title: Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

text: BACKGROUND Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.


title: Estimating the probability of New Zealand regions being free from COVID-19 using a stochastic SEIR model

text: This report describes a method for estimating the probability that there are no infected or pre-symptomatic individuals in a populations on a basis of historical data describing the number of cases in consecutive days. The method involves fitting a stochastic version of Susceptible Exposed Infected Recovered model, and using the model to calculate the probability that the number of both exposed and infected individuals is equal to 0. The model is used to predict the current probabilities for all District Health Boards in New Zealand. These probabilities are highly correlated with the number of days with no new cases of COVID-19.


title: Pre exposure Hydroxychloroquine use is associated with reduced COVID19 risk in healthcare workers

text: Abstract Background: While several trials are ongoing for treatment of COVID-19, scientific research on chemoprophylaxis is still lacking even though it has potential to delay the pandemic allowing us time to complete research on vaccines. Methods: We have conducted a cohort study amongst Health Care Workers (HCW) exposed to COVID-19 patients, at a tertiary care center in India where there was an abrupt cluster outbreak within on duty personnel. HCWs who had voluntarily taken hydroxychloroquine (HCQ) prior to exposure were considered one cohort while those who had not were considered to be another. All participants with a verifiable contact history were tested for COVID-19 by rtPCR. The two cohorts were comparable in terms of age, gender, comorbidities and exposure. The primary outcome was incidence rates of rtPCR positive COVID-19 infection amongst HCQ users and non - users. Results: 106 healthcare workers were examined in this cohort study of whom 54 were HCQ users and rest were not. The comparative analysis of incidence of infection between the two groups demonstrated that voluntary HCQ usage was associated with lesser likelihood of developing SARS-CoV-2 infection, compared to those who were not on it, X2=14.59, p<0.001. None of the HCQ users noted any serious adverse effects. Conclusions: This study demonstrated that voluntary HCQ consumption as pre-exposure prophylaxis by HCWs is associated with a statistically significant reduction in risk of SARS-CoV-2. These promising findings therefore highlight the need to examine this association in greater detail among a larger sample using Randomised Controlled Trials (RCT).


title: Time to use the p-word? Coronavirus enters dangerous new phase

text: As outbreaks surge worldwide, scientists fear that COVID-19 might soon become pandemic As outbreaks surge worldwide, scientists fear that COVID-19 might soon become pandemic


title: Altruism and Vaccination Intentions: Evidence from Behavioral Experiments

text: Vaccine hesitancy has been on the rise throughout much of the world for the past two decades. At the same time, existing pro-vaccination public health communication strategies have proven ineffective. We present a novel approach to increase vaccination intentions, which appeals to individuals' other-regarding preferences. Specifically, we assess how vaccination intentions are influenced by the presence of people who cannot vaccinate, such as the immunosuppressed, newborns or pregnant women, using a game where there is a passive player whose welfare depends on the decisions of other, active players. Results from a survey experiment targeting parents and from a laboratory experiment provide support for a twofold positive effect of the presence of the passive player on vaccination intentions. These findings suggest messages that invoke altruistic, other-regarding preferences may be an effective approach to increasing vaccination intentions. Our findings could be extended to other campaigns where the population is invited to adopt behaviors that can help the most susceptible people, as is the case of the self-quarantine measures adopted during the outbreak of CoVID-19 at the beginning of 2020. If the attention of people is focused on the positive effect that they can have on those that cannot protect themselves, then the message may be more effective and people may be more responsive.


title: Diagnostics and spread of SARS-CoV-2 in Western Africa: An observational laboratory-based study from Benin

text: Information on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread in Africa is limited by fragile 2 surveillance systems and insufficient diagnostic capacity. 3 We assessed the coronavirus disease-19 (COVID-19)-related diagnostic workload in Benin, Western Africa, 4 characterized SARS-CoV-2 genomes from 12 acute cases of COVID-19, used those together with public data to 5 estimate SARS-CoV-2 transmission dynamics in a Bayesian framework, validated a widely used diagnostic dual target 6 RT-PCR kit donated to African countries, and conducted serological analyses in 68 sera from confirmed COVID-19 7 cases and from febrile patients sampled before the predicted SARS-CoV-2 introduction. 8 We found a 15-fold increase in the monthly laboratory workload due to COVID-19. Genomic surveillance showed 9 introductions of three distinct SARS-CoV-2 lineages. SARS-CoV-2 genome-based analyses yielded an R0 estimate of 10 4.4 (95% confidence interval: 2.0-7.7), suggesting intense spread of SARS-CoV-2 in Africa. RT-PCR-based tests 11 were highly sensitive but showed variation of internal controls and between diagnostic targets. Commercially available 12 SARS-CoV-2 ELISAs showed up to 25% false-positive results depending on antigen and antibody types, likely due 13 to unspecific antibody responses elicited by acute malaria according to lack of SARS-CoV-2-specific neutralizing 14 antibody responses and relatively higher parasitemia in those sera. 15 We confirm an overload of the diagnostic capacity in Benin and provide baseline information on the usability of 16 genome-based surveillance in resource-limited settings. Sero-epidemiological studies needed to assess SARS-CoV-2 17 spread may be put at stake by low specificity of tests in tropical settings globally. The increasing diagnostic challenges 18 demand continuous support of national and supranational African stakeholders.


