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S7 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S8 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S9 bioRxiv preprint doi: https://doi.org/10.1101/871327; this version posted December 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
Fig S10
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Fig S11
| https://docslib.org/doc/8202235/genomic-and-transcriptomic-evidence-for-descent-from-plasmodium-and-loss-of-blood-schizogony-in-hepatocystis-parasites-from-naturally-infected-red-colobus-monkeys |
Appreciation: Bernard Häring: a moral theologian whose soul matched his scholarship
German Redemptorist Fr. Bernard Häring, the foremost Catholic moral theologian of the 20th century and a leading advocate for church reform before, during and after the Second Vatican Council, died in the Redemptorist monastery in Gars-am-Inn, Germany, July 3. He was 85 and had been in active retirement in Gars since 1986.
Bernard Häring: a moral theologian whose
soul matched his scholarship
German Redemptorist Fr. Bernard Häring, the foremost Catholic
moral theologian of the 20th century and a leading advocate for church reform
before, during and after the Second Vatican Council, died in the Redemptorist
monastery in Gars-am-Inn, Germany, July 3. He was 85 and had been in active
retirement in Gars since 1986.
Häring was a priest medic in the German army in World War II.
He published a ground-breaking work of moral theology,
The Law of
Christ
, translated into more than a dozen languages. A professor of moral
theology at the Alfonsian Academy in Rome from 1950 to 1986, he was a most
influential
peritus
at Vatican II. He was also an indefatigable,
globetrotting missionary for Christian spirituality and church renewal and a
staunch opponent of legalism and hypocrisy in the church.
The objective facts of Häring's life can never capture the
spirit of the person. On the other hand, in reflecting on Häring's life
and contribution, I must admit to my own sympathies and prejudgments.
Häring has been teacher, mentor, spiritual director, friend and supporter
to me.
I first encountered him teaching moral theology at the Alfonsian
Academy in Rome in 1959. His approach changed my thinking dramatically. I was
instrumental in bringing him to the United States for the first time, in 1963.
He later spent many months each year teaching and giving retreats in the United
States. He was a bulwark of support for me in my own struggles with the
Vatican. I thank God for his example, strength, advice and encouragement.
What made Häring the person he was? What explains his life and work? Like
all Christians, he had to answer the gospel question of Jesus: "Who do you say
that I am?" Häring's answer reveals much about him. "Jesus is for me Son
of Man, which means above all that he is `one of us.' He is Son of God, the
Father's unsurpassable offering and assent to us. He is the prophet, the
nonviolent but also powerful unmasker of all false images of God, of every
religious falsification, the perfect worshiper in spirit and in truth." This
basic commitment and faith help us to understand Häring the moral
theologian, the church reformer and the deeply spiritual Christian person.
His 1954
The Law of Christ
proposed a biblical, liturgical,
Christological and life-centered moral theology. He pioneered a new approach to
moral theology that opposed the method of the manuals with their concern for
training confessors for the sacrament of penance by learning how to distinguish
what is sinful and the degrees of sinfulness.
Häring's moral theology was based on the covenant -- the good
news of God's loving gift for us and our grateful response. Christians are
called to growth and continual conversion in their moral life and in their
multiple relationships with God, neighbor, world and self. He staunchly opposed
any legalism that made God into a controller rather than a gracious savior.
Two significant developments occurred in his moral theology. The
earlier Häring, as indicated by the title of
The Law of Christ
,
still saw law as the primary model of the Christian life. But in 1978 his new
three-volume moral theology, written this time in English, was titled
, which indicates the move to a more relational model
for the moral life and the rejection of a legal model.
The second development involved a growing emphasis on the healing
power of nonviolence. Häring was truly a person of peace who often
candidly and forcefully stood up for his position, but his manner was always
nonviolent. Even among nations the later Häring emphasized the need for
nonviolence, although he did not totally exclude all use of force.
Some criticized Häring's moral theology for its lack of
scientific rigor and its often homiletic style. There is some truth in these
criticisms. Häring was never primarily an academic writing learned tomes
in search of academic promotions and acclaim. He wrote for the church and the
people of the church. However, his work came from a deep and creative
intelligence that helped to reshape the entire discipline of Catholic moral
theology in the post-conciliar era. In his various writings he also showed a
broad knowledge not only of theology and scripture but also of sociology,
psychology and medicine.
The German Redemptorist was a prolific author, writing about 90
volumes in moral theology, spirituality and church reform. In addition he was
an indefatigable speaker, going all over the globe to give lectures,
conferences and retreats. Häring spoke fluent German, French, Italian,
English, Spanish, Portuguese and Polish and even learned Russian during the
war. He traveled and lectured extensively in Europe, Africa, Asia and the
United States.
Long before Vatican II made it popular, he was involved in
ecumenical dialogue. During the war he defied military orders and ministered as
a priest not only to Catholics but to Protestants. On the Russian front he
baptized many Orthodox children in the midst of the savagery of war. His
doctoral dissertation, "The Holy and the Good," done in Tübingen, Germany,
in 1947, showed his familiarity with many Protestant thinkers. After the
council he served as a visiting professor for a semester at three non-Catholic
institutions here in the United States: Brown University, Yale Divinity School
and Union Theological Seminary.
As a church reformer, Häring played a significant role in
Vatican II. Pope John XXIII wrote a letter praising and thanking Häring
for his
The Law of Christ
. In his diary Pope John mentioned that he had
read with great joy and complete agreement Häring's book on what he hoped
the council would do. Pope Paul VI, in his first year as pope, invited
Häring to give the annual retreat to him and the Roman curia and
encouraged him to speak frankly and without fear.
Häring also contributed to the council documents. He served
on the pre-conciliar and conciliar commissions and was the secretary of the
editorial committee that drafted the Pastoral Constitution on the Church in the
Modern World. Cardinal Fernando Cento, the co-president of the mixed commission
in charge of that document, publicly referred to Häring as "the
quasi-father of
Gaudium et Spes
."
Häring consistently opposed legalism and religious
falsification wherever he found them. During the council he frequently
addressed groups of bishops and the press. His honesty and forthright comments
were widely appreciated.
In 1968, he publicly disagreed with the encyclical
Humanae
Vitae
, which condemned artificial contraception. I will never forget my own
exhilaration when Häring readily agreed to sign the statement of dissent
from
Humanae Vitae
that we had proposed here in the United States the
day after the encyclical was issued.
His reaction to Pope John Paul II's 1993 encyclical
Veritatis
Splendor
was especially strong. "Let us ask our pope: Are you sure your
confidence in your supreme human, professional and religious competence in
matters of moral theology and particularly sexual ethics is truly justified?
... We should let the pope know that we are wounded by the many signs of his
rooted distrust and discouraged by the manifold structures of distrust which he
has allowed to be established."
Behind Bernard Häring the theologian and church reformer
stood Bernard Häring the person of prayer and deep spirituality. Anyone
who spent any length of time with him recognized he was truly a person living
in the presence of God. There was an interior calm and peace in Häring
that showed through in all that he did even when he strongly opposed what he
considered religious falsification. ðHäring was often involved in
pastoral work and spent much time giving retreats and spiritual conferences all
over the world. He took a special interest in setting up houses of prayer for
religious orders where people could come to attend to their own spiritual
lives. He gave spiritual conferences not only to lay people, priests and
sisters throughout the world, but also to many non-Catholics. For example, he
annually gave a retreat to the members of the Church of the Savior in
Washington and Baltimore.
Häring's sacramental and prayerful spirituality was the basis
for his life and work. He was brought up in a very pious and traditional German
family. Throughout his life, he practiced what he preached about continual
conversion and growth in one's life with God.
Häring served the church as a committed, holy, intelligent,
and courageous person. His legacy is an example and sign of hope for all who
struggle for conversion in our lives and in our church.
| http://natcath.org/NCR_Online/archives2/1998c/071798/071898h.htm |
Materials | Free Full-Text | Optimal Design of High-Strength Ti‒Al‒V‒Zr Alloys through a Combinatorial Approach
The influence of various Zr contents (0& ndash;45 wt.%) on the microstructure and mechanical properties of Ti6Al4V alloy was investigated through a combinatorial approach. The diffusion multiples of Ti6Al4V& ndash;Ti6Al4V20Fe& ndash;Ti6Al4V20Cr& ndash;Ti6Al4V20Mo& ndash;Ti6Al4V45Zr were manufactured and diffusion-annealed to obtain a large composition space. Scanning electron microscopy, electron probe micro-analysis, and a microhardness system were combined to determine the relationships among the composition, microstructure, and hardness of these alloys. The Ti& ndash;6Al& ndash;4V& ndash;30Zr alloy was found to contain the thinnest & alpha; lath and showed peak hardness. X-ray diffraction and transmission electron microscope results indicated that after quenching from the & beta;-field, the metastable & alpha;& Prime;-phase formed; moreover, at the secondary aging stage, the metastable & alpha;& Prime;-phase acted as precursor nucleation sites for the stable & alpha;-phase. The bulk Ti6Al4V30Zr alloy was manufactured. After aging at 550 & deg;C, the alloy showed excellent balance of strength and ductility, and the tensile strength was 1464 MPa with a moderate elongation (8.3%). As the aging temperature increased, the tensile strength and yield strength of the alloys rose, but the total elongation decreased. The lamella thickness and volume fraction of the & alpha;-phase were the major factors that had great impacts on the mechanical properties.
Optimal Design of High-Strength Ti‒Al‒V‒Zr Alloys through a Combinatorial Approach
by
Di Wu 1 ,
Yueyan Tian 1 ,
Ligang Zhang 1,2 ,
Zhenyu Wang 1 ,
Jinwen Sheng 1 ,
Wanlin Wang 3 ,
Kechao Zhou 4,* and
Libin Liu 1,2,4,*
1
School of Material Science and Engineering, Central South University, Changsha 410083, China
2
Key Laboratory of Non-Ferrous Metallic Materials Science and Engineering, Ministry of Education, Changsha 410083, China
3
School of Metallurgy and Environment, Central South University, Changsha 410083, China
4
State Key Laboratory of Powder Metallurgy, Changsha 410083, China
*
Authors to whom correspondence should be addressed.
Materials 2018 , 11 (9), 1603; https://doi.org/10.3390/ma11091603
Received: 13 August 2018 / Revised: 25 August 2018 / Accepted: 27 August 2018 / Published: 4 September 2018
Abstract
:
The influence of various Zr contents (0–45 wt.%) on the microstructure and mechanical properties of Ti6Al4V alloy was investigated through a combinatorial approach. The diffusion multiples of Ti6Al4V–Ti6Al4V20Fe–Ti6Al4V20Cr–Ti6Al4V20Mo–Ti6Al4V45Zr were manufactured and diffusion-annealed to obtain a large composition space. Scanning electron microscopy, electron probe micro-analysis, and a microhardness system were combined to determine the relationships among the composition, microstructure, and hardness of these alloys. The Ti–6Al–4V–30Zr alloy was found to contain the thinnest α lath and showed peak hardness. X-ray diffraction and transmission electron microscope results indicated that after quenching from the β-field, the metastable α″-phase formed; moreover, at the secondary aging stage, the metastable α″-phase acted as precursor nucleation sites for the stable α-phase. The bulk Ti6Al4V30Zr alloy was manufactured. After aging at 550 °C, the alloy showed excellent balance of strength and ductility, and the tensile strength was 1464 MPa with a moderate elongation (8.3%). As the aging temperature increased, the tensile strength and yield strength of the alloys rose, but the total elongation decreased. The lamella thickness and volume fraction of the α-phase were the major factors that had great impacts on the mechanical properties.
Keywords:
combinatorial alloy design
;
diffusion multiple
;
Ti6Al4VxZr
;
microstructure and mechanical properties
;
phase transformation
Graphical Abstract
1. Introduction
Titanium and its alloys are widely used in the aerospace industry due to their exceptional strength-to-weight ratio, high crack propagation resistance, outstanding fatigue properties, considerable hardening ability, and good corrosion resistance [ 1 , 2 ]. Ti–6Al–4V is one of the most important and widely used titanium alloys in the aerospace industry because of its optimum comprehensive mechanical properties. However, its application is limited because of its low strength [ 3 , 4 , 5 ]. These problems can be overcome by adding alloying element(s) to the Ti–6Al–4V alloy to enhance its strength. Hence, new alloy systems need to be designed to satisfy the requirements of the new environment.
Zirconium (Zr) and titanium (Ti) possess similar physicochemical properties and belong to the same main group in the periodic table of chemical elements. Zirconium and Ti can form complete solid solution for hcp-structure low-temperature α-phase and bcc-structure high-temperature β-phase [ 6 ]. Previous research has shown the apparent influences of alloy element Zr on the microstructure and mechanical properties of Ti alloys. Schmuki [ 7 ], Liu [ 8 ], and Ho [ 9 ] have investigated the microstructure and mechanical properties of Ti–Zr binary alloys, and the results have shown that the phase composition and mechanical properties of these binary alloys varied remarkably with changes in Zr content. Moreover, previous studies [ 10 , 11 , 12 , 13 ] showed that Zr had significant influence on the properties of many multicomponent Ti alloys. The influence of Zr content on the structure and properties of ternary Ti–Nb–Zr alloys was investigated by Zhou [ 10 ], and the result showed that increasing Zr content decreased the strength of the alloy but increased the ductility. Chen [ 11 ] investigated the effect of Zr on the structure and mechanical and thermal properties of Ti–Al–N-based coating, and noted that the addition of Zr promoted the formation of cubic domains and retarded the formation of stable wurtzite AlN, which led to high hardness during thermal annealing. Liang [ 12 ] investigated the microstructure and mechanical properties of Ti–5Al–3V–30Zr alloy that has undergone various annealing heat treatments, and the alloy has shown good mechanical properties. However, the strengthening mechanism and phase transformation of the Ti–5Al–3V–30Zr alloy has not yet been reported. Recently, a series of Ti–6Al–4V–xZr (0 ≤ x ≤ 20) alloys were investigated by Jing [ 13 ], and Zr was selected as a partial substitutable element for Ti in Ti–6Al–4V alloys. The new Ti–6Al–4V–20Zr alloy exhibited good compositive performances (i.e., balance of strength and ductility), showing its great potential for high-strength structural applications in the aerospace industry. Zirconium could be a suitable element to modify Ti and Ti alloys.
Only partial alloy compositions of the Ti–6Al–4V–xZr system that may have a relatively good performance have been investigated. Thus, the study of the Ti–6Al–4V–xZr system with a wide range of composition provides many opportunities for the optimization of alloy composition. The conventional one-alloy-at-a-time methods are time-consuming and costly, and may prove hard to enforce. Therefore, a combinatorial approach was used in our research.
The diffusion-multiple approach has been used to determine very complex phase diagrams for many systems [ 14 , 15 ]. In addition to phase diagram mapping, the diffusion multiples have the ability to create continuous composition gradients of solid solutions, which could be used to map material properties with different kinds of micro-probes [ 16 , 17 ]. Through this approach, Zhang et al. [ 18 ] have established a database of composition-dependent elastic modulus and hardness of the Ti–Zr–Ta systems and provided an essential guide for the alloy design of new-type bio-titanium alloys. Chen [ 19 ] mapped the microstructural and mechanical data of Ti–Al–Mo alloys. Wu [ 20 ] also investigated the effects of Cr addition on the microstructures and hardness of Ti6Al4V alloy, and the result can be used to accelerate the discovery of high-strength titanium alloys.
The purpose of this work was to investigate the effects of Zr on the microstructures and mechanical properties of Ti–6Al–4V alloy in an effort to develop a new high-strength titanium alloy for aerospace application. Firstly, the alloying element Zr was added to increase the strength of the Ti–6Al–4V alloy, and then the plasticity of the alloy could be improved by thermal processing and heat treatment. The microstructure, mechanical properties, and phase transition of Ti–6Al–4V–30Zr alloy that has undergone various annealing heat treatments were also investigated.
2. Materials and Methods
A diffusion multiple is a combination of several diffusion couples and triples arranged in one sample according to a designed geometry [
21
,
22
,
23
]. The Ti6Al4V–Ti6Al4V20Fe–Ti6Al4V20Cr–Ti6Al4V20Mo–Ti6Al4V45Zr diffusion multiple was manufactured using the method shown in
Figure 1
. The continuous and large-range composition gradients of the alloying elements were formed by long-time diffusion annealing. Combined with different kinds of microprobes, we rapidly analyzed the different properties in the large composition space to build the composition-microstructure-property relationship. In this study, the diffusion-multiple approach was employed to investigate the influence of using varied Zr contents on the structure and mechanical properties of Ti–6Al–4V alloy.
All parts for the diffusion multiples were cut via electrical discharge machining (EDM, Central South University, Changsha, China). The dimensions of the pieces are shown in
Figure 1
a. The diffusion multiple included two Ti‒6Al‒4V bricks with dimensions of 12 mm × 12 mm × 10 mm; two Ti‒6Al‒4V‒45Zr, one Ti‒6Al‒4V‒20Cr, and one Ti‒6Al‒4V‒20Mo plates with dimensions of 12 mm × 12 mm × 3 mm; and one Ti‒6Al‒4V‒20Cr, one Ti‒6Al‒4V‒20Fe, and one Ti‒6Al‒4V‒20Mo plates with dimensions of 16 mm × 12 mm × 3 mm. The materials used for the diffusion-multiple included Ti‒6Al‒4V and Ti‒6Al‒4V‒45Zr. The materials were prepared from high purity Ti (99.95%), Zr (99.7%), Al (99.99%), and V (99.95%) using arc-melting technique in an argon atmosphere. The actual compositions of Ti‒6Al‒4V and Ti‒6Al‒4V‒45Zr, which were measured via inductively coupled plasma atomic emission spectrometry (Northwest Institute for Non-ferrous Metal Research, Xi’an, China), are listed in
Table 1
.
The bonding faces of the diffusion multiple were mechanically polished via a standard metallographic procedure to a final level of 0.3 µm alumina powder. As shown in
Figure 1
a, two diffusion multiples Ti6Al4V–Ti6Al4V20Mo–Ti6Al4V45Zr and Ti6Al4V–Ti6Al4V20Cr–Ti6Al4V45Zr with three bricks of alloys were clamped in steel fixtures and diffusion-annealed at 1000 °C for 4 h in a vacuum (about 10
−3
Pa). Afterward, the bonding faces of the diffusion multiple with three bricks were ground and polished, and the diffusion multiple with three bricks of alloys and two bricks of diffusion multiple were clamped in steel fixtures again, as shown in
Figure 1
b. Afterward, the diffusion multiples were sealed into an evacuated quartz tube and annealed at 1100 °C for 240 h to obtain a wide range of compositions. In this work, we will investigate the effects of Zr content on the microstructure and properties of Ti–6Al–4V alloy, which is located in the blue box area in
Figure 1
c. Then, the samples were solution-treated at the β-phase regions (1050 °C) for 6 h and water quenched. The quenched samples were aged at 600 °C and 650 °C for 6 h following water quenching. The heat treatment system of the diffusion multiples is shown in
Figure 2
. Finally, the diffusion multiples were mounted, ground, and polished by standard metallographic techniques.
Before microhardness tests, the binary and ternary diffusion region range was determined with electron probe micro-analysis (EPMA Central South University, Changsha, China) on a JEOL JXA-8230 microprobe with 20 kV, 20 nA and 40° take-off angle. Microhardness system was used to test hardness (BUEHLER5104 Central South University, Changsha, China), the intervals of the indentations were 100 μm, and the applied load was 500 mN with a hold time of 15 s. Field emission scanning electron microscope (FESEM Central South University, Changsha, China) was used to characterize the microstructure of the diffusion multiples (JEOL-JSM 7001F Central South University, Changsha, China). Finally, the composition on both sides of the indentation was measured by quantitative EPMA analysis again. The lamellar thickness of the α-phase was obtained by calculating the average values of those incising the diagonals of the SEM micrographs (ASTM: E112-12 Central South University, Changsha, China).
The alloy buttons of Ti‒6Al‒4V‒30Zr were prepared from high purity Ti (99.95%), Zr (99.7%), Al (99.99%), and V (99.95%) via arc-melting technique in an argon atmosphere. The buttons (~10 g each) were heat-treated the same as the diffusion multiple samples. Phase structures were examined through X-ray diffraction (XRD) (XRD-6000, Shimadzu, Japan). Transmission Electron Microscopy (TEM Central South University, Changsha, China) was used to investigate phase transformation and phase composition (Titan G260-300 Central South University, Changsha, China).
The bulk alloy of Ti‒6Al‒4V‒30Zr was prepared using sponge titanium, pure Zr, pure Al, and Ti–V master alloys through a double-vacuum arc-melting process. The ingot with 200 mm in length and 160 mm in diameter was first β-fogged down at 1000 °C and subsequently forged at 820 °C to 40 mm thick and 80 mm wide bars. The β-transus temperature of the alloy was determined metallographically and was found to be 800 ± 5 °C. The samples from the as-forged material were first solution-treated at 820 °C for 0.5 h and followed by air cooling. Afterward, the samples were aged at 500 °C, 550 °C, 600 °C, and 650 °C for 6 h and followed by air cooling. Optical microscopy (OM Central South University, Changsha, China) was used to characterize the forged alloy, which was etched in Kroll’s reagent (3% HF + 9% HNO
3
+ 88% H
2
O). The microstructures were investigated using FESEM (JEOL-JSM 7001F Central South University, Changsha, China). Tensile testing was carried out on a MTS810 testing machine (Central South University, Changsha, China) and driven at a crosshead speed of 2 mm/min. Bone-shaped plate specimens with a 25 mm gauge length, 4 mm gauge width, and 3 mm gauge thickness were prepared for tensile tests.
3. Results and Discussion
3.1. Microstructure of Ti6Al4VxZr Alloys Taken from Ti6Al4V–Ti6Al4V45Zr Diffusion Multiple
Figure 3 plots the composition changes as a function of diffusion distance for the Ti6Al4V–Ti6Al4V45Zr system. Zirconium content reduced gradually to 0 with the increase in diffusion distance. The Zr atom mainly substituted Ti, and the contents of Al and V almost remained constant.
Figure 4 shows the backscatter electron micrographs of the Ti‒6Al‒4V‒xZr alloys. These SEM micrographs were taken from different places of the diffusion multiples. The Zr content of the Ti‒6Al‒4V‒xZr alloys were around 8, 15, 22, 28, and 30 wt.%. As shown in Figure 4 a,b, the Ti‒6Al‒4V and Ti‒6Al‒4V‒8Zr displayed coarse α′ martensitic lath. When the Zr content increased to 15–22 wt.%, the structure morphology of the alloys was similar to the Ti‒6Al‒4V alloy, and the thickness and fractional volume of the martensitic lath decreased. When 28 wt.% Zr was added, very fine martensitic laths were observed ( Figure 4 e). When the alloy contained 30 wt.% or more Zr, no α′ martensitic lath was visible in the SEM images, and β-phase became the dominant phase ( Figure 4 f). The β-phase was entirely retained during quenching when the Zr content exceeded 30 wt.%, perhaps because the alloying element Zr acted as a weak β stabilizer, which will suppress the formation of α′ martensite. The alloys contained 38 and 45 wt.% Zr also exhibit a single β phase, as shown in Figure 4 g,f. This result indicated that the martensitic start (Ms) temperature dropped below room temperature after 30 wt.% Zr was added. Importantly, ω and α″ phases are too fine to be observed through the backscattered image. Previous research has shown that the martensite phase transformation from β→α″ takes place during water quenching in Ti‒Al‒V‒Zr alloys [ 12 ]. This result means that the quenched Ti‒6Al‒4V‒30Zr alloy was comprised mainly of the β-and α″ phases, which could be verified in the TEM results.
The influences of various Zr contents on the microstructures of the Ti‒6Al‒4V alloy after aging at 600 °C are shown in
Figure 5
. These SEM images were taken from the diffusion multiple and the contents of the Zr from 0–45 wt.%. As shown in
Figure 5
, the volume fraction of the α-phase decreased monotonously, and the lamellar thickness of the α-phase initially decreased and then increased as Zr contents increased. As shown in
Figure 5
a, the Ti‒6Al‒4V alloy displays the coarse basket-weave microstructure, and the lamellar thickness of the α-phase was approximately 1000 nm. Based on the increase of Zr contents, the lamellar thickness of the α-phase remarkably decreased. When the alloy contained 30 wt.% Zr, the alloy displayed ultrafine α grains compared with other alloys. The nanoprecipitation phase were hardly observable through SEM microscopy. However, further increasing the Zr content increased the lamellar thickness of the α-phase.
The series of SEM micrographs showing the α precipitate morphologies for various Zr contents after aging at 650 °C for 6 h is shown in Figure 6 . At 650 °C, the precipitates were coarser and had less volume fraction than in the lower aging temperatures. Moreover, the finest acicular α precipitates appeared in the alloy with compositions of approximately 30 wt.% Zr.
The quantitative statistics of the lamellar thickness of the α-phase based on digital image processing are shown in
Figure 7
. After aging at 600 °C and 650 °C, the α lamellar thickness of Ti6Al4V reached to 1000 and 1200 nm, respectively. Increasing the Zr content to 30 wt.% decreased the thickness of the α-phase to 50 and 70 nm, respectively, and the Ti‒6Al‒4V‒30Zr alloy had ultrafine grains. When the Zr content was below 30 wt.%, the martensite transition temperature was below room temperature. After quenching from the β-field, an α′ martensite distribution was obtained. The microstructures of the aged alloys were remarkably dependent on the martensite quenching structure. During aging at 600 °C for 6 h, Ti‒6Al‒4V‒xZr alloys underwent phase transition between α′ martensite to α-phase, and the mutual diffusion of Al, V, and Zr elements occurred between α- and β-phases. When Zr content increased to 30 wt.%, and the metastable α″- or ω-phases occurred in the β-matrix after quenching. These nano-sized particles may act as heterogeneous nucleation sites for α-phase and increase the nucleation rate of the α-phase during the aging treatment. The ultrafine structures of Ti‒6Al‒4V‒30Zr alloy resulted from the increase of α-nucleation rate. When the Zr content was increased to 38 wt.% or greater, only the retained β-phase was observed, and no other structures units acted as heterogeneous nucleation site for α-phase, which resulted in the decrease of α-nucleation rate and coarser α-phase.
3.2. Influence of the Zr on the Hardness after Beta-Annealing and after Aging
Figure 8
shows that the hardness and composition of quenched and aged Ti‒6Al‒4V‒xZr alloys change as a function of diffusion distance. The results show that Zr had notable influence on hardness. The hardness of quenched alloys increased with Zr content and peaked as the Zr content in Ti‒6Al‒4V reached approximately 30 wt.%. When the content of Zr was 30 wt.%, its hardness was 541 MPa, which was approximately 30% higher than that of the Ti‒6Al‒4V alloy. This result indicates that the hardness of quenched alloys strongly depends on their microstructures. As mentioned above, the quenched alloy exhibited the nanoscale and microscale martensitic lath when the Zr content was approximately 30 wt.%. The fine martensitic lath generated a mass of α″/β-interfaces, which hindered dislocation motion and improved alloy hardness [
24
]. As described above, Zhang et al. [
25
] found the martensite α″ and the high strength in the Ti‒5Al‒3V‒30Zr alloy and reported that the metastable α″ martensite can increase the strain-hardening exponent, resulting to the increase of hardness. When the alloys contained 45 wt.% Zr, the mount of α″ precipitates decreased or even disappeared, which may result to decrease in hardness. This finding agreed with the findings in Majumdar′s [
26
] study, where the hardness dropped to a minimum when the Zr content was about 50 wt.% in the beta-annealed titanium alloys.
After aging at 600 °C, the hardness increased from 439 MPa to 605 MPa as Zr content increased from 0 wt.% to 30 wt.% and then decreased, as shown in Figure 8 b. After aging at 650 °C, the hardness decreased slightly. This result was mainly due to the increase in α-lath thickness and decrease in the volume fraction of the α-phase, (i.e., hardness tends to change after aging at 650 °C similar to that after aging at 600 °C). The Ti‒6Al‒4V‒30Zr alloy displayed a fine scale dispersion of the α-phase and showed a hardness of about 605 MPa, which was a 35% improvement upon that of the Ti‒6Al‒4V alloy. The strengthening mechanisms were chiefly precipitation, grain refinement, and solid solution reinforcement. Compared with the Ti‒6Al‒4V alloy, the Ti‒6Al‒4V‒30Zr alloy had a larger number of α precipitates after the addition of 30 wt.% Zr, and the α lath was finer and generated a mass of α/β-interfaces and close interlaminar spacings, which effectively hindered dislocation-slipping according to the Orowan relationship. Previous research [ 27 , 28 , 29 , 30 , 31 , 32 ] has shown that the α/β-phase boundary in titanium alloys fall into two obvious categories, namely, coherent and incoherent phase boundaries. In titanium alloys, the α/β-phase boundary with fine and uniform α-phase is the coherent phase boundary, and the phase boundary with coarse microstructures belongs to the incoherent phase boundary. The interfacial bonding strength of the coherent phase boundary is stronger than that of the incoherent phase boundary, which gives the hardness and finest α lamellar qualities of the Ti‒6Al‒4V‒30Zr alloy compared with other alloys. The chemical compositions of the α- and β-phases after aging at 600 °C were also determined. Table 1 shows that the α- and β-phases have almost the same Zr contents, which were homogeneously distributed inside the α- and β-phases. Previous studies have shown that Zr mainly functioned as a solution-strengthening element. High concentration of Zr solute atoms in the α- and β-phase results in distorted lattice and increased dislocation density due to the different atomic dimensions between Zr and Ti. The strength enhancement of the Ti‒6Al‒4V‒30Zr alloy could also be caused by solid solution-strengthening [ 33 , 34 ].
The tensile strengths of a series of Ti‒Al‒V‒Zr alloys are shown in Figure 8 d. The composition of the alloys were Ti‒6Al‒4V, Ti‒6Al‒4V‒5Zr, Ti‒6Al‒4V‒10Zr, Ti‒6Al‒4V‒15Zr, Ti‒6Al‒4V‒20Zr [ 13 ], Ti‒5Al‒3V‒30Zr [ 12 ], and Ti‒5Al‒3V‒47Zr [ 35 ]. The tendency of the diffusion multiple to change in hardness was comparable with the strength variable trend obtained using the alloy method. Zhang et al. [ 12 ] reported that Ti5Al3V30Zr had the largest tensile strength of 1407 MPa among the Ti‒Al‒V‒Zr alloys. As described above, Ti‒6Al‒4V‒30Zr is likely to be the most promising high-strength candidate alloy among the Ti‒6Al‒4V‒xZr alloys.
3.3. XRD and STEM Results of Ti‒6Al‒4V‒30Zr Alloy
Figure 9 shows the XRD spectrums of the as-quenched and as-aged Ti‒6Al‒4V‒30Zr alloys. The results show that the as-quenched microstructures of Ti‒6Al‒4V‒30Zr were α″ lath martensite and β-matrix. No other phase was observed at this stage. The hexagonal close-packed structure of the α-phase was seen after aging at 600 °C and 650 °C for 6 h. The α-phase should have evolved from the quenched α″ phase.
Figure 10 shows the microstructural features of Ti‒6Al‒4V‒30Zr alloy in the quenched condition. The nanoscale precipitates of the α″ phase were homogeneously distributed and clearly visible in the bright-field image. These α″ laths had two orientations, which were perpendicular to each other. The presence of α″ nanosize laths was not detected by SEM, which may be due to the absence in compositional variation between the α″- and β-matrix. Figure 10 b shows the [011] β-zone axis electron diffraction patterns with additional reflections next to {202} positions, which arose from the α″ phase. In Figure 10 b, extra diffraction spots were observed and identified as that of the orthorhombic α″ phase besides diffraction spots of the original β-phase. A high-angle annular dark field (HAADF) image recorded from one of the additional α″ reflections is shown in Figure 10 c. This image confirms the presence of nanometer-scale, quenched-in α″ precipitates within the β-grains. The average thickness of α″ laths is around 30 nm. Guo et al. [ 36 ] have also reported the metastable α″ phase in 40.2Ti–51.1Zr–4.5Al–4.2V alloy, with the mean width of α″ laths as ~46 nm. Liang et al. [ 25 ] have found the single martensite α″ in the Ti‒5Al‒3V‒30Zr alloy and reported that the metastable α″ martensite transformation arose from tensile stress and could increase the strain-hardening exponent significantly, which will result in high hardness. In the aged stage, the α-phase is generated, and the fine α″ martensite may serve as the nucleation site of the α-phase. Figure 10 c shows the EDS mapping result from this sample, exhibiting the atoms distribution in the green square. The results indicate that the compositional fluctuations were not obvious in the Zr, Al, and V content, and all the alloy components were evenly distributed in the beta-annealed condition. This result indicates a shear-type β-to-α″ phase transformation without composition difference from the β-phase.
The microstructural feature of the Ti‒6Al‒4V‒30Zr alloy aged at 600 °C is shown in
Figure 11
. The nanometer-scale α precipitates were homogeneously distributed within β-grains as clearly shown in the bright-field images in
Figure 11
a. Compared with the quenched condition, the nanoscale α-phases also had two orientations, which were perpendicular to each other. The same crystal orientation of α and α″ laths indicates that α″ precipitates act as heterogeneous nucleation sites for the α precipitates in Ti‒6Al‒4V‒30Zr. The dimensions for the secondary α-phase were ~200 nm long and ~60 nm wide, and the spacing of the α precipitates in the β-matrix was ~20 nm in width. The nanoscale β-laths was another reason that resulted to the peak hardness of the Ti‒6Al‒4V‒30Zr alloy.
Figure 11
b shows the [111] β-zone axis electron diffraction patterns with additional reflections at 1/2 {110} β-positions, as well as reciprocal lattice streaking. These additional reflections were arose from secondary α-phases.
Figure 11 c shows a HAADF-STEM image of the Ti‒6Al‒4V‒30Zr alloy after aging at 600 °C. Figure 11 d,e show EDS atom maps with square regions of the aged sample containing an α plate, which has a distinct color. A compositional profile across the α plate is shown in Figure 11 f. A comparison of the chemical composition of the α- and β-phases is given in Table 2 . The EDS mapping reveals an enrichment in Al and depletion in V in the α-phase and an enrichment in V and depletion in Al in the β-phase (i.e., Al is an α-stabilizer and V is a β-stabilizer). Zirconium was homogenized in the α- and β-phases (i.e., Zr is a neutral element). The microstructural feature of the Ti‒6Al‒4V‒30Zr alloy aged at 650 °C is shown in Figure 12 . Compared with the alloy aged at 600 °C, the precipitates of the Ti‒6Al‒4V‒30Zr were coarser, and the dimensions for the secondary α-phase were ~200 nm long and ~110 nm wide. The chemical compositions of the α- and the β-phases after aging at 650 °C were also determined and listed in Table 2 , which shows that the α- and β-phases have almost the same Zr contents, and the Zr was homogeneously distributed inside the α- and β-phases.
As shown in
Figure 11
and
Figure 12
, the aged Ti‒6Al‒4V‒30Zr alloy displays an ultrafine-grained microstructure. The α precipitates were nucleated preferentially at the grain boundaries, such as prior β-grain boundaries and β/ω interfaces, and other lattice defects, such as dislocations and sub-boundaries [
37
,
38
]. The composition of the alloy and the specific heat treatment experienced by the alloy were major factors in determining whether these sites have a decisive effect on α-nucleation. In the current study, the Ti‒6Al‒4V‒30Zr alloy had a low dislocation density for the β-field annealing. The TEM and XRD examinations showed that the quenched Ti‒6Al‒4V‒30Zr alloy had homogeneously-distributed nanoscale precipitates of the α″ phase, which will act as the nucleation site for α-phase during aging. Moreover, both α- and α″- phases have two variants, and the angle between the two variants is 90 degrees. As a consequence of the α″-assisted heterogeneous nucleation, a relatively large number of nanosized α precipitates were formed and uniformly distributed within the β-matrix. These nanosized α precipitates create lots of grain boundaries, which inhibit the dislocation motion and result in the strengthening effect.
3.4. Structure and Mechanical Properties of the Forged Ti‒6Al‒4V‒30Zr Alloy
The overall composition of the as-forged alloy, which was measured via inductively coupled plasma atomic emission spectrometry, is presented in Table 3 . The β-transus temperature was 800 °C. The optical microscope image and XRD pattern of the as-forged alloy is shown in Figure 13 . As shown in Figure 13 , the alloy consisted of β-microstructure and α″-phase, and no spherical α-phase (primary α) can be observed due to the alloy forging in the β-single phase zone.
Figure 14
shows the microstructure of the forged alloy after the β-solution was treated and aged at different temperatures. As shown in
Figure 14
, each aged alloy displays a typical basket-weave structure of α- and β-phases. When the temperature of the aging treatment was relatively low (500 °C), the needle-like secondary α-phase formed within the β-matrix. Denser dispersion of the α precipitate were present with higher aspect ratios. As the aging temperature increased, the secondary α coarsened, and its volume fraction decreased gradually. Notably, the stagger α precipitates were distributed in the β-matrix with non-uniform size, which is a little different from the α-phase morphology taken from the diffusion multiples. This result may be because forged alloy always introduces numerous grain boundaries, dislocations, and internal stress. These defects increase the strain energy and interfacial energy, which decreases the stability of the system. The assumption is that coarser second α formed at the stage of cooling from the β-field results to finer second α formed at the aging stage.
The influence of aging temperature on the tensile properties of Ti‒6Al‒4V‒30Zr alloy after super-transus solution treatment is shown in
Figure 15
. The tensile properties and stress-strain curves after solution treatment and aging at various temperatures are shown in
Figure 15
a,b. After aging at 500 °C, the tensile strength and yield strength reached 1540 MPa and 1473 MPa, and the breaking elongation reached 6.4%. When aged at 550 °C, the alloy had a good combination of strength and plasticity, the tensile and strength yield strength were 1464 MPa and 1377 MPa, respectively, with moderate elongation (8.3%). When aged at 650 °C, the alloy had the lowest value of 1235 MPa for yield strength and 1303 MPa for tensile strength, and highest elongation of 11.2%. Overall, increasing the aging temperature decreases tensile and yield strengths of the alloys but increases the total elongation.
The tensile properties of titanium alloy are significantly influenced by the microstructures, especially the size and volume fraction of the secondary α-phase. According to the Hall–Petch formula, the strength of the alloys increase with the decrease in mean width of the α-grains. As shown in
Figure 14
, when the aging temperature is 500 and 550 °C, the mean thickness of α grains is about 90 and 150 nm, and the strength of the alloys reaches 1540 and 1464 MPa, respectively. Whereas, when the aging temperature increases to 600 and 650 °C, the strength of the alloys decreases to 1360 and 1303 MPa. The increase of grain boundaries density is accompanied by the decrease of grain size. The gain boundaries act as strong obstacles to the dislocation motion and prevent dislocation from moving. The increase in strength resulted from the increase in dislocation density, which is responsible for dislocation tangle.