title: Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency

text: Background: Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors. Methods: We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data. Results: Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with [≥]1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with [≥]1 comorbidity. Conclusion: We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.


title: Preliminary estimation of the novel coronavirus disease (COVID-19) cases in Iran: a modelling analysis based on overseas cases and air travel data

text: As of 1 March 2020, Iran has reported 987 COVID-19 cases and including 54 associated deaths. At least six neighboring countries (Bahrain, Iraq, Kuwait, Oman, Afghanistan and Pakistan) have reported imported COVID-19 cases from Iran. We used air travel data and the cases from Iran to other Middle East countries and estimated 16533 (95% CI: 5925, 35538) COVID-19 cases in Iran by 25 February, before UAE and other Gulf Cooperation Council countries suspended inbound and outbound flights from Iran.


title: Vytr hypothesis for the prophylactic and therapeutic efficacy of GS-5734 treatment in humans with COVID-19

text: In December 2019, many pneumonia cases were reported without an appar-ent cause but were associated with seafood and wet markets in Wuhan, China Clinical features were similar to pneumonia, and SARS-CoV-2 (formerly 2019-nCoV) was determined as the causative pathogen. To date, there are no effective antiviral drugs for the targeted treatment of coronavirus disease 2019 (COVID-19). We provide the VITYALA YETHINDRA (VYTR) hypothesis for the prophylactic and therapeutic efficacy of GS-5734 treatment in humans with COVID-19. Prophylactic GS-5734 treatment may prevent SARS-CoV-2 induced disease and lung lesions in participants inoculated with SARS-CoV-2 and potentially inhibit SARS-CoV-2 replication. Therapeutic GS-5734 treatment may show a reduction in the severity of symptoms, reduce viral repli-cation, the complete eradication of lung lesions in some participants and decrease in the extent of lesions in 50% of participants may be possible. As broad-spectrum drugs are capable of inhibiting coronavirus infections, GS-5734 should be considered a broad-spectrum, first-line drug and may inhibit coronavirus infections and COVID-19. More clinical trials are needed to prove that GS-5734 (Remdesivir) is a safe and effective drug for the treatment of COVID-19.


title: Antibody tests for identification of current and past infection with SARS-CoV-2.

text: BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. OBJECTIVES To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. SEARCH METHODS We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. SELECTION CRITERIA We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). DATA COLLECTION AND ANALYSIS We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). MAIN RESULTS We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. AUTHORS' CONCLUSIONS The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.


title: SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?

text: In a side-by-side comparison of evolutionary dynamics between the 2019/2020 SARS-CoV-2 and the 2003 SARS-CoV, we were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected. The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence. Any existing pools of SARS-CoV-2 progenitors would be particularly dangerous if similarly well adapted for human transmission. To look for clues regarding intermediate hosts, we analyze recent key findings relating to how SARS-CoV-2 could have evolved and adapted for human transmission, and examine the environmental samples from the Wuhan Huanan seafood market. Importantly, the market samples are genetically identical to human SARS-CoV-2 isolates and were therefore most likely from human sources. We conclude by describing and advocating for measured and effective approaches implemented in the 2002-2004 SARS outbreaks to identify lingering population(s) of progenitor virus.


title: Epidemiological Tools that Predict Partial Herd Immunity to SARS Coronavirus 2

text: The outbreak of SARS coronavirus 2 (SARS-CoV-2), which occurred in Wuhan, China in December 2019, has caused a worldwide pandemic of coronavirus disease 2019 (COVID-19). However, there is a lack of epidemiological tools to guide effective public policy development. Here we present epidemiological evidence that SARS-CoV-2 S type exited Wuhan or other epicenters in China earlier than L type and conferred partial resistance to the virus on infected populations. Analysis of regional disparities in incidence has revealed that a sharp decline in influenza epidemics is a useful surrogate indicator for the undocumented spread of SARS-CoV-2. The biggest concern in the world is knowing when herd immunity has been achieved and scheduling a time to regain the living activities of each country. This study provides a useful tool to guide the development of local policies to contain the virus.


title: A COVID-19 Reopening Readiness Index: The Key to Opening up the Economy

text: With respect to reopening the economy as a result of the COVID-19 restrictions, governmental response and messaging have been inconsistent, and policies have varied by state as this is a uniquely polarizing topic. Considering the urgent need to return to normalcy, a method was devised to determine the degree of progress any state has made in containing the spread of COVID-19. Using various measures for each state including mortality, hospitalizations, testing capacity, number of infections and infection rate has allowed for the creation of a composite COVID -19 Reopening Readiness Index. This index can serve as a comprehensive reliable and simple-to-use metric to assess the level of containment in any state and to determine the level of risk in further opening. As states struggle to contain the outbreak and at the same time face great pressure in resuming economic activity, an index that provides a data-driven and objective insight is urgently needed.