The breaking elongation percentage of Ti‒6Al‒4V‒30Zr alloy increases with the increase of the α-phase thickness. Major deformation mechanisms in titanium alloys were found to be dislocation glide and tangle [ 34 ]. The decrease of the grain size will lessen the thickness of lamellas and lamellar spacing of the α-phase, which will reduce the activity space of dislocation and induce the decrease of breaking elongation [ 39 , 40 , 41 ]. Moreover, the volume fraction of α-phase is another important factor that has great impacts on mechanical properties. The general trend is that the tensile strength of the alloy increases by increasing the volume fraction of the α-phase, but the elongation decreases. Dehghan-Manshadi also reported that the hardness of Ti-5553 alloy increases monotonously with the increase of volume fraction of α-phase from 0 to 80% [ 42 ]. This case might be because the crystal structure of β-phase is bcc, but the structure of α-phase is hcp, and bcc is easier to deform than the hcp structure. Therefore, excessive α-phase will cause plasticity degradation of the alloy. Du et al. [ 43 ] reported that, when the volume fraction of α-phase in the alloy is about 60%, the alloy may have the best overall performance.
4. Conclusions
In the current study, the diffusion multiples of Ti6Al4V–Ti6Al4V20Fe–Ti6Al4V20Cr–Ti6Al4V20Mo–Ti6Al4V45Zr were manufactured to obtain a large composition space. Scanning electron microscopy, EPMA, and a microhardness system were combined to determine the relationships among the composition, microstructure, and hardness of these alloys. The microstructure, mechanical properties, and phase transition of Ti‒6Al‒4V‒30Zr alloy were also investigated. The following findings are reported:
(1)
When the Zr content increased to 30 wt.%, the quenched α′ phase decreased and disappeared, and the lamellar thickness of α-phase decreased to nanoscale, which resulted to maximum hardness of the quenched and aged alloy. When the Zr content further increased, the lamellar thickness of the α-phase increased, and the hardness decreased.
(2)
Both HAADF-STEM and XRD were used to determine the microstructure and phase composition after quenching and aging of the Ti‒6Al‒4V–30Zr alloy. The quenched alloy displayed homogeneously distributed nanoscale α″ phases, which will be the nucleation site of α-phase during aging.
(3)
The forged Ti–6Al–4V–30Zr alloy in the β-solution and aging showed the non-uniform secondary α-phase distribution in the matrix. By increasing the aging temperature from 500 °C to 650 °C, the tensile strength and yield strength of the alloys rose, but the total elongation decreased. The lamella thickness and volume fraction of the α-phase were the major factors that had great impacts on the mechanical properties. As the lamella thickness and volume fraction of the α-phase increased, the tensile strength of the alloy decreased, but the elongation decreased.
Author Contributions
D.W., L.L., and K.Z. designed the study; D.W., Z.W., and J.S. conducted the experiments; D.W., Y.T., L.Z., and W.W. analyzed the results; and D.W., L.L., and K.Z. contributed to preparation of the manuscript.
Funding
The work was funded by National Key Technologies R & D Program of China (Grant No. 2016YFB0701301), National Key Basic Research Program of China (973 Program) (Grant No. 2014CB644000), National Natural Science Foundation of China (Grant No. 51671218, 51501229), and State Key Laboratory of Powder Metallurgy, Central South University, Changsha, China.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. The fabrication process of Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiple: ( a ) two diffusion multiples with three bricks of alloys were manufactured with steel fixtures; ( b ) Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiple manufactured with steel fixtures; and ( c ) cross-sectional schematics of the Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiples.
Figure 1. The fabrication process of Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiple: ( a ) two diffusion multiples with three bricks of alloys were manufactured with steel fixtures; ( b ) Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiple manufactured with steel fixtures; and ( c ) cross-sectional schematics of the Ti6Al4V-Ti6Al4V20Fe-Ti6Al4V20Cr-Ti6Al4V20Mo-Ti6Al4V45Zr diffusion multiples.
Figure 2. Heat treatment schedule for the Ti6Al4V‒Ti6Al4V20Fe‒Ti6Al4V20Cr‒Ti6Al4V20Mo‒Ti6Al4V45Zr diffusion multiple (this figure is not to scale.).
Figure 2. Heat treatment schedule for the Ti6Al4V‒Ti6Al4V20Fe‒Ti6Al4V20Cr‒Ti6Al4V20Mo‒Ti6Al4V45Zr diffusion multiple (this figure is not to scale.).
Figure 3. ( a ) Optical image of hardness indentation grid at the Ti6Al4V–Ti6Al4V45Zr diffusion multiple; ( b ) variation in the composition as a function of distance for the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 3. ( a ) Optical image of hardness indentation grid at the Ti6Al4V–Ti6Al4V45Zr diffusion multiple; ( b ) variation in the composition as a function of distance for the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 4. SEM, backscattered electron images of beta annealed Ti6Al4VxZr alloys taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 4. SEM, backscattered electron images of beta annealed Ti6Al4VxZr alloys taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 5. SEM, backscattered electron images of Ti6Al4VxZr alloys after aging at 600 °C taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 5. SEM, backscattered electron images of Ti6Al4VxZr alloys after aging at 600 °C taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 6. SEM, backscattered electron images of Ti6Al4VxZr alloys after aging at 650 °C taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 6. SEM, backscattered electron images of Ti6Al4VxZr alloys after aging at 650 °C taken from the Ti6Al4V–Ti6Al4V45Zr diffusion multiple.
Figure 7. Width of α phase as function of Zr content after aging at 600 °C and 650 °C.
Figure 7. Width of α phase as function of Zr content after aging at 600 °C and 650 °C.
Figure 8. Composition-hardness relationship of the series Ti6Al4VxZr alloys: ( a ) after beta annealing; ( b , c ) after aging at 600/650 °C; ( d ) hardness of aged alloys compared with reference.
Figure 8. Composition-hardness relationship of the series Ti6Al4VxZr alloys: ( a ) after beta annealing; ( b , c ) after aging at 600/650 °C; ( d ) hardness of aged alloys compared with reference.
Figure 9. XRD patterns of solution-treated and as-aged Ti6Al4V30Zr alloy.
Figure 9. XRD patterns of solution-treated and as-aged Ti6Al4V30Zr alloy.
Figure 10. Microstructural feature of the Ti6Al4V30Zr alloy after beta annealing at 1050 °C: ( a ) bright field (BF) image showing α″ laths; ( b ) SAD (selected area electron diffraction) pattern with [113] β zone axis; ( c ) HAADF-STEM images; ( d ) The EDS mapping of Zr, V, Al, and Ti atoms.
Figure 10. Microstructural feature of the Ti6Al4V30Zr alloy after beta annealing at 1050 °C: ( a ) bright field (BF) image showing α″ laths; ( b ) SAD (selected area electron diffraction) pattern with [113] β zone axis; ( c ) HAADF-STEM images; ( d ) The EDS mapping of Zr, V, Al, and Ti atoms.
Figure 11. Microstructural feature of the Ti6Al4V30Zr alloy after aging at 600 °C: ( a ) bright field (BF) image; ( b ) SAD pattern with [111] β zone axis; ( c , d ) HAADF-STEM images showing α phase; ( e ) the EDS mapping of Zr, V, Al, and Ti atoms; ( f ) the composition profiles along the arrows shown in ( d ).
Figure 11. Microstructural feature of the Ti6Al4V30Zr alloy after aging at 600 °C: ( a ) bright field (BF) image; ( b ) SAD pattern with [111] β zone axis; ( c , d ) HAADF-STEM images showing α phase; ( e ) the EDS mapping of Zr, V, Al, and Ti atoms; ( f ) the composition profiles along the arrows shown in ( d ).
Figure 12. Microstructural feature of the Ti6Al4V30Zr alloy after aging at 650 °C: ( a ) BF image; ( b ) SAD pattern with [111] β zone axis; ( c , d ) HAADF-STEM images showing α phase; ( e ) the EDS mapping of Zr, V, Al, and Ti atoms; ( f ) the composition profiles along the arrows shown in ( d ).
Figure 12. Microstructural feature of the Ti6Al4V30Zr alloy after aging at 650 °C: ( a ) BF image; ( b ) SAD pattern with [111] β zone axis; ( c , d ) HAADF-STEM images showing α phase; ( e ) the EDS mapping of Zr, V, Al, and Ti atoms; ( f ) the composition profiles along the arrows shown in ( d ).
Figure 13. As-forged Ti6Al4V30Zr alloy: ( a ) Optical microscope image; ( b ) XRD pattern.
Figure 14. SEM, backscattered electron images of the Ti6Al4V30Zr alloy after solution treated at 820 °C and aged at different temperatures: ( a ) 500 °C; ( b ) 550 °C; ( c ) 600 °C; ( d ) 650 °C.
Figure 14. SEM, backscattered electron images of the Ti6Al4V30Zr alloy after solution treated at 820 °C and aged at different temperatures: ( a ) 500 °C; ( b ) 550 °C; ( c ) 600 °C; ( d ) 650 °C.
Figure 15. Tensile test results of the alloy solution treated at 820 °C and aged for 6 h: ( a ) tensile properties vary with aging temperature; ( b ) stress-strain curves.
Figure 15. Tensile test results of the alloy solution treated at 820 °C and aged for 6 h: ( a ) tensile properties vary with aging temperature; ( b ) stress-strain curves.
Table 1. Chemical composition of the as-received Ti–6Al–4V and Ti–6Al–4V–45Zr (wt.%).
Table 1. Chemical composition of the as-received Ti–6Al–4V and Ti–6Al–4V–45Zr (wt.%).
Element Al V Zr Fe O N C Ti Ti6Al4V 6.37 3.61 - 0.13 0.18 0.02 0.02 Bal. Ti6Al4V45Zr 6.47 3.63 44.85 0.15 0.11 0.02 0.01 Bal.
Table 2. Chemical composition of the α phase and the β phase in the Ti6Al4V30Zr alloy after aging at 600/650 °C (as shown in Figure 11 d and Figure 12 d).
Table 2. Chemical composition of the α phase and the β phase in the Ti6Al4V30Zr alloy after aging at 600/650 °C (as shown in Figure 11 d and Figure 12 d).
Aging Temperature Position Phase wt.% V wt.% Zr wt.% Ti wt.% Al 600 °C 1 # α 1.9 34.4 56.7 7 2 # α 1.5 35.6 55.7 7.1 3 # β 13 28.8 55.5 2.7 4 # β 14.5 28.8 54.3 2.4 650 °C 1 # α 1.8 34.9 55.9 7.3 2 # α 1.9 34.5 56.2 7.4 3 # β 10.5 34.1 52.6 2.7 4 # β 10.3 33.2 52.5 2.8
Table 3. The chemical composition of titanium ingot (balance Ti, wt.%).
Table 3. The chemical composition of titanium ingot (balance Ti, wt.%).
| https://www.mdpi.com/1996-1944/11/9/1603/html |
(PDF) OECD Series on Adverse Outcome Pathways No. 23 Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation
PDF | On Dec 15, 2022, Lucia Vergauwen and others published OECD Series on Adverse Outcome Pathways No. 23 Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation | Find, read and cite all the research you need on ResearchGate
OECD Series on Adverse Outcome Pathways No. 23 Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation
DOI: 10.1787/b1bf0bea-en
Lucia Vergauwen
United States Environmental Protection Agency
University of Antwerp
OECD Series on Adverse Outcome Pathways No. 23
Deiodinase 2 inhibition
leading to increased
mortality via reduced
anterior swim bladder
inflation
Lucia Vergauwen,
Evelyn Stinckens,
Daniel L. Villeneuve,
Dries Knapen
https://dx.doi.org/10.1787/b1bf0bea-en
1
Deiodinase 2 inhibition leading to
increased mortality via reduced
anterior swim bladder inflation
Series on Adverse Outcome Pathways No. 23
AOP No. 156 in the AOP-Wiki platform
2
Foreword
ThisAdverseOutcomePathway(AOP)onDeiodinase2inhibitionleadingtoincreased
mortalityviareducedanteriorswimbladderinflation,hasbeendevelopedunderthe
auspices ofthe OECD AOPDevelopment Programme, overseen bythe Extended Advisory
Group onMolecularScreeningand Toxicogenomics(EAGMST),which isanadvisory group
under theWorkingPartyof the National Coordinatorsforthe Test Guidelines Programme
(WNT) and the Working Party on Hazard Assessment (WPHA) .
The AOPhas beenreviewed for compliance with the AOP development principles following
the EAGMSTcoaching approach.The scientificreview was subsequently conductedby the
UK National Cent refor the 3Rs,following the OECD AOP reviewprinciples outlined in the
Guidance Documenton the scientific review ofAOPs. This AOP was endorsedby the WNT
and the WPHA on 3 August 2022 .
ThroughendorsementofthisAOP,theWNTandtheWPHAexpressconfidenceinthe
scientific review processthat the AOP hasundergoneand accept the recommendation of
theEAGMSTthat theAOPbe disseminatedpublicly.Endorsement doesnotnecessarily
indicate that the AOP is now considered atool for direct regulatory application.
The OECD'sChemicalsandBiotechnologyCommitteeagreedto declassificationofthis
AOP on 4 November 2022.
Thisdocumentis beingpublished underthe responsibilityof theOECD'sChemicalsand
Biotechnology Committee.
Theoutcomeofthecompliancecheckandofthescientificreviewarepubliclyavailable
respectivelyinthe AOPWikiandthe eAOPPortaloftheAOPKnowledgeBaseatthe
3
Authors:
Lucia Vergauwen [1], [[email protected]]
Evelyn Stinckens [1], [[email protected]]
Dan Villeneuve [2], [[email protected]]
Dries Knapen [1], [[email protected]] [1]
[1] Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences,
University of Antwerp, Universiteitsplein 1,2610 Wilrijk, Belgium
[2] United States Environmental ProtectionAgency, Mid-Continent Ecology Division, 6201
Congdon Blvd, Duluth, MN, USA
4
Abstract
ThisAOP describesthesequenceof eventsleadingfromdeiodinase inhibitiontoincreasedmortality via
reducedanteriorswimbladderinflation.Disruptionofthethyroidhormonesystemisincreasinglybeing
recognized as an important toxicity pathway that cancause many adverse outcomes, including disruption of
developmentalprocesses.Threetypesofiodothyroninedeiodinases(DIO1-3)havebeendescribedin
vertebratesthatactivateorinactivateTHsandarethereforeimportantmediatorsofTHaction.TypeII
deiodinase (DIO2)has thyroxine (T4) asa preferred substrateand is mostly importantfor converting T4 to
themorebiologically active triiodothyronine(T3).InhibitionofDIO2 therefore reducesT3levels.Thyroid
hormonesare critical inregulating developmentalprocesses andthyroid hormonedisruptioncan interfere
with normaldevelopment. Swimbladder inflationisknown to beunder TH control (Brown etal., 1988; Liu
and Chan, 2002).Many fish species havea swim bladder which isa gas-filled organthat typically consists
of twochambers (Robertsonet al.,2007). Theposterior chamberinflates duringearly developmentin the
embryonic phase, whilethe anterior chamber inflates duringlate development in the larvalphase. Boththe
posterior and the anterior chamber have an important rolein regulating buoyancy, and the anterior chamber
has anadditional rolein hearing (Robertsonet al.,2017). ThisAOP describeshow inhibition ofDIO2 reduces
levelsofT3,therebyprohibitingproperinflationoftheanteriorchamber.Duetoitsroleinregulating
buoyancy, this resultsin reduced swimming performance.Since reduced swimming performanceresults in
adecreasedabilitytoforageandavoidpredators,thisreduceschancesofsurvival.Thefinaladverse
outcome is a decreaseof the population growth rate. Since many AOPseventually lead to this more general
adverseoutcomeatthepopulationlevel,themorespecificandinformativeadverseoutcomeatthe
organismallevel,increasedmortality,isusedintheAOPtitle.SupportforthisAOP ismainlybased on
chemical exposures in zebrafish and fathead minnows (Cavallin et al., 2017; Godfrey et al.,2017; Stinckens
et al., 2020).
This AOP is part ofa larger AOP network describing howdecreased synthesis and/or decreased biological
activation of THsleads to incomplete orimproper inflation of theswim bladder, leading toreduced swimming
performance, increasedmortality and decreased population trajectory(Knapen et al.,2018; Knapen etal.,
2020;Villeneuve etal.,2018).Other thanthedifference in deiodinase(DIO)isoform, thecurrentAOP is
identicaltothe corresponding AOPleadingfromDIO1inhibitiontoincreasedmortalityviaanteriorswim
bladderinflation (https://aopwiki.org/aops/158).The overall importanceof DIO1versus DIO2in fishisno t
exactly clear. DIO2inhibitors are often alsoinhibitors of DIO1 (Olker etal., 2019; Stinckens et al. 2018). In
the ToxCast DIO2 inhibition single concentration assay, 304 out of 1820 chemicals were positive and 177of
these were also positive for DIO1 inhibition (viewedon 5/7/2022). This complicatesthe distinction between
the relative contributionof DIO1 and DIO2 inhibitionto reduced swim bladder inflation. The current stateof
the art suggests thatDIO2 is more important than DIO1in regulating swim bladder inflation. Six out ofseven
DIO1inhibitors impairedposterior chamber inflation,but almostallof thesecompounds alsoinhibitDIO2
(Stinckenset al.,2018)) .Tetrachlorobisphenol A(TCBPA), theonly compoundthatinhibits DIO1and not
DIO2, had noeffect onthe posteriorswim bladder.Exposureto strongDIO2 inhibitorson theother hand
affected posteriorchamber inflation and/or surfacearea in all cases.Therefore the current AOP may be of
higher biological relevancecompared to AOP 158. Starting from reduced T3 levels, this AOP is identical to
theAOP leadingfromthyroperoxidase inhibitionleadingto increasedmortalityvia reducedanteriorswim
bladder inflation (https://aopwiki.org/aops/159).
5
Table of contents
Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder
inflation1
11
Sex : AllkeyeventsinthisAOPareplausiblyapplicabletobothsexes.Sexdifferencesarenotoften
investigated in tests using early life stages of fish.For zebrafish and fathead minnow, itis currently unclear
whethersex-relateddifferencesareimportantindeterminingthemagnitudeofthechangesacrossthe
sequence ofevents inthis AOP. Differentfish specieshave different sexdetermination anddifferentiation
strategies.Zebrafish donothave identifiableheteromorphicsexchromosomes andsexis determinedby
multiplegenesandinfluencedbytheenvironment(NagabhushanaandMishra,2016).Zebrafishare
undifferentiatedgonochoristssincebothsexesinitiallydevelopanimmatureovary(MaackandSegner,
2003).Immature ovarydevelopmentprogresses untilapproximatelythe onsetof thethirdweek. Later,in
female fish immature ovaries continue todevelop further, while male fish undergo transformation of ovaries
into testes. Final transformation into testesvaries among male individuals, however finishes usually around
6 weeks post fertilization. Since the anterior chamberinflates around 21 days postfertilization in zebrafish,
sex differences are expected to play a minor role in the current AOP. Fathead minnow gonad differentiation
alsooccursduringlarvaldevelopment.FatheadminnowsutilizeaXYsexdeterminationstrategyand
markers can be used to genotype sex inlife stages where the sex is not yet clearly defined morphologically
(Olmstead et al., 2011). Ovarian differentiation starts at 10 dphfollowed by rapid development (Van Aerle et
al., 2004). At 25 dph germ cells of all stages up to the primary oocytes stage were present and at120 dph,
vi tellogenicoocytes werepresent.Thegerm cells(spermatogonia)of thedevelopingtestesonly entered
meiosis around90 –120 dph. Maturetestes with spermatozoaare presentaround 150 dph.Since theanterior
chamber inflates around 14 days post fertilization (9 dph) in fathead minnows, sex differences are expected
to play a minor role in the current AOP.
Essentiality of the Key Events
Overall, theconfidence in thesupporting data foressentiality of KEswithin the AOPis moderate. Thereis
evidencefrom deiodinaseknockdownsshowing thelink with reducedposterior chamberinflationand the
essentialityfordownstreameffects,butanteriorchamberinflationwasnotstudied.Thereisadditional
indirect evidence that reduced thyroidhormone synthesiscauses reduced anteriorswim bladderinflation:
Chopraetal.(2019)showedthatknockdownofdualoxidase,importantforthyroidhormonesynthesis,
reduced anteriorswim bladderinflation. Itshould be notedthat dualoxidase alsoplays arole in oxidative
stress. Thereis also evidencethat alleviation ofthe effect onanterior chamberinflation reduces theeffect
on swimming performance.
Weight of Evidence Summary
Biological plausibility : see Table. Overall, the weight of evidence for the biological plausibility of the KERs
in the AOP is moderate sincethere is empirical support for an association between the sets of KEsand the
KERs are plausiblebased on analogy toaccepted biological relationships, but scientificunderstanding is not
completely established.
Empiricalsupport : seeTable. Overall,the empiricalsupport forthe KERsin theAOP ismoderate since
dependent changes in sets of KEs following exposure to several specific stressorshas been demonstrated,
with limited evidence for dose and temporal concordance and some uncertainties.
Quantitative Consideration
There is somelevel ofquantitative understanding that can formthe basis for development ofa quantitative
AOP.QuantitativerelationshipsbetweenreducedT3andreducedanteriorchamberinflationwere
established. The latter is particularly critical for linking impaired swim bladder inflation to TH disruption.
12
Considerations for Potential Applications of the AOP
A growingnumberofenvironmentalpollutantsareknown toadverselyaffectthethyroidhormone system,
andmajorgapshavebeenidentifiedinthetoolsavailablefortheidentification,andthehazardandrisk
assessment of thesethyroid hormone disrupting chemicals.Villeneuve et al. (2014)discussed the relevance
of swim bladder inflation asa potential key eventand endpoint of interestin fish tests. Knapen etal. (2020)
provide an exampleof how the adverseoutcome pathway (AOP) framework andassociated data generation
can address currenttesting challengesin thecontext offish early- life stagetests, andfish tests ingeneral.
While theAOPisonlyapplicabletofish,someoftheupstreamKEsarerelevantacrossvertebrates. The
taxonomic domainofapplicability call oftheKEs canbefoundon therespectivepages.A suiteofassays
coveringalltheessentialbiologicalprocessesinvolvedintheunderlyingtoxicologicalpathwayscanbe
implementedinatieredscreeningandtestingapproachforthyroidhormonedisruptioninfish,usingthe
levels of assessment ofthe OECD’s ConceptualFrameworkfor theTesting andAssessmentof Endocrine
Disrupting Chemicals as a guide. Specifically,for this AOP, deiodinase inhibition can be assessed using an
in chemico assay, measurements of T3levels could be added tothe Fish Embryo Acute Toxicity(FET) test
(OECDTG236),theFishEarlyLifeStageToxicity(FELS)Test(OECDTG210)andtheFishSexual
Development Test(FSDT)(OECD TG234), andassessmentsof anteriorchamberinflation andswimming
performance could be added to the FELSTest and FSDT.
Thyroid hormone system disruption causes multiple unspecific effects. Addition of TH measurements could
aid in increasingthe diagnosticcapacity of abattery ofendpoints sincethey are specific to theTH system.
A batteryofendpointswould ideally include theMIE,theAO andTHlevelsas the causallink.Itis alsoin
this philosophythat TH measurements arecurrently being consideredas one ofthe endpoints inproject 2.64
oftheOECDTGworkplan,“InclusionofthyroidendpointsinOECDfishTestGuidelines”.WhileT3
measurements showed low levels ofvariation and were highly predictive ofdownstream effects in dedicated
experimentstosupportthisAOP,morevariabilitymaybepresentinotherstudies.Becauseoftherapid
development in fish, it is important to compare T3 levels within specific developmental stages. For example,
clear changes inT3 levels have been observedin zebrafish at 14,21 and 32 dpf (Stinckenset al., 2020) and
infatheadminnowsat4,6,10,14,18and21dpf(Nelsonetal.,2016;Cavallinetal.,2017)usingliquid
chromatography tandem mass spectrometry (LC−MS/MS).
13
References
Brown, C.L., Doroshov, S.I., Nunez, J.M., Hadley, C., Vaneenennaam, J., Nishioka, R.S., Bern, H.A., 1988.
MATERNALTRIIODOTHYRONINEINJECTIONSCAUSEINCREASESINSWIMBLADDERINFLATION
| https://www.researchgate.net/publication/366444894_OECD_Series_on_Adverse_Outcome_Pathways_No_23_Deiodinase_2_inhibition_leading_to_increased_mortality_via_reduced_anterior_swim_bladder_inflation |
IN RE ADOPTION OF N.J.A.C | 775 A.2d 629 (2001) | a2d62911355 | Leagle.com
The opinion of the court was delivered by ALLEY J.A.D. Lenscrafters appeals from the adoption of an administrative rule...a2d62911355
IN RE ADOPTION OF N.J.A.C. 13:38-1.3(f)
View Case
Cited Cases
Citing Case
775 A.2d 629 (2001)
341 N.J. Super. 536
In re ADOPTION OF N.J.A.C. 13:38-1.3(f) by the State Board of Optometrists.
Superior Court of New Jersey, Appellate Division. https://leagle.com/images/logo.png
Argued May 30, 2001.
Decided June 29, 2001.
Attorney(s) appearing for the Case
William Harla, argued the cause for appellant, (Decotiis, Fitzatrick, Gluck, Hayden & Cole, attorneys; Mr. Harla, of counsel; Gregory J. Bevelock, on the brief).
Carmen A. Rodriguez, Deputy Attorney General, argued the cause for respondent, (John J. Farmer, Jr., Attorney General, attorney; Andrea M. Silkowitz, of counsel; Ms. Rodriguez, on the brief).
Before Judges PRESSLER, CIANCIA and ALLEY.
Superior Court of New Jersey, Appellate Division.
[775 A.2d 630]
The opinion of the court was delivered by ALLEY, J.A.D.
Lenscrafters appeals from the adoption of an administrative rule by the State Board of Optometrists, in particular, N.J.A.C.13:38-1.3(f). We hold that the regulation is contrary to the statute that purportedly authorized it and thus is invalid.
The Legislature has recognized optometry as a profession. N.J.S.A.45:12-1. In a case we decided seventeen years ago, Matter of Kaufman,194 N.J.Super. 124,476 A.2d 319(App.Div.1984), we were concerned with charges that two optometrists were practicing their profession in violation of N.J.S.A.45:12-11(u). We concluded that they were not. In our decision, we observed,
Some history of the conflict between optometrists and opticians may be found in New Jersey Optometric Assn. v. Hillman-Kohan, 144 N.J.Super. 411, 365 A.2d 956 (Ch.Div.1976), aff'd 160 N.J.Super. 81, 388 A.2d 1299 (App.Div.1978). A source of tension between the two groups is that each is separately permitted to fabricate eyeglasses. This results in the potential for economic competition between the opticians and the optometrists.
[194 N.J.Super.at 127,476 A.2d 319].
The operation in this area of "conflict" and "tension" continues, and their manifestations include the adoption of and challenge to the regulation now before us.
Some background concerning Kaufmanis appropriate. There, optometrists had a practice functioning as a department in a commercial building. Their practice was adjacent to an optician's facility in the same building, and the optician was the landlord of the optometrists. The only two operations in the building were those of the optician and the optometrists. The optometrists paid rent based on a percentage of gross receipts. A statute then in effect, but since repealed, N.J.S.A.45:12-11(u), prohibited the following:
Practicing optometry in any retail or commercial store or office not exclusively devoted to the practice of optometry or other health care professions where materials or merchandise are displayed pertaining to a business or commercial undertaking not bearing any relation to the practice of optometry or other health care professions; providing, however, that any optometrist practicing in premises of this type prior to January 1, 1963, shall be permitted to continue in his present location; but when and if any optometrist, who is a lessee or an employee of a lessee, vacates such premises no other optometrist shall be permitted to practice in said vacated premises. Practicing optometry under a false or assumed name, or upon a salary, commission, or any other basis of compensation, while directly or indirectly employed by or associated or connected as an optometrist with any person, association or corporation other than one who possesses a valid unrevoked certificate of registration as an optometrist or a physician licensed in and for the State of New Jersey and who has an actual legal residence within the State.
The State Board of Optometrists found that these optometrists had violated prohibitions of the statute. We disagreed, strictly construing the statute because we considered it generally penal in nature. Kaufman, supra,194 N.J.Super.at 132-33,476 A.2d 319. We rejected the Board's contention that there must be a physical separation between the establishments of an optometrist and an optician, found that they may be located within the same facility, adjacent to each other, and determined that an optometrist in that situation could dispense eyeglasses from his own office. We also set aside the Board's finding that appellants had violated N.J.S.A.45:12-11(u)'s prohibition against "practicing optometry... on a salary, commission or any other basis of compensation, while directly or indirectly employed by or associated or connected as an optometrist with any person, association or corporation other than one who holds a valid unrevoked certificate of registration as an optometrist..." Id.at 135,476 A.2d 319. We concluded,
The record does not support the Board's determination that appellants receive compensation from Eyelab. Indeed, the record establishes that appellants pay rent to their landlord, the opticians. We have considered the fact that appellants make use of the equipment, located on the rental premises in the additional space on the bottom floor of the building. That evidence is not sufficient to establish a violation of this penal statute.
Neither the existence of the landlord-tenant relationship here nor the use of the same advertising agency, similar logos or the same hours of operation compel an inference of oneness. The Board's assertion of a violation of the statutory proscription is not supported by competent proof. We conclude that there is no sustainable basis for the Board's determination, and that it must be set aside as arbitrary, capricious and unreasonable. In re Suspension of Heller, 73 N.J. 292, 309, 374 A.2d 1191 (1977) and Campbell v. Dept. of Civil Service, 39 N.J. 556, 562, 189 A.2d 712 (1963).
[ Ibid.]
As opposed to the procedural posture in Kaufman,which was an appeal from the Board's finding that optometrists had violated statutory prohibitions, this appeal is from the Board's adoption of a regulation, which the Board asserts was done pursuant to statute. The statute that the Board invokes as authority for the regulation became effective in 1992, well after the Kaufmandecision, and reads as follows:
N.J.S.A.45:12-9.12. Practice of optometry at retail store or office permitted if identified as independent doctor; outside control or interference with practice prohibited
Notwithstanding any other provision of law to the contrary, an optometrist shall not be prohibited from practicing optometry at a rented location in a retail or commercial store or office or ophthalmic dispenser's office, provided the optometrist is identified as an independent doctor of optometry; and, provided further, that the landlord or any officer, employee or agent of the landlord or any other person who does not possess a valid certificate of registration as an optometrist or physician in this State shall not directly or indirectly control, influence, interfere with or supervise the professional judgment of the optometrist in the practice of optometry, including but not limited to, the level or type of care or services rendered or the professional fees charged therefor, except as otherwise provided by P.L.1969, c. 232 (C. 14A:17-1 et seq.).
This statute forms part of a broader enactment, the Consumer Access to Eye Care Act of 1991, codified at N.J.S.A.45:12-1, 45:12-9.8 to -9.12 (the Act). In contrast with prior legislation, which focused on ensuring a high standard of care, see Abelson's Inc. v. N.J. State Board of Optometrists,5 N.J. 412, 420-421,75 A.2d 867(1950), an apparent aim of the Act is promoting increased access to eye care by authorizing optometrists to receive training, testing, and certification to utilize and prescribe a variety of medications whose prescription previously had not been within their province. See N.J.S.A.45:12-9.8 to 9.11.
The Act also permitted optometrists to practice in settings that had previously been prohibited. Optometrists formerly had been forbidden from practicing within a store "not bearing any relation to the practice of optometry," N.J.S.A.45:12-11(u) (repealed), such as, for example "a general department store or a jewelry store," Kaufman, supra,194 N.J.Super.at 124,476 A.2d 319. In contrast, the Act permits an optometrist, subject to specified conditions, to practice optometry "at a rented location in a retail or commercial store." N.J.S.A.45:12-9.12.
This new right-to-rent provision in the Act is an entirely different statute than the one examined in Kaufman, supra,which has been repealed. The result in Kaufman,while informative and useful, does not determine the validity of the adoption of the administrative regulation that is before us. The Act makes it clear that an optometrist is not prohibited from engaging in his or her profession "at a rented location in a retail or commercial store or office ...," subject to specified conditions, only the last of which allegedly is before us in this matter, namely the prohibition that the landlord "shall not directly or indirectly control, influence, interfere with or supervise the professional judgment of the optometrist in the practice of optometry...." N.J.S.A.45:12-9.12.
We now examine the regulation before us in this appeal in order to determine Lenscrafters' challenge to its validity. This regulation, N.J.A.C.13:38-1.3(f), provides as follows:
Optometrists shall not participate in any arrangement or agreement, with any person other than an associate, whereby any remuneration received by that person in payment for the provision of space, facilities, equipment, products, drugs, personnel, marketing or management services used by the optometrists is to be determined or calculated as a fixed percentage of, or otherwise dependent upon, the income or receipts derived from the practice of optometry. Nothing in this subsection shall preclude an optometrist from entering into a bona fide profit sharing plan or retaining the services of a collection agency.
The record reflects that this regulation was proposed in 1999, and that the Board received five written comments about the proposed regulation, two of which addressed section (f), which is before us on this appeal. One comment objected to the provision as inconsistent with the statute and the other contended that it was contrary to our decision in
Kaufman.
The Board rejected these objections and adopted the rules on March 29, 2000. Because in August of that year "sunset" requirements were scheduled to cause all the Board's regulations in
N.J.A.C.
13:38 to expire, the Board proposed the readoption of its regulations on July 3, 2000. 32
N.J.R.
2370. In response to the proposed re-promulgation, the Board again received five comments, two of which were similar to the arguments received with respect to
[775 A.2d 634]
the original proposal. The Board adopted N.J.A.C.13:38 on August 8, 2000, effective September 18, 2000, and published its comments at 32 N.J.R.3446 on September 18, 2000.
We accord considerable weight and deference to the agency's construction of a statute it administers and to the agency's expertise, and an agency's regulations are presumed valid. New Jersey Educ. Ass'n v. Board of Trustees, Public Employees' Retirement System,327 N.J.Super. 326, 332,743 A.2d 353(App. Div.2000). Nevertheless, we will sustain a challenge to a regulation that plainly is not supported by the statute which it is to implement, and thus legislatively is not authorized, Matter of Adoption of Amendments to N.J.A.C. 6:28-2.10, 3.6 and 4.3,305 N.J.Super. 389, 402, 702 A.2d 838 (App.Div.1997), and we will also do so if the regulation is arbitrary, unreasonable, or capricious. New Jersey State League of Municipalities v. Dept. of Cmty. Affairs,158 N.J. 211, 222,729 A.2d 21(1999).
Generally, "[t]he power of the State Board of Optometrists to make rules is limited to the statutory authority given them by the Legislature." New Jersey State Bd. Of Optometrists v. Lichtman,32 N.J.Super. 278, 281,108 A.2d 289(App. Div.1954). The powers granted to the Board are "for the protection of the public against ignorance and incapacity and deception and fraud." Abelson's, supra,5 N.J.at 419,75 A.2d 867. The Board's actions, like those of any administrative agency, are entitled to "a presumption of reasonableness," and "the party who challenges the validity of that action has the burden of showing it was arbitrary, unreasonable or capricious." Boyle v. Riti,175 N.J.Super. 158, 166,417 A.2d 1091(App. Div.1980). See also, New Jersey Educ. Ass'n, supra,327 N.J.Super.at 332,743 A.2d 353.
We recognize that the imposition of some limits upon an optometrist's permissible rental arrangements is consistent with the legislative goal of "ban[ning] practices and procedures tending to ... the lowering of the standards of service" and "protection of the public against ... deception and fraud." Abelson's, supra,5 N.J.at 420-421,75 A.2d 867. We must keep in view the alleged evil that the regulation is aimed at controlling, here, revenue-based rent agreements.
We conclude that the regulation before us is invalid as being plainly not authorized by the statute, because it bans revenue-based rent in contexts that the statute itself never authorized or even addressed.
The statute, N.J.S.A.45:12-9.12, generally permits "practicing optometry at a rented location in a retail or commercial store," and only within that context does it forbid an arrangement in which a landlord is able to "directly or indirectly control [or]... influence ... the professional judgment of the optometrist in the practice of optometry." The regulation, however, would bar optometrists generally from entering into any agreement with
any person other than an associate, whereby any remuneration ... for the provision of space ... [or] facilities ... used by the optometrists is to be determined or calculated as a fixed percentage of, or otherwise dependent upon, the income or receipts derived from the practice of optometry.
The regulation is silent about the relevant factor that the statute sets forth as the express predicate for the regulation of rental arrangements, namely, that the arrangement exists with one who is able to "directly or indirectly control, influence, interfere with or supervise the professional judgment of the optometrist in the practice of optometry." In our view, this leads to
[775 A.2d 635]
two possible interpretations of the Board's view of the statute, and each utterly lacks any rational basis.
The first interpretation is that the Board considered that Legislature's intent was to ban all leasing of space by optometrists on a percentage of revenue basis. There is no authority for such a view, however, and it lacks a rational basis because the Legislature has done the opposite. It has provided, with specified exceptions, that
an optometrist shall not be prohibited from practicing optometry at a rented location in a retail or commercial store or office or ophthalmic dispenser's office, provided the optometrist is identified as an independent doctor of optometry....
[ N.J.S.A.45:12-9.12.]
The specified exception that is relevant here is just that, an exception to the general right to lease created by N.J.S.A.45:12-9.12, namely, the prohibition on leasing when the landlord is able to "directly or indirectly control, influence, interfere with or supervise the professional judgment of the optometrist in the practice of optometry...."
The other possible interpretation is that the Board considered the mere existence of a percentage leasing arrangement ipso factoto constitute the prohibited "control" or "influence." This approach is also flawed. It would render superfluous the statutory condition, "directly or indirectly control, influence, interfere with, or supervise the professional judgment of the optometrist in the practice of optometry...." This would be contrary to the firmly established principle of statutory interpretation that words used by the Legislature have a purpose and a meaning and that we cannot assume that the Legislature used superfluous or meaningless language. See McCann v. Clerk of Jersey City,168 N.J. 285,773 A.2d 1151(2001)(slip op. at 10); Macysyn v. Hensler,329 N.J.Super. 476, 485,748 A.2d 591(App.Div.2000); Verniero v. Beverly Hills, Ltd., Inc.,316 N.J.Super. 121, 126,719 A.2d 713(App.Div.1998). In addition, the Board necessarily would have reached such a conclusion without any support in the form of factual findings, since it held no hearings, gathered no evidence other than in the form of obtaining public comments, and made no findings of fact in connection with the regulation's adoption. Moreover, the regulation in effect interprets the Act to authorize termination of a longstanding common practice of paying rent to a shopping mall landlord based on a percentage of gross income. We stated in Kaufman, supra,194 N.J.Super.at 135,476 A.2d 319, that the "landlord-tenant relationship" of the optometrists in that case, which included rent based on a percentage of revenue, did not "compel an inference of oneness ...," even when combined with other factors, namely, "use of the same advertising agency, similar logos, or the same hours of operation...." Significantly, these percentage of revenue leasing arrangements by optometrists are not confined to this state. See, for example, Bronstein v. Board of Registration in Optometry,403 Mass. 621,531 N.E.2d 593, 595-96 (1988), in which the court determined that such a lease arrangement did not constitute illegal fee-splitting by an optometrist and observed:
A percentage lease is an efficient device for figuring the actual value of rented space, and can also serve as a hedge against inflation for the landlord. See State ex rel. Bd. of Optometry v. Sears, Roebuck & Co., 102 Ariz. 175, 177, 427 P.2d 126 (1967). Note, The Percentage Lease—Its Functions and Drafting Problems, 61 Harv.L.Rev. 317, 318-320 (1948). A percentage lease gives [the] landlord an opportunity to share in [the] tenant's success without being saddled with long-term low rental agreements. In leases of shopping center stores its use is virtually universal. In other retail establishments its use is hardly less. 1 M.R. Friedman, Leases § 6.1, at 158-159 (2d ed.1983).
A categorical ban on such rent arrangements in all contexts would threaten to sever many consumers from ready access to their vision care providers, because it would operate to drive a number of optometrists out of their mall locations. There is no authority whatever in the statute for such a result.
The Board has called our attention to cases from other states, but we are persuaded that those cases support rather than undermine our conclusion that the regulation is invalid. While the cases from other jurisdictions cannot bind us in our task of construing the New Jersey statute before us now, we are satisfied that they can inform our interpretation. To be sure, some cases from other jurisdictions have presented fact patterns in which economic cooperation between an optometrist and his landlord may have been so pervasive that the landlord was effectively engaging in the unauthorized practice of optometry, seeDanny R. Veilleux, Annotation, What Constitutes Practice of "Optometry,"82 A.L.R.4th816, §§ 13-15 (1990). We are unable to agree, however, that the out-of-state cases support a conclusion that N.J.S.A.45:12-9.12 authorizes the regulation. We are satisfied, indeed, that revenue-based rent alone, absent other control or cooperation, does not constitute pervasive enough cooperation between an optometrist and his landlord to justify the regulation.
The general approach of cases from other jurisdictions that declined to uphold various business arrangements of optometrists was to take the rent arrangements as merely one factor to consider in determining whether a non-professional had too much control over a professional practice. See, e.g., California Ass'n of Dispensing Opticians v. Pearle Vision Center, Inc.,143 Cal.App.3d 419,191 Cal.Rptr. 762, 768 (1983) (Pearle's franchise agreement was illegal because it gave Pearle power to control facets of the optometrist's practice of optometry that was pervasive, including treatment decision, inventory, supplies); People ex rel. Dunbar v. Lee Optical Co. of Denver,168 Colo. 345,452 P.2d 21, 26-27 (1969) (lease arrangements alone were insufficient evidence of control, and case was remanded for further fact-finding); State v. Zale Jewelry Co. of Wichita,179 Kan. 628,298 P.2d 283, 287-290 (1956) (corporate landlord that advertised optometrist's services, kept optometrist's books and received revenue-based rent, had such extensive control that the optometrist was its employee and it was engaged in practice of optometry); Sears Roebuck & Co. v. State Bd. Of Optometry,213 Miss. 710,57 So.2d 726, 733-736 (1952) (corporate landlord that kept optometrist's books and received revenue-based rent engaged in practice of optometry).
Furthermore, the out-of-state cases allowing landlords to collect revenue-based rent from optometrists generally followed the same approach: the rent arrangements were upheld because the landlord's overall control over the professional practice was not excessive.
See State ex rel. Bd. of Optometry v. Sears, Roebuck & Co.,
102 Ariz. 175
,
427 P.2d 126
, 127-129 (1967) (corporate landlord who advertised optometrist's services, reserved right to audit optometrist's books and received revenue-based rent, did not practice optometry);
S.S. Hollender, Inc., v. Morqus,
156
Fla.
173, 23 So.2d 89, 91 (1945) (revenue-based rent alone did not constitute a landlord's practice of optometry);
Wyoming State
[775 A.2d 637]
Bd. of Examiners of Optometry v. Pearle Vision Center, Inc.,767 P.2d 969, 978-979 (Wyo.1989) (extensive financial arrangements between landlord and optometrist did not demonstrate unlicensed corporate practice of optometry, in absence of direct showing that landlord "inhibit[ed] the freedom necessary for the optometrist to practice in a manner which assures that the interests of the patient are given primary consideration.")
The case law from other jurisdictions is, perhaps predictably, not entirely consistent from state to state. But acknowledging that the precise wording of the applicable statutes indeed varies, one conclusion at least can be drawn from the cases from the various jurisdictions to which we have referred: in none of the cases has revenue-based rent alone been sufficient to make the landlord an unlicensed practitioner of optometry, absent other indicia of control or influence over the professional practice.
We have determined that the disputed regulation manifestly is not authorized by the statute. Indeed, it purports to prohibit an arrangement the Legislature has permitted, subject to particular exceptions. More than mere revenue-based rent from an optometrist is needed for a landlord to have control and influence of the nature forbidden by N.J.S.A.45:12-9.12.
Accordingly, we hold that N.J.A.C.13:38-1.3(f) is invalid.
| https://www.leagle.com/decision/20011404775a2d62911355 |
Investigation into how government increased the number of ventilators available to the NHS in response to COVID-19 - National Audit Office (NAO) report
This investigation provides an account of how public money was used to increase the number of ventilators available to the NHS.
Report – Value for money
Date: 30 Sep 2020
Topics: Business and industry
, Commercial and financial management
, Commercial and regulation
, COVID-19
, Health and social care
, Procurement and contract management
Departments: Cabinet Office
, Department of Health and Social Care
On this page
Background to the investigation
Scope of the investigation
Concluding remarks
Downloads
Publication details
Press release
Background to the investigation
Ventilators are medical devices that assist or replace a patient’s breathing. Patients with COVID-19 who are admitted to hospital often have problems breathing. On arrival in hospital a patient’s blood oxygen level is measured. If it is low, then the patient may be given: standard oxygen therapy using a mask; non-invasive ventilation where oxygen is delivered under pressure via a mask or helmet; or invasive mechanical treatment using a mechanical ventilator, which takes over a patient’s breathing. Treatment is a judgement for clinicians and patients may undergo more than one treatment during a stay in hospital.
Jump to downloads
From March 2020, in response to the COVID-19 pandemic, the government increased the number of ventilators available to the NHS. It did this through the Department of Health & Social Care (DHSC), by purchasing ventilators on the global market, as part of a wider DHSC and NHS England and NHS Improvement (NHSE&I) oxygen and ventilation programme; and by the Cabinet Office’s ‘ventilator challenge’, to encourage UK businesses to design and manufacture more mechanical ventilators.
Scope of the investigation
In this investigation we explain:
what ventilators are and how they are used in treating COVID-19 (Part One);
government’s objectives and performance in increasing the number of ventilators available to the NHS (Part Two);
how DHSC purchased ventilators (Part Three); and
Cabinet Office’s ventilator challenge (Part Four).
This investigation is part of a programme of work the National Audit Office is undertaking to support Parliament in its scrutiny of government’s response to COVID-19.
Concluding remarks
Both Cabinet Office and DHSC started their ventilator programmes on the basis that securing as many mechanical ventilators as possible, as quickly as possible, was necessary to safeguard public health. This urgency was reflected in their approach of: getting the programmes up and running very quickly; protecting their private-sector partners from financial risk; making early commitments to contracts; paying cash upfront for ventilators before they could be inspected; showing a willingness to accept that prices were higher than the normal market rate; deliberately supporting multiple ventilator challenge options; and drawing significantly on technical expertise and capacity from the private sector. In total, the departments spent a total of £569 million across both programmes.
Ultimately, the anticipated urgent demand for ventilators in mid-April did not materialise. Instead, on 15 April Ministers decided to adopt new targets to provide additional resilience in the system and prepare for a potential second wave. By this point, the departments’ earlier urgency meant that the majority of purchase contracts had been entered into, and the task turned into one of identifying the best mix of devices, ensuring they were delivered, identifying which options were no longer required to meet government’s targets and managing the programmes’ overall cost. While the two departments were not able to meet the initial target of 18,000 mechanical ventilators by the end of April, they made substantial progress towards the later target of 30,000 by the end of June. While the number of ventilators now significantly exceeds demand, this means there is more spare capacity should it ever be needed.
Inevitably, given the approach the departments took, the overall costs of both programmes are higher than we, or the departments, would expect to see in normal times. However, both departments maintained sufficient record of their programmes’ rationale, the key spending decisions they took and the information they had to base those on. They also put in place effective programme management, controlled costs where they could and recovered some of their committed spending once it became apparent that fewer ventilators were needed than they had originally believed.
Read more about our work on the government’s response to the coronavirus pandemic.
“The government acted quickly to secure the thousands of ventilators it thought it may need to safeguard public health. In the event far fewer ventilators were required than was anticipated during the first phase of the pandemic, resulting in a stockpile that may be needed for future peaks in clinical need.
“As with all aspects of its pandemic response, the government should ensure that the learning from this experience is used to enhance its contingency planning for future public health emergencies.”
Gareth Davies, head of the NAO
Downloads
Report - Investigation into how government increased the number of ventilators available to the NHS in response to COVID-19 (.pdf — 328 KB)
Summary - Investigation into how government increased the number of ventilators available to the NHS in response to COVID-19 (.pdf — 99 KB)
ePub - Investigation into how government increased the number of ventilators available to the NHS in response to COVID-19 (.epub — 3 MB)
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ISBN: 9781786043351 [ Buy a hard copy of this report ]
HC: 731, 2019-21
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Modern slavery statement | https://www.nao.org.uk/reports/increasing-ventilator-capacity-in-response-to-COVID-19/ |
Study of Chemoradiotherapy Combined With Cetuximab in Nasopharyngeal Carcinoma - Full Text View - ClinicalTrials.gov
Study of Chemoradiotherapy Combined With Cetuximab in Nasopharyngeal Carcinoma (REPLACE)
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: NCT01271439 Recruitment Status :
Completed First Posted : January 6, 2011 Last Update Posted : August 13, 2013
Sponsor:
Zhejiang Cancer Hospital
Wenzhou Medical University
The First Affiliate Hospital of Guangxi Medical College
Xijing Hospital
Hunan Cancer Hospital
Jiangxi Provincial Cancer Hospital
Wuhan Union Hospital, China
Wuhan University
Hubei Cancer Hospital
Tongji University
Affiliated Cancer Hospital of Shantou University Medical College
Shenzhen People's Hospital
First People's Hospital of Foshan
Information provided by (Responsible Party):
Zhao Chong, Sun Yat-sen University
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:
This is an open, multicenter phase Ⅱ clinical trial. The purpose of this study is to evaluate acute toxicity and efficacy of cetuximab (C225) combined with IMRT + neoadjuvant chemotherapy in advanced T stage of nasopharyngeal carcinoma. Besides, to figure out the relationship between patient outcome and EGFR gene copy number, expression and mutation.
Condition or disease Intervention/treatment Phase Nasopharyngeal Carcinoma Drug: Cetuximab Phase 2
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) Actual Enrollment : 60 participants Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Phase II Study of Neoadjuvant Chemotherapy + IMRT Combined With Cetuximab in Advanced T Stage of Nasopharyngeal Carcinoma Study Start Date : September 2010 Actual Primary Completion Date : June 2012 Actual Study Completion Date : December 2012
Resource links provided by the National Library of Medicine
Drug Information available for: Cetuximab
Genetic and Rare Diseases Information Center resources: Nasopharyngeal Carcinoma
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 Experimental: cetuximab Drug: Cetuximab 400mg/m2 intravenous infusion the week before radiotherapy, 250mg/m2 intravenous infusion weekly for 6 weeks during radiotherapy Other Name: C225
Outcome Measures
Primary Outcome Measures
:
3 Month Complete Response Rate + Partial Response Rate [ Time Frame: 3 Months ]
According to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, Complete response was defined as disappearance of all target lesions, Partial response was defined as at least a 30% reduction in the sum of the longest diameter of target lesions.
Secondary Outcome Measures
:
One-year locoregional control rate [ Time Frame: 1 year ]
locoregional control rate: from the time when finish treatment to persistence or recurrence in the nasopharyngeal and/or cervical region.
Three-year locoregional control rate [ Time Frame: 3 years ]
locoregional control rate: from the time when finish treatment to persistence or recurrence in the nasopharyngeal and/or cervical region.
One-year disease free survival rate [ Time Frame: 1 year ]
disease free survival rate: from the time when finish treatment to first failure at any site.
Three-year disease free survival rate [ Time Frame: 3 years ]
disease free survival rate: from the time when finish treatment to first failure at any site.
One-year overall survival rate [ Time Frame: 1 year ]
overall survival rate: from the time when finish treatment to death of any cause.
Three-year overall survival rate [ Time Frame: 3 years ]
overall survival rate: from the time when finish treatment to death of any cause.
The relationship between 3 years overall survival rate and expression of EGFR [ Time Frame: 3 years ]
all patients must have sufficient pretreatment tumor biopsy specimens.
Use EORTC QLQ-C30(version 3.0) and EORTC QLQ-H&N35(Version 1.0) to access the quality of life [ Time Frame: 3 years ]
collect date before treatment, the week using neoadjuvant chemotherapy, every week during radiotherapy, 6 months and every year after all treatment finished.
The relationship between 3 years overall survival rate and amplification of EGFR [ Time Frame: 3 years ]
all patients must have sufficient pretreatment tumor biopsy specimens.
The relationship between 3 years overall survival rate and mutation of EGFR [ Time Frame: 3 years ]
all patients must have sufficient pretreatment tumor biopsy specimens.
Eligibility Criteria
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 69 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Histologic diagnosis of nasopharyngeal carcinoma
Range from 18～69 years old
T3-4，N0-2，M0 (AJCC 2009)
KPS ≥ 80
Nonmetastatic diseases
WBC count ≥ 4×109/L，Hemoglobin ≥ 100g/L， platelet count ≥ 100×109/L
ALT or AST < 1.5×ULN、bilirubin < 1.5×ULN
0Serum creatinine < 1.5×ULN
Exclusion Criteria:
Distance metastases
Previously treated (surgery，chemotherapy, radiation therapy，EGFR targeted therapy or immunotherapy)
Second malignancy within 5 years
Precious therapy with an investigational agent
Uncontrolled seizure disorder or other serious neurologic disease
≥ Grade Ш allergic reaction to any drug including in this study
Clinically significant cardiac or respiratory disease
Creatinine clearance < 30ml/min
Drug or alcohol addition
Do not have full capacity for civil acts
Severe complication, active infection
Concurrent immunotherapy or hormone therapy for other diseases
Pregnancy or lactation
Locations
Layout table for location information China, Guangdong Cancer Center, Sun Yat-sen University Guangzhou, Guangdong, China, 510060
Sun Yat-sen University
Zhejiang Cancer Hospital
Wenzhou Medical University
The First Affiliate Hospital of Guangxi Medical College
Xijing Hospital
Hunan Cancer Hospital
Jiangxi Provincial Cancer Hospital
Wuhan Union Hospital, China
Wuhan University
Hubei Cancer Hospital
Tongji University
Affiliated Cancer Hospital of Shantou University Medical College
Shenzhen People's Hospital
First People's Hospital of Foshan
Investigators
Layout table for investigator information Principal Investigator: Chong Zhao Sun Yat-sen University Principal Investigator: Yunfeng Zhou Wuhan University
Layout table for additonal information Responsible Party: Zhao Chong, MD, Sun Yat-sen University ClinicalTrials.gov Identifier: NCT01271439 History of Changes Other Study ID Numbers: REPLACE First Posted: January 6, 2011 Key Record Dates Last Update Posted: August 13, 2013 Last Verified: November 2011
| https://clinicaltrials.gov/show/NCT01271439 |
Cancers | Free Full-Text | FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC
Although targeted therapy has improved the survival rates in the last decade, non-small-cell lung cancer (NSCLC) is still the most common cause of cancer-related death. The challenge of identifying new targets for further effective therapies still remains. The FAMily with sequence similarity 83 (FAM83) members have recently been described as novel oncogenes in numerous human cancer specimens and shown to be involved in epidermal growth factor receptor (EGFR) signaling. Here, gene expression of FAM83A and B was analyzed in a cohort of 362 NSCLC patients using qPCR. We further investigated relations in expression and their prognostic value. Functional assays in NSCLC cell lines were performed to evaluate FAM83A and B involvement in proliferation, anchorage-independent growth, migration, and the EGFR pathway. We observed a highly increased gene expression level of FAM83A (ø = 68-fold) and FAM83B (ø = 20-fold) which resulted in poor survival prognosis (p < 0.0001 and p = 0.002). Their expression was influenced by EGFR levels, pathway signaling, and mutation status. Both genes affected cell proliferation, and FAM83A depletion resulted in reduced migration and anchorage-independent growth. The results support the hypothesis that FAM83A and B have different functions in different histological subtypes of NSCLC and might be new therapeutic targets.
FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC
Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, D-69126 Heidelberg, Germany
2
Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), D-69120 Heidelberg, Germany
3
Microbial Energy Conversion and Biotechnology, Department of Biology, Technische Universität Darmstadt, D-64287 Darmstadt, Germany
4
Institute of Pathology, Heidelberg University Hospital, D-69120 Heidelberg, Germany
5
Department of Surgery, Thoraxklinik at Heidelberg University Hospital, D-69126 Heidelberg, Germany
6
Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, D-69126 Heidelberg, Germany
7
Department of Pneumology and Critical Care Medicine, Thoraxklinik at Heidelberg University Hospital, D-69126 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019 , 11 (5), 652; https://doi.org/10.3390/cancers11050652
Received: 27 March 2019 / Revised: 8 May 2019 / Accepted: 9 May 2019 / Published: 11 May 2019
(This article belongs to the Special Issue Molecular Profiling of Lung Cancer )
Review Reports
Versions Notes
Abstract
:
Although targeted therapy has improved the survival rates in the last decade, non-small-cell lung cancer (NSCLC) is still the most common cause of cancer-related death. The challenge of identifying new targets for further effective therapies still remains. The FAMily with sequence similarity 83 (FAM83) members have recently been described as novel oncogenes in numerous human cancer specimens and shown to be involved in epidermal growth factor receptor (EGFR) signaling. Here, gene expression of
FAM83A
and
B
was analyzed in a cohort of 362 NSCLC patients using qPCR. We further investigated relations in expression and their prognostic value. Functional assays in NSCLC cell lines were performed to evaluate
FAM83A
and
B
involvement in proliferation, anchorage-independent growth, migration, and the EGFR pathway. We observed a highly increased gene expression level of
FAM83A
(ø = 68-fold) and
FAM83B
(ø = 20-fold) which resulted in poor survival prognosis (
p
< 0.0001 and
p
= 0.002). Their expression was influenced by EGFR levels, pathway signaling, and mutation status. Both genes affected cell proliferation, and
FAM83A
depletion resulted in reduced migration and anchorage-independent growth. The results support the hypothesis that
FAM83A
and
B
have different functions in different histological subtypes of NSCLC and might be new therapeutic targets.
Keywords:
NSCLC
;
FAM83A
;
FAM83B
;
biomarker
;
EGFR-TKI
1. Introduction
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide [ 1 ]. While a steady increase in survival is observed for most cancer types, advances have been slow for lung cancer which is typically diagnosed at an advanced stage, with a five-year survival rate of only 5% [ 2 ]. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is further classified into the main histological groups large-cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SQCC), and adenocarcinoma (ADC) [ 3 ]. Personalized medicine and the identification of molecular targets in tumors represent a promising field of novel therapy approaches. Patients treated with inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutant proteins have shown improved survival [ 4 ]. In NSCLC, activating mutations in the EGF receptor account for about 15% of the mutations in adenocarcinoma. Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib or monoclonal antibodies are approved drugs for the treatment of locally advanced or metastatic NSCLC harboring EGFR mutations [ 5 ]. Nevertheless, the plasticity of cancer cells and the compensatory activation of downstream pathways often result in resistance to targeted therapies [ 6 , 7 ]. Consequently, new oncogenes need to be found showing significantly increased expression in cancer cells to circumvent resistance and to access alternative proliferation and cell growth cascades.
The members of the FAMily with sequence similarity 83 (FAM83) have been discovered to be upregulated in a variety of cancer specimens with the potential to serve as new targets [ 8 , 9 ]. The protein family is characterized by a highly conserved domain of unknown function (DUF1669) at the N-terminus, while the C-terminal regions vastly differ in the different family members [ 10 ]. A recent study could determine isoforms of the casein kinase 1 (CK1) family as interactors of the DUF1669 of FAM83 proteins [ 11 ]. FAM83A and B proteins have been identified as possible key regulators in the EGFR pathway in breast cancer cells, leading to the development of resistance to TKIs [ 7 , 12 , 13 ]. However, the biological role of FAM83A and B in cancer cells, especially in NSCLC, still remains unclear, while a detailed understanding is critical to develop novel therapeutic approaches.
In the current study, we investigated the expression and function of
FAM83A
and
B
in NSCLC in general and in relation to the EGFR pathway. The analyses revealed that both genes might serve as effective new diagnostic and prognostic biomarkers in NSCLC, with severe impact on various biological functions.
2. Results
2.1. FAM83A and B Are Highly Overexpressed in NSCLC
To investigate their potential diagnostic properties in NSCLC, gene expression of FAM83A and FAM83B was analyzed by qPCR in a cohort including 362 patients ( Table 1 ).
FAM83A was overexpressed in the tumor tissue in 90% of all patients, reaching up to a 10,000-fold amount of mRNA compared to non-neoplastic tissue ( Figure 1 A). Besides, we observed differences between ADC (92-fold overexpression) and SQCC (26-fold overexpression) ( Figure 1 B). For FAM83B , a median 20.23-fold overexpression was determined ( Figure 1 D), with an even larger difference between expression in ADC and expression in SQCC ( Figure 1 E). In ADC tumor tissue, the FAM83B gene was overexpressed with a 3.76-fold median. In contrast to this, the data regarding SQCC revealed a 109.8-fold expression. A further subdivision of the data into male and female patients did not reveal major differences in FAM83B expression ( Figure 1 F), while a higher median FAM83A level was detected in male patients with ADC compared to females ( Figure 1 C). In line with the observations of the expression patterns, a correlation analysis revealed that FAM83A expression did not relate to FAM83B expression in thedistinct histologies ( Table 2 ). These data emphasize the hypothesis that the two genes have different roles in NSCLC.
2.2. FAM83A and FAM83B Are Prognostic Markers for NSCLC
To get an insight into the prognostic value of FAM83A and B gene expression, a univariate analysis was used to estimate the effect of high versus low expression on the overall survival of the patient cohort. The cut-off value to separate the whole cohort into two groups was calculated with a biomathematical tool for each gene (see material and method section). Both genes had a significantly impaired effect on the prognosis of the patients, represented by increased hazard ratios ( FAM83A : HR 1.965 (1.366–2.817), FAM83B : 1.808 (1.252–2.612) Table 3 ). A multivariate analysis confirmed that FAM83A and B seem to be robust prognostic markers, with a highly significant negative effect on the overall survival of the patients ( Table 3 ). Kaplan–Meier plots were used to visualize the overall survival over time. Corresponding to the data from Cox regression, a clear prognostic effect was seen for the two genes ( Figure 2 A,B). Furthermore, the expression profile of the genes was investigated depending on histology ( Figure 2 C–F) and gender ( Figure 2 G–J). High FAM83A expression in general led to poor survival in all patients, while the outcome was worse in patients with ADC ( p = 0.002, Figure 2 C) compared to patients with SQCC ( p = 0.013, Figure 2 E). While the median overexpression of FAM83B in ADC was relatively low ( Figure 1 E), elevated FAM83B tumor expression had a highly significant effect on the outcome ( Figure 2 D). A low expression of FAM83B in SQCC was only identified in 10 patients, thus the data must be interpreted with caution ( Figure 2 F). Increased FAM83A expression affected prognosis negatively for both genders, with a higher effect in females ( p < 0.0001, Figure 2 G,I). The survival rate after five years was approx. 90% for females with a low gene expression compared with about 50% for females with a high FAM83A expression. In contrast, the expression level of FAM83B showed a significant negative impact in males but not in females ( Figure 2 H,J).
2.3. The Expression Levels of FAM83A and B Are Related to EGFR Expression In Vitro and In Vivo
Previous studies in breast cancer cells have identified FAM83A and B as interactors of different components within the EGFR pathway, like PI3K or RAF [ 9 , 13 ]. Within this context, several experiments have indicated that they mediate resistance to different inhibitors targeting the EGFR or downstream effectors such as Akt and mTOR [ 14 ]. In NSCLC, driver mutations in the EGFR gene have been found in about 15% of all ADCs [ 5 , 15 ]. Therefore, the expression of FAM83A and B was analyzed in tumor tissue of NSCLC patients with ADC expressing either wild-type EGFR (79 patients) or EGFR signaling activating mutations (29 patients, Table 4 ). In contrast to other studies, the overexpression of either FAM83A or FAM83B in tumors harboring mutant EGFR could not be confirmed ( Figure 3 A,C). Conversely, FAM83A expression was significantly higher ( p < 0.005) in patients with wildtype EGFR, while for FAM83B, no significant difference was observed. A correlation analysis was performed focusing on the relation between EGFR expression in the histological types ADC and SQCC and FAM83A and B expression within the patient cohort depicted in Table 1 ( Figure 3 B,D). Interestingly, the analysis revealed that in SQCC, the levels of FAM83B and EGFR slightly correlated ( r = 0.51) ( Figure 3 D). For FAM83A , a correlation with EGFR failed to be relevant ( Figure 3 B). The results were underlined by an approach in 12 NSCLC cell lines in which the absolute copy number of both genes was estimated ( Figure 3 E). Here, the copy numbers of FAM83B and EGFR in SQCC cell lines highly correlated ( r = 1). Besides, the highest amount of FAM83A mRNA in ADC cell lines was found in H1975. This cell line harbors a L858R/T790M double mutation in the EGFR gene, suggesting a potential impact on FAM83A expression in this cell line. These findings indicate a relation between the two FAM83 genes and the expression level of EGFR .
2.4. Influence of FAM83A and FAM83B on Biological Functions in NSCLC Cell Lines
Proliferation, the ability of migration, and anchorage-independent growth (AIG) are essential characteristics of tumor cells. The involved pathways are highly regulated. The identification of specific oncogenes which participate in these functions represents an emerging field in targeted therapy research. As both FAM83A and B were significantly overexpressed in NSCLC, their biological function was investigated in several NSCLC cell lines to obtain insight into their role in cancer cells. Therefore, the genes were downregulated using siRNA-mediated depletion, and the effects on cell viability, migration, and AIG were evaluated ( Figure 4 ). As FAM83A was mainly overexpressed in patients with lung adenocarcinoma, ADC cell lines expressing different amounts of FAM83A were analyzed. A549 is a wild-type-EGFR cell line that showed lower expression of FAM83A compared to the other used cell lines H1975 and H2228 ( Figure 3 E). H1975 cells harbor EGFR mutations, while H2228 contains a wild-type EGFR but also an EML4-ALK rearrangement. Since FAM83B was observed to be highly overexpressed in patients with SQCC, analyses were performed in the SQCC cell lines H1869, 2106T, and 161735T. The primary cell line 161735T was confirmed to be derived from squamous epithelium by the expression of the specific markers p63, cytokeratin 5/6, and cytokeratin 14 [ 16 , 17 ] ( Figure S1 ). Downregulation of FAM83 expression was confirmed by qPCR ( Figure 4 A for FAM83A and Figure 4 E for FAM83B ), and single siRNAs were pooled. The knockdown efficacy of the single siRNAs is shown in Figure S2 . It was not possible to confirm the knockdown by western blot because of the lack of specific commercial antibodies. Moreover, producing specific antibodies for the current project failed, since the obtained antibodies appeared not to be suitable to detect transiently overexpressed FAM83A and B in different cell lines [ 18 ]. FAM83A depletion led to a highly significant decrease of all investigated properties. Only in H2228, proliferation was less restricted than in other cell lines, and an effect on AIG was not observed ( Figure 4 B,D). In the SQCC cell lines, an impact of FAM83B could not be confirmed, except for a slight negative influence on proliferation. The highest knockdown efficiency among the SQCC cell lines was achieved in the tumor-derived cell line 161735T ( Figure 4 E). Here, the ability of AIG was impaired upon FAM83B depletion, while proliferation was poorly affected ( Figure 4 F,H). As the cells did not migrate through the pores of transwells, the influence of FAM83B expression could not be determined ( Figure 4 G). The results indicate that both FAM83A and B are involved in cell proliferation and that FAM83A also regulates migration and AIG.
2.5. Impact of TKI Treatment and EGFR Inhibition on FAM83A and B Gene Expression and Cell Viability
In addition to the assays analyzing the biological function of FAM83A and B in NSCLC, the relation of FAM83A and B to EGFR signaling was investigated in the ADC cell lines H1975 and HCC827. H1975 cells harbor a L858R/T790M double mutation in the EGFR gene which is known to mediate resistance to first-generation TKIs. HCC827 cells showed the highest EGFR copy number and contain an exon 19 deletion leading to enhanced activity of EGFR. The cells were treated with the TKIs erlotinib and AZD9291 (osimertinib) that block the phosphorylation of EGFR kinase domain. Consequently, downstream signaling pathways are adversely affected, resulting in reduced proliferation and tumorigenicity. Erlotinib is a reversible small-molecule ATP analogue which has been found to be most effective in advanced NSCLC patients with a tumor containing exon 19 deletions or a L858R mutation in exon 21 of the gene encoding the EGFR kinase domain [ 19 , 20 ]. AZD9291 is an irreversible third-generation TKI, specific for mutant EGFR and especially targets the T790M resistance mutation [ 21 ]. As we observed a relation between the expression of EGFR and those of FAM83A and B , we further investigated whether they might be affected by EGFR-targeted TKI treatment in NSCLC cell lines ( Figure 5 ). Previous studies have shown that FAM83A and B mediate resistance to TKIs in breast cancer cells [ 9 , 13 , 14 ]. Thus, we analyzed whether TKIs like erlotinib and AZD9291 influence FAM83A and B expression in NSCLC cell lines. First, cells were treated with 0.1 µM, 1 µM, and 10 µM AZD9291 and erlotinib, and gene expression of FAM83A and B was analyzed by qPCR. In H1975, evaluation of the data revealed a predominantly negative impact of either TKI treatment on both genes ( Figure 5 A). In HCC827, there was only a slight effect on FAM83B expression ( Figure 5 B). In contrast to this, FAM83A was significantly diminished. Regarding the general toxicity of the TKIs, cell numbers were evaluated upon treatment ( Figure 5 C,D). In H1975, treatment with 10 µM of either TKI led to the highest decrease of cell viability. AZD9291 had an overall more effective impact which is based on its characteristic to specifically target the T790M mutation found in H1975 ( Figure 5 C). In HCC827, both TKIs led to a cell number reduction of 40–50% regardless of the concentration ( Figure 5 D). To investigate the influence of FAM83A and B on drug sensitivity, the cells were treated with siRNA pools. The knockdown of the genes was very efficient and affected cell proliferation in both cell lines ( Figure 5 E,F). In contrast to the effect of FAM83B downregulation in SQCC cell lines, depletion of the gene in the ADC cell lines led to a significantly impaired cell viability ( Figure 5 E,F), although the absolute copy number was relatively low in these cells ( Figure 3 E). The siRNA-mediated depletion of FAM83A and B followed by TKI treatment of H1975 enhanced the negative impact of the TKIs on cell viability compared to the control ( Figure 5 G). The effect of erlotinib was not influenced by FAM83B depletion, though. Besides, knockdown of the two genes only led to a slightly greater reduction of the cell number in HCC827 ( Figure 5 H). These results indicate an additive effect of FAM83A and B downregulation and TKI treatment in NSCLC, leading to a higher cell toxicity. In compliance with the data from the previous experiments, FAM83A and B expression seems to be affected differently depending on the EGFR mutation status and EGFR regulation.
3. Discussion
Advanced-stage NSCLC remains largely incurable as a consequence of the high flexibility of cancer cells and multiple regulatory feedback loops resulting in therapy resistance [ 6 ]. Consequently, novel oncogenes that are highly overexpressed in tumor tissue and can serve as new targets have to be found. The members A and B of FAM83 were recently described to be highly upregulated in several cancer specimens [ 14 ]. Their function in cancer cells is largely unknown, and especially their role in lung cancer remains unclear. In order to acquire a better understanding of FAM83A and B in NSCLC and to assess their possible diagnostic and prognostic values, we investigated the genes regarding their expression patterns and involvement in biological functions. While FAM83A was upregulated in ADC, FAM83B expression was elevated especially in SQCC. These observations correspond to those of previous studies that could identify elevated amounts of the genes in tumor tissue of the respective histology [ 22 , 23 ]. Gene overexpression in general may indicate a tumor-promoting role, while variances in expression levels related to tumor subtypes suggest different roles and importance in the maintenance and tumorigenicity of the cancer cells. This might be underlined by the correlation analysis that showed poor relation between FAM83A and B in the two sub-histologies. Our multivariate analyses could further validate both genes as robust prognostic markers regarding the overall survival of the patients. Here, elevated expression of the genes affected survival negatively, and additional distinction of the patient cohort into the main histologies revealed a highly significant influence of FAM83A expression in ADC and SQCC, while FAM83B showed an impairment only in patients with ADC. In a recent study, high FAM83B expression was observed to relate to a better disease-free survival in SQCC, while an effect on overall survival was not observed [ 23 ]. In agreement with this, our analyses did not show an influence of FAM83B expression on the overall survival of patients with SQCC. However, instead of a rather positive effect, opposite results were obtained. As we chose the cut-off over all patients, only 10 patients were included for high FAM83B expression within SQCC, and the Kaplan–Meier plot did not result in an evaluable survival analysis. Nevertheless, when using the median gene expression in SQCC as a cut-off (as published in [ 23 ]), the results did not match those from the above-mentioned study [ 18 ]. The discrepancy might be based on the different methods used for the detection of FAM83B expression levels. While we measured gene expression by qPCR and normalized the values with respect to two housekeeper genes, in the study of Okabe et al. [ 23 ], immunohistochemical quantification was performed. Overexpression in tumor tissue was examined by western blot analysis, although the reliability of the applied antibody is uncertain for this type of analysis, as the size of the resulting single bands differ more than 20% from the predicted size and is not supported by experimental and/or bioinformatics data (Atlas Antibodies Cat# HPA031464, RRID: AB_10599973). Thus, the results appear questionable, while it might be taken into account that differences might also be due to the analysis of different ethnical groups (Asian and Caucasian) [ 24 ].
In HER2-positive breast cancer, resistance to the monoclonal anti-HER2 antibody trastuzumab has been correlated to FAM83A overexpression [ 12 , 25 ]. HER2 is amplified in about 20% of all breast cancer patients [ 26 ] and is a member of the same receptor tyrosine kinase family as EGFR which is known to be mutated in 15% of patients with lung ADC [ 15 ]. Because of its involvement in PI3K/Akt and MAPK signaling, FAM83B has also been shown to confer a decreased sensitivity to PI3K, Akt, and mTOR inhibitors in immortalized human mammary epithelial cells [ 13 ]. In lung ADC, FAM83B expression has been shown to be significantly elevated in tumors with wild-type EGFR [ 27 ], while in our patient samples, a significant difference was not observed. Here again, differences in quantification methods might be responsible for the divergent results. Moreover, the study from Yamaura et al. only included Japanese patients [ 24 , 27 ]. Interestingly, our analysis of lung ADC patients revealed that FAM83A had lower expression in tumors with a mutant variant of EGFR. However, it cannot be excluded that additional mutations in the tumor, like KRAS or BRAF, might influence FAM83A and/or B expression. Nonetheless, a correlation between EGFR expression and FAM83A and B was identified in SQCC patients as well as in cell lines. These data indicate a relation between the genes.
In addition to the evaluation of
FAM83
expression in tumor tissue, functional assays were performed in several NSCLC cell lines. In agreement with previous studies,
FAM83A
and
B
depletion had a significant effect on the proliferation and AIG of ADC cells [
8
,
9
,
27
]. We were able to show that downregulation of
FAM83A
resulted in impaired migration. Even in A549, which showed lower
FAM83A
expression compared to the other cell lines, depletion of the gene negatively affected all of the investigated cellular functions. This might indicate that
FAM83A
is highly regulated and that downregulation of the gene significantly impairs important properties in ADC cells with overall lower expression values, too. The effects on the cell line H2228, which contains an
EML4-ALK
rearrangement, were restricted to a significantly decreased number of migrating cells. In SQCC cells, a precise role of
FAM83B
could not be determined. Despite the high knockdown efficiency in 161735T, relatively high copy numbers were still detected in
FAM83B
-depleted samples. This might result in sufficient amounts of
FAM83B
in the cells to maintain major regulation mechanisms. In this case, a more effective downregulation of
FAM83B
might lead to more conclusive results, as a slight tendency of adversely affected proliferation and AIG was observed. The two ADC cell lines H1975 and HCC827 were further analyzed regarding the relation between
FAM83A
and
B
expression and EGFR inhibition and regarding possible effects of TKI treatment on the gene expression of
FAM83A
and
B
. Our data lead to the assumption that the impact of TKI treatment on gene expression highly depends on the mutational variant of EGFR. Further knockdown approaches revealed that only in H1975 cells an additive effect on proliferation could be observed. As in HCC827 cells
FAM83A
expression was already significantly decreased by TKI treatment, the additional knockdown did not result in further changes regarding cell viability. Nonetheless, validation in a larger patient cohort is mandatory to clarify the relation between
FAM83A
and
B
expression and the EGFR mutation status. In general, patients who undergo surgery are not tested for molecular alterations when the tumor is completely resected. Only surgical patients developing metastasis at a later time or patients with recurrence of tumor disease are retrospectively analyzed for EGFR mutations. Consequently, sufficient tissue amounts of patients with EGFR mutations are rarely available. Sampling material suitable for RNA analysis from stage IV patients is difficult to obtain, as well. Thus, collection of cryoconserved biopsies in inoperable patients might circumvent these obstacles to investigate the prognostic value of
FAM83A
and
B
in late stages.
Our work demonstrate that both
FAM83A
and
B
have high potential to serve as diagnostic and prognostic biomarkers in NSCLC. Their function and impact seem to be strongly related to tumor histology and EGFR expression and signaling. Future studies shall clarify more in detail the involvement of FAM83A and B in EGFR signaling in NSCLC. Therefore, further approaches should also focus on possible effects of
FAM83A
and
B
expression on the status of EGFR activation. Interaction studies might give hints on binding partners playing a role in developing resistance to targeted EGFR therapies. Since overcoming of resistance will be a major key for the enhancement of the survival rates in NSCLC, FAM83A and B are highly potential targets for intervention and development of effective therapeutic approaches.