title: Urban food sovereignty: urgent need for agroecology and systems thinking in a post-COVID-19 future

text: The current COVID-19 pandemic has brought attention to challenges associated with our dominant industrial food system in the U.S. The general public now has more appreciation for farm workers and meatpacking employees, as well as those in grocery stores and in food transportation who are suddenly recognized as essential frontline workers. It apparently takes a crisis for us to focus clearly on the fragility of this system and the lives of people on whom we depend. In this commentary we discuss the definition of food sovereignty, how it manifests in urban areas, and how the COVID-19 pandemic can trigger viable responses to increase urban food sovereignty. While recognizing and appreciating the value of trade and comparative advantages of some regions with long seasons to produce food for others, there is strong reason to explore the potentials of local and urban production and governance to avoid serious impacts of unexpected interruptions in the world order.


title: Our Experiences with Plastic and Reconstructive Surgery Procedures during Coronavirus Disease 2019 Pandemic

text: Background: The novel Coronavirus Disease 2019 (COVID-19) has rapidly become a health threat worldwide and has been declared global pandemic by the World Health Organization. Possible transmission routes, including respiratory droplets, close contact, and aerosol propagation, have put plastic and reconstructive healthcare professionals at high risk, especially during surgical procedures. The aim of this study was to summarize and share our experience of infection control measures and corresponding outcomes during the COVID-19 pandemic. Methods: Infection control measures, including workflow optimization, useful epidemiologic survey methods, and personal full protective clothing, were discussed. Characteristics and outcomes of emergency cases and elective cases under local and general anesthesia during the COVID-19 pandemic were summarized. Results: A hierarchy of interventions were applied mainly from 4 aspects. First, administration control and online consultation significantly decreased patient attendance. Second, a triage workflow was established to identify high-/low-risk patients, with clinical manifestations (fever, fatigue, cough, nasal discharge, etc), epidemiologic survey, blood test, chest computed tomographic scan, and coronavirus test if necessary. Third, strict environmental control was adopted using increasing ventilation, isolated room for inpatients, etc. Fourth, proper rotation of healthcare staff was ensured to reduce workload and minimize possible contact. A total of 904 emergency interventions, 2561 local anesthesia, and 570 general anesthesia were performed during this period, and none of the cases/healthcare professionals were found to be infected. Conclusions: Our experience could help global plastic and reconstructive healthcare professionals to get better preparation and continue to give qualified medical services during the COVID-19 pandemic. Proper adjustments should be taken according to their own clinical settings.


title: Reference data based insights expand understanding of human metabolomes

text: The human metabolome has remained largely unknown, with most studies annotating ∼10% of features. In nucleic acid sequencing, annotating transcripts by source has proven essential for understanding gene function. Here we generalize this concept to stool, plasma, urine and other human metabolomes, discovering that food-based annotations increase the interpreted fraction of molecular features 7-fold, providing a general framework for expanding the interpretability of human metabolomic “dark matter.”


title: Recommendation for the diagnosis and treatment of novel coronavirus infection in children in Hubei (Trial version 1)

text: Since December 2019, a cluster of patients have been diagnosed to be infected with 2019 novel coronavirus (2019-nCoV) in Wuhan, China The epidemic has been spreading to other areas of the country and abroad A few cases have progressed rapidly to acute respiratory distress syndrome and/or multiple organ function failure The epidemiological survey has indicated that the general population is susceptible to 2019-nCoV A total of 14 children (6 months to 14 years of age, including 5 cases in Wuhan) have been confirmed to be infected with 2019-nCoV in China so far In order to further standardize and enhance the clinical management of 2019-nCoV infection in children, reduce the incidence, and decrease the number of severe cases, we have formulated this diagnosis and treatment recommendation according to the recent information at home and abroad


title: Identification of industrial robot frequency response function for robotic milling using operational modal analysis

text: Abstract Impact hammer experiments are typically used for identifying the Frequency Response Function (FRF) of six-degree-of-freedom (6-dof) industrial robots for machining applications. However, the modal properties of 6-dof industrial robots change as a function of robot arm configuration. Hence, describing the robot’s modal parameters within its workspace requires off-line impact hammer experiments performed at discrete robot end effector positions, which are costly and time consuming. Instead, it is more efficient to calculate the robot FRF using Operational Modal Analysis (OMA), a method that utilizes data acquired during the actual machining process. This paper presents an OMA approach to identify the robot FRF from measured milling forces and robot tool tip vibrations. Analysis of the milling process data reveal that periodic forces produced in the milling process are accompanied by background white noise that induce broadband excitation across the robot structure’s frequency spectrum. Hence, the tool tip vibration signal contains the signature of the structure’s free response that enables the use of OMA to estimate the robot’s FRF. The FRF calculated using OMA is shown to be in good agreement with results obtained from impact hammer experiments.


title: Experts’ conservative judgment and containment of COVID-19 in early outbreak

text: We present the case of the outbreak and containment of COVID-19 in its early stage and analyze the causes for conservative judgment of the disease control experts who are blamed for delayed action and inadequate response by the government. We find that the disease control experts have a clear tendency and preference to make conservative judgment about the epidemic risk of a low probability and high impact new disease. This conservative preference may have been a major factor in the judging and communicating the risk of COVID-19 epidemic. The experts’ perception of the epidemic risk is affected by their habitual thinking facing a low probability event with uncertain progression. Their conservative preference is augmented by political concerns due to the high social and political impact of the event and the potential political consequence of a false judgment. Balancing personal payoffs of decision options, the experts’ rational choice would lean towards a conservative decision. We propose a three-factor decision model that integrates habitual thinking, political concerns and rational choice to explain the experts’ conservative judgment, and corroborate the model with evidences from the case. We conclude the paper with policy implications for improving experts’ role in public health emergency response.