4. Materials and Methods
4.1. Tissue Sample Collection, Characterization and Preparation
Tissue samples were provided by the Lung Biobank Heidelberg, a member of the accredited Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, the BioMaterialBank Heidelberg, and the Biobank platform of the German Center for Lung Research (DZL). The use of biomaterial and data for this study was approved by the local ethics committee of the Medical Faculty Heidelberg (S-270/2001). All patients included in the study signed an informed consent. Tumor and matched distant (>5 cm) normal lung tissue samples from NSCLC patients who underwent resection for primary lung cancer at the Thoraxklinik at University Hospital Heidelberg, Germany, were collected between 2003 and 2015. All diagnoses were made according to the 2004 WHO classification for lung cancer by at least two experienced pathologists [
28
]. Tumor stage was designated according to the 7th edition of the UICC tumor, node, and metastasis [
29
]. Tissues were snap-frozen within 30 minutes after resection and stored at −80 °C until the time of analysis. For nucleic acid isolation, 10–15 tumor cryosections (10–15 µm each) were prepared for each patient. The first and the last sections in each series were stained with hematoxylin and eosin (H&E) and were reviewed by an experienced lung pathologist to determine the proportions of viable tumor cells, stromal cells, normal lung cell cells, infiltrating lymphocytes, and necrotic areas. Only samples with a viable tumor content ≥50% were used for subsequent analyses. In our manuscript, we investigated two different patient cohorts: the main cohort consisting of 362 patients (
Table 1
), and the EGFR cohort including 108 patients (
Table 4
). The EGFR cohort partly overlapped with the main patient cohort but also included several other patients.
4.2. Cultivation of Cells
Cells were cultivated under humidified conditions at 37 °C and 5% CO
2
. The adenocarcinoma cell lines A549 (ATCC
®
CCL-185™) and H1975 (ATCC
®
CRL-5908™) and the squamous cell carcinoma cell lines 2106T and 2427T (in-house derived cell lines, [
30
]) were cultivated in DMEM/Ham’s F-12 (Thermo Fisher Scientific, Schwerte, Germany) with 10% fetal bovine serum (FBS, Thermo Fisher Scientific) and 1 × GlutaMAX™ (Thermo Fisher Scientific). For HCC827 (ATCC
®
CRL-2868™, ADC), H2228 (ATCC
®
CRL-5935™, ADC), and HCC15 (DSMZ ACC-496, SQCC), RPMI 1640 (Thermo Fisher Scientific) completed with 10% FBS was used. The complete growth medium for the SQCC cell line H1869 (ATCC
®
CRL-5900™) was ACL-4 medium supplemented with 10% FBS. As this cell line in part remained in suspension and did not attach completely, the medium supernatant was included for all experimental approaches. For the ADC cell line A427, EMEM (Thermo Fisher Scientific) with 10% FBS was used. The patient-derived primary cell lines 4950T, 170162T, and 161735T were cultivated in serum-free DMEM/Ham’s F-12 with epithelial airway growth factors (Promocell, Heidelberg, Germany) and ROCK inhibitor (Rho-associated, coiled-coil containing protein kinase inhibitor; Stemcell Technologies, Cologne, Germany).
4.3. Transient Gene Knockdown by siRNA Transfection
Cells were seeded in 12-well plates at a density of 4–5 × 10
4
cells/well and kept in the incubator at 37 °C and 5% CO
2
overnight. For transfection, Lipofectamine™ RNAiMax (Thermo Fisher Scientific) was used according to the manufacturer’s protocol. The final siRNA concentration was 10 nM. Treated cells were incubated for 72 h at 37 °C and 5% CO
2
. The following siRNAs were used: targeting
FAM83A
: Hs_FAM83A_2 ccagaccgtcaagcacaacaa, Hs_FAM83A_3 ccggaacatcctctccaagtt, Hs_BJ-TSA-9_4 cagcgccactgtgtacttcca (Qiagen, Hilden, Germany); targeting
FAM83B
: SASI_Hs01_00046208 atagccttcccgtgatgag, SASI_Hs01_00046209 aactgaacaaccttgtttc, SASI_Hs01_00046210 attcgatgaggaagaatgc (Merck KGaA, Darmstadt, Germany).
For transfection approaches in 24-well plates, 2–2.5 × 10
5
cells were seeded per well, and the protocol was adjusted according to the manufacturer’s instructions. As a control, AllStars Negative Control siRNA (Qiagen) was used. Efficiency was confirmed by quantitative Real-Time PCR, and suitable siRNAs were pooled.
4.4. Tyrosine Kinase Treatment
Cells were seeded in 24-well plates at densities of either 8 × 10 4 cells/well or 2–3 × 10 4 cells/well if they were transfected with siRNA prior to TKI treatment. The growth medium was replaced by serum-free medium for 16 h. Afterwards, the cells were treated with 10 µM, 1 µM, and 0.1 µM AZD9291 (ApexBio Technology, Houston, TX, USA) or erlotinib (Cell Signaling Technology, Frankfurt A.M., Germany) in growth medium for 24 h. As a control, growth medium with 0.1% DMSO was used. The experiments were repeated three times with three or four technical repeats each.
4.5. Total RNA Isolation and cDNA Synthesis
For RNA isolation from patient tumor tissue, a tumor content of ≥50% was the minimum prerequisite. A total of 10–15 tumor cryosections (10–15 µm) from each patient were sliced, and the first as well as the last section of a series were stained with H&E. A lung pathologist determined the proportion of viable tumor cells, stromal cells, healthy lung cells, and necrotic areas. Total RNA was isolated from patient tissue using an AllPrep DNA/RNA/miRNA Universal kit (Qiagen) according to the manufacturer’s instructions. An RNeasy Mini kit (Qiagen) was used to isolate RNA from the cell lines. Afterwards, the quality of total RNA was assessed by utilizing an Agilent 2100 Bioanalyser and an Agilent RNA 6000 Nano kit (Agilent Technologies, Boeblingen, Germany). With the Transcriptor First Strand cDNA Synthesis kit (Roche, Basel, Switzerland), total RNA was transcribed to complementary DNA and used for quantitative polymerase chain reaction (qPCR). A complete description of the procedure is provided elsewhere [
31
].
4.6. Quantitative Real-Time Polymerase Chain Reaction (qPCR)
Volumes of 5 µL cDNA (corresponding to 5 ng of isolated total RNA) were utilized for qPCR with the LightCycler480
®
(Roche) in 384-well plates according to the Minimum Information for Publication of qPCR Experiments (MIQE) guidelines [
32
]. Universal ProbeLibrary (UPL) assay (Roche) was used as the amplification and detection system. Gene-specific primers (TIB Molbiol, Berlin, Germany) were combined with the primaQuant 2 × qPCR Probe-MasterMix (Steinbrenner Laborsysteme, Wiesenbach, Germany). Threshold cycle (C
t
) values were evaluated with the LightCycler480
®
software release 1.5 and the 2nd derivative maximum method (Roche). For the comparison of gene expression in tumor and non-malignant samples, the relative expression of the genes (normalized to the housekeepers) was calculated (ΔC
t
values). The same procedure was performed for the comparison in EGFR-wild-type and -mutant samples. The following primers and UPLs were used for the detection of
FAM83A
and
B, EGFR
, and the two housekeeper genes
ESD
and
RPS18
: FAM83A forward (UPL #12, 5′-CAGATCTCTGACAGTCACCTCAAG-3′), FAM83A reverse (UPL #12, 5′-CTGCCTGACTTGGCACAGTA-3′), FAM83B forward (UPL #20, 5′-GCATTCGGTGTCTTCATTAGC-3′), FAM83B reverse (UPL #20, 5′-TCTTGTCTTGTCTACCAAAAAGGTT-3′), EGFRv1 forward (UPL #50, 5′-ACACAGAATCTATACCCACCAGAGT-3′), EGFRv1 reverse (UPL #50, 5′-ATCAACTCCCAAACGGTCAC-3′), ESD forward (UPL #50, 5′-TCAGTCTGCTTCAGAACATGG-3′), ESD reverse (UPL #50, 5′-CCTTTAATATTGCAGCCACGA-3′), RPS18 forward (UPL #46, 5′-CTTCCACAGGAGGCCTACAC-3′), RPS18 reverse (UPL #46, 5′-CGCAAAATATGCTGGAACTTT-3′). The complete procedure is described elsewhere [
31
].
4.7. Proliferation Assay and Quantification of Cells by Lactate Dehydrogenase (LDH) Activity Measurement
Cells were quantified by measuring the LDH activity with a cytotoxicity detection kit according to the manufacturer’s instructions (Roche Diagnostics GmbH, Mannheim, Germany). Briefly, the cells that were previously treated with siRNA and/or tyrosine kinase inhibitors were lysed and centrifuged for 3 min at 13,000 rpm at room temperature. The supernatant was then further processed. The assay was repeated in three independent biological approaches using three or four technical repeats each.
4.8. Soft Agar Assay
One characteristic of tumor cells is their ability of anchorage independent growth. The soft agar assay was used to estimate this ability, e.g., after siRNA knockdown of a target gene (protocol adopted from Liu, F. [ 33 ]).
The cells, previously transfected in a 12-well plate, were harvested and diluted to a final concentration of 1 × 10
4
cells/ml in complete culture medium. Then, 3 mL of the cell suspension was mixed with low-melt agarose (Bio&Sell GmbH, Feucht/Nuernberg, Germany) to a final agarose concentration of 0.36% and plated onto a bottom layer of 0.75% agarose in complete culture medium in 60 mm culture dishes. The plates were incubated at 37 °C and 5% CO
2
for two to three weeks. The colonies were stained with 0.04% (
w/v
) crystal violet in 2% (
v/v
) ethanol in Dulbecco’s Phosphate-Buffered Saline (DPBS, Thermo Fisher Scientific) for 30 min to 1 h at room temperature. Colonies with diameters of at least 100 µm were then counted in 10 randomly selected squares which were engraved into the bottom of the dishes (
Figure S3
). The experiment was performed three times with two technical replicates per treatment.
4.9. Migration Assay
The in vitro tumor cell migration assay using ThinCerts™ (Greiner Bio-One GmbH, Frickenhausen, Germany) was adopted from Schneider, M. [ 34 ]. Cells were cultivated in 12-well plates and treated with the respective siRNAs. Thereupon, the growth medium was replaced by serum-free medium for 16 h at 37 °C and 5% CO 2 . The cells were then treated with 10 µg/mL mitomycin C (Merck KGaA) in 1 mL serum-free medium for 2 h in the incubator to inhibit further cell proliferation. Afterwards, 5 × 10 4 cells in 300 µL serum-free medium were transferred onto the ThinCert™ which was placed into a 12-well plate containing 500 µL of full growth medium. After 24 h at 37 °C in a CO 2 incubator, the cells that had migrated through the ThinCert™ were detached and quantified by LDH activity measurement. The experiment was performed three times with four technical repeats each to ensure reproducibility and reliable results.
4.10. Statistical Analyses
qPCR data were statistically analyzed using REMARK criteria [
35
] with SPSS 24.0 for Windows. The primary endpoint of the study was overall survival. The overall survival was calculated from the date of surgery until the last date of contact or death. Univariate analysis of survival data was performed according to Kaplan and Meier and using the Cox proportional hazards model. The cut-off between high and low expression was identified by CutOff Finder version 2.1 (Translational Tumor Research Team, Institute of Pathology, Charité—Universitätsmedizin Berlin;
Figure S4
). The log-rank test was used to test the significance of the differences between the groups. A
p
-value of less than 0.05 was considered significant. Multivariate survival analysis was performed using the Cox proportional hazards model. The non-parametric Mann–Whitney
U
test was used to investigate significant differences between the patient groups. For cell-based assays, unpaired t-test was performed. The Spearman ranked correlation coefficient test was performed for correlation analyses. Visualization of the qPCR data was made by GraphPad Prism 5.
5. Conclusions
With the data from qPCR, we could show that FAM83A and FAM83B are potential new diagnostic and prognostic biomarkers for distinct NSCLC subtypes. Further, their role seems to be highly regulated by different factors, including histology, mutational status, and EGFR signaling. Because of their high overexpression in tumor compared to non-neoplastic tissue, they might be interesting new targets in NSCLC personalized therapies and enhance the specificity and efficiency of treatments against cancer cells.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/11/5/652/s1 , Figure S1: Immunofluorescence in primary cell line 161735T, Figure S2: Proof of siRNA-mediated knockdown efficiency, Figure S3: Spheroids for soft agar assay, Figure S4: Determination of cut-off for statistical analyses.
Author Contributions
Conceptualization, S.R. and M.A.S.; Data curation, A.W., F.L., H.W., P.C., F.J.F.H., T.M. and M.A.S.; Formal analysis, S.R. and M.A.S.; Funding acquisition, T.M. and M.M.; Investigation, S.R. and D.W.; Project administration, M.M. and M.A.S.; Supervision, M.A.S.; Visualization, S.R. and M.A.S.; Writing—original draft, S.R.; Writing—review & editing, D.W., A.W., F.L., H.W., P.C., F.J.F.H., T.M., M.M. and M.A.S.
Funding
The Federal Ministry of Education and Research, Germany, the German Center for Lung Research (DZL) in part financially supported this study (82DZL00402).
Acknowledgments
The authors would like to thank Martin Fallenbuechel, Carmen Hoppstock, Elizabeth Chang Xu, Christa Stolp, Andrea Bopp, and Anna-Lena Volckmar for expert technical support.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. The FAMily with sequence similarity 83 ( FAM83 ) genes FAM83A and FAM83B are highly overexpressed in non-small-cell lung cancer (NSCLC). The waterfall plots depict the x-fold change expression of FAM83A and FAM83B in tumor vs. normal tissue. ( A ) FAM83A expression in all patient samples, ( B ) separated by histology, ( C ) and furthermore by gender; ( D – F ) corresponding plots for FAM83B . Equal expression of the genes in tumor and adjacent non-neoplastic tissue was set to 1 (dotted line); Ø = median overexpression.
Figure 1. The FAMily with sequence similarity 83 ( FAM83 ) genes FAM83A and FAM83B are highly overexpressed in non-small-cell lung cancer (NSCLC). The waterfall plots depict the x-fold change expression of FAM83A and FAM83B in tumor vs. normal tissue. ( A ) FAM83A expression in all patient samples, ( B ) separated by histology, ( C ) and furthermore by gender; ( D – F ) corresponding plots for FAM83B . Equal expression of the genes in tumor and adjacent non-neoplastic tissue was set to 1 (dotted line); Ø = median overexpression.
Figure 2. FAM83A and FAM83B expression has a prognostic value in NSCLC patients. Effect of ( A ) FAM83A and ( B ) FAM83B tumor expression on the overall survival of all patients, ( C , D ) of patients with ADC and ( E , F ) SQCC, and ( G , H ) of female and ( I , J ) male patients.; p < 0.05 was considered significant.
Figure 2. FAM83A and FAM83B expression has a prognostic value in NSCLC patients. Effect of ( A ) FAM83A and ( B ) FAM83B tumor expression on the overall survival of all patients, ( C , D ) of patients with ADC and ( E , F ) SQCC, and ( G , H ) of female and ( I , J ) male patients.; p < 0.05 was considered significant.
Figure 3. Relation between FAM83A and B expression and EGFR status and expression. ( A ) Relative expression of FAM83A in patients with wild-type EGFR and mutational variants normalized to the housekeeper genes ESD and RPS18 . As relative expression is depicted (∆C t ), lower values correspond to a higher expression. ( B ) Correlation plots between FAM83A and EGFR expression in the tumor tissue. ( C , D ) represent the respective results for FAM83B . ( E ) Absolute copy number of FAM83A , FAM83B , and EGFR in ADC and SQCC cell lines. The correlations were estimated using the Spearman’s rank correlation coefficient. For statistical analysis, Mann–Whitney U test was performed (** p < 0.005, ns = not significant).
Figure 3. Relation between FAM83A and B expression and EGFR status and expression. ( A ) Relative expression of FAM83A in patients with wild-type EGFR and mutational variants normalized to the housekeeper genes ESD and RPS18 . As relative expression is depicted (∆C t ), lower values correspond to a higher expression. ( B ) Correlation plots between FAM83A and EGFR expression in the tumor tissue. ( C , D ) represent the respective results for FAM83B . ( E ) Absolute copy number of FAM83A , FAM83B , and EGFR in ADC and SQCC cell lines. The correlations were estimated using the Spearman’s rank correlation coefficient. For statistical analysis, Mann–Whitney U test was performed (** p < 0.005, ns = not significant).
Figure 4. Investigation of the role of FAM83A and B in NSCLC cell lines. ( A ) FAM83A depletion efficiency. ( B – D ) Effect of decreased gene expression in ADC cell lines on ( B ) proliferation, ( C ) migration, and ( D ) ability of anchorage-independent growth (AIG). Relative cell or spheroid number of cells after FAM83A knockdown (kd) compared to control (c). ( E – H ) Corresponding results for FAM83B . At least three independent biological replicates were used. Significance was determined using the unpaired t -test (*** p < 0.0001, ** p < 0.005, * p < 0.05).
Figure 5.
Relation between
FAM83A
and
B
and the EGFR pathway in ADC cell lines. (
A
) Gene expression of
FAM83A
and
B
after treatment with the tyrosine kinase inhibitors (TKIs) AZD9291 and erlotinib in H1975 and (
B
) in HCC827. The TKIs were applied at concentrations of 0.1 µM, 1 µM, and 10 µM for 24 h. (
C
) Effect of TKI treatment on cell viability in H1975 and (
D
) HCC827 cells. (
E
) siRNA-mediated depletion of
FAM83A
and
B
and its impact on cell proliferation in H1975 and (
F
) HCC827 (Relative cell number after
FAM83
knockdown (kd) compared to control (c)). (
G
) Influence of
FAM83A
and
B
depletion on TKI treatment in H1975 and (
H
) HCC827 cells. The dotted line at 1 represents either the expression (
A
,
B
,
E
,
F
,) or the cell number (
C
,
D
,
G
,
H
) in control-treated cells. At least three independent biological replicates were used. Significance of expression and cell viability variation were estimated using unpaired
t
-test (***
p
< 0.0001; **
p
< 0.005; *
p
< 0.05).
Figure 5. Relation between FAM83A and B and the EGFR pathway in ADC cell lines. ( A ) Gene expression of FAM83A and B after treatment with the tyrosine kinase inhibitors (TKIs) AZD9291 and erlotinib in H1975 and ( B ) in HCC827. The TKIs were applied at concentrations of 0.1 µM, 1 µM, and 10 µM for 24 h. ( C ) Effect of TKI treatment on cell viability in H1975 and ( D ) HCC827 cells. ( E ) siRNA-mediated depletion of FAM83A and B and its impact on cell proliferation in H1975 and ( F ) HCC827 (Relative cell number after FAM83 knockdown (kd) compared to control (c)). ( G ) Influence of FAM83A and B depletion on TKI treatment in H1975 and ( H ) HCC827 cells. The dotted line at 1 represents either the expression ( A , B , E , F ,) or the cell number ( C , D , G , H ) in control-treated cells. At least three independent biological replicates were used. Significance of expression and cell viability variation were estimated using unpaired t -test (*** p < 0.0001; ** p < 0.005; * p < 0.05).
Table 1. Patient characteristics of the cohort investigated in the project.
Table 1. Patient characteristics of the cohort investigated in the project.
Gene expression Analyses Parameter n (%) Parameter n (%) Median Age 65 (38–88) P Stage Gender 362 IA 37 10 Male 250 69 IB 90 25 Female 112 31 IIA 70 19 Histology IIB 51 14 Adeno 211 58 IIIA 105 29 Squamous 151 42 IIIB 9 2 Therapy ECOG OP 212 59 0 320 88 OP/RT 13 4 1 32 9 OP/CT 100 28 2 4 1 OP/RT/CT 37 10 n.d. 8 2
Table 2. Spearman correlation between FAM83A and B expression in the two main NSCLC histological types ADC and SQCC.
Table 2. Spearman correlation between FAM83A and B expression in the two main NSCLC histological types ADC and SQCC.
FAM FAM83B Histology p -Value FAM83A r = 0.21 ADC 0.0025 FAM83A r = 0.35 SQCC <0.0001
Expression values from the tumor tissue were used for the analysis. A value of r = 1 depicts complete correlation.
Table 3. Univariate and multivariate analysis of FAM83A and B .
Table 3. Univariate and multivariate analysis of FAM83A and B .
Univariate Analysis Variable (high vs. low) Significance Hazard Ratio (95% CI) FAM83A <0.0001 1.965 (1.366–2.817) FAM83B 0.002 1.808 (1.252–2.612) Multivariate Analysis Variable Significance Hazard Ratio (95% CI) FAM83A (high vs. low) <0.0001 1.980 (1.370–2.857) Stage <0.0001 1.076 (1.050–1.103) Age 0.018 1.024 (1.004–1.045) Sex (female vs. male) 0.062 0.664 (0.431–1.022) Histology (ADC vs. SQCC) 0.391 0.853 (0.593–1.227) FAM83B (high vs. low) 0.001 2.283 (1.393–3.745) Stage <0.0001 1.073 (1.047–1.100) Age 0.018 1.024 (1.004–1.044) Sex (female vs. male) 0.084 0.682 (0.442–1.052) Histology (ADC vs. SQCC) 0.036 1.663 (1.034–2.672)
The expression of a gene is estimated significant with p < 0.05. The effect of overall survival was analyzed, including the variables FAM83 expression (high vs. low), tumor stage, age, sex (female vs. male), and histology (adenocarcinoma, ADC, vs. squamous cell carcinoma, SQCC).
Table 4. Characteristics of the patients in the epidermal growth factor receptor (EGFR) cohort.
Table 4. Characteristics of the patients in the epidermal growth factor receptor (EGFR) cohort.
Gene Expression Analyses Parameter n (%) Parameter n (%) Median Age 62 (40–81) P Stage Gender 108 IA 12 11 Male 57 53 IB 34 31 Female 51 47 IIA 4 4 Histology IIB 14 13 Adeno 108 100 IIIA 35 32 Therapy IIIB 4 4 OP 52 48 IV 5 5 OP/RT 8 7 ECOG OP/CT 30 28 0 88 81 OP/RT/CT 18 17 1 17 16 EGFR Driver Mutation 29 27 2 2 2 Exon 19 14 13 n.d. 1 1 Exon 20 1 1 Exon 21 14 13
MDPI and ACS Style
Richtmann, S.; Wilkens, D.; Warth, A.; Lasitschka, F.; Winter, H.; Christopoulos, P.; Herth, F.J.F.; Muley, T.; Meister, M.; Schneider, M.A. FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC. Cancers 2019, 11, 652.
https://doi.org/10.3390/cancers11050652
AMA Style
Richtmann S, Wilkens D, Warth A, Lasitschka F, Winter H, Christopoulos P, Herth FJF, Muley T, Meister M, Schneider MA. FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC. Cancers. 2019; 11(5):652.
https://doi.org/10.3390/cancers11050652
Chicago/Turabian Style
Richtmann, Sarah, Dennis Wilkens, Arne Warth, Felix Lasitschka, Hauke Winter, Petros Christopoulos, Felix J. F. Herth, Thomas Muley, Michael Meister, and Marc A. Schneider. 2019. "FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC" Cancers11, no. 5: 652.
https://doi.org/10.3390/cancers11050652
| https://www.mdpi.com/2072-6694/11/5/652/html |
Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption
Mondala PK, Vora AA, Zhou T, Lazzari E, Ladel L, Luo X, Kim Y, Costello C, MacLeod AR, Jamieson CHM, Crews LA. Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Cell Stem Cell. 2021 Apr 1;28(4):623-636.e9. doi: 10.1016/j.stem.2020.12.017. Epub 2021 Jan 20.
Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption
Phoebe K Mondala, Ashni A Vora, Tianyuan Zhou, Elisa Lazzari, Luisa Ladel, Xiaolin Luo, Youngsoo Kim, Caitlin Costello, A Robert MacLeod, Catriona H M Jamieson, Leslie A Crews, Phoebe K Mondala, Ashni A Vora, Tianyuan Zhou, Elisa Lazzari, Luisa Ladel, Xiaolin Luo, Youngsoo Kim, Caitlin Costello, A Robert MacLeod, Catriona H M Jamieson, Leslie A Crews
Abstract
In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.
Trial registration:ClinicalTrials.govNCT04398485.
Keywords:CXCR4; IRF4; MYC; antisense oligonucleotide; bone marrow; cancer stem cells; cell cycle; interferon regulatory factor 4; multiple myeloma; translational research.
Conflict of interest statement
Declaration of interests T.Z., X.L., Y.K., and A.R.M. are current or past employees of Ionis Pharmaceuticals and Ionis has filed an international patent application related to this work. All other authors declare no competing interests.
Copyright © 2020 Elsevier Inc. All rights reserved.
Figures
Figure 1.. Characterization of IRF4 pathway activation in a patient-derived pre-clinical MM model
(A) Representative live animal bioluminescence imaging of serial transplant recipients of MM9-PDX-derived cells (1:1 ratio of human cells isolated from the bone marrow and plasmacytomas of MM PDX mice; 106 cells transplanted per mouse). Image shows mice harboring representative average engraftment levels across all transplanted animals, compared with a non-transplanted control mouse. (B) Quantification of human kappa light chain levels in MM9-PDX mouse plasma (n = 17). (C)
IRF4
gene expression levels (transcripts per million [TPM]) by RNA sequencing in newly diagnosed (n = 2) and high-risk (n = 3) primary MM samples. (D) Gene expression heatmap showing 117 differentially expressed IRF4 target genes in high-risk disease (plasma cell leukemia [PCL]) versus newly diagnosed MM samples. (E) Intranuclear flow cytometry histograms showing human IRF4 protein expression in total CD38+ cells from primary MM9 MNCs and MM9-PDX bone marrow (BM), compared with a representative normal age-matched bone marrow control and negative (no antibody) control. IRF4 protein expression quantification is shown as median fluorescence intensity (MFI) in the CD38++ fractions of primary MM9 versus MM9-PDX BM. (F) Flow-cytometry-based quantification of intranuclear IRF4 expression in MM9-PDX tissues. MFI values were quantified in the live, CD38++ population of cells from engrafted mouse BM, peripheral blood (PB), and plasmacytomas (PCs) 9 weeks after transplant (n = 4). Graph shows means ± SEM. (G) Double-labeling immunohistochemical analysis (IHC) of human IRF4 and human CD138 expression in tissue sections from the BM of serially transplantedMM9-PDX mice. Scale bar represents 100 μm. (H) Gene set enrichment analysis (GSEA) of top 10 Reactome pathways (false discovery rate [FDR] q-values
Figure 2.. Selective antisense oligonucleotides targeting IRF4…
Figure 2.. Selective antisense oligonucleotides targeting IRF4 reduce MM cell viability commensurate with reduced IRF4…
Figure 2.. Selective antisense oligonucleotides targeting IRF4 reduce MM cell viability commensurate with reduced IRF4 and c-MYC expression and induction of cell cycle arrest
(A) Luminescence-based cell viability (CellTiter Glo) assays showing representative dose response curves of H929 and RPMI-8226 myeloma cells (left) and quantification of biological replicate assays performed in H929 cells (right) after treatment with increasing doses of human (h)IRF4-targeted ASOs for 5 days (n = 3 to 4 biological replicates analyzed from separate passages of cells). (B) Quantitative RT-PCR analyses showing human
IRF4
expression in representative dose response curves of H929 and RPMI-8226 myeloma cells (left) and quantification of biological replicate assays performed in H929 cells (right) treated with increasing doses of hIRF4-targeted ASOs for 48 h (n = 3 to 4 biological replicates analyzed in separate passages of cells). (C) Flow-cytometry-based quantification of intranuclear human IRF4 protein expression in H929 and RPMI-8226 cells treated with hIRF4 ASO-4 (left) and hIRF4 ASO-Lead (right). MFI values quantified within the live, CD38+ population of cells after treatment with ASOs for 72 h (n = 3 biological replicates analyzed from separate passages of cells). (D)
IRF4
mRNA expression in H929 cells treated with control ASO agents, including 2–10 μM Ctrl ASO and ASO specific for a non-IRF4 target (human
MALAT1
Figure 3.. IRF4 inhibition reduces primary patient-derived…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare hematopoietic stem cell development in normal human immune cell xenografts
(A) Intranuclear flow cytometric analyses showing MFI of IRF4 protein expression in CD38+ and CD138+ cell populations in the bone marrow and peripheral blood of MM9-PDX mice treated with human-specific (h)IRF4 ASOs (n = 5 hIRF4 ASO-4 and n = 4 hIRF4 ASO-Lead), control (Ctrl) ASO (n = 4), or PBS (vehicle, n = 4) as in Figure 5. (B) Immunofluorescence analyses of human IRF4 protein, with DAPI staining both mouse and human nuclei, in the bone marrow of control or ASO-treated MM9-PDX mice. Sections from a non-transplanted (no tp) control animal show no IRF4 immunoreactivity. Scale bars represent 100 μm (20×); 20 μm (100×). (C) NanoString analysis of top differentially expressed human transcripts in total RNA from the bone marrow of treated mice. # represents IRF4 target genes (Shaffer et al., 2008). (D–F) Human-cord-blood-engrafted mice were treated with hIRF4 ASO-Lead (n = 5), Ctrl ASO (n = 4), or PBS (n = 5). Frequencies of total human hematopoietic cells (CD45+; D), B cells (CD19+; E), and lineage-negative hematopoietic stem and progenitor cells (Lin−, CD34+; F) were determined by flow cytometry. (G and H) IRF MFI in total hematopoietic (G) and B cell populations (H). Graphs show means ± SEM; *p
Figure 2.. Selective antisense oligonucleotides targeting IRF4 reduce MM cell viability commensurate with reduced IRF4 and c-MYC expression and induction of cell cycle arrest
(A) Luminescence-based cell viability (CellTiter Glo) assays showing representative dose response curves of H929 and RPMI-8226 myeloma cells (left) and quantification of biological replicate assays performed in H929 cells (right) after treatment with increasing doses of human (h)IRF4-targeted ASOs for 5 days (n = 3 to 4 biological replicates analyzed from separate passages of cells). (B) Quantitative RT-PCR analyses showing human
IRF4
expression in representative dose response curves of H929 and RPMI-8226 myeloma cells (left) and quantification of biological replicate assays performed in H929 cells (right) treated with increasing doses of hIRF4-targeted ASOs for 48 h (n = 3 to 4 biological replicates analyzed in separate passages of cells). (C) Flow-cytometry-based quantification of intranuclear human IRF4 protein expression in H929 and RPMI-8226 cells treated with hIRF4 ASO-4 (left) and hIRF4 ASO-Lead (right). MFI values quantified within the live, CD38+ population of cells after treatment with ASOs for 72 h (n = 3 biological replicates analyzed from separate passages of cells). (D)
IRF4
mRNA expression in H929 cells treated with control ASO agents, including 2–10 μM Ctrl ASO and ASO specific for a non-IRF4 target (human
MALAT1
). (E) Quantitative RT-PCR analysis of
MYC
expression in hIRF4 ASO-treated H929 cells (n = 3 biological replicates analyzed from separate passages of cells). (F) Colony formation assay of H929 cells after treatment with hIRF4-targeted ASOs (n = 3 individual wells analyzed per condition). (G and H) Flow cytometric gating strategy (G) and quantification (H) of cell cycle status in H929-FUCCI cells treated with hIRF4 ASO (n = 3 individual wells analyzed per condition). Bar graphs show means ± SEM; *p
Figure 3.. IRF4 inhibition reduces primary patient-derived…
Figure 3.. IRF4 inhibition reduces primary patient-derived MM cell viability ex vivowhile sparing normal…
Figure 3.. IRF4 inhibition reduces primary patient-derived MM cell viability ex vivowhile sparing normal B cell populations
(A–D) Luminescence-based
ex vivo
MM9-PDX cell viability assays (A and B) and quantitative RT-PCR analyses (C and D) of BM and PC-derived human cells treated with increasing doses of hIRF4 ASOs, vehicle (PBS) control, or control ASO (up to 2 μM) for 5 days (viability) or 2 days (qPCR; n = 3 individual wells analyzed per tissue for each assay). (E) Flow cytometry quantification of intranuclear IRF4 expression in primary MNCs from normal bone marrow (NBM) compared with low-risk (smoldering and newly diagnosed MM) and high-risk MM (PCL). MFI was quantified within the live, CD19+, CD3+, CD14+, or CD38++ populations of cells (n = 3–5 samples per group). (F) Reduced hIRF4 protein expression in NBM samples treated with hIRF4 ASO-Lead (2 μM) compared with PBS control for 3 days. (G) Unchanged CD19+ B cell frequency after treatment with hIRF4 ASOs as in (F). Graphs show means ± SEM; *p
Figure 4.. Human IRF4-targeted ASOs reduce tumor…
Figure 4.. Human IRF4-targeted ASOs reduce tumor burden and IRF4 expression in xenograft models and…
Figure 4.. Human IRF4-targeted ASOs reduce tumor burden and IRF4 expression in xenograft models and improve overall survival
(A and B) For human (h)IRF4 ASO treatment in a subcutaneous xenograft MM model using MM.1R cells, tumor-bearing non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice were injected subcutaneously with control (Ctrl) ASOs or IRF4 ASOs (25 or 50 mg/kg [mpk]), or PBS, 5 times per week for 3 weeks (n = 12 mice per group). Average tumor size (A) and quantitative RT-PCR analysis (B) of human
IRF4
mRNA expression in tumors from ASO or control mice are shown. (C–E) In a MM.1R dissemination model, MM cells were transplanted into NSG mice intravenously, followed by treatment with IRF4 ASOs or controls. (C and D) Tumor burden estimated by qPCR of relative human β-actin levels (C) and human
IRF4
mRNA expression (D) in the bone marrow of hIRF4 ASO-treated MM.1R disseminated mice that received three daily doses of ASOs at 50 mg/kg (n = 4 per group). (E) Overall survival analysis in the MM.1R dissemination model. Graphs with errors bars show means ± SD; *p
Figure 5.. Human IRF4-targeted ASOs reduce overall…
Figure 5.. Human IRF4-targeted ASOs reduce overall tumor burden and myeloma engraftment in a PDX…
Figure 5.. Human IRF4-targeted ASOs reduce overall tumor burden and myeloma engraftment in a PDX model of high-risk MM
MM9-PDX mice were treated with human (h)IRF4 ASOs, non-targeting control (Ctrl) ASO, or PBS for 2 weeks (n = 4 to 5 animals per group). (A and B) Representative live animal bioluminescence images (A) and quantification of normalized (background-subtracted) luminescent signal (B) in a subset of mice from each treatment group (n = 3 per condition). Mice housed together were imaged together (up to 5 mice per image), and individual mouse images were cropped and shown in groups according to treatment condition. (C) Average tumor numbers in treated MM9-PDX mice. (D–F) Flow cytometric analyses of live, CD38+ (D), CD138+ (E), and CD319+ (F) cell frequencies in the BM and peripheral blood (PB) of MM9-PDX mice treated with hIRF4 ASOs (n = 5 for hIRF4 ASO-4; n = 4 for hIRF4 ASO-Lead), Ctrl ASO (n = 4), or PBS (vehicle; n = 4). Tissues from a non-transplanted (no tp) control animal are shown for comparison. Graphs with error bars show means ± SEM; *p
Figure 6.. IRF4 ASOs reduce IRF4 expression…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare hematopoietic stem cell development in normal human immune cell xenografts
(A) Intranuclear flow cytometric analyses showing MFI of IRF4 protein expression in CD38+ and CD138+ cell populations in the bone marrow and peripheral blood of MM9-PDX mice treated with human-specific (h)IRF4 ASOs (n = 5 hIRF4 ASO-4 and n = 4 hIRF4 ASO-Lead), control (Ctrl) ASO (n = 4), or PBS (vehicle, n = 4) as in Figure 5. (B) Immunofluorescence analyses of human IRF4 protein, with DAPI staining both mouse and human nuclei, in the bone marrow of control or ASO-treated MM9-PDX mice. Sections from a non-transplanted (no tp) control animal show no IRF4 immunoreactivity. Scale bars represent 100 μm (20×); 20 μm (100×). (C) NanoString analysis of top differentially expressed human transcripts in total RNA from the bone marrow of treated mice. # represents IRF4 target genes (Shaffer et al., 2008). (D–F) Human-cord-blood-engrafted mice were treated with hIRF4 ASO-Lead (n = 5), Ctrl ASO (n = 4), or PBS (n = 5). Frequencies of total human hematopoietic cells (CD45+; D), B cells (CD19+; E), and lineage-negative hematopoietic stem and progenitor cells (Lin−, CD34+; F) were determined by flow cytometry. (G and H) IRF MFI in total hematopoietic (G) and B cell populations (H). Graphs show means ± SEM; *p
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Targeted therapy of multiple myeloma.
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Figure 5.. Human IRF4-targeted ASOs reduce overall tumor burden and myeloma engraftment in a PDX model of high-risk MM
MM9-PDX mice were treated with human (h)IRF4 ASOs, non-targeting control (Ctrl) ASO, or PBS for 2 weeks (n = 4 to 5 animals per group). (A and B) Representative live animal bioluminescence images (A) and quantification of normalized (background-subtracted) luminescent signal (B) in a subset of mice from each treatment group (n = 3 per condition). Mice housed together were imaged together (up to 5 mice per image), and individual mouse images were cropped and shown in groups according to treatment condition. (C) Average tumor numbers in treated MM9-PDX mice. (D–F) Flow cytometric analyses of live, CD38+ (D), CD138+ (E), and CD319+ (F) cell frequencies in the BM and peripheral blood (PB) of MM9-PDX mice treated with hIRF4 ASOs (n = 5 for hIRF4 ASO-4; n = 4 for hIRF4 ASO-Lead), Ctrl ASO (n = 4), or PBS (vehicle; n = 4). Tissues from a non-transplanted (no tp) control animal are shown for comparison. Graphs with error bars show means ± SEM; *p
Figure 6.. IRF4 ASOs reduce IRF4 expression…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare hematopoietic stem cell development in normal human immune cell xenografts
(A) Intranuclear flow cytometric analyses showing MFI of IRF4 protein expression in CD38+ and CD138+ cell populations in the bone marrow and peripheral blood of MM9-PDX mice treated with human-specific (h)IRF4 ASOs (n = 5 hIRF4 ASO-4 and n = 4 hIRF4 ASO-Lead), control (Ctrl) ASO (n = 4), or PBS (vehicle, n = 4) as in Figure 5. (B) Immunofluorescence analyses of human IRF4 protein, with DAPI staining both mouse and human nuclei, in the bone marrow of control or ASO-treated MM9-PDX mice. Sections from a non-transplanted (no tp) control animal show no IRF4 immunoreactivity. Scale bars represent 100 μm (20×); 20 μm (100×). (C) NanoString analysis of top differentially expressed human transcripts in total RNA from the bone marrow of treated mice. # represents IRF4 target genes (Shaffer et al., 2008). (D–F) Human-cord-blood-engrafted mice were treated with hIRF4 ASO-Lead (n = 5), Ctrl ASO (n = 4), or PBS (n = 5). Frequencies of total human hematopoietic cells (CD45+; D), B cells (CD19+; E), and lineage-negative hematopoietic stem and progenitor cells (Lin−, CD34+; F) were determined by flow cytometry. (G and H) IRF MFI in total hematopoietic (G) and B cell populations (H). Graphs show means ± SEM; *p
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Figure 4.. Human IRF4-targeted ASOs reduce tumor burden and IRF4 expression in xenograft models and improve overall survival
(A and B) For human (h)IRF4 ASO treatment in a subcutaneous xenograft MM model using MM.1R cells, tumor-bearing non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice were injected subcutaneously with control (Ctrl) ASOs or IRF4 ASOs (25 or 50 mg/kg [mpk]), or PBS, 5 times per week for 3 weeks (n = 12 mice per group). Average tumor size (A) and quantitative RT-PCR analysis (B) of human
IRF4
mRNA expression in tumors from ASO or control mice are shown. (C–E) In a MM.1R dissemination model, MM cells were transplanted into NSG mice intravenously, followed by treatment with IRF4 ASOs or controls. (C and D) Tumor burden estimated by qPCR of relative human β-actin levels (C) and human
IRF4
mRNA expression (D) in the bone marrow of hIRF4 ASO-treated MM.1R disseminated mice that received three daily doses of ASOs at 50 mg/kg (n = 4 per group). (E) Overall survival analysis in the MM.1R dissemination model. Graphs with errors bars show means ± SD; *p
Figure 5.. Human IRF4-targeted ASOs reduce overall…
Figure 5.. Human IRF4-targeted ASOs reduce overall tumor burden and myeloma engraftment in a PDX…
Figure 5.. Human IRF4-targeted ASOs reduce overall tumor burden and myeloma engraftment in a PDX model of high-risk MM
MM9-PDX mice were treated with human (h)IRF4 ASOs, non-targeting control (Ctrl) ASO, or PBS for 2 weeks (n = 4 to 5 animals per group). (A and B) Representative live animal bioluminescence images (A) and quantification of normalized (background-subtracted) luminescent signal (B) in a subset of mice from each treatment group (n = 3 per condition). Mice housed together were imaged together (up to 5 mice per image), and individual mouse images were cropped and shown in groups according to treatment condition. (C) Average tumor numbers in treated MM9-PDX mice. (D–F) Flow cytometric analyses of live, CD38+ (D), CD138+ (E), and CD319+ (F) cell frequencies in the BM and peripheral blood (PB) of MM9-PDX mice treated with hIRF4 ASOs (n = 5 for hIRF4 ASO-4; n = 4 for hIRF4 ASO-Lead), Ctrl ASO (n = 4), or PBS (vehicle; n = 4). Tissues from a non-transplanted (no tp) control animal are shown for comparison. Graphs with error bars show means ± SEM; *p
Figure 6.. IRF4 ASOs reduce IRF4 expression…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare…
Figure 6.. IRF4 ASOs reduce IRF4 expression and pathway activation in MM9-PDX mice and spare hematopoietic stem cell development in normal human immune cell xenografts
(A) Intranuclear flow cytometric analyses showing MFI of IRF4 protein expression in CD38+ and CD138+ cell populations in the bone marrow and peripheral blood of MM9-PDX mice treated with human-specific (h)IRF4 ASOs (n = 5 hIRF4 ASO-4 and n = 4 hIRF4 ASO-Lead), control (Ctrl) ASO (n = 4), or PBS (vehicle, n = 4) as in Figure 5. (B) Immunofluorescence analyses of human IRF4 protein, with DAPI staining both mouse and human nuclei, in the bone marrow of control or ASO-treated MM9-PDX mice. Sections from a non-transplanted (no tp) control animal show no IRF4 immunoreactivity. Scale bars represent 100 μm (20×); 20 μm (100×). (C) NanoString analysis of top differentially expressed human transcripts in total RNA from the bone marrow of treated mice. # represents IRF4 target genes (Shaffer et al., 2008). (D–F) Human-cord-blood-engrafted mice were treated with hIRF4 ASO-Lead (n = 5), Ctrl ASO (n = 4), or PBS (n = 5). Frequencies of total human hematopoietic cells (CD45+; D), B cells (CD19+; E), and lineage-negative hematopoietic stem and progenitor cells (Lin−, CD34+; F) were determined by flow cytometry. (G and H) IRF MFI in total hematopoietic (G) and B cell populations (H). Graphs show means ± SEM; *p
| https://ichgcp.net/clinical-trials-registry/publications/142178-selective-antisense-oligonucleotide-inhibition-of-human-irf4-prevents-malignant-myeloma-regeneration |
Studies | Download Table
Download Table | Studies from publication: Systematic review of outpatient services for chronic pain control | AIM OF REPORT. This report reviews the evidence about the effectiveness of treatments for chronic pain. While treatment of chronic pain is usually seen as an integrated service, this report concentrates on the individual interventions that constitute the service. HOW THE... | Minors, Systemics and Diabetic Neuropathy | ResearchGate, the professional network for scientists.
Studies
Source publication
Systematic review of outpatient services for chronic pain control
Article
Full-text available
Henry Mcquay
Andrew Moore
C Eccleston
[...]
Amanda C de C Williams
AIM OF REPORT. This report reviews the evidence about the effectiveness of treatments for chronic pain. While treatment of chronic pain is usually seen as an integrated service, this report concentrates on the individual interventions that constitute the service. HOW THE RESEARCH WAS CONDUCTED. Searches of databases and journals identified over 15,...
Contexts in source publication
Context 1
... actual trials used in the analysis, the treatments used, numbers in each group, mean % maxTOTPAR and numbers of patients with > 50% maxTOTPAR are shown in Table 7. The calculated number of patients in each treatment group with > 50% maxTOTPAR was derived from 45 actual treatments using the relationship between mean % maxTOTPAR and percentage > 50% maxTOTPAR. ...
Context 2
... actual and calculated numbers of patients in each group with > 50% maxTOTPAR are shown in Table 7. The equation to the regression line was: ...
May 2021
[...]
Bhavika Chowdhury
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available for this condition. Recommended pharmacothe...
Citations
... 3 TENS is used worldwide as a non-pharmacological technique for the relief of pain whatever may the cause and its uses to relieve cancer-related pain have gained popularity. 4 A Systematic review probably the first on TENS was published in 1990s and since then the uncertainty of this technique in the efficacy of relieving chronic and acute pain persists.
[5]
[6][7] Aim of this study is to evaluate the effectiveness of TENS in orthodontic pain, by doing the metanalysis based on the available studies. ...
... More serious complications include agranulocytosis and aplastic anemia [4]. The numbers needed to harm for carbamazepine were 3.4 for minor adverse effects vs. 24 for severe adverse effects
[16]
. Other drugs proven effective for trigeminal neuralgia pain control include lamotrigine, baclofen, and pizonidine. ...
Calcitonin Gene-Related Peptide and Trigeminal Neuralgia
[8]
... Although a large number of cancer patients develop chemotherapy-induced neuropathy, there is still insufficient data in the literature regarding the use of TENS for the treatment of neuropathic pain in this patient population. Studies have been conducted in patients with diabetic polyneuropathy, peripheral mononeuropathy of traumatic origin, in painful cervical radiculopathy, and in patients with chronic pain that includes a neuropathic component
[38]
[39][40][41][42][43][44][45][46]. Based on nine controlled studies, with 200 treated cases of neuropathic pain, EFNS states that TENS therapy is superior to a placebo in reducing pain [18]. ...
TENS Improves Cisplatin-Induced Neuropathy in Lung Cancer Patients
Article
Full-text available
Oct 2022
MED LITH
Sanja Tomanovic Vujadinovic
Nela Ilic
Ivan Selakovic
Una Nedeljkovic
Dragana Jovanovic
Background: Cisplatin-induced peripheral neuropathy is a common complication of cisplatin therapy, which develops in most patients with lung cancer. There are no effective preventive measures and once it occurs there is no effective therapy, except symptomatic. In this study, we aimed to assess the effect of transcutaneous electrical nerve stimulation (TENS) therapy on the pain intensity and the quality of life of patients with cisplatin-induced neuropathy. Material and Methods: A prospective cohort study was performed from 2013 to 2018, at the Clinical Center of Serbia. After the initial evaluation of 106 newly diagnosed patients with lung cancer, 68 patients did not have peripheral neuropathy. These 68 patients continued in the study and started the cisplatin chemotherapy. Forty of these patients developed cisplatin-induced neuropathy, which was manifested by neuropathic symptoms and proven by ENG examination. All patients with cisplatin-induced neuropathy were treated with TENS therapy. Their neuropathic pain and quality of life were evaluated using the following questionnaires at diagnosis, after cisplatin therapy and after four weeks of TENS use: DN4, VAS scale, EORTC QLQ-C30 and FACT-L. Results: Two thirds (68%) of the patients with cisplatin-induced neuropathy were male and the majority were smokers (70%). Adenocarcinoma was the most common (38%), followed by squamous (33%) and small-cell carcinoma (28%). The application of TENS therapy had a positive effect on reducing the neuropathic pain and increasing the quality of life for patients with painful cisplatin-induced neuropathy. The VAS and DN4 scores significantly decreased after TENS therapy, in comparison to its values after cisplatin therapy (p < 0.001). After TENS therapy, patients had significantly higher values in most of the domains of EORTC QLQ-C30 and FACT- L, in comparison with the values after cisplatin therapy (p < 0.001). Conclusion: The application of TENS therapy has a positive effect on reducing neuropathic pain and increasing the quality of life for patients with lung cancer and cisplatin-induced neuropathy.
... There has been a longstanding debate about the clinical efficacy of TENS since its introduction into mainstream healthcare in the early 1970s [2]. The first systematic reviews on TENS were published in mid 1990s and raised uncertainty about the clinical efficacy of TENS for acute and for chronic pain
[3]
[4][5]. This uncertainty remains unresolved to this day. ...
... "There is a requirement for a randomised trial to address the issue. . . . Without it, a potentially valuable intervention may be underused, or a useless intervention may continue in use" (
[3]
, p. 49). "There is insufficient evidence to draw any conclusions about the effectiveness of transcutaneous electrical nerve stimulation (TENS) for the treatment of chronic pain in adults . . . ...
Does TENS Reduce the Intensity of Acute and Chronic Pain? A Comprehensive Appraisal of the Characteristics and Outcomes of 169 Reviews and 49 Meta-Analyses
Article
Full-text available
Oct 2021
MED LITH
Carole A. Paley
Priscilla G. Wittkopf
Gareth Jones
Mark I. Johnson
Background and Objectives: Uncertainty about the clinical efficacy of transcutaneous electric nerve stimulation (TENS) to alleviate pain spans half a century. There has been no attempt to synthesise the entire body of systematic review evidence. The aim of this comprehensive review was to critically appraise the characteristics and outcomes of systematic reviews evaluating the clinical efficacy of TENS for any type of acute and chronic pain in adults. Materials and Methods: We searched electronic databases for full reports of systematic reviews of studies, overviews of systematic reviews, and hybrid reviews that evaluated the efficacy of TENS for any type of clinical pain in adults. We screened reports against eligibility criteria and extracted data related to the characteristics and outcomes of the review, including effect size estimates. We conducted a descriptive analysis of extracted data. Results: We included 169 reviews consisting of eight overviews, seven hybrid reviews and 154 systematic reviews with 49 meta-analyses. A tally of authors’ conclusions found a tendency toward benefits from TENS in 69/169 reviews, no benefits in 13/169 reviews, and inconclusive evidence in 87/169 reviews. Only three meta-analyses pooled sufficient data to have confidence in the effect size estimate (i.e., pooled analysis of >500 events). Lower pain intensity was found during TENS compared with control for chronic musculoskeletal pain and labour pain, and lower analgesic consumption was found post-surgery during TENS. The appraisal revealed repeated shortcomings in RCTs that have hindered confident judgements about efficacy, resulting in stagnation of evidence. Conclusions: Our appraisal reveals examples of meta-analyses with ‘sufficient data’ demonstrating benefit. There were no examples of meta-analyses with ‘sufficient data’ demonstrating no benefit. Therefore, we recommend that TENS should be considered as a treatment option. The considerable quantity of reviews with ‘insufficient data’ and meaningless findings have clouded the issue of efficacy. We offer solutions to these issues going forward.
... 11 Elektroterapi konusundaki meta-analiz ve sistematik derleme gibi kanıt piramidinin en üst düzeyini oluşturan yayınlar ise 1990 yılından itibaren literatürde yer almıştır. [12]
[13]
[14] Elektroterapi uygulamaları ile ilgili kanıt düzeylerinin detaylı olarak incelendiği meta-analizlerden biri 2001 yılında yayınlanan Philadelphia panelidir. Bu panelde; bel, diz ve omuz ağrısı olan hastalarda egzersiz ve elektroterapi uygulamalarının kanıt düzeyleri incelenmiştir. ...
Elektroterapide Kanıta Dayalı Uygulamalar
Chapter
Full-text available
Sep 2021
Z. Özlem Yürük
Gülbin Ergin
Demek Biçki
Nuray Kırdı
Kanıta dayalı uygulamalar; sağlık profesyonellerinin uzmanlık alanlarını ve hasta ihtiyaçlarını, en iyi araştırma kanıtları ile sentezleyerek, uygun ve etkili hizmet sunumu için klinik karar verme sürecini içeren çok aşamalı bir kavramdır. Son yıllarda Fizyoterapi ve Rehabilitasyon'da kanıta dayalı uygulamaların önemi giderek artmaktadır. Kanıta dayalı uygulamaların amacı; fizyoterapi ve rehabilitasyon hizmetinin yüksek kalite standartlarına ulaşmasını sağlamaktır. Elektroterapi; düz ve alternatif akımlar, ses ve basınç dalgaları, manyetik alan ve elektromyografik biofeedback gibi elektrofiziksel ajanların değerlendirme ve tedavi amacıyla kullanılmasına yönelik fizyoterapi ve rehabilitasyon yöntemlerindendir. Elektroterapinin kliniklerde profesyonel olarak kullanımı 20.yüzyılın ortalarında yaygınlaşmıştır ve günümüze kadar çok sayıda araştırma yapılmıştır. Elektroterapi uygulamalarında en doğru kanıtların kullanılması tedavide en doğru parametreler ile en etkili sonuçların elde edilmesini sağlar. Bu bölümde; elektroterapide en doğru kanıta ulaşmak için izlenmesi gereken basamaklar, bulunan kanıtların fizyoterapistin deneyimi ve hastaların beklentileri ile bütünleştirme süreci ve klinik karar verme deneyiminde önemli noktalar ele alınmıştır. Anahtar Kelimeler: Elektroterapi; fizyoterapi; kanıta dayalı uygulamalar; rehabilitasyon
... Initially, strong evidence was rare, 3,4 many systematic reviews failed to establish strong supporting evidence, and there were numerous complications associated with the large and cumbersome units that were utilized for decades.
[5]
[6][7] As the technology (and perhaps identification of appropriate patient candidates and technical expertise of interventionalists and surgeons) improved, the evidence-basis of SCS assessed via systematic reviews began to improve in the latter part of the first decade of this millennium. 8,9 The demonstrated efficacy of neuromodulation for neuropathic pain conditions increased dramatically over the past decade as the quantity and caliber of published clinical results burgeoned. ...
No Zero Sum in Opioids for Chronic Pain: Neurostimulation and the Goal of Opioid Sparing, Not Opioid Eradication
Article
Full-text available
Jun 2021
Michael E Schatman
Erika A Petersen
Dawood Sayed
... Hyaluronic acid and its derivatives have been reported to reduce pain in knee arthritis although few studies have shown long lasting results. 3,
4
. Double blind randomized controlled trials in the first large multicenter recently showed that hyaluronic acid is also effective in chronic shoulder pain. ...
Effectiveness and Safety of Hyaluronic Acid for Chronic Shoulder Pain
Article
May 2021
S. A. Zeb
Y. M. Khan
M. A. Khanzada
S. Ismat
Objective: To elucidate the functional outcomes of Hyaluronic acid for chronic painful shoulder with improvement of pain and functional scores Study Design: Descriptive study Place and Duration: Study was conducted in Dr.Sulaimanal HabibHospital, Riyadh, KSAfor period of one year June, 2019 to June, 2020. Methodology: Ninety patients with Tendinitis and Rotator cuff syndrome were included in this study. Patients demographics including age, sex, body mass index and complete medical profile were recorded after taking written consent. Injection was given in an aseptic technique in subacromial space in controlled setting with 1 ml of lignocaine 1 percent, 2 ml 0.5 percentmarcaine and 4 ml of hyaluronic acid. The functional outcomes were assessed by Constant Murley scoring. Follow-up was taken at 6 weeks and at 12 weeks and patients satisfaction was recorded. Results: Out of 90 patients 54 (60%) were males while 40% were females with mean age 49.8±10.283 years. Constant Murley score at baseline was 55.18±9.70 and at 6 weeks it was increased to 63.48±7.86 and at final follow-up it was 81.9±12.46. A significant improvement was found at 6 and 12 weeks with p-value <0.05. 5 (5.56%) patients showed complications. None of the patients had severe complication. 75 (83.33%) patients were satisfied. Conclusion: It is concluded that Hyaluronic acid action replaces the traditional form of corticosteroid treatment of chronic shoulders pain associated with Rotator cuff tear and tendinitis. Keyword: Tendinitis, Rotator cuff syndrome, Hyaluronic acid, Range of motion
... In 1997, McQuay et al.
[148]
published a systematic review of 37 RCTs on TENS for chronic pain that found a lack of evidence on which to judge effect. McQuay et al. concluded: "The issue is one of dose. ...
... None of the RCTs [in our systematic review] used doses of TENS which approached this. Duration of treatment was less than 4 weeks in 83% of the trials, and in 85% of the trials stimulation occurred less than 10 h per week, with 67% of the patients having less than ten sessions of TENS."
[148]
p. 48. ...
... In 1997, McQuay et al. published a Health Technology Assessment of outpatient services for pain control in the U.K.
[148]
. McQuay et al. concluded "TENS is of no value in acute pain." and "The use of TENS in chronic pain may well be justified but it has not been seen." ...
Resolving Long-Standing Uncertainty about the Clinical Efficacy of Transcutaneous Electrical Nerve Stimulation (TENS) to Relieve Pain: A Comprehensive Review of Factors Influencing Outcome
Article
Full-text available
Apr 2021
MED LITH
Mark I Johnson
Pain is managed using a biopsychosocial approach and pharmacological and non-pharmacological treatments. Transcutaneous electrical nerve stimulation (TENS) is a technique whereby pulsed electrical currents are administered through the intact surface of the skin with the intention of alleviating pain, akin to 'electrically rubbing pain away'. Despite over 50 years of published research, uncertainty about the clinical efficacy of TENS remains. The purpose of this comprehensive review is to critically appraise clinical research on TENS to inform future strategies to resolve the 'efficacy-impasse'. The principles and practices of TENS are described to provide context for readers unfamiliar with TENS treatment. The findings of systematic reviews evaluating TENS are described from a historical perspective to provide context for a critical evaluation of factors influencing the outcomes of randomized controlled trials (RCTs); including sample populations, outcome measures, TENS techniques, and comparator interventions. Three possibilities are offered to resolve the impasse. Firstly, to conduct large multi-centered RCTs using an enriched enrolment with randomized withdrawal design, that incorporates a 'run-in phase' to screen for potential TENS responders and to optimise TENS treatment according to individual need. Secondly, to meta-analyze published RCT data, irrespective of type of pain, to determine whether TENS reduces the intensity of pain during stimulation, and to include a detailed assessment of levels of certainty and precision. Thirdly, to concede that it may be impossible to determine efficacy due to insurmountable methodological, logistical and financial challenges. The consequences to clinicians, policy makers and funders of this third scenario are discussed. I argue that patients will continue to use TENS irrespective of the views of clinicians, policy makers, funders or guideline panel recommendations, because TENS is readily available without prescription; TENS generates a pleasant sensory experience that is similar to easing pain using warming and cooling techniques; and technological developments such as smart wearable TENS devices will improve usability in the future. Thus, research is needed on how best to integrate TENS into existing pain management strategies by analyzing data of TENS usage by expert-patients in real-world settings.
... Cognitive behavioral therapy (CBT) is an effective nonpharmacologic intervention for chronic pain, 17 but CBT is not well studied in diabetes and chronic pain. 18 CBT interventions improve functioning and quality of life in a variety of chronic pain settings, 17,
[19]
[20][21][22] but many rural and underserved communities lack the health care infrastructure to provide CBT. For example, in some Alabama counties 1 in 3 adults aged ≥50 years has diagnosed diabetes, up to 75% report chronic pain, and up to 38% live below the federal poverty level. ...
Peer-Delivered Cognitive Behavioral Training to Improve Functioning in Patients With Diabetes: A Cluster-Randomized Trial
Article
Jan 2020
ANN FAM MED
Susan J. Andreae
Lynn J. Andreae
Joshua S. Richman
Andrea L. Cherrington
Monika M. Safford
Purpose:
Cognitive behavioral therapy (CBT)-based programs delivered by trained community members could improve functioning and pain in individuals who lack access to such programs. We tested the effectiveness of a peer-delivered diabetes self-management program integrating CBT principles in improving physical activity, functional status, pain, quality of life (QOL), and health outcomes in individuals with diabetes and chronic pain.
Methods:
In this community-based, cluster-randomized controlled trial, intervention participants received a 3-month, peer-delivered, telephone-administered program. Attention control participants received a peer-delivered general health advice program. Outcomes were changes in functional status and pain (Western Ontario and McMaster Universities Osteoarthritis Index), QOL (Short Form 12), and physiologic measures (hemoglobin A1c, systolic blood pressure, body mass index); physical activity was the explanatory outcome.
Results:
Of 195 participants with follow-up data, 80% were women, 96% African Americans, 74% had annual income <$20,000, and 64% had high school education or less. At follow-up, compared with controls, intervention participants had greater improvement in functional status (-10 ± 13 vs -5 ± 18, P = .002), pain (-10.5 ± 19 vs -4.8 ± 21, P = .01), and QOL (4.8 ± 8.8 vs 3.8 ± 8.8, P = .001). Physiologic measures did not change significantly in either group. At 3 months, a greater proportion of intervention than control participants reported no pain or did other forms of exercise when pain prevented them from walking for exercise.
Conclusion:
This peer-delivered CBT-based intervention improved functioning, pain, QOL, and self-reported physical activity despite pain in individuals with diabetes and chronic pain. Trained community members can deliver effective CBT-based interventions in rural and under-resourced communities.
| https://www.researchgate.net/figure/Studies_tbl4_13748803 |
A Catalogue of the Muscidae (Diptera) of the Neotropical Region | Zootaxa
A Catalogue of the Muscidae (Diptera) of the Neotropical Region
Authors C. J.B. DE CARVALHO
Depto Zool., Univ. Federal do Paraná, C.P. 19020, Curitiba, 81.531–980, Brazil
M. S. COURI
Museu Nacional, Rio de Janeiro, Depto Entomol., Rio de Janeiro, 20.940–040, Brazil
A. C. PONT
Oxford University Museum of Natural History, Parks Road, Oxford OX1 3PW, U.K.
D. PAMPLONA
Museu Nacional, Rio de Janeiro, Depto Entomol., Rio de Janeiro, 20.940–040, Brazil
S. M. LOPES
Museu Nacional, Rio de Janeiro, Depto Entomol., Rio de Janeiro, 20.940–040, Brazil
DOI: https://doi.org/10.11646/zootaxa.860.1.1
Keywords: Diptera, Catalogue, Muscidae, Neotropical
Abstract
The Muscidae (Diptera) of the Neotropical Region are catalogued. 843 extant and 3 extinct species in 84 genera are listed together with their synonyms, giving a total of 1209 names. References are given to the original descriptions and the subsequent taxonomic, biological and applied literature, the location of types, and the geographic distribution. A comprehensive bibliography is provided. There are one new specific synonym, one new generic synonym, 15 new combinations, one new specific name, two new generic names, and one re-instated name (with a second one that is accepted here but is being formally re-instated in a paper listed as "in press").
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Published
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Vol. 860 No. 1: 16 Feb. 2005
Section
Monograph | https://www.biotaxa.org/Zootaxa/article/view/zootaxa.860.1.1 |
Safety and Immunogenicity Study of Recombinant Modified Vaccinia Virus Ankara (MVA) Virus to Treat HIV Infection - Full Text View - ClinicalTrials.gov
Safety and Immunogenicity Study of Recombinant Modified Vaccinia Virus Ankara (MVA) Virus to Treat HIV Infection
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: NCT00386633 Recruitment Status :
Completed First Posted : October 11, 2006 Last Update Posted : January 27, 2015
Sponsor:
Bavarian Nordic
Information provided by:
Bavarian Nordic
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:
At the end of 2004 there were more than 40 million people infected worldwide with HIV, with an estimated 16,000 new infections every day (Joint United Nations Programme on HIV/AIDS [UNAIDS], 2004). The HIV epidemic threatens whole societies particularly in Africa and Asia and rates of infections in the Western countries have also increased over the last few years. However, despite more than 15 years of research, an effective vaccine against HIV and acquired immunodeficiency syndrome (AIDS) has still not been developed.
There is considerable evidence that cellular immune responses can effectively control HIV-1 replication during acute and chronic infections thereby possibly protecting individuals from infection and preventing the spread of HIV. To be truly effective in the general population, a vaccine must induce responses specific to immunologically conserved regions. The epitope-based vaccine MVA-mBN32 represents a very logical approach to this problem because of its potential to elicit a polyfunctional immune response and to focus these responses to conserved epitopes.
In this study the safety, tolerability, and immunogenicity of a recombinant MVA-BN® vaccine expressing cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) epitopes of HIV-1 (MVA-mBN32) in 36 healthy volunteers will be examined. This will include a full analysis of CD4+ T helper cells and CD8+ CTL responses to these epitopes, to establish the potential of such a homologous prime-boost vaccine approach to induce a broad cell-mediated response to different HIV antigens.
Condition or disease Intervention/treatment Phase HIV Infections Biological: MVA-mBN32 Phase 1
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 : 36 participants Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Prevention Official Title: Phase I, Open, Sequential Vaccination Study on Safety and Tolerability of Two Different Doses of a Recombinant MVA HIV Polytope Vaccine (MVA-mBN32) in HIV-negative 18-50 Year Old Healthy Volunteers Study Start Date : October 2006 Actual Study Completion Date : November 2007
MedlinePlus related topics: HIV/AIDS Safety Vaccines
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 1 Lower dosage: 10E7_TCID50 Biological: MVA-mBN32 3 immunizations; first study group: 10E7_TCID50 Active Comparator: 2 10E8_TCID50 Biological: MVA-mBN32 3 immunizations; second study group: 10E8_TCID50
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Safety [ Time Frame: 40 w ]
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 50 Years (Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes
Criteria
Age 18 - 50
Women must have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to vaccination.
Women of childbearing potential must have used an acceptable method of contraception.
Troponin I within normal institutional limits.
Adequate renal function
Adequate hepatic function
Electrocardiogram (ECG) without abnormal findings
Negative HIV test for HIV-1 prior to immunization
HLA-A2, HLA-A3 or HLA-B7 positive.
Written informed consent of the subject after information of the risks and benefits of the study are provided in a language the subject clearly understands, and before any study specific procedure.
Ultrasound of the abdomen without clinically significant abnormalities.
Exclusion Criteria:
Pregnant or breast-feeding women.
Uncontrolled serious infection, i.e. not responding to antimicrobial therapy.
History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject.
History of or suspected or active autoimmune disease. Persons with vitiligo or thyroid disease taking thyroid replacement are not excluded.
Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment.
Any condition which might interfere with study objectives or would limit the subject's ability to complete the study or to be compliant in the opinion of the investigator.
History of coronary heart disease, myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor.
History of an immediate family member (father, mother, brother, or sister) who died due to ischemic heart disease before age 50 years.
Ten percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's risk assessment tool. (http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof) NOTE: This criterion applies only to volunteers 20 years of age and older.
Chronic administration (defined as more than 14 days) of systemic immuno-suppressant drugs during a period starting from six months prior to administration of the vaccine and ending at study conclusion. (Corticosteroid nasal sprays are permissible. Persons who have used topical and inhaled steroids can be enrolled after their therapy is completed).
Locations
Layout table for location information Germany LMU-Munich, Department of Infectious Diseases and Tropical Medicine Munich, Germany, 80799
Sponsors and Collaborators
Bavarian Nordic
Investigators
Layout table for investigator information Study Director: Elke Jordan, PhD Bavarian Nordic
Layout table for additonal information Responsible Party: Monika Fluer, Bavarian Nordic ClinicalTrials.gov Identifier: NCT00386633 History of Changes Other Study ID Numbers: HIV-POL-001 First Posted: October 11, 2006 Key Record Dates Last Update Posted: January 27, 2015 Last Verified: January 2015
Keywords provided by Bavarian Nordic:
Vaccine Safety T-cell epitope Acquired Immune Deficiency Syndrome Virus HIV Preventive Vaccine
Additional relevant MeSH terms:
| https://clinicaltrials.gov/ct2/show/study/NCT00386633 |
Revelation 4 NKJV [an error occurred while processing this directive] Parallel
NKJV Parallel GRK [BSB CSB ESV HCS KJV ISV NAS NET NIV NLT GRK]
New King James Version Greek Study Bible
1 After these things I looked, and behold, a door standing open in heaven. And the first voice which I heard was like a trumpet speaking with me, saying, “Come up here, and I will show you things which must take place after this.” 1 Μετὰ ταῦτα εἶδον καὶ ἰδοὺ θύρα ἠνεῳγμένη ἐν τῷ οὐρανῷ καὶ ἡ φωνὴ ἡ πρώτη ἣν ἤκουσα ὡς σάλπιγγος λαλούσης μετ’ ἐμοῦ λέγων Ἀνάβα ὧδε καὶ δείξω σοι ἃ δεῖ γενέσθαι μετὰ ταῦτα
2 Immediately I was in the Spirit; and behold, a throne set in heaven, and One sat on the throne. 2 εὐθέως ἐγενόμην ἐν Πνεύματι καὶ ἰδοὺ θρόνος ἔκειτο ἐν τῷ οὐρανῷ καὶ ἐπὶ τὸν θρόνον καθήμενος
3 And He who sat there was like a jasper and a sardius stone in appearance; and there was a rainbow around the throne, in appearance like an emerald. 3 καὶ ὁ καθήμενος ὅμοιος ὁράσει λίθῳ ἰάσπιδι καὶ σαρδίῳ καὶ ἶρις κυκλόθεν τοῦ θρόνου ὅμοιος ὁράσει σμαραγδίνῳ
4 Around the throne were twenty-four thrones, and on the thrones I saw twenty-four elders sitting, clothed in white robes; and they had crowns of gold on their heads. 4 καὶ κυκλόθεν τοῦ θρόνου θρόνους εἴκοσι τέσσαρες καὶ ἐπὶ τοὺς θρόνους εἴκοσι τέσσαρας πρεσβυτέρους καθημένους περιβεβλημένους ἐν ἱματίοις λευκοῖς καὶ ἐπὶ τὰς κεφαλὰς αὐτῶν στεφάνους χρυσοῦς
5 And from the throne proceeded lightnings, thunderings, and voices. Seven lamps of fire were burning before the throne, which are the seven Spirits of God. 5 Καὶ ἐκ τοῦ θρόνου ἐκπορεύονται ἀστραπαὶ καὶ φωναὶ καὶ βρονταί καὶ ἑπτὰ λαμπάδες πυρὸς καιόμεναι ἐνώπιον τοῦ θρόνου ἅ εἰσιν τὰ ἑπτὰ Πνεύματα τοῦ Θεοῦ
6 Before the throne there was a sea of glass, like crystal. And in the midst of the throne, and around the throne, were four living creatures full of eyes in front and in back. 6 καὶ ἐνώπιον τοῦ θρόνου ὡς θάλασσα ὑαλίνη ὁμοία κρυστάλλῳ καὶ ἐν μέσῳ τοῦ θρόνου καὶ κύκλῳ τοῦ θρόνου τέσσαρα ζῷα γέμοντα ὀφθαλμῶν ἔμπροσθεν καὶ ὄπισθεν
7 The first living creature was like a lion, the second living creature like a calf, the third living creature had a face like a man, and the fourth living creature was like a flying eagle. 7 καὶ τὸ ζῷον τὸ πρῶτον ὅμοιον λέοντι καὶ τὸ δεύτερον ζῷον ὅμοιον μόσχῳ καὶ τὸ τρίτον ζῷον ἔχων τὸ πρόσωπον ὡς ἀνθρώπου καὶ τὸ τέταρτον ζῷον ὅμοιον ἀετῷ πετομένῳ
8 The four living creatures, each having six wings, were full of eyes around and within. And they do not rest day or night, saying: “Holy, holy, holy, Lord God Almighty, Who was and is and is to come!” 8 καὶ τὰ τέσσαρα ζῷα ἓν καθ’ ἓν αὐτῶν ἔχων ἀνὰ πτέρυγας ἕξ κυκλόθεν καὶ ἔσωθεν γέμουσιν ὀφθαλμῶν καὶ ἀνάπαυσιν οὐκ ἔχουσιν ἡμέρας καὶ νυκτὸς λέγοντες Ἅγιος ἅγιος ἅγιος Κύριος ὁ Θεός ὁ Παντοκράτωρ ὁ ἦν καὶ ὁ ὢν καὶ ὁ ἐρχόμενος
9 Whenever the living creatures give glory and honor and thanks to Him who sits on the throne, who lives forever and ever, 9 Καὶ ὅταν δώσουσιν τὰ ζῷα δόξαν καὶ τιμὴν καὶ εὐχαριστίαν τῷ καθημένῳ ἐπὶ τῷ θρόνῳ τῷ ζῶντι εἰς τοὺς αἰῶνας τῶν αἰώνων
10 the twenty-four elders fall down before Him who sits on the throne and worship Him who lives forever and ever, and cast their crowns before the throne, saying: 10 πεσοῦνται οἱ εἴκοσι τέσσαρες πρεσβύτεροι ἐνώπιον τοῦ καθημένου ἐπὶ τοῦ θρόνου καὶ προσκυνήσουσιν τῷ ζῶντι εἰς τοὺς αἰῶνας τῶν αἰώνων καὶ βαλοῦσιν τοὺς στεφάνους αὐτῶν ἐνώπιον τοῦ θρόνου λέγοντες
11 “You are worthy, O Lord, To receive glory and honor and power; For You created all things, And by Your will they exist and were created.” 11 Ἄξιος εἶ ὁ Κύριος καὶ ὁ Θεὸς ἡμῶν λαβεῖν τὴν δόξαν καὶ τὴν τιμὴν καὶ τὴν δύναμιν ὅτι σὺ ἔκτισας τὰ πάντα καὶ διὰ τὸ θέλημά σου ἦσαν καὶ ἐκτίσθησαν
The Holy Bible, New King James Version, Copyright © 1982 Thomas Nelson. All rights reserved. Greek and Hebrew Study Bible courtesy Bible Hub and the Discovery Bible team.
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Matthew 4 - International Critical Commentary NT - Bible Commentaries - StudyLight.org
Matthew 4, International Critical Commentary NT, One of over 125 Bible commentaries freely available, this commentary has been a highly regarded academic-level commentary on the Bible.
Commentaries
Matthew 4
International Critical
Verses 1-99
(3) 4:1-11. He was prepared for His ministry by temptation. An expansion of Mark 1:1; Mark 1:12 Mark 1:12, Mark 1:13
( M)1. Then was Jesus led into the wilderness by the Spirit to be tempted by the devil.] Mk. has: “And straightway the spirit driveth Him into the wilderness. And He was in the wilderness forty days, being tempted by Satan.”—τότε] For Mk.’s καὶ εὐθύς, see on 3:16.—ὁ Ἰησοῦς�
(M)2. And having fasted forty days and forty nights, He was afterwards hungry.] Mk. has only the “forty days,” omitting the fasting and the hunger (which Lk. also has). But he has the obscure, “And he was with the wild beasts,” which Mt. omits. The verse reminds us of the fasting of Moses, Exodus 34:28. For the form ἐπείνασα, see Blass, pp. 40, 47. Lk. has: “And He ate nothing in those days; and when they were accomplished He was hungry.” Vv. 3-10 are not in Mk. Lk. has a parallel narrative, but the temptations are in a different order, and the descriptive verses differ in phraseology. There is also less verbal agreement here in the dialogue than there is in 3:7-12 = Luke 3:7-17. As in that case the two Evangelists may have drawn from independent written or oral sources.
(
X
)
3.
And the tempter came and said to Him, If thou art God’s Son, say that these stones become loaves
.] Lk. has: “And the devil said to Him, If thou art God’s Son, say to this stone that it become a loaf.”—καὶ προσελθὼν—εἶπεν] Lk. has εἶπεν δέ. προσέρχεσθαι a favourite word in Mt. It occurs 52 times: in
Mar_6
, in
Luk_10
.—ὁ πειράζων] a reminiscence of Mk.’s παραζόμενος—υἱὸς θεοῦ] Cf.
Dalm.
Words
, 274 ff.—οἱ λίθοι] Lk. has the singular. For Mt.’s predilection for plurals, see on 8:26.
(
X
)
4.
And He answered and said, It is written, Not upon bread alone shall man live, but upon every utterance that proceedeth through the mouth of God
.] Lk. has: “And Jesus answered him, It is written that, Not upon bread alone shall man live.” The quotation is from
Deuteronomy 8:3
in the language of the
LXX.
B has τῷ before ἐκπορευομένῳ, but A F Luc omit. In Deuteronomy the writer describes how the Israelites in their wanderings learned that natural products do not always suffice to support life. They were thus led to live in dependence on the creative word of God. Christ restates this principle as valid for Himself. He will rely upon God’s will for the necessities of life. The tempter implied that Sonship involved power to perform miracles. Christ neither affirms nor denies this, but replies that God, if it be His will, can provide food for His needs. Cf.
John 4:34
. For an earlier application of
Deu 8:3
, cf. Wisd. 16:26.
(X)5. Then the devil taketh Him into the holy city, and placed Him upon the wing of the temple.] Lk. has: “And he led Him to Jerusalem, and planed Him upon the wing of the temple.”—τὴν ἁγίαν πόλιν] Cf. 27:53, Revelation 11:2, Revelation 21:2, Revelation 11:10, Revelation 22:19, Daniel 9:24, To 13:9.—πτερύγιον] For the diminutive form, see Blass, p. 63.—παραλαμβάνει] The historic presents here and in the succeeding verses are striking; see Introduction, p. lx.
(X)6. And he saith to Him, If Thou art God’s Son, cast Thyself down: for it is written, that His angels He charges concerning Thee: and upon( their) hands they shall bear Thee, lest Thou strike against a stone Thy foot.] Lk. has: “And he said to Him, If Thou art God’s Son, cast Thyself hence down. For it is written, that His angels He charges concerning Thee, to guard Thee; and that upon (their) hands they shall bear Thee, lest Thou dash against a stone Thy foot.” The quotation is from Psalms 90:11, Psalms 90:12. Mt omits τοῦ διαφυλάξαι σε ὲν (πᾶσαις) ταῖς ὁδοῖς σου, and Lk. omits ἐν (πᾶσαις) ταῖς ὁδοῖς σου, which would not have been suitable to this context.
(X)7. Jesus said to him, Again it is written, Thou shalt not tempt the Lord thy God.] Lk. has: “And Jesus answered and said to him that, It has been said,” etc. The quotation is from Deuteronomy 6:16in the words of the LXX.
(X)8. Again the devil taketh Him unto an exceeding high mountain, and showeth Him all the kingdoms of the world and their glory.] Lk. has: “And taking Him up, he showed Him all the kingdoms of the inhabited world in a moment of time.” Lk.’s�
(X)9. And said to Him, All these things will I give Thee, if Thou wilt fall down and worship me.] Lk. has: “And the devil said to Him, To Thee I will give all this authority and their glory: because to me it has been delivered; and to whomsoever I will, I give it. Thou, therefore, if Thou wilt worship before me, all shall be Thine.”