The COVID-19 Pandemic and Transportation Engineering


title: Trace, Quarantine, Test, Isolate and Treat: A Kerala Model of Covid-19 Response

text: Kerala reported the first three cases of coronavirus in India in late January. Kerala, one of Indias most densely populated states, which makes its success in fighting the Covid-19 all the more commendable. Moreover, an estimated 17% of its 35 million population employed or lives elsewhere, more than 1 million tourists visit each year, and hundreds of students study abroad, including in China. All of this mobility makes the state more vulnerable to contagious outbreaks. What is the strategy behind the success story? This paper compares the situation of COVID-19 pandemic in major states and Kerala by the different phase of lockdown, and also highlights Keralas fight against the pandemic. We used publicly available data from https://www.covid19india.org/ and Covid-19 Daily Bulletin (Jan 31-May 31), Directorate of Health Services, Kerala (https://dashboard.kerala.gov.in/). We calculate the phase-wise period prevalence rate (PPR) and the case fatality rate (CFR) of the last phase. Compared to other major states, Kerala showed better response in preventing pandemic. The equation for the Keralas success has been simple, prioritized testing, widespread contact tracing, and promoting social distance. They also imposed uncompromising controls, that were supported by an excellent healthcare system, government accountability, transparency, public trust, civil rights and importantly the decentralized governance and strong grass-root level institutions. The proactive measures taken by Kerala such as early detection of cases and extensive social support measures can be a model for India and the world. Keywords: Covid-19, Kerala, India, Testing, Tracing, Pandemic.


title: The potential effect of the African population age structure on COVID-19 mortality

text: Currently (mid May 2020), most active cases of COVID-19 are found in Europe and North America while it is still in the initial phases in Africa. As COVID-19 mortality occurs mainly in elderly and as Africa has a comparably young population, the death rates should be lower than on other continents. We calculated standardised mortality ratios (SMR) using age-specific case fatality rates for COVID-19 and the age structure of the population of Africa and of other continents. Compared to a European or Northern American population, the standardised mortality ratio was only 0.22 and 0.25, respectively, corresponding to reduction of deaths rates to a quarter. Compared to the Asian and Latin American & Caribbean population, the SMR was 0.43 and 0.44, respectively, corresponding to half the death rate for Africa. It is useful to quantify the isolated effect of the African age-structure on potential COVID-19 mortality for illustrative and communication purposes, keeping in mind the importance of public health measures that have been shown to be effective in reducing cases and deaths. The different aspect of age pyramids of a European and an African population are striking and the potential implications for the pandemic are often discussed but rarely quantified.


title: Impaired glucose metabolism in patients with diabetes, prediabetes and obesity is associated with severe Covid-19

text: Background: Identification of risk factors of severe Covid-19 is critical for improving therapies and understanding SARS-CoV-2 pathogenesis. Methods: We analyzed 184 patients hospitalized for Covid-19 in Livingston, New Jersey for clinical characteristics associated with severe disease. Results: The majority of Covid-19 patients had diabetes mellitus (DM) (62.0%), Pre-DM (23.9%) with elevated FBG, or a BMI > 30 with normal HbA1C (4.3%). SARS-CoV-2 infection was associated with new and persistent hyperglycemia in 29 patients, including several with normal HbA1C levels. Forty-four patients required intubation, which occurred significantly more often in patients with DM as compared to non-diabetics. Conclusions: Severe Covid-19 occurs in the presence of impaired glucose metabolism in patients with SARS-CoV-2 infection. The association of dysregulated glucose metabolism and severe Covid-19 suggests a previously unrecognized manifestation of primary SARS-CoV-2 infection. Exploration of pathways by which SARS-CoV-2 impacts glucose metabolism is critical for understanding disease pathogenesis and developing therapies.


title: A Cross-National Design to Estimate Effects of COVID-Induced Non-Pharmacological Interventions

text: We describe a research initiative that will explore the economic and social effects not of the COVID-19 itself but of the policies and information environment that COVID-19 spawned We will exploit the substantial intra and inter-country temporal and geographic variation in non-pharmacological intervention policies induced by the COVID-19 disease We will use data from ongoing household-based panel studies from 10 countries and rich administrative data from an eleventh Six of the ten household panels have already fielded or will shortly field COVID-related questions to their main samples A seventh, the PSID, has fielded questions to samples of the Child Development Supplement and Transition into Adulthood Supplement The PSID and the other three panels will include COVID related questions in their next regular survey All of them will be completed in 2021


title: Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity

text: The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.


title: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

text: The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.


title: SARS-CoV-2 asymptomatic and symptomatic patients and risk for transfusion transmission

text: Oral swabs, sputum and blood samples from 18 patients with SARS-CoV-2 infection were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) testing. Whereas oral swabs or sputum from the lower respiratory tract were tested RT-PCR positive in all patients, RNAemia was neither detected in 3 patients without symptoms nor in 14 patients with flu-like symptoms, fever or pneumonia. The only patient with RNAemia suffered from acute respiratory distress syndrome (ARDS) and was artificially ventilated in an intensive care unit. Risk for SARS-CoV-2 transmission through blood components in asymptomatic SARS-CoV-2 infected individuals therefore seems negligible but further studies are needed.


Special Coverage on COVID-19: What Should EPs Say about COVID-19 to Discharged ED Patients?


Aquinas, education and the theory of illumination


title: Fast and accurate diagnostics from highly multiplexed sequencing assays

text: Scalable, inexpensive, accurate, and secure testing for SARS-CoV-2 infection is crucial for control of the novel coronavirus pandemic. Recently developed highly multiplexed sequencing assays that rely on high-throughput sequencing (HMSAs) can, in principle, meet these demands, and present promising alternatives to currently used RT-qPCR-based tests. However, the analysis and interpretation of HMSAs requires overcoming several computational and statistical challenges. Using recently acquired experimental data, we present and validate an accurate and fast computational testing workflow based on kallisto and bustools, that utilize robust statistical methods and fast, memory efficient algorithms for processing high-throughput sequencing data. We show that our workflow is effective at processing data from all recently proposed SARS-CoV-2 sequencing based diagnostic tests, and is generally applicable to any diagnostic HMSAs.


title: Increased serum levels of soluble TNF-Î± receptor is associated with mortality of ICU COVID-19 patients

text: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 10M patients and resulted in 505K deaths worldwide as of 30th June 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute Respiratory Distress Syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines such as TNF- and IL-6 being reported. TNF- levels are increased during the cytokine storm in very ill patients and soluble receptors for IL-6 and IL-2 are present in the blood of COVID-19 patients, Objectives: To elucidate the involvement of serum levels of soluble TNF-Receptor of severe and mild COVID-19 patients to determine for severity of disease. Method: We recruited 16 severe COVID-19 patients in the ICU on ventilator support and 26 milder COVID-19 patients who were hospitalised but not within the intensive care unit (ICU) between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. After harvesting of whole blood the serum was isolated and soluble TNF-Receptor levels measured by ELISA. Results: Serum levels of the usually inhibitory soluble TNF receptor 1 (sTNFaR1) were significantly elevated in severe COVID-19 patients at admission to ICU. High serum levels of sTNFaR1 were associated with mortality of severe COVID-19 patients treated within ICU. Conclusions: This pilot study demonstrates for role of STNF-aR1 receptor in severity of disease. Future studies should examine whether lower levels of systemic sTNFaR1 at admission may indicate a better disease outcome.


title: Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressed BHK21 cells

text: The global pandemic of Coronavirus disease 2019 (COVID-19) is a disaster for human society. A convenient and reliable in vitro neutralization assay is very important for the development of neutralizing antibodies, vaccines and other inhibitors. In this study, G protein-deficient vesicular stomatitis virus (VSVdG) bearing full-length and truncated spike (S) protein of SARS-CoV-2 were evaluated. The virus packaging efficiency of VSV-SARS-CoV-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S. A neutralization assay for antibody screening and serum neutralizing titer quantification was established based on VSV-SARS-CoV-2-Sdel18 pseudovirus and human angiotensin-converting enzyme 2 (ACE2) overexpressed BHK21 cell (BHK21-hACE2). The experimental results can be obtained by automatically counting EGFP positive cell number at 12 hours after infection, making the assay convenient and high-throughput. The serum neutralizing titer of COVID-19 convalescent patients measured by VSV-SARS-CoV-2-Sdel18 pseudovirus assay has a good correlation with live SARS-CoV-2 assay. Seven neutralizing monoclonal antibodies targeting receptor binding domain (RBD) of SARS-CoV-2-S were obtained. This efficient and reliable pseudovirus assay model could facilitate the development of new drugs and vaccines.


title: Association of age, sex, comorbidities, and clinical symptoms with the severity and mortality of COVID-19 cases: a meta-analysis with 85 studies and 67299 cases

text: Background: A new pathogenic disease named COVID-19 became a global threat, first reported in Wuhan, China, in December 2019. The number of affected cases growing exponentially and now, more than 210 countries confirmed the cases. Objective: This meta-analysis aims to evaluate risk factors, the prevalence of comorbidity, and clinical characteristics in COVID-19 death patients compared to survival patients that can be used as a reference for further research and clinical decisions. Methods: PubMed, Science Direct, SAGE were searched to collect data about demographic, clinical characteristics, and comorbidities of confirmed COVID-19 patients from January 1, 2020, to May 17, 2020. Meta-analysis was performed with the use of Review Manager 5.3 Results: Eighty-five studies were included in Meta-analysis, including a total number of 67,299 patients with SARS-CoV-2 infection. Males are severely affected or died than females (OR = 2.26, p < 0.00001; OR = 3.59, p < 0.00001) are severely affected, or died by COVID-19 and cases with age [≥]50 are at higher risk of death than age <50 years (OR=334.23). Presence of any comorbidity or comorbidities like hypertension, cardiovascular disease, diabetes, cerebrovascular disease, respiratory disease, kidney disease, liver disease, malignancy significantly increased the risk of death compared to survival (OR = 3.46, 3.16, 4.67, 2.45, 5.84, 2.68, 5.62, 2.81,2.16). Among the clinical characteristics such as fever, cough, myalgia, diarrhea, abdominal pain, dyspnea, fatigue, sputum production, chest tightness headache and nausea or vomiting, only fatigue (OR = 1.31, 95%) and dyspnea increased the death significantly (OR= 1.31, 4.57). The rate of death of COVID-19 cases is 0.03-times lower than the rate of survival (OR = 0.03). Conclusion Our result indicates that male patients are affected severely or died, the rate of death is more in the age [≥]50 group, and the rate of death is affected by comorbidities and clinical symptoms.