(
X
)
10.
Then saith Jesus to him, Away, Satan: for it is written, The Lord thy God shah thou worship, and Him alone shah thou serve
.] Lk. has: “And Jesus answered and said to him, It is written,” etc. The quotation comes from
Deuteronomy 6:13
. B has there φοβηθήσῃ, and omits μόνῳ. But A has προσκυνήσεις and μόνῳ
1
a favourite word with Mt., generally takes a dative; cf. 2:2, 8, 11, 4:9, 8:2, 9:18, 14:33, 15:25, 18:26, 28:9.
(X)11. Then the devil leaveth Him.] Lk. has: “And having accomplished every temptation, the devil departed from Him for a time.” Mt. now returns to Mark 1:12.
(M) And, behold, angels came and were ministering to Him.] Mk.has: “And the angels were ministering to Him.” For τότε, see on 2:7; for καὶ ἰδού, 1:20; and for προσῆλθον, v. 3.
6.
περὶ σοῦ]
S
1 adds: “that they should keep thee,” assimilating to Lk.
8.τοῦ κόσμου] S1 “of this world.”
καὶ τὴν δόξαν αὐτῶν] Omit S1.
9.S1 has: “And said to Him, These kingdoms and their glory Thou hast seen. To Thee will I give them, if,” etc.
10.
ὂπαγε] So א B C *
al
1 f k. Add όπίσω μου C2 D
al
S
2. S1has “behind.”
11.διάβολος] S1 S2 add “for a time,” assimilating to Lk.
The three temptations are clearly symbolical. That is suggested at the outset by “was led by the Spirit,” an external representation of an inward experience. The first temptation was to put to the test His own consciousness of divine “Sonship.” The “Son of God” could change stones into loaves when necessity arose. In answer, Christ refuses thus to test His own convictions. He would act only as God willed. The second was a temptation to put God to the test. If the “Son of God” were in danger, God would protect Him. In answer, Christ appeals to Scripture for proof that such testing was forbidden. The third was a temptation to grasp at once and by one act the Messianic sovereignty of the world, which His consciousness of Messiahship led Him to expect in the future. For answer, Christ finally dismisses (ὕπαγε Σατανᾶ) the tempter. The service of God to which He was pledged forbade the premature hastening of events by methods which involved rebellion against God’s will. Lk. has the last two temptations in the reverse order, and consequently no ὕπαγε Σατανᾶ. His arrangement avoids the double change of scene which is found in Mt.—desert to Jerusalem, Jerusalem to a high mountain. On the other hand, Mt.’s arrangement is probably due to his belief that the offer of universal monarchy formed the fitting climax to the series. By inserting the mountain, the editor may have intended to draw a contrast between the mountain upon which Christ refused Messianic power with that other mountain (28:16) upon which at a later period He told His disciples that all power was given to Him in heaven and upon earth. It seems probable that the three temptations are artificially connected with Mk.’s brief statement (1:12, 13), where the whole scene takes place in the wilderness. “He was in the wilderness forty days, being tempted.” There He was with the beasts, and there presumably angels ministered to Him. But in Mt., after the first temptation, we leave the wilderness, and the ministration of angels presumably took place on the high mountain.
C.—4:12-15:20. MINISTRY IN GALILEE = Mark 1:14-23
(1) 12-17. Appearance in Galilee. From Mark 1:1; Mark 1:14 Mark 1:14, Mark 1:15
(M)12,13. And when He heard that John was delivered up, He departed into Galilee. And having left Nazara, He came and settled atCapḥarnaum , which is on the lake, in the districts of Zabulon and Naphtali.] Mk. has: “And after that John was delivered up, Jesus came into Galilee.” For� Mark 1:23, because he wishes to make it the subject of a fulfilment of prophecy.—τὴν παραθαλασσίαν] Capharnaum, whether identified with Tell Ḥûmor KhânMinyeh (see Sanday, Sacred Sites, 36 ff.), being on the shore of the lake.—ἐν ὁρίοις Ζαβουλὼν καὶ Νεφθαλείμ]. This geographical note is necessary to explain the bearing of the following quotation:
( O)14. In order that it might be fulfilled which was spoken through Isaiah the prophet, saying.] For the formula, see on 1:22. The quotation comes from Isaiah 9:1, Isaiah 9:2.
(O)15. Land of Zebulon, land of Naphtali, way of the sea, over Jordan, Galilee of the nations.]
(O)16. The people which( was) sitting in darkness saw a great light. And for those sitting in a region and shadow of death, light rose for them.] The editor seems to be quoting a Greek version, otherwise he would hardly have rendered דרך by the accusative ὁδόν. In the original it is the object of a verb; but Mt., who wrests the words from the context and omits the verbs, would, if translating from the Hebrew, have rendered ὁδός just as he has given us γῆ, not γῆν. ὁδόν can only be due to careless copying from a version before him. This version was not the LXX., which differs a good deal from Mt.’s rendering. B of the LXX. has not ὁδὸν θαλάσσης but these words stand in LXX. אo a A Q, and were found in Aquila and Theodotion. Mt. presumably had before him a Greek version which was either different from the LXX., or was an early form of the LXX., containing ὁδὸν θαλάσσης In the latter case he has adapted the verbs to suit his context. We need not inquire as to the exact signification of the geographical terms in the original. The editor tears the words from their context, because he saw in them a prophecy of the fact that Christ went to Galilee to begin His ministry, and settled for that purpose at Capharnaum, which became from henceforth His headquarters. Isaiah had spoken of Galilee (Γαλιλαία τῶν ἐθνῶν). He had also spoken of ὁδὸν θαλάσσης, and Capharnaum was παραθαλασσία. Isaiah had spoken also of Zebulon and Naphtali, and Capharnaum was in the territory of these tribes. The prophet had said of these places that their inhabitants should see a great light. When Christ began His work amongst them this was fulfilled. Whatever, therefore, may have been the original signification of דרך הים, or of its Greek equivalent ὁδὸν θαλάσσης, it is hardly possible to doubt that Mt. had in mind when he copied the words the lake of Galilee, and described Capharnaum as τὴν παραθαλασσίαν to make his meaning clear.
Γῆ Ζαβουλὼν καὶ γῆ Νεφθαλείμ] LXX. has χώρα Ζαβουλὼν ἡ γῆ Νεφθαλείμ.—ὁδὸν θαλάσσης] See above.—πέραν τοῦ Ἰορδάνου] So LXX., the usual equivalent of עבר הירדן.—Γαλιλαία τῶν ἐθνῶν] So LXX.—ὁ λαὸς ὁ καθήμενος ἐν σκότει] LXX. B has πορευόμενος after the Heb., but A καθήμενος—εἰδε φῶς μέγα] LXX. ἴδετε B, εἴδετε א* Γ, εἶδε א c.—καὶ τοῖς καθημένοις] LXX. οἱ κατοικοῦντες.—ἐν χώρᾳ καὶ σκιᾷ θανάτου] So LXX. (om. καί B א*).—φῶς�
(M)17. From that time Jesus began to preach, and to say, Regent: for the kingdom of the heavens is at hand.] Mk. has κηρύσσων τὸ εὐαγγέλιον τοῦ θεοῦ, καὶ λέγων ὅτι Πεπλήρωται ὁ καιρὸς καὶ ἤγγικεν ἡ βασιλεία τοῦ θεοῦ Μετανοεῖτε καὶ πιστεύετε ἐν τῷ εὐαγγελίῳ—ἀπὸ τότε] The editor contrasts this early period of the preaching of the kingdom with a later preaching of His death and resurrection; cf. 16:21, and abbreviates the statement of the contents of Christ’s preaching. For his habit of retaining only one of Mk.’s many double expressions of an idea or fact, see Introduction, p. xxiv. He has already assimilated the statement of the contents of the Baptist’s preaching to this verse, cf. 3:2.
13.Καφαρναούμ] So א B D Z 33 latt.—Ναζαρά] אb B * X Z 33 k Orig. Ναζαρέθ, א* D al
16.ἐν χώρᾳ καὶ σκιᾷ] S1 has: “in sorrow and in the shadow of death”; S2 “in the shadows of death.”
17.μετανοεῖτε] Om. S1 S2 k Blass.
(2) 18-22. The calling of four disciples. From Mark 1:16; Mark 1:16-20 Mark 1:16-20
(M)18. And walking by the sea of Galilee, He saw two brethren, Simon called Peter, and Andrew his brother, casting a net into the sea: for they were fishermen.] Mk. has: “And passing by the sea of Galilee, He saw Simon and Andrew the brother of Simon casting in the sea: for they were fishermen.”
περιπατῶν δέ] for Mk.’s καὶ παράγων, Mt. prefers the construction with δέ, and avoids Mk.’s iteration of the same pronoun παράγων παρά, cf. 17:18, 24:1. He inserts δύο�
Wörterb. der griech. Eigennamen
; and
Deissm.
Bib. Stud.
p. 315.
Ἀνδρέας] is a not uncommon Greek name. It occurs of a Jew in an Olympian inscription of b.c. 169,
Ditt.
Syll.
301. 5. Mt. substitutes βάλλοντας�
Isaiah 19:8
.—ἦσαν γὰρ ἁλιεῖς] For the occurrence of this clause in Mt. and Mk. as a proof of dependence of one Gospel on the other, see
Hor. Syn.
p. 43. ἁλιεύς occurs from Homer downwards. For the first cent. a.d., cf.
Ox. Pap.
II. 294, 6.
(M)19. And He saith to them, Come after Me, and I will make you fishers of men.] Mk. has: “And Jesus said to them, Come after Me, and I will make you to become fishers of men.” Mt. omits γενέσθαι as superfluous. For ὀπίσω as a preposition, see Blass, p. 129.—δεῦτε ὀπίσω] is Semitic.
(M)20. And they immediately left the nets and followed Him.] Mk. has; “And immediately they left the nets and followed Him.” Mt. substitutes οἱ δέ for Mk.’s καί. See on v. 18, and Introduction, p. xx.
(M)21. And going forward thence, He saw two other brethren, James the son of Zebedee, and John his brother, in the boat with Zebedee their father, mending their nets. And He called them.] Mk. has: “And going forward a little, He saw James the son of Zebedee, and John his brother, these also in the boat mending the nets.” Mt. inserts ἐκεῖθεν, which occurs 12 times in this Gospel, 5 in Mk., 3 in Lk., 2 in Jn. He inserts also ἄλλους δύο�
(M)22. And they immediately left the boat and their father, and followed Him.] Mk. has: “And they left their father Zebedee in the boat with the hired servants, and went after Him.” Mt. substitutes οἱ δέ for καί as in v. 20, and ἠκολούθησαν αὐτῷ for�
(3) Illustrations of His teaching and work, 4:23-9:34
( a) Anticipatory sketch, 4:23-25
23-25.The editor now comes to Mark 1:21-22. He has already (4:13) spoken of the entry into Capharnaum, and therefore omits it here. Mark 1:21, b speaks of teaching in the synagogue. But here the editor wishes to develop his scheme of giving illustrations of Christ’s teaching and work in successive sections. He therefore inserts at this point an introductory sketch of Christ’s activity in these two respects, 4:23-25. The teaching in the synagogue at Capharnaum becomes a synagogal teaching throughout the country, and a summary of Christ’s work of healing is added.
( E) And Jesus passed through the whole of Galilee, teaching in their synagogues, and preaching the good news of the kingdom, and healing every sickness and every disease among the people. And the rumour about Him went into all Syria: and they brought to Him all who were in evil plight, holden with manifold sicknesses and torments, demoniacs, and lunatics, and paralytics; and He healed them. And there followed Him many multitudes from Galilee, and Decapolis, and Jerusalem, and beyond, Jordan.]
The phraseology of this editorial summary is largely borrowed from Mk.
For καὶ περιῆγεν—διδάσκων, cf. Mark 6:6καὶ περιῆγε—διδάσκων; for ἐν ὅλῃ τῇ Γαλιλαίᾳ, Mark 1:39εἰς ὅλην τὴν Γαλιλαίαν; for κηρύσσων τὸ εὐαγγέλιον, Mark 1:14; for� Mark 1:28ἐξῆλθε δὲ ἡ� Mark 1:32ἔφερον πρὸς αὐτὸν πάντας τοὺς κακῶς ἔχοντας; for ποικίλαις νόσοις—καὶ ἐθεράπευσεν αὐτούς, Mark 1:34καὶ ἐθεράπευσεν—ποικίλαις νόσοις; for δαιμονιζομένους, Mark 1:32; for ἠκολούθησαν αὐτῷ ὄχλοι πολλοί, Mark 5:24ἠκολούθει αὐτῷ ὄχλος πολύς, cf. Mark 3:7; for Δεκάπολις, Mark 5:20, Mark 5:7:31; for Ἰεροσολύμων καὶ Ἰουδαίας καὶ πέραν τοῦ Ἰορδάνου, Mark 3:8.
(E)23.τὸ εὐαγγέλιον τῆς βασιλείας] i.e.the good news that the kingdom was near, cf. v. 17. εὐαγγέλιον in Cl. Gk. is the reward given to a bearer of good news. So in 2 Samuel 4:10. In later writers it means, as here, the good news itself. So in Lucian, Plutarch.—μαλακία] only in Mt. amongst New Testament writers, cf. 9:35, 10:1.—συναγωγαῖς] For the history of the synagogues, see Schürer, 11. ii, 52 ff.
(E)24.Συρία] never occurs in Mk.—συνέχομαι] in this sense only here and in Lk. and Acts amongst the New Testament writers.—βάσανος of disease only here.—βασάνοις συνεχομέος] occurs in a different sense in 4 Mac 15:32.—δαιμουίζεσθαι] in this sense only in late writers.—παραλυτικός] a New Testament word, Mt. and Mk. Lk. (5:18, 24) and twice in Acts has παραλελυμένος—σεληνιαζομένος] i.e.epileptic, again in 17:15; a late and rare word.—καὶ ἐθεράπενσεν αὐτούς D a b c g1 h have καὶ πάντας ἐθεράπευσεν Cf. 8:16, 12:15, 14:36.
(
E
)
25.
ὄχλοι πολλοί] the plural is characteristic of Mt. He has the plural ὄχλοι about 30 times, the singular 16 times. Mk. has the singular about 37 times, the plural once.
1
. In Lk. the numbers are more equally balanced.
Δεκαπόλεως] occurs twice in Mk. For its history, see Schürer, II. i, 94; DB., art. “Decapolis.”
Ἰεροσολύμων] is here treated as a neuter plural. In 2:3 it is fem. sing. The aspirated form is apparently due to association with ἱερός. Cf. West. and Hort, Introduction
2
, p. 313; Blass, p. 31. Mk. and Mt. (except in 23:37) always have this form. Cf. Blass, p. 31.—πέραν τοῦ Ἰορδάνου] is the עֵבֶר חַיַרְדֵּן the Mishna, and the Peræa of Josephus. For its extent, see Schürer, 11. i. 3, 4;
DB.
, art. “Peræa.”
The reason why the editor now gives his illustration of Christ’s teaching before that of His work is probably to be found in the next verse of Mk., viz. 1:22, which describes the effect of Christ’s preaching. He therefore here inserts the Sermon on the mountain, 5-7:27, and closes it with this verse from Mark 1:22= Matthew 7:27, Matthew 7:28.
Mthe Second Gospel.
Xpassages in which Mt. and Lk. agree closely, borrowed from an unknown source or sources.
Dalm.
Dalman.
LXX.
The Septuagint Version.
1
The editor (or his source) either had προσκυνήσεις (rather than φοβηθήσῃ = Heb. חירא) in his copy of the LXX., or has substituted it for φοβηθήση to emphasize the antithesis with προσκυνήσης of v. 5. Cf. Introduction, p. xxxi.
S
Syriac version: Sinaitic MS.
ali.e. with other uncial MSS.
S
Syriac version: Curetonian.
Oquotations from the Old Testament borrowed from a collection of Messianic prophecies. See pp.61 f.
Deissm.
Deissmann.
Ditt.
Dittenberger
Sylloge
.
Hor. Syn. Horœ Synopticœ(Hawkins).
Ox. Pap. Oxyrhynchus Papyri.
Eeditorial passages.
1
10:l, but D S1 latt have the singular also here
DB. Dictionary of the Bible(Hastings).
2
On the Sermon on the Mount, see especially the article of Votaw in
DB.
, Extra Volume, pp. 1ff.
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Marine Safety (Domestic Commercial Vessel) Levy Bill 2018
C2018B00038
Marine Safety (Domestic Commercial Vessel) Levy Bill 2018
- C2018B00038
Registered 28 Feb 2018 Introduced HR 28 Feb 2018
Details
C2018B00038
Table of contents.
2016‑2017‑2018
The Parliament of the
Commonwealth of Australia
HOUSE OF REPRESENTATIVES
Presented and read a first time
Marine Safety (Domestic Commercial Vessel) Levy Bill 2018
No. , 2018
(Infrastructure and Transport)
A Bill for an Act to impose a levy on certain domestic commercial vessels, and for related purposes
Contents
1............ Short title............................................................................................. 1
3............ Definitions.......................................................................................... 2
4............ Leviable domestic commercial vessel.................................................. 3
5............ Extension to external Territories.......................................................... 3
6............ Extraterritorial operation...................................................................... 3
7............ Act to bind Crown.............................................................................. 4
8............ Imposition of levy............................................................................... 4
9............ Amount of levy................................................................................... 4
10.......... Advice by AMSA............................................................................... 6
11.......... Persons liable to pay levy.................................................................... 7
12.......... Treatment of partnerships.................................................................... 8
13.......... Treatment of unincorporated associations........................................... 8
14.......... Treatment of trusts with multiple trustees............................................ 8
15.......... Act does not impose a tax on property of a State................................ 8
16.......... Disallowance of certain rules.............................................................. 9
17.......... Incorporation of material, etc............................................................. 10
A Bill for an Act to impose a levy on certain domestic commercial vessels, and for related purposes
The Parliament of Australia enacts:
1 Short title
This Act is the Marine Safety (Domestic Commercial Vessel) Levy Act 2018 .
2 Commencement
(1) Each provision of this Act specified in column 1 of the table commences, or is taken to have commenced, in accordance with column 2 of the table. Any other statement in column 2 has effect according to its terms.
Commencement information Column 1 Column 2 Column 3 Provisions Commencement Date/Details 1. The whole of this Act The day after this Act receives the Royal Assent.
Note: This table relates only to the provisions of this Act as originally enacted. It will not be amended to deal with any later amendments of this Act.
(2) Any information in column 3 of the table is not part of this Act. Information may be inserted in this column, or information in it may be edited, in any published version of this Act.
3 Definitions
In this Act:
AMSA means the Australian Maritime Safety Authority.
certificate of survey has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
domestic commercial vessel has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
eligible financial year means:
(a) the financial year beginning on 1 July 2019; or
(b) a later financial year.
leviable domestic commercial vessel has the meaning given by section 4.
Marine Safety (Domestic Commercial Vessel) National Law has the meaning given by section 17 of the Marine Safety (Domestic Commercial Vessel) National Law Act 2012 .
National Standard for Commercial Vessels has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
owner of a vessel has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
partnership has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
trust has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
trustee has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
Uniform Shipping Laws Code has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
vessel has the same meaning as in the Marine Safety (Domestic Commercial Vessel) National Law.
4 Leviable domestic commercial vessel
(1) For the purposes of this Act, leviable domestic commercial vessel means a domestic commercial vessel that is not included in a class of domestic commercial vessels specified in rules in force under subsection (2).
(2) The Minister may, by legislative instrument, make rules for the purposes of subsection (1).
(3) Before making rules under subsection (2), the Minister must consult AMSA.
5 Extension to external Territories
This Act extends to every external Territory.
6 Extraterritorial operation
This Act applies within and outside Australia.
7 Act to bind Crown
This Act binds the Crown in right of each of the States, of the Australian Capital Territory and of the Northern Territory. However, it does not bind the Crown in right of the Commonwealth.
8 Imposition of levy
Full‑year levy
(1) If a vessel is a leviable domestic commercial vessel on 1 July in an eligible financial year, levy is imposed on the vessel in respect of the financial year.
Pro‑rata levy
(2) If:
(a) on 1 July in an eligible financial year, a vessel:
(i) does not exist; or
(ii) is not a leviable domestic commercial vessel; and
(b) a later day in the eligible financial year is the first or only day in the eligible financial year on which the vessel is a leviable domestic commercial vessel;
levy is imposed on the vessel in respect of the eligible financial year.
9 Amount of levy
Full‑year levy
(1) The amount of levy that subsection 8(1) imposes on a leviable domestic commercial vessel in respect of an eligible financial year is the amount ascertained in accordance with rules in force under subsection (2).
Note: See also subsection 33(3A) of the Acts Interpretation Act 1901 .
(2) The Minister may, by legislative instrument, make rules for the purposes of subsection (1).
Note: See also section 16 (disallowance of rules).
Pro‑rata levy
(3) The amount of levy that subsection 8(2) imposes on a leviable domestic commercial vessel in respect of an eligible financial year is the amount worked out using the formula:
where:
full‑year amount means the amount of levy that would have been worked out under subsection (1) of this section if the vessel:
(a) had existed; and
(b) had been a leviable domestic commercial vessel;
on 1 July in the eligible financial year.
number of days in the pro‑rata period means the number of days in the period:
(a) beginning at the start of the day mentioned in paragraph 8(2)(b); and
(b) ending at the end of the eligible financial year.
(4) If the amount worked out using the formula in subsection (3):
(a) is not an amount of whole dollars; and
(b) exceeds $1;
the amount is to be rounded to the nearest dollar (rounding 50 cents upwards).
(5) If the amount worked out using the formula in subsection (3) is less than $1, the amount is to be rounded upwards to $1.
Minister to seek advice
(6) Before making rules under subsection (2), the Minister must request AMSA to give advice about the rules that should be made.
(7) In deciding whether to make rules under subsection (2), the Minister must have regard to:
(a) any relevant advice given by AMSA under section 10; and
(b) such other matters (if any) as the Minister considers relevant.
10 Advice by AMSA
(1) If the Minister requests AMSA, under subsection 9(6), to give advice, AMSA must give the requested advice to the Minister.
(2) In giving advice under subsection (1), AMSA must have regard to the principle that amounts received on behalf of the Commonwealth by way of levy imposed by this Act should be sufficient, over time, to offset expenditure that:
(a) has been, or is likely to be, incurred on or after 1 July 2019 by AMSA in connection with things done under the Marine Safety (Domestic Commercial Vessel) National Law; and
(b) is not offset by fees charged, or likely to be charged, under section 150 of the Marine Safety (Domestic Commercial Vessel) National Law.
(3) For the purposes of subsection (2), if an amount is paid to AMSA, on behalf of the Commonwealth, by way of an advance on account of levy imposed by this Act, the advance (to the extent to which it discharges liability for the levy) is taken to be an amount received on behalf of the Commonwealth by way of levy imposed by this Act.
Exceptions
(4) For the purposes of the application of subsection (2) to expenditure incurred, or likely to be incurred, by AMSA during a period specified in rules in force under subsection (6), disregard so much of the expenditure as equals the amount specified in those rules in relation to that period.
(5) Paragraph (2)(a) does not apply to one or more things that are:
(a) specified in rules in force under subsection (6); or
(b) done under the Marine Safety (Domestic Commercial Vessel) National Law.
(6) The Minister may, by legislative instrument, make rules for the purposes of subsection (4) or (5).
11 Persons liable to pay levy
Certificate of survey in force for vessel
(1) If:
(a) a certificate of survey is in force for a leviable domestic commercial vessel; and
(b) a particular person is:
(i) the holder of the certificate; and
(ii) the sole owner of the vessel;
the person is liable to pay levy imposed by this Act on the vessel.
(2) If:
(a) a certificate of survey is in force for a leviable domestic commercial vessel; and
(b) subsection (1) does not apply to the vessel;
the following persons are jointly and severally liable to pay levy imposed by this Act on the vessel:
(c) the holder of the certificate;
(d) the owner, or each of the owners, of the vessel.
Other vessels
(3) If:
(a) none of the preceding subsections of this section applies to a leviable domestic commercial vessel; and
(b) a particular person is the sole owner of the vessel;
the person is liable to pay levy imposed by this Act on the vessel.
(4) If none of the preceding subsections of this section applies to a leviable domestic commercial vessel, the owners of the vessel are jointly and severally liable to pay levy imposed by this Act on the vessel.
12 Treatment of partnerships
(1) This Act applies to a partnership as if it were a person, but with the changes set out in this section.
(2) A liability that would otherwise be imposed on the partnership by this Act is imposed on each partner instead, but may be discharged by any of the partners.
(3) For the purposes of this Act, a change in the composition of a partnership does not affect the continuity of the partnership.
13 Treatment of unincorporated associations
(1) This Act applies to an unincorporated association as if it were a person, but with the changes set out in this section.
(2) A liability that would otherwise be imposed on the association by this Act is imposed on each member of the association’s committee of management instead, but may be discharged by any of the members.
14 Treatment of trusts with multiple trustees
(1) If a trust has 2 or more trustees, this Act applies to the trust as if it were a person, but with the changes set out in this section.
(2) A liability that would otherwise be imposed on the trust by this Act is imposed on each trustee instead, but may be discharged by any of the trustees.
15 Act does not impose a tax on property of a State
(1) This Act has no effect to the extent (if any) to which it imposes a tax on property of any kind belonging to a State.
(2) In this section, property of any kind belonging to a State has the same meaning as in section 114 of the Constitution.
16 Disallowance of certain rules
Scope
(1) This section applies to rules made under subsection 9(2).
Disallowance
(2) Either House of the Parliament may, following a motion upon notice, pass a resolution disallowing the rules. For the resolution to be effective:
(a) the notice must be given in that House within 15 sitting days of that House after the copy of the rules was tabled in the House under section 38 of the Legislation Act 2003 ; and
(b) the resolution must be passed, in pursuance of the motion, within 15 sitting days of that House after the giving of that notice.
(3) If neither House passes such a resolution, the rules take effect on the day immediately after the last day upon which such a resolution could have been passed if it were assumed that notice of a motion to disallow the rules was given in each House on the last day of the 15 sitting day period of that House mentioned in paragraph (2)(a).
(4) If:
(a) notice of a motion to disallow the rules is given in a House of the Parliament within 15 sitting days of that House after the copy of the rules was tabled in that House under section 38 of the Legislation Act 2003 ; and
(b) at the end of 15 sitting days of that House after the giving of that notice of motion:
(i) the notice has not been withdrawn and the motion has not been called on; or
(ii) the motion has been called on, moved and (where relevant) seconded and has not been withdrawn or otherwise disposed of;
the rules are then taken to have been disallowed, and subsection (3) does not apply to the rules.
(5) Section 42 (disallowance) of the Legislation Act 2003 does not apply to the rules.
17 Incorporation of material, etc.
Despite section 14 of the Legislation Act 2003 of the Commonwealth, rules made under this Act may make provision for or in relation to a matter by applying, adopting or incorporating any matter contained in any written instrument in force or existing from time to time, including but not limited to:
(a) the National Standard for Commercial Vessels; and
(b) the Uniform Shipping Laws Code.
| https://www.legislation.gov.au/Details/C2018B00038/Html/Text |
医药政策:参考定价、其他定价和采购政策的影响 - Acosta, A - 2014 | Cochrane Library
*Drug Costs; *Health Expenditures; Cost Control; Cost Sharing; Drug and Narcotic Control; Economics, Pharmaceutical; Health Services Needs and Demand; Insurance, Health, Reimbursement [economics]
医药政策：参考定价、其他定价和采购政策的影响
Appendices
Appendix 1. Search strategies
1. CENTRAL, Cochrane Library
#1 MeSH descriptor: [Drug Costs] this term only
#2 MeSH descriptor: [Economics, Pharmaceutical] this term only
#3 MeSH descriptor: [Fees, Pharmaceutical] this term only
#4 MeSH descriptor: [Prescription Fees] this term only
#5 MeSH descriptor: [Pharmaceutical Preparations] explode all trees and with qualifiers: [Economics ‐ EC]
#6 MeSH descriptor: [Drug Prescriptions] this term only and with qualifiers: [Economics ‐ EC]
#7 MeSH descriptor: [Drug Substitution] this term only and with qualifiers: [Economics ‐ EC]
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
#9 MeSH descriptor: [Pharmaceutical Preparations] explode all trees
#10 MeSH descriptor: [Drug Prescriptions] this term only
#11 MeSH descriptor: [Drug Substitution] this term only
#12 #9 or #10 or #11
#13 MeSH descriptor: [Economics] this term only
#14 MeSH descriptor: [Health Expenditures] this term only
#15 MeSH descriptor: [Costs and Cost Analysis] this term only
#16 MeSH descriptor: [Health Care Costs] this term only
#17 MeSH descriptor: [Cost Control] this term only
#18 MeSH descriptor: [Cost Savings] this term only
#19 MeSH descriptor: [Commerce] this term only
#20 MeSH descriptor: [Rate Setting and Review] this term only
#21 #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
#22 MeSH descriptor: [Policy] this term only
#23 MeSH descriptor: [Health Policy] this term only
#24 MeSH descriptor: [Health Care Reform] this term only
#25 MeSH descriptor: [National Health Programs] this term only
#26 MeSH descriptor: [Policy Making] this term only
#27 MeSH descriptor: [Government Regulation] this term only
#28 MeSH descriptor: [Legislation, Drug] this term only
#29 MeSH descriptor: [Politics] this term only
#30 (policy or policies or politics or plan or plans or planning or program* or regulat* or legislat*):ti,ab
#31 #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30
#32 (reference or index or "volume based" or reimburs* or "best available") near/3 (price or prices or pricing) near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#33 (max* or minim* or reimburs* or ceiling or fixed) near/3 (price or prices or pricing or cost or costs) near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#34 (price or prices) near/3 (control or controls or caps or negotiat* or compar* or cut or cuts or freez*) near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#35 ("price volume" or "cost plus") near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#36 (profit near/3 regulat* or profit near/3 limit*) near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#37 (procure* or purchas* or rebate or acquisition or econom* or financ* or sale or sales) near/3 (policy or policies or intervention*) near/3 (drug or drugs or pharmaceutic* or medicines or medicat*):ti,ab
#38 #32 or #33 or #34 or #35 or #36 or #37
#39 (drug or drugs or pharmaceutic* or medicines or medicat*) near/6 (cost or costs or fee or fees or expenditure* or expense* or price or prices or pricing or spending* or purchas* or procure* or acquisition or sale or sales) near/6 (policy or policies or intervention* or politics or plan or plans or planning or program* or regulat* or legislat*):ti,ab
#40 #8 and #31
#41 #12 and #21 and #31
#42 #38 or #39 or #40 or #41
2. MEDLINE In‐Process & Other Non‐Indexed Citations and MEDLINE, Ovid
# Searches Results
1Drug Costs/11364
2Economics, Pharmaceutical/2379
3Fees, Pharmaceutical/1105
4Prescription Fee/939
5exp Pharmaceutical Preparations/ec [Economics]4131
6Drug Prescriptions/ec [Economics]2562
7Drug Substitution/ec [Economics]36
8or/1‐718829
9exp Pharmaceutical Preparations/587714
10Drug Prescriptions/20886
11Drug Substitution/487
12or/9‐11606182
13Economics/26629
14Health Expenditures/12736
15"Costs and Cost Analysis"/40253
16Health Care Costs/24066
17Cost Control/19418
18Cost Savings/7866
19Commerce/16300
20"Rate Setting and Review"/2438
21or/13‐20138351
22Policy/457
23Health Policy/47001
24Health Care Reform/26362
25National Health Programs/23941
26Policy Making/11218
27Government Regulation/16371
28Legislation, Drug/8329
29Politics/38756
30(policy or policies or politics or plan or plans or planning or program* or regulat* or legislat*).ti,ab.1890437
31or/22‐301987077
32((reference or index or volume based or reimburs* or best available) adj3 (price or prices or pricing) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.141
33((max* or minim* or reimburs* or ceiling or fixed) adj3 (price or prices or pricing or cost or costs) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.219
34((price or prices) adj3 (control or controls or caps or negotiat* or compar* or cut or cuts or freez*) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.156
35((price volume or cost plus) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.5
36(profit adj3 (regulat* or limit*) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.1
37((procure* or purchas* or rebate or acquisition or econom* or financ* or sale?) adj3 (policy or policies or intervention?) adj3 (drug or drugs or pharmaceutic* or medicines or medicat*)).ti,ab.57
38or/32‐37493
39((drug or drugs or pharmaceutic* or medicines or medicat*) adj6 (cost or costs or fee or fees or expenditure? or expense? or price or prices or pricing or spending? or purchas* or procure* or acquisition or sale?) adj6 (policy or policies or intervention? or politics or plan or plans or planning or program* or regulat* or legislat*)).ti,ab.1491
408 and 315191
4112 and 21 and 311508
4238 or 39 or 40 or 416931
43randomized controlled trial.pt.340079
44controlled clinical trial.pt.85448
45multicenter study.pt.151515
46(randomis* or randomiz* or randomly).ti,ab.487333
47groups.ab.1210865
48(trial or multicenter or multi center or multicentre or multi centre).ti.128649
49(intervention* or controlled or control group or compare or compared or (before adj5 after) or (pre adj5 post) or pretest or pre test or posttest or post test or quasiexperiment* or quasi experiment* or evaluat* or effect? or impact? or time series or time point? or repeated measur*).ti,ab.6850206
50or/43‐497373617
51exp Animals/16427399
52Humans/12629645
5351 not (51 and 52)3797754
54comment.pt.521909
55editorial.pt.319891
56cochrane database of systematic reviews.jn.9224
57comment on.cm.521908
58review.pt.1748075
59review.ti.227088
60or/53‐596198639
6150 not 605001053
6242 and 612934
63201012*.ed. or 2011*.ed,yr. or 2012*.ed,yr.2315721
6462 and 63481
3. EconLit, ProQuest
4. PAIS International, ProQuest
5. World Wide Political Science Abstracts, ProQuest
ALL("drug" or "drugs" or pharmaceutic* or "medicines" or medicament*) AND ALL(regulat* or requirement* or restrict* or monitor* or control* or "legislation" or "law" or "laws" or "act" or "acts" or "policy" or "policies" or "politics" or reform* or "system" or "systems" or "plan" or "plans" or "planning" or program* or strateg*) NEAR/3 ALL("price" or "prices" or "pricing" or purchas* or procure* or "sale" or "sales") AND ALL("randomised" or "randomized" or "randomly" or "trial" or "intervention" or "interventions" or "controlled" or "control group" or "control groups" or "before and after" or "pre and post" or "pretest" or "pre test" or "posttest" or "post test" or quasiexperiment* or "quasi experiment" or "quasi experiments" or "quasi experimental" or evaluat* or "effect" or "effects" or impact or "impacts" or "time series" or "time point" or "time points" or "repeated measure" or "repeated measures" or "repeated measurement" or "repeated measurements") NOT ALL("narcotic" or “narcotics” or "crime" or "crimes" or "war" or "wars" or terror* or weapon* or "drug abuse" or "illicit drug" or "illicit drugs" or "drug trafficking")
6. INRUD Bibliography
Search field: All Non‐Indexed Text Fields
{price} or {pricing} or {purchas} or {procure}
AND
{regulat} or {requirement} or {restrict} or {monitor} or {control} or {legislation} or {law} or {act} or {policy} or {policies} or {politics} or {reform} or {system} or {plan} or {program} or {strateg}
AND
{randomis} or {randomiz} or {randomly} or {intervention} or {control group} or {compar} or {before and after} or {pretest} or {posttest} or {pre test} or {post test} or {quasiexperiment} or {quasi experiment} or {evaluat} or {effect} or {impact} or {time series} or {time point} or {repeated measur}
7. Embase, Ovid
1. (regulat$ or requirement? or restrict$ or monitor$ or control$).tw.
2. (legislation? or law? or act? or policy or policies or politics or reform$ or system? or plan$ or program$ or strateg$).tw. or Drug Legislation/ or Policy/ or Health Care Policy/ or Politics/ or Drug Program/
3. (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$).tw. or exp Pharmaceutics/ or exp Drug/ or Prescription/ or "Drug Use"/ or Drug Utilization/
4. *Cost Control/ and 3 and 2
5. ((control$ or containment or curtailment or reduc$ or save or saving) adj3 cost?).tw.
6. ((cost? or expenditure? or expense?) adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw.
7. 5 and 6 and 2
8. ((control$ or reduc$ or cut$ or regulat$ or negotiat$ or fix$) adj3 (price? or pricing)).tw.
9. ((price? or pricing) adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw.
10. 8 and 9 and 2
11. (reference$ adj3 (price? or pricing)).tw.
12. (index$ adj3 (price? or pricing)).tw. and 3
13. ((maxim$ or minim$) adj3 (cost? or price? or pricing)).tw. and 3
14. (cost? effect$ adj3 (price? or pricing)).tw. and 3
15. (reimburs$ adj1 contract?).tw. and 3
16. (*Drug Cost/ or *Pharmacoeconomics/) and (1 or 2)
17. *Hospital Purchasing/ and 3
18. (purchas$ adj3 (group? or join$ or hospital? or shared)).tw.
19. ((group? or join$ or hospital? or shared) adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw.
20. 18 and 19 and 2
21. (procurement$ adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw. and 2
22. (acquisition cost? adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw. and 2
23. (rebate? adj3 (drug or drugs or pharmaceutic$ or medicines or medicament? or medicat$)).tw. and 2
24. (generic adj3 (price? or pricing or substitut$)).tw. and 3
25. ((price? or pricing) adj3 (policy or policies or regulat$ or negotiat$)).tw. and 3
26. (rate? adj1 return).tw. and 3
27. (profit$ adj3 regulat$).tw. and 3
28. 4 or 7 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
29. Randomized Controlled Trial/
30. (randomised or randomized).tw.
31. experiment$.tw.
32. (time adj series).tw.
33. (pre test or pretest or (posttest or post test)).tw.
34. evaluat$.tw.
35. Comparative Study/
36. or/29‐35
37. 28 and 36
38. Nonhuman/
39. 37 not 38
40. medlinex00ae.cr.