title: Modelling the epidemic trend of the 2019-nCOV outbreak in Hubei Province, China

text: As of 8am 30th January (Beijing Time) 2020, Approximate 8000 cases across the world have been confirmed. It's necessary to simulate epidemic trend of the 2019-nCOV outbreak in Hubei Province, the hardest-hit area. By SEIR simulation, the predicted epidemic peak in Hubei will be within 28th January 2020 to 7th February 2020, up to 7000-9000 infectious cases in total. The estimate above was based on some assumptions and limitations exited.


title: A distinct phylogenetic cluster of Indian SARS-CoV-2 isolates

text: From an isolated epidemic, COVID-19 has now emerged as a global pandemic. The availability of genomes in the public domain following the epidemic provides a unique opportunity to understand the evolution and spread of the SARS-CoV-2 virus across the globe. The availability of whole genomes from multiple states in India prompted us to analyse the phylogenetic clusters of genomes in India. We performed whole-genome sequencing for 64 genomes making a total of 361 genomes from India, followed by phylogenetic clustering, substitution analysis, and dating of the different phylogenetic clusters of viral genomes. We describe a distinct phylogenetic cluster (Clade I / A3i) of SARS-CoV-2 genomes from India, which encompasses 41% of all genomes sequenced and deposited in the public domain from multiple states in India. Globally 3.5% of genomes, which till date could not be mapped to any distinct known cluster fall in this newly defined clade. The cluster is characterized by a core set of shared genetic variants – C6312A (T2016K), C13730T (A88V/A97V), C23929T, and C28311T (P13L). Further, the cluster is also characterized by a nucleotide substitution rate of 1.4 × 10−3 variants per site per year, lower than the prevalent A2a cluster, and predominantly driven by variants in the E and N genes and relative sparing of the S gene. Epidemiological assessments suggest that the common ancestor emerged in the month of February 2020 and possibly resulted in an outbreak followed by countrywide spread, as evidenced by the low divergence of the genomes from across the country. To the best of our knowledge, this is the first comprehensive study characterizing the distinct and predominant cluster of SARS-CoV-2 in India.


title: Moral Distress During COVID19: Residents in Training are at High Risk

text: Abstract The ethics and moral dilemmas of rationing care are particularly acute to all health care providers as we tackle the COVID19 crisis In normal times, first responders and clinicians face moral angst in situations when they are not able to follow their inner values, however studies show this angst is highly intensified in a disaster setting 1-3 Why? Public health emergencies may require clinicians to change their practice, such as the need to prioritize the community above the individual in fairly allocating scarce resources


title: Effectiveness of interventions targeting air travellers for delaying local outbreaks of SARS-CoV-2

text: Background: We evaluated if interventions aimed at air travellers can delay local SARS-CoV-2 community transmission in a previously unaffected country. Methods: We simulated infected air travellers arriving into countries with no sustained SARS-CoV-2 transmission or other introduction routes from affected regions. We assessed the effectiveness of syndromic screening at departure and/or arrival & traveller sensitisation to the COVID-2019-like symptoms with the aim to trigger rapid self-isolation and reporting on symptom onset to enable contact tracing. We assumed that syndromic screening would reduce the number of infected arrivals and that traveller sensitisation reduces the average number of secondary cases. We use stochastic simulations to account for uncertainty in both arrival and secondary infections rates, and present sensitivity analyses on arrival rates of infected travellers and the effectiveness of traveller sensitisation. We report the median expected delay achievable in each scenario and an inner 50% interval. Results: Under baseline assumptions, introducing exit and entry screening in combination with traveller sensitisation can delay a local SARS-CoV-2 outbreak by 8 days (50% interval: 3-14 days) when the rate of importation is 1 infected traveller per week at time of introduction. The additional benefit of entry screening is small if exit screening is effective: the combination of only exit screening and traveller sensitisation can delay an outbreak by 7 days (50% interval: 2-13 days). In the absence of screening, with less effective sensitisation, or a higher rate of importation, these delays shrink rapidly to less than 4 days. Conclusion: Syndromic screening and traveller sensitisation in combination may have marginally delayed SARS-CoV-2 outbreaks in unaffected countries.


title: Compassionate Use of Tocilizumab in Severe SARS-CoV2 Pneumonia. When late administration is too late.

text: Introduction Tocilizumab is an interleukin 6 receptor antagonist which has been used for the treatment of severe SARS-CoV-2 pneumonia (SSP), aiming to ameliorate the cytokine release syndrome (CRS) -induced acute respiratory distress syndrome (ARDS). However, there is no data about the best moment for its administration along the course of the disease. Methods We provided tocilizumab on a compassionate-use basis to patients with SSP hospitalized (excluding intensive care and intubated cases) who required oxygen support to have a saturation >93%. Primary endpoint was intubation or death after 24 hours of its administration. Patients received at least one dose of 400 mg intravenous tocilizumab during March 8-2020, through April 20-2020. Findings A total of 207 patients were studied and 186 analysed. The mean age was 65 years and 68% were male. A co-existing condition was present in 68 % of cases. At baseline, 114 (61%) required oxygen support with FiO2 >0.5 % and 72 (39%) <0.5%. Early administration of tocilizumab, when the need of oxygen support was still below FiO2 <0.5%, was significantly more effective than given it in advanced stages (FiO2 >0.5 %), achieving lower rates of intubation or death (13% vs 37% repectively, p<0.001). Interpretation The benefit of tocilizumab in severe SARS-Cov-2 pneumonia is only expected when it is administrated before the need of high oxygen support.


title: Genomic epidemiology of SARS-CoV-2 in Guangdong Province, China

text: Highlights: 1) 1.6 million molecular diagnostic tests identified 1,388 SARS-CoV-2 infections in Guangdong Province, China, by 19th March 2020; 2) Virus genomes can be recovered using a variety of sequencing approaches from a range of patient samples. 3) Genomic analyses reveal multiple virus importations into Guangdong Province, resulting in genetically distinct clusters that require careful interpretation. 4) Large-scale epidemiological surveillance and intervention measures were effective in interrupting community transmission in Guangdong Summary: COVID-19 is caused by the SARS-CoV-2 coronavirus and was first reported in central China in December 2019. Extensive molecular surveillance in Guangdong, China's most populous province, during early 2020 resulted in 1,388 reported RNA positive cases from 1.6 million tests. In order to understand the molecular epidemiology and genetic diversity of SARS-CoV-2 in China we generated 53 genomes from infected individuals in Guangdong using a combination of metagenomic sequencing and tiling amplicon approaches. Combined epidemiological and phylogenetic analyses indicate multiple independent introductions to Guangdong, although phylogenetic clustering is uncertain due to low virus genetic variation early in the pandemic. Our results illustrate how the timing, size and duration of putative local transmission chains were constrained by national travel restrictions and by the province's large-scale intensive surveillance and intervention measures. Despite these successes, COVID-19 surveillance in Guangdong is still required as the number of cases imported from other countries is increasing.


title: A Scalable, Easy-to-Deploy, Protocol for Cas13-Based Detection of SARS-CoV-2 Genetic Material

text: The COVID-19 pandemic has created massive demand for widespread, distributed tools for detecting SARS-CoV-2 genetic material. The hurdles to scalable testing include reagent and instrument accessibility, availability of highly-trained personnel, and large upfront investment. Here we showcase an orthogonal pipeline we call CREST (Cas13-based, Rugged, Equitable, Scalable Testing) that addresses some of these hurdles. Specifically, CREST pairs commonplace and reliable biochemical methods (PCR) with low-cost instrumentation, without sacrificing detection sensitivity. By taking advantage of simple fluorescence visualizers, CREST allows for a binary interpretation of results. CREST may provide a point-of-care solution to increase the distribution of COVID-19 surveillance.


title: Predicting Health Disparities in Regions at Risk of Severe Illness to inform Healthcare Resource Allocations during Pandemics

text: Pandemics including COVID-19 have disproportionately affected socioeconomically vulnerable populations. To create a repeatable modelling process to identify regional population centers with pandemic vulnerability, readily available COVID-19 and socioeconomic variable datasets were compiled, and linear regression models were built during the early days of the COVID-19 pandemic. The models were validated later in the pandemic timeline using actual COVID-19 mortality rates in states with high population densities, with New York, New Jersey, Connecticut, Massachusetts, Louisiana, Michigan and Pennsylvania showing the strongest predictive results. Our models have been shared with the Department of Health Commissioners of each of these states as input into a much needed pandemic playbook for local healthcare agencies in allocating medical testing and treatment resources.


title: Genomic variations of SARS-CoV-2 suggest multiple outbreak sources of transmission

text: We examined 169 genomes of SARS-CoV-2 and found that they can be classified into two major genotypes, Type I and Type II. Type I can be further divided into Type IA and IB. Our phylogenetic analysis showed that the Type IA resembles the ancestral SARS-CoV-2 most. Type II was likely evolved from Type I and predominant in the infections. Our results suggest that Type II SARS-CoV-2 was the source of the outbreak in the Wuhan Huanan market and it was likely originated from a super-spreader. The outbreak caused by the Type I virus should have occurred somewhere else, because the patients had no direct link to the market. Furthermore, by analyzing three genomic sites that distinguish Type I and Type II strains, we found that synonymous changes at two of the three sites confer higher protein translational efficiencies in Type II strains than in Type I strains, which might explain why Type II strains are predominant, implying that Type II is more contagious (transmissible) than Type I. These findings could be valuable for the current epidemic prevention and control.