41. 39 not 40
8. NHSEED, Cochrane Library
#1(regulat* or requirement* or restrict* or monitor* or control*):ti,ab
#2(legislation* or law or laws or act or acts or policy or policies or politics or reform* or system or systems or plan or plans or program* or strateg*):ti,ab
#3MeSH descriptor Policy Making, this term only
#4MeSH descriptor Legislation, Drug, this term only
#5MeSH descriptor Public Policy, this term only
#6MeSH descriptor Health Policy, this term only
#7MeSH descriptor Politics, this term only
#8MeSH descriptor Health Care Reform, this term only
#9(#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8)
#10(drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#11MeSH descriptor Pharmaceutical Preparations explode all trees
#12MeSH descriptor Drug Prescriptions explode all trees
#13MeSH descriptor Drug Utilization, this term only
#14(#10 OR #11 OR #12 OR #13)
#15MeSH descriptor Cost Control, this term only
#16MeSH descriptor Cost Savings, this term only
#17(#15 OR #16)
#18(#17 AND #9 AND #14)
#19(control* or containment or curtailment or reduc* or save or saving) NEAR/3 (cost or costs):ti,ab
#20(cost or costs or expenditure* or expense*) NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#21(#19 AND #20 AND #9)
#22(control* or reduc* or cut* or regulat* or negotiat* or fix*) NEAR/3 (price* or pricing):ti,ab
#23(price* or pricing) NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#24(#22 AND #23 AND #9)
#25reference* NEAR/3 (price* or pricing):ti,ab
#26index* NEAR/3 (price* or pricing):ti,ab
#27(#26 AND #14)
#28(maxim* or minim*) NEAR/3 (cost or costs or price* or pricing):ti,ab
#29(#28 AND #14)
#30(cost or costs) NEAR/4 (price* or pricing):ti,ab
#31(#30 AND #14)
#32(reimburs* NEAR/1 contract*):ti,ab
#33MeSH descriptor Drug Costs, this term only
#34MeSH descriptor Economics, Pharmaceutical, this term only
#35(#33 OR #34)
#36(#1 OR #9)
#37(#35 AND #36)
#38MeSH descriptor Purchasing, Hospital, this term only
#39MeSH descriptor Group Purchasing, this term only
#40(#38 OR #39)
#41(#40 AND #14)
#42purchas* NEAR/3 (group* or join* or hospital* or shared):ti,ab
#43(group* or join* or hospital* or shared) NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#44(#42 AND #43 AND #9)
#45procurement* NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#46(acquisition NEXT cost*) NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#47(#46 AND #9)
#48rebate* NEAR/3 (drug or drugs or pharmaceutic* or medicines or medicament* or medicat*):ti,ab
#49generic NEAR/3 (price* or pricing or substitut*):ti,ab
#50(#49 AND #14)
#51(price* or pricing) NEAR/3 (policy or policies or regulat* or negotiat*):ti,ab
#52(#51 AND #14)
#53(rate* NEAR/1 return):ti,ab
#54(#53 AND #14)
#55(profit* NEAR/3 regulat*):ti,ab
#56(#18 OR #21 OR #24 OR #25 OR #27 OR #29 OR #31 OR #32 OR #37 OR #41 OR #44 OR #45 OR #47 OR #48 OR #50 OR #52 OR #54 OR #55)
9. LILACS, VHL (IAH search interface)
(cost or costs or expend$ or expens$ or price or prices or pricing or purchas$ or costo or costos or gasto$ or gasta$ or precio or precios or compra$ or adquisicion$ or custo or custos or preco or precos or aquisicao$ or despesa or adquisicao) and (drug or drugs or pharmaceutic$ or medicin$ or medicament$ or farmaceutic$ or droga or remedio) and (regulat$ or requirement$ or restrict$ or monitor$ or contro$ or legislat$ or law or laws or policy or policies or reform$ or system$ or program$ or regulacion or requisito$ or politica$ or sistema$ or seguimiento or regulacao$ or condicao$ or seguimento or acompanhamento or exigencia) and (randomi$ or randomly or azar or acaso or aleat$ or control$ or intervention$ or intervencion$ or intervencao or intervencoes or evaluat$ or evaluar or evaluacion or avaliar or impact$) [Words]
10. International Political Science Abstracts (IPSA)
S5S1 and S2 and S3 and S455
S4TX (random* or intervention* or control* or compar* or evaluat* or "time series" or pretest or posttest or "pre test" or "post test" or impact* or chang* or effect* or experiment*)117558
S3TX (regulat* or requirement* or restrict* or monitor* or control* or legislation or law or laws or act or acts or policy or policies or politics or reform* or system or systems or plan* or program* or strateg*)189060
S2TX (cost or costs or price* or pricing or expenditure* or expense* or procurement* or reimburs* or purchas* or rebate* or profit*)14426
S1TX (drug or drugs or pharmaceutic* or medicines or medicament*)774
11. OpenSIGLE (now called OpenGrey)
Keywords:drug or drugs or pharmaceutical or pharmaceuticals or medicaments or medicines
AND
Keywords:price or prices or pricing or purchase or purchased or purchasing or procurement
12. WHOLIS, WHO
Search field: ‘Words or phrase’
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Summary of findings for the main comparison. Reference pricing policy compared to no reference pricing
Reference pricing policy compared to no reference pricing Population:Patients with drug insurance Settings:Canada, US, Germany Intervention:Reference pricing Comparison:No reference pricing Outcomes Impact Median relative effect (range) No of studies Quality of the evidence (GRADE) Insurer's cumulative drug expenditures one year after the transition period Reference drugs + cost share drugs:Median relative cumulative drug expenditures of ‐18% (range: from ‐36% to 3%)2 studies 1⊕⊕⊝⊝ low Insurer's drug expenditures one year after the transition period Reference drugs + cost share drugs:Median relative drug expenditures of ‐10% (range: from ‐53% to 4%)4 studies 2⊕⊕⊝⊝ low Drug use one year after the transition period Reference drugs:Median relative change in prescriptions of 15% (range: from ‐14% to 166%)4 studies⊕⊕⊝⊝ low Cost share drugs:Median relative change in prescriptions of ‐39% (range: from ‐87% to ‐17%)3 studies⊕⊕⊝⊝ low Healthcare utilisationNo studies meeting the inclusion criteria were found‐‐ Health outcomesNo studies meeting the inclusion criteria were found‐‐ Adverse eventsNo studies meeting the inclusion criteria were found‐‐ Reference drugs:drugs that determine the reference price level. There is no cost share by the patients for these drugs, which are fully reimbursed. The expectation is that reference pricing will lead to an increase in use of these drugs. Cost share drugs:drugs in the same group as the reference drugs that cost more. Patients have to pay the difference between reference price drugs and the price of these drugs. The expectation is that reference pricing will lead to a decrease in use of these drugs. Reference drugs + cost share drugs: both the reference drugs and the cost share drugs. The expectation is that reference pricing will lead to little or no change in the overall use of these drugs.GRADE Working Group grades of evidence High quality:Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality:Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality:Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality:We are very uncertain about the estimate.1.Puig 2007was not considered for the median because this study reported the outcome different than the other two studies (mean monthly savings of total lovastatin and simvastatin sales).2. We only included Pharmacare data fromGrootendorst 2005.
Summary of findings for the main comparison. Reference pricing policy compared to no reference pricing
Summary of findings 2. Index pricing compared to no index pricing
Index pricing compared to no index pricing Population:Norwegian citizens taking one of the following drugs: citalopram (depression), omeprazol (antiulcer), cetirizin (allergy), loratadin (allergy), enalapril (high blood pressure) and lisinopril (high blood pressure), simvastatin (high cholesterol) or amlodipin (high blood pressure) Settings:Norway Intervention:Index pricing Comparison:No index pricing Outcomes Relative effect (95% CI) No of studies Quality of the evidence (GRADE) Drug use 6 months after policy start dateGeneric citalopram: 55% (95% CI 11 to 98%)Brand citalopram: ‐43% (95% CI ‐67 to ‐18%)1 study⊕⊕⊝⊝ low Drug prices 6 months after policy start dateGeneric drug prices: ‐5.3% (95% CI NA)Brand drugs prices: ‐1.1% (95% CI NA)1 study⊕⊕⊝⊝ low Drug expendituresNo studies meeting the inclusion criteria were found‐‐ Healthcare utilisationNo studies meeting the inclusion criteria were found‐‐ Health outcomesNo studies meeting the inclusion criteria were found‐‐ Adverse eventsNo studies meeting the inclusion criteria were found‐‐ CI:Confidence intervalGRADE Working Group grades of evidence High quality:Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality:Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality:Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality:We are very uncertain about the estimate.
Summary of findings 2. Index pricing compared to no index pricing
Summary of findings 3. Maximum prices compared to no maximum prices for drug expenditures
Maximum prices compared to no maximum prices for drug expenditures Population:Patients taking statins Settings:Andalusia, Spain Intervention:Maximum prices Comparison:No maximum prices Outcomes Relative effect (95% CI) No of studies Quality of the evidence (GRADE) Drug expenditure one year after the transition period21.4% (95% CI 19.0 to 23.7%) in volume of sales for total statins1 study⊕⊝⊝⊝ Very low 1 Drug pricesNo studies meeting the inclusion criteria were found‐‐ Healthcare utilisationNo studies meeting the inclusion criteria were found‐‐ Health outcomesNo studies meeting the inclusion criteria were found‐‐ Drug useNo studies meeting the inclusion criteria were found‐‐ Adverse eventsNo studies meeting the inclusion criteria were found‐‐ CI:Confidence intervalGRADE Working Group grades of evidence High quality:Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality:Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality:Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality:We are very uncertain about the estimate. 1High risk of bias due to the intervention not being independent of other changes.
Figures and Tables -
Summary of findings 3. Maximum prices compared to no maximum prices for drug expenditures
Summary of findings 4. Reference pricing versus no reference pricing: drug expenditures
STUDY ID REFERENCE PRICE FOR EFFECTS ON EXPENDITURES OF*** OUTCOME ABSOLUTE CHANGE LEVEL, IMMEDIATE AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, IMMEDIATE AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 1/2 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 1 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 2 YEARS AFTER TRANSITION PERIOD (95% CI) NOTESGrootendorst 2002*ACE inhibitorsReference drugs + cost share drugsACE inhibitors. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month18,203(‐1611 to 38,017)5%(0% to 10%)5%(‐2% to 10%)4%(‐3% to 10%)1%(‐8% to 9%)Price year not specified in study papersCCBsReference drugs + cost share drugsCCBs. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month‐91,547(‐122,082 to ‐61,011)‐19%(‐26% to ‐13%)‐18%(‐30% to ‐5%)‐16%(‐36% to 5%)‐14%(‐51% to 23%)Price year not specified in study papersNitratesReference drugs + cost share drugsNitrates. Pharmacare expenditures per 100,000 senior citizens. Canadian dollar per month‐66,473 (‐72,620 to ‐60,326)‐50% (‐55% to ‐46%)‐47% (‐52% to ‐41%)‐‐Price year not specified in study papersGrootendorst 2005NSAIDs (RP 1)Reference drugs + cost share drugsAverage monthly expenditure per day of therapy dispensed (Canadian dollars 2004) for Pharmacare (Ph) and Patient (Pa)Ph:‐0.08 (‐0.12 to ‐0.04)Pa: 0.00 (‐0.03 to 0.02)Ph: ‐9.6%(95% CI NA)Pa: NA‐Ph: ‐8.8% (95% CI NA)Pa: 690% (95% CI NA)Ph: ‐8.3% (95% CI NA)Pa: 571% (95% CI NA)Last estimated effect at 19 monthsNSAIDs (RP 2)Reference drugs + cost share drugsAverage monthly expenditure per day of therapy dispensed (Canadian dollars 2004) for Pharmacare (Ph) and Patient (Pa)Ph:‐0.31 (‐0.36 to ‐0.27)Pa: 0.07 (0.04 to 0.10)Ph: ‐37% (95% CI NA)Pa: 550% (95% CI NA)‐Ph: ‐53% (95% CI NA)Pa: 500% (95% CI NA)‐Marshall 2002*H2RAsReference drugs + cost share drugsH2RAs. Pharmacare expenditures per 100000 senior citizens. Canadian dollar per month‐45,139(‐50,096 to ‐40,183)‐39%(‐44% to ‐35%)‐38%(‐44% to ‐31%)‐35%(‐45% to ‐25%)‐30%(‐48% to ‐12%)Price year not specified in study papersGrootendorst 2006ACE inhibitorsReference drugs + cost share drugsAll ACE inhibitors. Drug plan expenditures per DDD dispensed. CAD‐0.04 (‐0.09 to 0.02)‐4% (95% CI NA)‐7% (95% CI NA)‐11% (95% CI NA)Price specified in study papersCCBsReference drugs + cost share drugsAll CCBs. Drug plan expenditures per DDD dispensed. CAD‐0.20(‐0.25 to ‐0.15)‐16% (95% CI NA)‐10% (95% CI NA)‐4% (95% CI NA)Price year not specified in study papersSawyer 198352 dosage forms of 25 multisource chemical entitiesReference drugs + cost share drugsMonthly Medicaid drug expenditures in Maryland. USD‐291276(‐478,458 to ‐104,094)‐0.87 per month (95% CI NA)Price year not specified in study papersBrekke 2011The RP covered six chemical substances: Citalopram, Omeprazol, Cetirizin, Loratadin, Enalapril and Lisinopril . The system was later extended with two additional substances; simvastatin and amlodipinCost share drugsChange in copayments NOKGeneric copayment ‐12.92 (95% CI NA)Brand‐name copayment ‐6.37 (95% CI NA)Generic copayment ‐12.76% (95% CI NA)Brand‐name copayment ‐14.82% (95% CI NA)*Results from reanalysis by reviewers.**NA = Not available.*** EFFECTS ON EXPENDITURES OF: Reference drugs, drugs that determine the reference price level. There is no cost share by the patients for these drugs, which are fully reimbursed. The expectation is that reference pricing will lead to an increase in use of these drugs. Cost share drugs, drugs in the same group as the reference drugs that cost more. Patients have to pay the difference between reference price drugs and the price of these drugs. The expectation is that reference pricing will lead to a decrease in use of these drugs. Reference drugs + cost share drugs, both the reference drugs and the cost share drugs. The expectation is that reference pricing will lead to little or no change in the overall use of these drugs.
Summary of findings 4. Reference pricing versus no reference pricing: drug expenditures
Table 1. Abbreviations
Abbreviations Complete nameACEAngiotensin converting enzymeARIMAAutoregressive integrated moving averageCBAControlled before and afterCCBDihydropyridine channel blockerCRMControlled repeated measuresEPOCEffective Practice and Organisation of CareH2RAHistamine‐2 receptor antagonistINNInternational non‐proprietary nameITSInterrupted time seriesOECDOrganisation for Economic Co‐operation and DevelopmentPPIProton pump inhibitorsPPRSPharmaceutical Price Regulation SchemeRCTRandomised controlled trialRMRepeated measuresRORRate of returnRPReference pricingRRRisk ratio (intervention vs control group)RR (adj)Risk ratio (adjusted for pre‐intervention differences) = RR post‐intervention/RR pre‐interventionWHOWorld Health Organization
Table 1. Abbreviations
STUDY ID / INTERVENTION PERIOD IN STUDY DRUGS INCLUDED IN ANALYSIS INTENSITY AND INCENTIVES EXEMPTIONS POLICY: REFERENCE PRICINGAronsson 20011993‐199612 different brand drugs: cimetidine, furosemide, atenolol, pindolol, propranolol, indomethacin, naproxen, allopurinol, paracetamol/codeine, diazepam, clomipramine, timololReference price: 10% above the price of the least expensive generic substituteNo information providedBrekke 20112003Drugs included in the analysis: brand‐names and generics and pharmaceutical expendituresUnder a reference pricing (RP) system, firms are free to set drug prices, but patient copayment is based on a RP, that is set by a regulator.More specifically, if a consumer chooses a drug that is priced higher than the RP, she has to pay the full difference between the RP and the actual drug price. Usually, the RP is set at a level somewhere between the lowest and highest drug price in the market.No information providedGrootendorst 2002For nitrates: October/November 1995 to May 1999 (March 1998 for some outcomes). For ACE inhibitors and CCBs: January 1997 to March 1998Nitrates (used for stable angina) for long term prophylaxis, ACE inhibitors (used for hypertension, congestive heart failure and diabetic nephropathy) and dihydropyridine CCBs (used for hypertension and stable angina)Reference price: Nitrates: Price of lowest priced regular‐release ISDN. ACE inhibitors and dihydropyridine CCBs: A fixed cost per 30 day supply. Incentives for physicians to prescribe lower dosages to not exceed monthly cap. Costs for the least‐expensive captopril, quinapril, and ramipril preparations available in pharmacies were covered. For other ACE inhibitors (enalapril, lisinopril, fosinopril, cilazapril, benazepril) patients were required to pay the difference, ranging from 2 to 62 Canadian Dollars per monthly supply. Reference prices in Canadian Dollar per 30 day supply were about 11 for H2RAs, 31 for dCCBs, 4 for nitrates and 27 for ACE inhibitors. Price year not reported.Special authority exemptions*: Nitrates, ACE inhibitors, CCBs. Therapeutic trial exemptions**: ACE inhibitors, CCBs. Automatic exemptions: Users of asthma or diabetes drugs: ACE inhibitors, CCBs. Residents of long term facilities: Nitrates. Prescriptions dispensed by specific specialists: CCBs, Nitrates. Some transdermal nitroglycerin patches were exempted from the reference pricing from January 1996 and March 1996. Suffciently low doses (not exceeding reference price for 30 day supply) were exempted from the reference pricing: ACE inhibitors, CCBS, nitrates (after September 1, 1998).Grootendorst 2005Pharmacare introduced two different forms of RP to the NSAIDs, Type 1 in April 1994 and Type 2 in November 1995Drug class NSAIDsUnder the policy, the less costly 'unrestricted' NSAIDs, enteric‐coated acetylsalicylic acid (ASA) (650 mg), ibuprofen, and naproxen remained fully reimbursed (at an average rate of about $0.23 daily). Pharmacare also began to reimburse acetaminophen (500 mg). The decision to provide full reimbursement for acetaminophen, ASA, ibuprofen, and naproxen was consistent with earlier recommendations by an independent academic research group, the BC Therapeutics Initiative, that these drugs be used as first line therapy for osteoarthritis (Therapeutics Initiative 1995).Patients intolerant of unrestricted NSAIDS or with specific diagnoses (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, collagen vascular disease, or gout) were eligible for exemption from the policy. Exemption for a ‘‘second line restricted’’ NSAID (nabumetone, piroxicam, tenoxicam, tiaprofenic acid, to‐ lmetin, sulindac, ketorolac, or diclofenac potassium) required failure on a first line restricted NSAID.Grootendorst 2006Jan 1994 to December 2000ACE inhibitors and CCBsReference pricing (RP) limits drug plan reimbursement of interchangeable medicines to a reference price, which is typically equal to the price of the lowest‐cost interchangeable drug.Under the RP policy, Pharmacare reimbursement of the ACE inhibitors enalapril, lisinopril, fosinopril, cilazapril, and benazepril was limited to $27 per month; the lower‐cost ACE inhibitors, captopril, quinapril, and ramipril remained fully reimbursed. Reimbursement of the dihydropyridine CCBs nifedipine, nicardipine and amlodipine was limited to $31 per month; felodipine remained fully reimbursed. Also, reimbursement of the sustained release forms of the CCBs diltiazem and verapamil was limited to the price of regular release versions of the equivalent dosage sizes of the same drugs. Beneficiaries who required a higher‐cost anti‐ hypertensive for medical reasons could be exempted from RP upon written petition by the physician.Hazlet 2002October 1995 toMarch 1996Histamine2 receptor antagonistsReference prices per 30 day supply were about 11 Canadian dollars for H2RAs (SeeGrootendorst 2002), lowest priced H2RA available. Special authority restrictions for reimbursement of PPIs, made H2RAs more attractive.Special authority exemptions*. Exemptions for low dosesKibicho 201220031. Antihypertensive drugs2. Antihyperlipidemic drugs3. Generic drugs4. Brand‐name drugsThe maximum allowable cost is a ceiling price set for generic and multisource brands that are chemically equivalent and have the same active ingredients (generic substitutes). Maximum allowable cost is similar to reference pricing used in Canada, which extends the concept of drug interchangeability to include chemically relatedactive ingredients that are pharmacologically equivalent (therapeutic substitutes).Instituting maximum allowable cost is the only policy designed to directly reduce the cost of generic drugs by limiting the amount that Medicaid can reimburse pharmacies.No information providedMarshall 2002October 1995 to May 1999Histamine2 receptor antagonistsSeeHazlet 2002SeeHazlet 2002McManus 2001June 1997 to December 1997RanitidineThe policy operated where there was more than one brand of a drug available through the Pharmaceutical Benefit Scheme and where the brands where therapeutically interchangeable. Generic substitution allowed. Premium on original brand Ranitidine 150 mg and 300 mg: $0,71 in May 1997. Price year not reported.No information providedMoreno‐Torres 2011December 2000This system was applied to products with the same active ingredient, pharmaceutical form, dosage and number of units for which there was at least one genericFor each group, a reference price was calculated as the weighted average selling price of the cheapest drug accounting for at least 20% of the market. This system established the maximum price that could be reimbursed by the NHS for any version of the same drug.No information providedNarine 2001October 1995 to November 1996Histamine2 receptor antagonistsSeeHazlet 2002SeeHazlet 2002Pavcnik 2002Oral antidiabetics: The first batch of reference pricing: 1989 to 1996 The second batch of reference pricing: 1994 to 1996 Anti‐ulcer drugs 1992 to 1996Oral antidiabetics and anti‐ulcer drugsNo information providedNo information providedPuig 2007January 2001 to October 2004Oral HMG‐CoA reductase inhibitors (statins): atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and cerivastatinReference pricing (RP) is a reimbursement policy that sets a maximum allowable cost that will be covered,RP systems can be grouped into different levels according to drug interchangeability. In September 2001 the Andalusian Public Health Service (henceforth APHS) introduced a new pharmaceutical procurement mechanism based on a more “intensive” RP system, including maximum prices.The previous situation was characterized by the absence of incentives to prescribe lower‐cost drugs with the same active ingredient, and by the absence of incentives for brand firms to lower prices even in the presence of lower‐priced generics.Seasonal fluctuations were controlled by including a term for August in the regression model. Seasonal variation is observed in the monthly periods resulting in a significant decrease during summer holidays (August).No information providedSawyer 1983September 1976 to October 197952 dosage forms of 25 multisource chemical entities, including ampicillin, chlordiazepoxide HCL(Librium), penicillin VK, propoxyphene HCL (Darvon) and tetracyklineState of Maryland used Maximum Allowable Costs ‐ Estimated Acquisition Costs (MAC‐EAC) procedures to reimburse community pharmacists for outpatient drugs dispensed to Medicaid patients. Maryland pharmacies billed Medicaid their usual and customary charges to the general public. Medicaid officials then determined the allowable cost for each claim by comparing billed charges against the appropriate MAC and/or EAC limits. Pharmacies were reimbursed the lowest established level (+ the flat dispensing fee).No information providedSchneeweiss 2002January 1997 ‐ April 1998 (for the outcome drug use)ACE inhibitorsSeeGrootendorst 2002SeeGrootendorst 2002Schneeweiss 2003January 1997 to April 1998CCBsSeeGrootendorst 2002SeeGrootendorst 2002Stargardt 2010January 2003 to December 2006Atorvastatin and other statinsReference pricing has been the subject of great debate since its introduction in Germany in 1989, the inclusion of statins was on 1 January 2005.Atorvastatin was classified as a ‘‘me‐too’’ drug and grouped with other statins, including generics. Additional co‐payments due to reference pricing for atorvastatin ranged from € 18.17 per package (30 mg/30 units) to € 109.00 per package (80 mg/100 units). As a result, pre‐ policy users of atorvastatin had to decide whether to switch to another statin to avoid additional co‐payments or to pay the difference between the price of atorvastatin and its reference pricing.In contrast to reference pricing in British Columbia, the German reference pricing system does not allow requests for exemption on a case‐by‐case basis, nor does it allow specific subgroups of patients to be excluded from the scheme POLICY: INDEX PRICINGBrekke 20031998‐2003Six groups of active substances: cetirizin (treatment of allergy), citalopram (antidepressant), enalapril (antihypertensive), lisinopril (antidepressant), loratadin (treatment of allergy) and omeprazol (treatment of gastro‐intestinal disorders)The levels of index prices relative to the prices of substitute drugs were not reported by the authors.When prescribing physician proscribes substitution of a generic in pharmacies POLICY: MAXIMUM PRICESPuig 20072004Oral HMG‐CoA reductase inhibitors (statins): atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and cerivastatinIn September 2001 the Andalusian Public Health Service (henceforth APHS) introduced a new pharmaceutical procurement mechanism based on a more “intensive” RP system, including maximum prices. In the APHS the reference price level is set at the level of the higher price of the two lowest‐priced products for each active ingredient with the same package size and dose strength. This system only works when and if physicians prescribe the active ingredient of the product. The pharmacies agreed with the regional government to dispense the lowest‐priced product for each active ingredient, independently of its generic status. In addition, economic incentives were introduced for physicians to prescribe using the non‐commercial name of the active ingredient.No information reported* Pharmacare may give special authority exemptions, based on therapeutic reasons provided by the physician in an application. Special authority exemptions were valid indefinitely for ACE inhibitors, CCBs and nitrates (after January 21, 1997) users. See Grootendorst 2002.** The physicians may apply for therapeutic trial exemptions in cases of intolerance or treatment failure or if the patient is frail. See Grootendorst 2002.*** In British Columbia Pharmacare covers all prescription drug costs for seniors with a dispensing deductible fee of CAD 200. Others can obtain similar coverage, but must pay a monthly.
Table 2. Intervention description
Table 3. Factors that could modify the effects of reference drug pricing
FACTOR CONDITION POTENTIAL EFFECTS OF CONDITIONS NOT FULFILLEDEquivalence of drugsThe drugs in the reference drug group should be therapeutically similar. If they are not, the patients may have to pay more to get the most effective drug ‐ or they may choose less effective drugsDrug use: Less shift towards cheaper drugsHealth: DecreaseHealthcare utilisation: IncreasePatient drug expenditures: IncreasedIncentivesAdequate incentives for patients, physicians, pharmacists and pharmaceutical companies to comply with the reference price systemDrug use: Less shift towards cheaper drugsDrug expenditures: Less savingsDrug prices: Less reductionsExemptionsReasonable mechanisms for exemptions for patients that need such for medical reasons. Too limited exemptions could lead to higher co‐payments of the most effective drug and to prescribing of less effective drugs by physicians. Too generous exemptions could reduce the savings, by not shifting the drug use towards cheaper drugsDrug use: Less shift towards cheaper drugsHealth: DecreaseHealthcare utilisation: IncreasePatient drug expenditures: IncreasedAvailability of drugsThe reference drugs and other cheap drug choices of the reference groups should be available. If not, more expensive drugs would be usedDrug expenditures: Less savingsDrug prices: Less reductionsPrice levelsTo achieve savings there should be significant price differences between the drugs in a reference group before the reference price system is introduced, with relatively high prices on the drugs most usedDrug expenditures: Less savingsDrug prices: Less reductionsElectronic information systemsThe administration costs, like time use for identifying, prescribing and dispensing the reference drugs and for handling exemption cases should be as low as possible. An electronic processing system would be useful and potentially time savingDrug use: Less shift towards cheaper drugsDrug expenditures: Less savingsDrug prices: Less reductions
Table 3. Factors that could modify the effects of reference drug pricing
Table 4. Reference pricing versus no reference pricing: Cumulative drug expenditures
STUDY ID POLICY: REFERENCE PRICE FOR EFFECTS ON CUMULATIVE EXPENDITURES OF**** OUTCOME ABSOLUTE CUMULATIVE DRUG EXPENDITURES, 1/2 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CUMULATIVE DRUG EXPENDITURES, 1/2 YEAR AFTER TRANSITION PERIOD (95% CI) ABSOLUTE CUMULATIVE DRUG EXPENDITURES, 1 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CUMULATIVE DRUG EXPENDITURES, 1 YEAR AFTER TRANSITION PERIOD (95% CI) ABSOLUTE CUMULATIVE DRUG EXPENDITURES, 2 YEARS AFTER TRANSITION PERIOD (95% CI) RELATIVE CUMULATIVE DRUG EXPENDITURES, 2 YEARS AFTER TRANSITION PERIOD (95% CI)Grootendorst 2002*ACE inhibitorsReference drugs + cost share drugsACE inhibitors. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month68554(17,064 to 154,173)3%(1% to 7%)144,630(18,603 to 270,657)3%(0% to 6%)153,191(35,666 to 342,047)2%(0% to 4%)CCBsReference drugs + cost share drugsCCBs. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month‐511,506(‐687,351 to ‐335,661)‐18%(‐25% to ‐12%)‐1,002,907(‐1,308,322 to ‐697,481)‐18%(‐24% to ‐13%)‐1,786,163(‐2,381,513 to ‐1,190,812)‐16%(‐22% to ‐11%)NitratesReference drugs + cost share drugsNitrates. Pharmacare expenditures per 100,000 senior citizens. Canadian dollar per month‐390,230 (‐422,501 to ‐357,958)‐48%(‐52% to ‐44%)‐‐‐‐Marshall 2002*H2RAsReference drugs + cost share drugsH2RAs. Pharmacare expenditures per 100,000 senior citizens. Canadian dollar per month‐261,347(‐292,070 to ‐230,623)‐38%(‐43% to ‐34%)‐482,978(‐529,961 to ‐435,995)‐36%(‐40% to ‐33%)‐882,353(‐957,349 to ‐807,356)‐34%(‐37% to ‐31%)Puig 2007lovastatinReference drugs + cost share drugsMean monthly savings of total lovastatin sales (%)Not reportedNot reportedNot reported10 months after intervention attributed to the RP revision applied (January 2004 – October 2004):Rest of Spain‐16.3% (−23.4 to −9.1)Andalusia ‐11.5% (‐3.5% to ‐19.5%)SimvastatinReference drugs + cost share drugsMean monthly savings of total simvastatin sales (%)Not reportedAfter intervention attributed to the initial application of RP to lovastatin (May 2002 – April 2003):Rest of Spain:16.7% (13.0% to 20.4%) of total lovastatin sales representing only 1.1% (0.9% to 1.3%) of total statins salesAndalusia: 23.7% (18.3% to 29.0%) representing only 1.3% (0.4% to 1.0%) of total statins salesNot reported10 months after intervention attributed to the RP revision applied (January 2004 – October 2004):Rest of Spain‐51.8% (‐48.9% to ‐54.6%)Andalusia: ‐29.7% (‐26.8% to ‐32.6%),Kibicho 20121. Antihypertensive drugs2. Antihyperlipidaemic drugs3. Generic drugs4. Brand‐name drugsReference drugs + cost share drugs***Total cumulative drug expenditures (USD)1: $18,562(‐$93 to $37,217)2: $15,322(‐$30,452 to$61,096)3: ‐$35,448(‐$50,470 to ‐$20,425)4: $69,331($21,553 to$117,109)Moreno‐Torres 2011All pharmaceuticals financed by the public sector in CataloniaTotal marketSaving per insured personEUR ‐4.06 (95% CI NA)‐1.54% (95% CI NA)*Results from reanalysis by reviewers. Negative values represent cost savings and positive values are cost increases.**NA = Not available.***Reference drugs (generic drugs) + cost share drugs (brand names).**** EFFECTS ON CUMULATIVE EXPENDITURES OF: Reference drugs, :drugs that determine the reference price level. There is no cost share by the patients for these drugs, which are fully reimbursed. The expectation is that reference pricing will lead to an increase in use of these drugs. Cost share drugs, drugs in the same group as the reference drugs that cost more. Patients have to pay the difference between reference price drugs and the price of these drugs. The expectation is that reference pricing will lead to a decrease in use of these drugs. Reference drugs + cost share drugs, both the reference drugs and the cost share drugs. The expectation is that reference pricing will lead to little or no change in the overall use of these drugs.
Table 4. Reference pricing versus no reference pricing: Cumulative drug expenditures
Table 5. Reference pricing versus no reference pricing: drug expenditures
STUDY ID REFERENCE PRICE FOR EFFECTS ON EXPENDITURES OF*** OUTCOME ABSOLUTE CHANGE LEVEL, IMMEDIATE AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, IMMEDIATE AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 1/2 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 1 YEAR AFTER TRANSITION PERIOD (95% CI) RELATIVE CHANGE IN LEVEL, 2 YEARS AFTER TRANSITION PERIOD (95% CI) NOTESGrootendorst 2002*ACE inhibitorsReference drugs + cost share drugsACE inhibitors. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month18,203(‐1611 to 38,017)5%(0% to 10%)5%(‐2% to 10%)4%(‐3% to 10%)1%(‐8% to 9%)Price year not specified in study papersCCBsReference drugs + cost share drugsCCBs. Pharmacare expenditure per 100,000 senior citizens. Canadian dollar per month‐91,547(‐122,082 to ‐61,011)‐19%(‐26% to ‐13%)‐18%(‐30% to ‐5%)‐16%(‐36% to 5%)‐14%(‐51% to 23%)Price year not specified in study papersNitratesReference drugs + cost share drugsNitrates. Pharmacare expenditures per 100,000 senior citizens. Canadian dollar per month‐66,473 (‐72,620 to ‐60,326)‐50% (‐55% to ‐46%)‐47% (‐52% to ‐41%)‐‐Price year not specified in study papersGrootendorst 2005NSAIDs (RP 1)Reference drugs + cost share drugsAverage monthly expenditure per day of therapy dispensed (Canadian dollars 2004) for Pharmacare (Ph) and Patient (Pa)Ph:‐0.08 (‐0.12 to ‐0.04)Pa: 0.00 (‐0.03 to 0.02)Ph: ‐9.6%(95% CI NA)Pa: NA‐Ph: ‐8.8% (95% CI NA)Pa: 690% (95% CI NA)Ph: ‐8.3% (95% CI NA)Pa: 571% (95% CI NA)Last estimated effect at 19 monthsNSAIDs (RP 2)Reference drugs + cost share drugsAverage monthly expenditure per day of therapy dispensed (Canadian dollars 2004) for Pharmacare (Ph) and Patient (Pa)Ph:‐0.31 (‐0.36 to ‐0.27)Pa: 0.07 (0.04 to 0.10)Ph: ‐37% (95% CI NA)Pa: 550% (95% CI NA)‐Ph: ‐53% (95% CI NA)Pa: 500% (95% CI NA)‐Marshall 2002*H2RAsReference drugs + cost share drugsH2RAs. Pharmacare expenditures per 100000 senior citizens. Canadian dollar per month‐45,139(‐50,096 to ‐40,183)‐39%(‐44% to ‐35%)‐38%(‐44% to ‐31%)‐35%(‐45% to ‐25%)‐30%(‐48% to ‐12%)Price year not specified in study papersGrootendorst 2006ACE inhibitorsReference drugs + cost share drugsAll ACE inhibitors. Drug plan expenditures per DDD dispensed. CAD‐0.04 (‐0.09 to 0.02)‐4% (95% CI NA)‐7% (95% CI NA)‐11% (95% CI NA)Price specified in study papersCCBsReference drugs + cost share drugsAll CCBs. Drug plan expenditures per DDD dispensed. CAD‐0.20(‐0.25 to ‐0.15)‐16% (95% CI NA)‐10% (95% CI NA)‐4% (95% CI NA)Price year not specified in study papersSawyer 198352 dosage forms of 25 multisource chemical entitiesReference drugs + cost share drugsMonthly Medicaid drug expenditures in Maryland. USD‐291276(‐478,458 to ‐104,094)‐0.87 per month (95% CI NA)Price year not specified in study papersBrekke 2011The RP covered six chemical substances: Citalopram, Omeprazol, Cetirizin, Loratadin, Enalapril and Lisinopril . The system was later extended with two additional substances; simvastatin and amlodipinCost share drugsChange in copayments NOKGeneric copayment ‐12.92 (95% CI NA)Brand‐name copayment ‐6.37 (95% CI NA)Generic copayment ‐12.76% (95% CI NA)Brand‐name copayment ‐14.82% (95% CI NA)*Results from reanalysis by reviewers.**NA = Not available.*** EFFECTS ON EXPENDITURES OF: Reference drugs, drugs that determine the reference price level. There is no cost share by the patients for these drugs, which are fully reimbursed. The expectation is that reference pricing will lead to an increase in use of these drugs. Cost share drugs, drugs in the same group as the reference drugs that cost more. Patients have to pay the difference between reference price drugs and the price of these drugs. The expectation is that reference pricing will lead to a decrease in use of these drugs. Reference drugs + cost share drugs, both the reference drugs and the cost share drugs. The expectation is that reference pricing will lead to little or no change in the overall use of these drugs.
Table 5. Reference pricing versus no reference pricing: drug expenditures
Table 7. Reference pricing versus no reference pricing: drug prices and patients' out‐of‐pocket payments
Table 7. Reference pricing versus no reference pricing: drug prices and patients' out‐of‐pocket payments
Table 8. Index pricing versus no index pricing: drug use
Table 8. Index pricing versus no index pricing: drug use
Table 9. Index pricing versus no index pricing: copayments and drug prices
Table 9. Index pricing versus no index pricing: copayments and drug prices
Table 10. Maximum prices versus no maximum prices: drug expenditures
| https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005979.pub2/appendices/zh_HANS |
Multiple steady states in distillation - CaltechTHESIS
Multiple steady states in distillation
Citation
Bekiaris, Nikolaos
(1995)
Multiple steady states in distillation.
Dissertation (Ph.D.), California Institute of Technology.
doi:10.7907/S6MC-5V73.
https://resolver.caltech.edu/CaltechETD:etd-09122007-075846
Abstract
NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.
We study multiple steady states in distillation. We first analyze the simplest case of ternary homogeneous azeotropic mixtures. We show that in the case of infinite reflux and an infinite number of trays ([...] case) one can construct bifurcation diagrams on physical grounds with the distillate flow as the bifurcation parameter. Multiple steady states exist when the distillate flow varies non-monotonically along the continuation path of the bifurcation diagram. We derive a necessary and sufficient condition for the existence of these multiple steady states based on the geometry of the distillation region boundaries. We also locate in the composition triangle the feed compositions that lead to these multiple steady states.
We further note that most of these results are independent of the thermodynamic model used. We show that the prediction of the existence of multiple steady states in the [...] case has relevant implications for columns operating at finite reflux and with a finite number of trays. Using numerically constructed bifurcation diagrams for specific examples, we show that these multiplicities tend to vanish for small columns and/or for low reflux flows. Nevertheless, the [...] multiplicities do exist for columns at realistic operating conditions. We comment on the effect of multiplicities on column design and operation for some specific examples.
We then extend the homogeneous mixture results to ternary heterogeneous mixtures. We study the [...] case in much more depth and detail by demonstrating how the [...] analysis can be applied to different column designs. More specifically, we show how the feasible distillate and bottom product paths can be located for tray or packed columns, with or without decanter and with different types of condenser and reboiler. We derive the fully detailed, necessary and sufficient condition for the existence of these multiple steady states based on the geometry of the product paths. Simulation results for finite columns show that the predictions carry over to the finite case.
The complete list of the [...] case predictions is presented. The implications of these multiplicities for column design, synthesis and simulation are demonstrated. More specifically, we show how the [...] predictions can be useful for the selection of the entrainer, the equipment and the separation scheme. We show that, in some cases, the column operation at an unstable steady state may have some advantages. The important issue of the effect of the thermodynamic phase equilibrium on the existence of multiplicities is discussed. Using the [...] analysis, we identify entire mixture classes for which multiplicities are inherent and robust. Mixtures with ambiguous VLE data are studied; we show that in some cases a slight VLE difference between models and/or experimental data may affect the existence of multiplicities while other, major VLE discrepancies do not. Finally, we identify the key issues and the pitfalls one should be cautious about when designing or computing the composition profile of an azeotropic distillation column with a commercial simulator.
Item Type: Thesis (Dissertation (Ph.D.)) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemical Engineering Thesis Availability: Public (worldwide access) Research Advisor(s): Morari, Manfred Thesis Committee: Morari, Manfred (chair) Gavalas, George R. Brady, John F. Wiggins, Stephen R. Defense Date: 10 May 1995 Record Number: CaltechETD:etd-09122007-075846 Persistent URL: https://resolver.caltech.edu/CaltechETD:etd-09122007-075846 DOI: 10.7907/S6MC-5V73 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 3503 Collection: CaltechTHESIS Deposited By: Imported from ETD-db Deposited On: 04 Oct 2007 Last Modified: 21 Dec 2019 03:55
Thesis Files
Preview PDF (Bekiaris_n_1995.pdf) - Final Version See Usage Policy. 10MB
| http://thesis.library.caltech.edu/3503/ |
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
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.
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
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.
Cite
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Assistive Technology (AT), for What?
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
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
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...
Critical Junctures in Assistive Technology and Disability Inclusion
| https://www.disabilityinnovation.com/publications?subject=mobility+social-inclusion&type=report+editorial+phd |
U.S. Census Bureau QuickFacts: Sioux County, Nebraska; Grant County, Nebraska; Hooker County, Nebraska; Nemaha County, Nebraska; Boyd County, Nebraska
Frequently requested statistics for: Sioux County, Nebraska; Grant County, Nebraska; Hooker County, Nebraska; Nemaha County, Nebraska; Boyd County, Nebraska
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A Study to Examine the Use of Zemplar to Increase Serum Calcium Levels in ICU Subjects - Full Text View - ClinicalTrials.gov
A Study to Examine the Use of Zemplar to Increase Serum Calcium Levels in ICU Subjects
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: NCT00053378 Recruitment Status :
Completed First Posted : January 28, 2003 Last Update Posted : August 2, 2006
Sponsor:
Information provided by:
Abbott
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:
A study to determine the effect of Zemplar on the regulation of serum calcium levels and the need for administration of elemental calcium in hypocalcemic intensive care patients
Condition or disease Intervention/treatment Phase Hypocalcemia Drug: paricalcitol injection (Zemplar) Behavioral: Effects on calcium regulation Behavioral: Administration of elemental Ca during hypocalcemic ICU pts. Phase 2
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) Enrollment : 45 participants Allocation: Randomized Intervention Model: Factorial Assignment Masking: Double Primary Purpose: Treatment Official Title: A Placebo-Controlled, Double-Blind Study to Examine the Use of Zemplar to Increase Serum Calcium Levels in ICU Subjects Study Start Date : January 2002
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Calcium
Drug Information available for: Calcium Gluconate Paricalcitol
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
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
The primary efficacy variable will be the change from Day 1 to last day of dosing in pH adjusted, serum ionized calcium levels.
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 and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
ICU patients APACHE III score between 70 - 150 at screening and within 24 hours of enrollment and a whole blood ionized calcium level less than 0.90 mmol/L or corrected whole blood calcium level less than or equal to 7.5 mg/dL.
Serum creatinine greater than 2.5 mg/dL
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): NCT00053378
Locations
Layout table for location information United States, California Merced Heart Association Merced, California, United States, 95340 United States, Colorado Denver Health Medical Center Denver, Colorado, United States, 80204 United States, Florida Outcomes Research Institute Hudson, Florida, United States, 34667 Florida Hospital Orlando, Florida, United States, 32803 United States, Illinois University of Chicago Chicago, Illinois, United States, 60637 United States, Kentucky Central Baptist Hospital Clinical Research Center Lexington, Kentucky, United States, 40503 United States, New York Strong Memorial Hospital Rochester, New York, United States, 14642 United States, Pennsylvania St. Luke's Hospital Bethlehem, Pennsylvania, United States, 18015 United States, Virginia Heart Care Associates Hopewell, Virginia, United States, 23860
Sponsors and Collaborators
Abbott
Investigators
Layout table for investigator information Study Director: Joel Z Melnick, M.D. Abbott
More Information
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information ClinicalTrials.gov Identifier: NCT00053378 History of Changes Other Study ID Numbers: M01-395 First Posted: January 28, 2003 Key Record Dates Last Update Posted: August 2, 2006 Last Verified: July 2006
Keywords provided by Abbott:
hypocalcemia, ionized calcium, intensive care
Additional relevant MeSH terms:
Layout table for MeSH terms Hypocalcemia Calcium Metabolism Disorders Metabolic Diseases Water-Electrolyte Imbalance Calcium Calcium-Regulating Hormones and Agents Physiological Effects of Drugs
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/ct2/show/NCT00053378 |
(PDF) Overeating in the Ts65Dn trisomic mouse model is associated with dopaminergic neurotransmission deficit in the prefrontal cortex
PDF | Individuals with Down syndrome (DS) have a higher prevalence of obesity than the general population. This has traditionally been attributed to... | Find, read and cite all the research you need on ResearchGate
Overeating in the Ts65Dn trisomic mouse model is associated with dopaminergic neurotransmission deficit in the prefrontal cortex
December 2022
DOI: 10.21203/rs.3.rs-2358600/v1
License
CC BY 4.0
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Marta Fructuoso
Marta Fructuoso
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Alvaro Fernandez
crg
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Ana Gallego
Ana Gallego
<here is a image b0efab6617d32bec-b70b9e5f868785f3>
Maria martinez de lagran
Centre for Genomic Regulation
Abstract and Figures
Individuals with Down syndrome (DS) have a higher prevalence of obesity than the general population. This has traditionally been attributed to endocrine issues and deficient exercise. However, the development of obesity is coupled with deficits in neural reward responses, and previous works showed dopaminergic disturbances in DS. We here tested the hypothesis that “hedonic” overeating may play a central role in the development of obesity as a consequence of sub-functional dopaminergic neurotransmission in a mouse model that bears in triplicate many most of the genes in trisomy 21, Ts65Dn. Meal pattern analysis in this trisomic mouse model (Ts65Dn), revealed an increased preference for energy-dense food. Trisomic mice also scored significantly higher in compulsivity and inflexibility tests as measured by limited access to energy-dense food and food adulteration with quinine hydrochloride. We detected reduced dopamine levels in the prefrontal cortex of Ts65Dn mice, and insensitivity to the dopamine D2receptor agonist (quinpirole) anorectic effect for palatable foods that may facilitate overeating in an attempt to restore optimal dopamine levels. Interestingly, impulsive and compulsive behaviors were significantly reduced when prelimbic-to-nucleus accumbens projections were activated in Ts65Dn mice using a chemogenetic approach. Our work unravels a new mechanism underlying vulnerability to the development of overeating in DS, which could pave the way towards novel and efficient interventions for obesity.
<here is a image 80eabba6b2e645d3-cdd6f5a0e9e24447>
Body weight increase and energy-intake in wild-type (WT) and Ts65Dn mice having free access energy-dense diets. (a) Experimental design (Experiment 1). Mice were individually housed in multi-take metabolic cages registering locomotor activity and meal pattern. During the habituation period (2 weeks), all mice received standard chow (SC). After two weeks, mice were allocated to receive free access to chocolate-mixture (CM) or high-fat diet (HF). After animals gained stable overweight ("Obesity Development"; eight weeks starting from the introduction of energy-dense diets), a battery of behavioral tests was used to characterize compulsive and inflexible behavior. (b) Mean body weight changes along the 8 weeks of the experiment in each experimental group in wild type (WT, circles) and Ts65Dn (TS, squares) mice. (c) Daily total energy intake (KJ consumed per body weight) by the genotype of each group. (d) Daily energy intake (KJ/day) by the genotype of each group. (e) Daily energy intake corrected by body weight (KJ/BW/day) of SC and CM in SC+CM mice of either genotype (left panel) and of SC and HF in SC+HF mice of either genotype. SC group: WT = 8, Ts65Dn = 8; SC + CM group: WT = 10, Ts65Dn = 10; SC + HF group WT = 9, Ts65Dn = 9. * p <0.05, ** p <0.01, *** p <0.001. In white comparisons between SC vs CM/HF, in brown for CM, and in green for HF. …
<here is a image d072713f3d56e1dd-656fb3a7ece47ff9>
Energy-dense foods induce "snacking-behaviors'' in wild-type (WT) and Ts65Dn (TS) mice. Bar plots represent the meal pattern of each type of food for each experimental group. For all figures, the left panel shows WT mice and the right panel shows Ts65Dn (TS) values. (a, b) Number of meals. (c, d) Average meal duration (min). (e, f) Eating rate (mg/s). Data are represented as mean ± SEM. SC group: WT = 8, Ts65Dn = 7; SC + CM group: WT = 9, Ts65Dn = 10; SC + HF group: WT = 8, Ts65Dn = 7. * p < 0.05, ** p <0.01, *** p <0.001. In the figures, only the significance of the intra-genotype CM vs SC (in SC+CM mice) HF vs SC (in SC+HF mice) is depicted. …
<here is a image 89cc217ec94106d2-ac8a071abc007778>
Limited access to energy dense foods revealed binge-like in Ts65Dn mice intake during the shortterm free access. (a) Limited access experiment schedule. (b) CM or (c) HF energy intake ad libitum and during the three consecutive days of one-hour limited access to CM/HF. (d) Increase of energy intake of CM and HF at the third day of limited access compared to ad libitum conditions. (e) SC-energy intake in ad libitum (left; ad lib) and in conditions of access to only SC of the limited access to CM or HF experiment (right, Limited). Note the significant increases in all groups. (f) Difference between the energy intake in limited access to CM or HF conditions (when only SC is available) and the total energy intake (SC+CM/ SC+HF) in ad libitum conditions. ad lib = ad libitum; Data are expressed as mean ± SEM. SC + CM group: WT = 9, Ts65Dn = 10; SC + HF group: WT = 7; Ts65Dn = 7. * p < 0.05; ** p < 0.01. …
<here is a image ed618d82ead64308-d3adab804eee420e>
Tissue levels of monoamines and their metabolites in the striatum (ST) of wild-type (WT) and Ts65Dn (TS) mice. At the end of the behavioral battery, animals were sacrificed, and the PFC and ST were dissected and collected for HPLC monoamine determination. Levels (ng/mg) in ST of (a) dopamine (DA) and (b) Homovanillic acid (HVA), a DA metabolite. In PFC, levels (ng/mg) of (c) dopamine (DA), (d) Homovanillic acid (HVA), and (e) 5-Hydroxyindoleacetic acid (5HIIA), a 5HT metabolite. SC group: WT = 5, Ts65Dn = 5; SC + CM group: WT =6, Ts65Dn = 6; SC + HF group: WT = 5; Ts65Dn = 5. Two-way ANOVA, Bonferroni; * p < 0.05; (a) comparisons showed are One-way ANOVA Bonferroni; * p < 0.05. …
<here is a image 746c5b6b3318e5d0-a32f252d9b4636f3>
+2
Evaluation of the anoretic effect of acute administration of quinpirole. (a) Mice received intraperitoneally administration of saline or 0.1 mg/Kg of quinpirole and were given they diet according to each experimental group. Food intake (in grams/body weight) 30 minutes after refeeding in (b) SC fed mice (c) SC+CM mice, and (d) SC+HF mice. Data are expressed as mean ± SEM. SC group: WT = 10, Ts65Dn = 9; SC + CM group: WT = 10, Ts65Dn = 9; SC + HF group: WT = 11; Ts65Dn = 10. * p ≤ 0.05; ** p ≤ 0.01. …
Figures - available via license: Creative Commons Attribution 4.0 International
Abbreviated title: Dopamine deficit and overeating in Ts65Dn mice
MartaFructuoso a,ÁlvaroFernández-Blanco a,AnaGallego-Román b,MaríaMartínezde
Lagrán a ,IlariodeToma a,KlausLangohr c,g,ElenaMartín-García b,c,d,RafaelMaldonado b,c,
Julien Dairou d, Nathalie Janel e, Mara Dierssen a,b,c,f
a Centre for GenomicRegulation (CRG),The BarcelonaInstitute ofScience andTechnology,08003 Barcelona,
Spain
b Laboratory of Neuropharmacology - Neurophar,Department of Medicine andLife Sciences, UniversitatPompeu
Fabra (UPF), Barcelona, Spain.
c Human Pharmaco logy and Clinical Neurosciences Research Group, Neurosciences ResearchProgram, Hospital
Del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain
d DepartamentdePsicobiologiai MetodologiadelesCiènciesdela Salut,UniversitatAutònomadeBarc elona
(UAB), Cerdanyola del Vallès, Barcelona, Spain.
d UniversitédeParis,LaboratoiredeChimieetBiochimiePharmacologiquesetToxicologique,UMR8601,
CNRS, F - 75013 Paris
e Universite de Paris, BFA, UMR 8251, CNRS, F - 75013 Paris, France
f Centro de Investigación Biomédica en Redde Enfermedades Raras (CIBERER), Spain
g Department ofStatistics andOperations Research, UniversitatPolitècnica deCatalunya/ BARCELONATECH,
Barcelona, Spain
Correspondence should be addressed to: Mara Dierssen: [email protected]
Phone: +34-93-3160140
Fax: +34-93-3160099
Numberofpages: 34,Numberoffiguresandtables: 7Figand2tables.Extendeddata:
extendedmethods,2figures. ,Numberofwordsforabstract:168 ,Numberofwordsfor
introduction: 357 , Number of words for discussion: 1438
Conflict of interest statement
The authors declare no competing financial inter ests.
Author contributions
MaraDierssen,MartaFructuoso,AlvaroFernández,AnaGallego,ElenaMartínandRafael
Maldonadodesignedtheexperimentsanddiscussedtheresults.MartaFructuoso,Alvaro
Fernández, Ana Gallego and María Martínez de Lagrán performed the experiments and Marta
Fructuoso,AlvaroFernándezandAnaGallegoanalyzedthebehavioralstudies.Marta
Fructuoso,JulienDairou,andNathalieJanelperformedandanalyzedthebioamine
2
determinationbyHPLC.IlariodeTomaperformedthecorrelationsandstatisticalanalysis
between the behavioraland the brainbioamine’s data. MartaFructuoso and Klaus Langohrdid
the statisticalanalysis of theresults. Marta Fructuosoand MaraDierssen wrote themanuscript.
andallauthorscommentedonpreviousversionsofthemanuscript.Allauthorsreadand
approved the final manuscript.
Funding and acknowledgements
ThisworkwassupportedbytheFondationJérômeLejeune#2002(MD,MML,MF, AF),
MINECO(PID2019-110755RB-I00/AEI/10.13039/501100011033,RTC2019-007230-1and
RTC2019-007329-1 (MD, AF, MML, IT),Fundació La Marató De TV3(201620-31) (EM.G,
MD,MML,MF,IT)and202212-30-31-32(MD,MML,AFB),EuropeanUnion’sHorizon
2020 research andinnovation programme undergrant agreement No 848077(MD, MML, MF,
AF ), BrainInitiative(1R01EB028159-01) (MD,MML)andgrants fromUniversitédeParis
andCNRS(JDandNJ).‘PlanNacionalSobreDrogasoftheSpanishMinistryofHealth’
(#PNSD-2019I006)andSpanishMinisteriodeCienciaeInnovación(ERA-NET)PCI2021-
122073-2AtoE.M.- G.Thelaboratoryof MDissupportedbyDIUEdelaGeneralitatde
Catalunya(GrupsConsolidats2017SGR926).Weacknowledgethesupport oftheSpanish
Ministry of Scienceand Innovationto the EMBLpartnership, the Centrode Excelencia Severo
Ochoa andthe CERCA Programme/ Generalitatde Catalunya.The CIBER ofRare Diseases
isaninitiativeoftheISCIII.CSreceivedtheFIgrantfromAgènciadeGestiód’Ajuts
Universitaris i de Recerca (AGAUR) dela Generalitat de Catalunya, AFB received anFPI- SO
fellowship(PRE2018-084504).J.DalsoacknowledgestheMassspectrometryplatformof
UMR 8601 laboratory.
Data availability
All the raw data and supplementary materials are available upo n request.
3
ABSTRACT
IndividualswithDownsyndrome(DS)haveahigherprevalenceofobesitythanthegeneral
population.Thishastraditionallybeenattributedtoendocrineissuesanddeficientexercise.
However, the development of obesity iscoupled with deficits in neural rewardresponses, and
previous worksshowed dopaminergicdisturbances inDS. Wehere testedthe hypothesisthat
“hedonic” overeating mayplay acentral rolein the developmentof obesityas a consequence
ofsub-functionaldopaminergicneurotransmissioninamousemodelthatbearsintriplicate
many mostof thegenesin trisomy21,Ts65Dn. Mealpattern analysisinthis trisomicmouse
model (Ts65Dn), revealed an increasedpreference for energy-dense food. Trisomicmice also
scored significantlyhigher incompulsivityand inflexibilitytests asmeasured bylimitedaccess
to energy-densefood and foodadulteration withquinine hydrochloride.We detectedreduced
dopamine levelsin theprefrontal cortexof Ts65Dn mice,and insensitivityto thedopamine D 2-
receptor agonist (quinpirole) anorectic effect for palatable foods that may facilitate overeating
inanattempttorestoreoptimaldopaminelevels.Interestingly,impulsiveandcompulsive
behaviors weresignificantly reducedwhen prelimbic- to-nucleusaccumbens projectionswere
activatedinTs65Dnmiceusingachemogeneticapproach.Ourworkunravelsanew
mechanism underlyingvulnerability tothe developmentof overeatingin DS,which couldpave
the way towards novel and efficient interventions for obesity.
SI GNIFICANCE STATEMENT
ObesityinDownsyndrome(DS)isclassicallyattributedtoendocrineissuesanddeficient
exercise, yet itsprevention andtreatment only basedon diet andphysical exercise hasnot been
successful. In part,this couldbe explained becauseindividuals withDS tendto overconsume
energy-dense foods,sothat “hedonic”overeating mayplaya centralrolein thedevelopment
of obesityin individualswith DS,suggesting thecontribution of reward-relatedmechanisms.
4
Here weshow thataltered dopaminergicneurotransmission inthe prefrontalcortex, involved
in rewardbrain networks,couldexplain theincreased vulnerabilityto overeatingandobesity
inDS.Wefoundthathigh-fatfoodsareespeciallydetrimentalforbehavioralcontrol(e.g.
flexibility, impulsivitymanagement)inaDSmouse mod el,theTs65Dn.Ourresultssuggest
that overeatingandlossofbehavioral controlcouldberelated tothereducedlevels ofdopamine
in theprefrontal cortex andto dysfunctionof prelimbic- to-nucleusaccumbens projections. Our
work unravels a new mechanism underlying vulnerability to the development ofovereating in
DS, which could pavethe way towards novel and efficient interventions for obesity. However,
the limitationisthat Ts65Dnmicebear intriplicatea numberofnon-HSA21 genesthatmay
interfere with the observed phenotype.
KEYWORDS: Down syndrome, obesity, overeating, prefrontal cortex, dopamine.
INTRODUCTION
Individuals withDownsyndrome (DS)presentahigh prevalenceofobesitycompared tothe
general population [1].This hasbeentraditionallyattributed toendocrinealterations,such as
leptin resistanceor thyroidgland dysfunction[2, 3],and toreducedexercising [4].However,
it has also been reportedthat DS adolescents and adultshave a tendency for snackingenergy-
dense foods,such assnacks andsweet beverages[5, 6].Snacking behavioris knownto activate
therewardsystemandmayleadtoreward-inducedovereating[7].Specifically,themedial
prefrontal cortex, partof themesocorticolimbic dopaminergic system,has arole in self-control
andrewardsensitivity[8].Consistentwiththesedata,weshowedthatthechemogenetic
inhibitionoftheactivityoftheprelimbic(PL)medialprefrontalcortex(mPFC)neurons
projectingtothenucleusaccumbens(NAc)core(PLmPFC-NAccorepathway)induced
compulsive food seeking[9]. Interestingly, elevated bodymass index (BMI) is associated with
decreased bloodflowinthePFC[10],andovereating hasbeenassociatedwithorbitofrontal
5
volumereductions[11,12].InDS,thereisreducedvolume[13]anddecreasedfunctional
connectivity[14]inthefrontalcortex,andgeneticpolymorphismsinthecatechol-O-
methyltransferase(COMTVal158Met)geneconferringlowerDAavailability[15].Reduced
concentrationsofDAhavebeendetectedinDSbrains[13],alongwithfrequentanhedonia
(reducedpleasureresponses),associatedwithpsychiatriccomorbidities[16]andincreased
impulsiveness[17].However,nostudieshaveaddressedthelinkbetweenimpairedPFC
dopaminergic system, the control of eating behavior and obesity in DS.
We hypothesize that obesity in individuals with DS may be contributed by an alteration of the
brain reward system[18, 19] that,in turn, mayincrease their riskof overeating sweetor fatty
foods. To address this question, we used a diet-induced paradigm, with free choice access to a
highly palatable(chocolate-mixture) dietorto ahigh-fat dietfor8 weeksin aDS mousemodel,
theTs(17 16)65Dn (Ts65Dn)mice.Wealsoinvestigatedcompulsiveandinflexiblebehaviors
and diet-induced changes in monoamine levels in the prefrontal cortex and striatum, related to
the reward-driven control of feeding. Finally, we designed a strategy to specifically target and
manipulate theexcitatoryprojectionsfromPL-mPFCtotheNAc coreinordertoreducethe
compulsive and inflexible behaviors we observed in Ts65Dn mice.
MATERIAL AND METHODS
Animal breeding and diets.
Ts(17 16 )65Dn(Ts65Dn)micewereobtainedthroughcrossingsofaB6EiC3Sna/A- Ts
(17 16 )65Dn(Ts65Dn)femaletoB6C3F1/JmalespurchasedfromTheJacksonLaboratory.
GenotypingwasperformedbyamplifyinggenomicDNAobtainedfromthemouse tailas
described in [20].The colonyof Ts65Dn micewas maintained inthe AnimalFacilities in the
BarcelonaBiomedicalResearchPark(PRBB,Barcelona,Spain).Micereceivedchowand
6
water adlibitumincontrolled laboratory conditionswith temperaturemaintained at22 ±1 oC
and humidity at55 ± 10%on a 12hlight/dark cycle (lightsoff 20:00h). The controlgroup (WT
= 8,Ts65Dn =8) wasgiven standardchow (SC; SDSdiets). Thesemice servedto assessthe
genotype-dependentdifferencesinfeedingbehaviorandbrainmonoaminelevelsinnon-
obesogenic conditions. In separate groups of animals, we used two free-choice diet conditions
tostudythepreferenceforsweetandfattyfoods,obesitydevelopment,theappearanceof
compulsive-likeeating,andassociatedneurochemicalchanges.Inoneexperimentalgroup,
mice hadfreeaccessto standardchow(SC),and topelletsofa chocolate-mixture(CM)diet
madefromequalamountsofBounty®,Snickers®,Mars®,andMilka®chocolateproducts
(WT = 10, Ts65Dn = 10; SC+CM group). In the second condition, mice had free access to SC
and a high-fat diet (HF;Test Diet)(WT =9, Ts65Dn= 9; SC+HFgroup). Pelletswere renewed
atleasttwiceaweektoensurethemaintenanceoftheirorganolepticproperties.Micefrom
bothgroupsweresubmittedtothebehavioralexperimentsandthestudyofbioamines.A
separate group ofmice ( WT= 11,Ts65Dn = 9)was givenan intraperitonealinjection of D2-
receptoragonist(quinpirole)toevaluatetheinvolvementofthedopaminergicsystemin
energy-dense food overeating. Finally, a third group of mice(WT = 12, Ts65Dn = 6; SC + HF
group) was used to tag and manipulate the PL-NAc core projectionsand had free access to SC
and HF diet. Other 6 WT animals whose PL-NAc projections were tagged with mCherrywere
usedasacontrolthatneuronalactivationwasinducedbyCNOadministration.All
experimentalprocedureswereapprovedbythelocalethicalcommittee(ComitéÉticode
Experimentación AnimaldelPRBB (CEEA-PRBB);procedurenumber MDS-12-1464P3),and
mettheguidelinesofthelocal(law32/2007)andEuropeanregulations(EUdirectiven°
86/609, EU decree 2001-486) and the Standards for the use of Laboratory Animals n° A5388-
01 (NIH).Theexperimentswereperformedbythesame experimenterin5months-oldmale
Ts65Dn and wild-type(WT) littermates, toallow the stabilizationof weight gain.Based on the
7
results from previouswork, we estimated thatfor a statisticalpower of 80%,a sample sizeof
eight/group would detect a 30% difference in the measured variables (alpha <0.01).
Experimental design.
Experiment 1. Diet-induced obesity and monoamine levels
For thediet-inducedobesity paradigm,we followedtheprotocol detailedin[21] .Briefly,all
mice wereindividually housedin PheCOMPmulti-take metaboliccages (Panlab)andprovided
withSCandwaterfortwoweekstoallowhabituationtothehousingconditions.After
habituation, micewere assignedto eachdiet condition,i.e. SCor freeaccess toeither CMor
HF. Micewere leftundisturbed foreight weeksto allowstableweight gain.We measuredbody
weight gainon aprecision scale,and themeal patternwas automaticallyrecorded andanalyzed
(see below) duringthe whole experimentalperiod. After theanimals reached stableweight, we
evaluated compulsiveovereatingand behavioralinflexibilityusing stand-alonetests.Finally,
micewereeuthanizedwithCO 2andthemonoaminecontentinstriatum(ST)andPFCwas
measured (Fig. 1a).
Feeding behavioranalysis . ThePheCOMPmulti-take metabolismcages (Panlab)providefine-
grain feeding behavior data fordetailed meal pattern analysis. Twofood dispensers containing
SC andCM orHFwere locatedinthe PheCOMPcages, counterbalancedbetweencages and
genotypes(foracompletedescription, see[22].Themealpatternwasanalyzedusingthe
COMPULSE software(Panlab). Weanalyzed thenumber andaverageduration ofmeals, the
totalfoodconsumed,andeatingrate(foodconsumedpersecond). Wecalculatedthe
food/energy intake,the circadianand ultradianfrequency distributionsof me als,and thesatiety
ratio (intermeal intervals divided by theamount (g) of food consumed inthe preceding meal).
Acustom-madeRcode,availableuponrequest,wasdevelopedtodeterminewhetherpellet
losswasproducedduringtheexperiment.Ifpelletlosswasdetected,datawerecorrected
accordingly.
8
Limited access to energy-dense foods. Access to CM or HFdiet was restricted to 1hduring the
21
ofadulteratedSCascomparedtonon -adulteratedSC. (c) ConsumptionofadulteratedSCintheSCgroup.
Percentageof (d) WTand (e) Ts65Dnmiceeatingthesameamount,30%less,ormorethan30%lessof
adulterated CMas comparedto non -adulteratedCM. (f) Consumption ofadulteratedCM inthe SC+CM group.
Percentageof (g) WTand (h) Ts65Dnmiceeatingthesameamount,30%less,ormorethan30%lessof
adulterated HF as compared to non -adulterated HF. (i) Consumption of adulterated HF in the SC+HF group.SC
group: WT = 8, Ts65Dn = 7; SC + CMgroup: WT = 10, Ts65Dn= 10; SC + HF group: WT = 9; Ts65Dn =7; * p
< 0.05.
LowdopaminelevelsinprefrontalcortexofTs65Dnmightfacilitateabnormalfeeding
behavior
To understandtheeffectof thedietson themonoaminecontentin thebrainsof WTandTs65Dn
mice, weperformed HPLC analysisin thestriatum (ST)and prefrontal cortex(PFC), atthe end
of the obesity development (Fig. 5, Supplementary Tables 1-2).
In theST, WTand Ts65Dnmice showedsimilar levelsof monoaminesand theirmetabolites
innon-obesogenicconditions(onlySC,SupplementaryTable1). Miceexposedto palatable
diets presented changesin striatal DAand HVA, comparedto mice givenonly SC (Two-way
ANOVA, diet effect, DA, F(2,28) = 3.461; p< 0.05; genotype effect DA, F(1,28) = 3.356; p
= 0.078; HVA,F(2,28) = 6.94; p = 0.0036), thechange being drivenby SC+CM mice(Fig. 5a-
In thePFC,diethasa differenteffectineach genotype(Two-wayANOVA,dietx genotype
interaction,DA,F(2,28)=5.20; p=0.012;Fig. 5c).Innon-obesogenicconditions Ts65Dn
mice showed lower DA levels as compared to WT mice. Interestingly, access to energy-dense
foodsleadtoareductionofPFC-DAinWTmice,beingmoredramaticforSC+CMmice;
whereas in Ts65D mice the reduction was only seen in SC+HFgroup. Indeed, as compared to
SC mice, accessto CM inTs65Dn mice leadto an increaseof the DAlevels in PFC(Fig. 5c,
One-wayANOVA,SupplementaryTable2).PrefrontalHVAlevelswereinfluencedbythe
dietinbothgenotypes(Two-wayANOVA,dieteffect,F(2,30)=7.81; p=0.0019)withan
increase oftheDA-metabolite inSC+CM mice(Fig.5d). Regarding5-HTsystem, miceof both
genotypeshavingaccesstoSC+HFshowedlowerconcentrationsof5-HIAA(Two-way
22
ANOVA,dieteffect,F(1,33)=4.07; p<0.05)inPFCascomparedtoSCmice,butno
significant genotype dependent changes in 5-HT were detected (Supplementary Table 2).
Figure5.Tissuelevelsofmonoaminesandtheirmetabolitesinthestriatum(ST)ofwild - type(WT)and
Ts65Dn(TS)mice. Attheendofthebehavioralbattery, animalsweresacrificed,andthe PFCandSTwere
dissected and collected for HPLCmonoamine determination. Levels (ng/mg)in ST of (a)dopamine(DA) and (b)
Homovanillic acid (HVA), a DAmetabolite. In PFC, levels (ng/mg)of (c) dopamine (DA), (d) Homovanillic acid
(HVA), and (e) 5- Hydroxyindoleaceticacid(5HIIA),a 5HTmetabolite.SC group:WT =5,Ts65Dn =5;SC +
CM group:WT =6,Ts65Dn= 6;SC+ HFgroup: WT=5; Ts65Dn=5. Two - wayANOVA, Bonferroni; * p <
0.05; (a) comparisons showed are One - way ANOVA Bonferroni; * p < 0.05.
Ts65Dn mice show a deficient inhibitory feeding response to energy-dense foods overeating
upon quinpirole administration
TofurtherexplorethegenotypicdifferencesobservedinDAsysteminmicegivenenergy-
dense foods, we evaluate the anoretic effectof quinpirole, a D2 dopaminergic receptor agonist
(Fig. 6a).Mice were givenan i.p.acute doseof quinpirole(0.1 mg/Kg),known toreduce the
intake of chocolate biscuits in rats during the first 15 minutes of refeeding [28].
Inourhands, SCmicereducedtheSCintakeduringthe30minutesfollowingtheD2– DA
receptor agonist administration,being the difference significantin Ts65Dn mice(Ts65Dn SC
23
intake (saline)vs. SCintake (quinpirole); Wilcoxontest, p= 0.027;Fig. 6b).In SC+CMgroup,
Ts65DnmiceatelessCMuponD2agonistadministrationbutthedifferencedidnotreach
statisticalsignificance(Fig.6c).Conversely,quinpiroleadministrationsignificantlyreduced
HF intake inWT mice (WTHF intake(saline) vs. HFintake (quinpirole);Wilcoxon test; p=
0.007) but not in Ts65Dn (Fig. 6d)
Figure 6 .Evaluationoftheanoreticeffectofacuteadministrationofquinpirole.(a) Micereceived
intraperitoneally administration of saline or0.1 mg/Kg of quinpiroleand weregiven theydiet accordingto each
experimental group.Food intake(in grams/bodyweight) 30minutesafter refeedingin (b) SC fedmice (c) SC+CM
mice,and (d) SC+HF mice.Dataareexpressedasmean±SEM.SCgroup: WT=10,Ts6 5Dn=9;SC+ CM
group: WT = 10, Ts65Dn = 9; SC + HF group: WT = 11; Ts65Dn = 10. * p ≤ 0.05; ** p ≤ 0.01.
Activation of PL-NAc projections rescues compulsive-like behavior in Ts65Dn mice.
Our resultsshowinflexibility andcompulsive-like behaviors,especiallyin micefedwith HF
diet.Recently,weshowedthatPL-NAccoreprojectionsmodulatedbyD2Rareinvolvedin
compulsive-likebehaviors[9],andTs65Dnshowedahypodopaminergicphenotypeanda
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| https://www.researchgate.net/publication/366520504_Overeating_in_the_Ts65Dn_trisomic_mouse_model_is_associated_with_dopaminergic_neurotransmission_deficit_in_the_prefrontal_cortex |
Can milk raise blood glucose? | Feline Diabetes Message Board - FDMB
If you give your cat regular 2% milk, can it raise the bg levels? I know milk has lactose which is a sugar, does anybody know for sure if it will? Thanks...
Can milk raise blood glucose?
If you give your cat regular 2% milk, can it raise the bg levels? I know milk has lactose which is a sugar, does anybody know for sure if it will? Thanks for your help.
This from the ASPCA "poison control center" oddly enough:
Is milk bad for cats? Unless they are spoiled or moldy, milk, cheese and other dairy foods are not considered to be poisonous to pets. However, cats do not possess significant amounts of lactase, the enzyme that breaks down lactose in milk. Feeding milk and milk-based products to cats can actually cause them to vomit or have diarrhea, which in severe cases could lead to inflammation of the pancreas. For this reason, it's always a good idea to check with your veterinarian before offering any "people food" to your pets.
The "inflammation to the pancreas" is what caught my eye.
And according to pets webmd cats can be lactose intolerant:
Cats and Dairy: Get the Facts WebMD discusses the facts about cats and dairy, and why substituting a saucer of milk for water may not be best for your kitten. By Wendy C. Fries WebMD Pet Health Feature Reviewed by D. West Hamryka, DVM Cats and milk: In children’s stories, it always seems to be a match made in heaven. Who hasn’t seen adorable illustrations of a kitten lapping at a saucer full of cream? As with so many romances, the one between cats and dairy isn’t quite what it’s cracked up to be. That’s because even though most cats adore a bit of milk, milk doesn’t always return the affection. Cat Care Keep your little kitty healthy and happy. Get advice about cat health and behavior from experts at WebMD. What to Do When Your Cat Gets Fat To Declaw or Not to Declaw Newborn Kitten Care Behavior Problems in Older Cats Gum Disease: A Common Cat Problem Exercising With Your Cat (Really!) Slideshow Foods Your Cat Should Never Eat You’ll be surprised to learn how many common foods are dangerous (or even deadly) to your cat. Related Links cat health, cat nutrition, cat behavior, cat health problems, cat symptoms, dog health © 2009 WebMD, LLC. All rights reserved. The main culprit is milk’s lactose, which many cats have trouble digesting. The result: diarrhea or stomach upset. Not exactly romantic. Do cats and dairy ever get along? Can cats drink milk? Here is what cat nutritionists and veterinarians told WebMD. Cats and Dairy Fact 1: Lactose Intolerance Is the Norm Just like people, cats can be lactose intolerant. And although we tend to think that’s a problem, it’s actually completely normal, says Linda P. Case, MS, adjunct assistant professor at the University of Illinois College of Veterinary Medicine and author of The Cat: Its Behavior, Nutrition, and Health. “The only time animals are exposed to lactose is when they’re babies -- in their mother’s milk," Case says. To digest lactose, a milk sugar, the human and feline digestive systems must contain the enzyme lactase. We have plenty of this enzyme in our systems at birth, and it helps us thrive on our mother’s milk. But as we grow up, it’s normal for people and cats to begin producing less lactase. Less lactase means less ability to digest lactose. The result may eventually be lactose intolerance. When a lactose-intolerant cat drinks milk, the undigested lactose passes through the intestinal tract, drawing water with it, according to the Cornell University College of Veterinary Medicine's web site. Bacteria in the colon also ferment the undigested sugars, producing volatile fatty acids. All that activity might lead to an upset tummy and induce vomiting. But the most common symptom of lactose intolerance in cats is diarrhea, usually within eight to 12 hours, says Susan G. Wynn, DVM, CVA, CVCH, an animal nutritionist in Atlanta and co-author of the Manual of Natural Veterinary Medicine. Cats and Dairy Fact 2: Many Cats Can Drink Milk Most of us have probably given our cats a bit of milk and never noticed a problem. That’s because some cats tolerate milk just fine, Wynn tells WebMD. How can you tell? Try offering your cat a tablespoon or two of milk. If you don’t see symptoms within a day, chances are good your cat will do fine with milk as an occasional treat. Still, most veterinarians don't recommend it. Cats don’t need milk, and the potential problems outweigh the potential benefits. Remember that treats of all sorts -- such as tuna, meat, cheese, or other “people foods” -- should make up no more than 5% to 10% of your cat’s diet. The rest of your cat's calories should come from a high-quality, nutritionally complete cat food. If you’re not sure what that means for your cat, talk to your veterinarian. Also, remember that offering table food to a cat often teaches a cat to be finicky
Carl
Thanks Carl but the question of raising blood glucose levels I did not see answered. When you have an OTJ kitty can giving a teaspoon of milk in the morning raise the bg numbers. I am just trying to figure out why Sparky's numbers rose.
In humans, apparently the answer is "yes" because it contains lactose:
Does milk raise blood sugar? In: Diabetes Diabetes Condition healthynow.com Wiki Answers > Categories > Health > Conditions and Diseases > Diabetes > Does milk raise blood sugar? Answer: Any food or drink other than water has some effect on the blood sugar level, yes. Answer Yes, milk does raise the blood sugar level because it contains lactose which is milk sugar. It also contains protein though, which will slow down the digestion of lactose. Also depending on the fat content, since milk is from an animal and the fat is saturated, it could speed up the digestion of the milk. Just remember, the three things that will slow down the digestion and thus the amount of sugar in the blood are protein, fiber, and fat (only if the fat is either mono or polyunsaturated.)
Carb Content of Milk Please Note: all carbohydrate values are approximate Milk (serving size 1 cup) Carbs (g) Milk, whole, 3.3 percent fat 11.3g Milk, low fat, 2 percent fat 11.7g Milk, low fat, 1 percent fat 11.6g Milk, fat free/ skimmed 11.9g Buttermilk, from skimmed milk 11.7g Milk, canned, evaporated, whole 3g Goats Milk 10g Soy Milk, regular 4g
just thinking, but if a kitty is lactose intolerant, then maybe he can't digest it, and it wouldn't raise his BG? But if he isn't lactose intolerant, does that mean he can digest it, and then it would raise the BG?
Unfortunately, I can't find the same type of answer specific to cats.
Carl
I'd say yes. I would assume it is the same as humans and it is one of the first things diabetics can reach for to bring up their BGs and try to sustain a longer hold on the higher numbers. In the hospital, milk is what the nurses kept bringing us to get into my mother when she was hypo and we were trying to keep her blood sugars up.
I was told recently that Heavy Whipping Cream is very low on carbs, and so J.D. was able to have a little of that for his birthday last week. He loves milk, and the treat of heavy whipping cream suited him just fine for one of his special treats.
Here's the thread:
http://felinediabetes.com/FDMB/viewtopic.php?f=28&t=55603&hilit=milk
| https://www.felinediabetes.com/FDMB/threads/can-milk-raise-blood-glucose.56795/ |
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