title: Climate effect on COVID-19 spread rate: an online surveillance tool

text: Background: COVID-19 outbreak poses an unprecedented challenge for societies, healthcare organizations and economies. In the present analysis we coupled climate data with COVID-19 spread rates worldwide, and in a single country (USA). Methods: Data of confirmed COVID-19 cases was derived from the COVID-19 Global Cases by the CSSE at Johns Hopkins University up to March 19, 2020. We assessed disease spread by two measures: replication rate (RR), the slope of the logarithmic curve of confirmed cases, and the rate of spread (RoS), the slope of the linear regression of the logarithmic curve. Results: Based on predefined criteria, the mean COVID-19 RR was significantly lower in warm climate countries (0.12± 0.02) compared with cold countries (0.24± 0.01), (P<0.0001). Similarly, RoS was significantly lower in warm climate countries 0.12± 0.02 vs. 0.25± 0.01 than in cold climate countries (P<0.001). In all countries (independent of climate classification) both RR and RoS displayed a moderate negative correlation with temperature R= -0.69, 95% confidence interval [CI], -0.87 to -0.36; P<0.001 and R= -0.72, 95% confidence interval [CI], -0.87 to -0.36; P<0.001, respectively. We identified a similar moderate negative correlation with the dew point temperature. Additional climate variables did not display a significant correlation with neither RR nor RoS. Finally, in an ancillary analysis, COVID-19 intra-country model using an inter-state analysis of the USA did not identify yet correlation between climate parameters and RR or RoS as of March, 19, 2020. Conclusions: Our analysis suggests a plausible negative correlation between warmer climate and COVID-19 spread rate as defined by RR and RoS worldwide. This initial correlation should be interpreted cautiously and be further validated over time, the pandemic is at different stages in various countries as well as in regions within these countries. As such, some associations may be more affected by local transmission patterns rather than by climate. Importantly, we provide an online surveillance dashboard (https://covid19.net.technion.ac.il/) to further assess the association between climate parameters and outbreak dynamics worldwide as time goes by


title: MRI of the lungs in patients with COVID-19: clinical case

text: Objective: To evaluate an applicability of lungs magnetic resonance imaging (MRI) in viral pneumonia patients including, but not limited to, COVID-19 in a setting of computed tomography (CT) limited availability. Methods: The study included 11 patients (4 with positive polymerase chain reaction (PCR) test for COVID-19). All of patients underwent an MRI scan of lungs using Single shot fast spin echo (SSFSE), LAVA 3D and IDEAL 3D, EPI Diffusion-weighted imaging (DWI) and Fast Spin Echo (FSE) T2WI without using respiratory or any other trigger. 3 patients also had CT scan. All scans were analyzed for Ground-glass opacity (GGO) and crazy-paving signs indicating potential viral pneumonia. Results: In 8 (67%) patients foci and zones of slight compaction of the parenchyma were visualized as "cloudy sky sign" on T2WI. GGO zones on CT corresponded to "cloudy sky sign" on MRI in patients who underwent both MRI and CT. Conclusion: Lung MRI allows to identify the signs of viral pneumonia and estimate the severity of the disease and the volume of pulmonary involvement, "cloudy sky sign" on MRI corresponds to GGO in CT. The method could be used in COVID-19 diagnosis. Further research will allow to assess accuracy of MRI compared to CT.


title: Multi-route respiratory infection: when a transmission route may dominate

text: The exact transmission route of many respiratory infectious diseases remains a subject for debate to date. The relative contribution ratio of each transmission route is largely undetermined, which is affected by environmental conditions, human behavior, the host and the microorganism. In this study, a detailed mathematical model is developed to investigate the relative contributions of different transmission routes to a multi-route transmitted respiratory infection. It is illustrated that all transmission routes can dominate the total transmission risk under different scenarios. Influential parameters considered include dose-response rate of different routes, droplet governing size that determines virus content in droplets, exposure distance, and virus dose transported to the hand of infector. Our multi-route transmission model provides a comprehensive but straightforward method to evaluate the transmission efficiency of different transmission routes of respiratory diseases and provides a basis for predicting the impact of individual level intervention methods such as increasing close-contact distance and wearing protective masks.


title: Human coronavirus reinfection dynamics: lessons for SARS-CoV-2

text: In the current SARS-CoV-2 pandemic a key unsolved question is the quality and duration of acquired immunity in recovered individuals. This is crucial to solve, however SARS-CoV-2 has circulated for under five months, precluding a direct study. We therefore monitored 10 subjects over a time span of 35 years (1985-2020), providing a total of 2473 follow up person-months, and determined a) their antibody levels following infection by any of the four seasonal human coronaviruses, and b) the time period after which reinfections by the same virus can occur. An alarmingly short duration of protective immunity to coronaviruses was found by both analyses. We saw frequent reinfections at 12 months post-infection and a substantial reduction in antibody levels as soon as 6 months post-infection.


title: How are adversities during COVID-19 affecting mental health? Differential associations for worries and experiences and implications for policy

text: Background: There are concerns that COVID-19 is having adverse effects on mental health. But it remains unclear whether this is being caused by worries over potential adversities due to the pandemic, or the toll of experiencing adverse events. Aims: To explore the time-varying longitudinal relationship between (i) worries about adversity, and (ii) experience of adversity, and both anxiety and depression and test the moderating role of socio-economic position. Methods: Data from 35,784 UK adults in the UCL COVID -19 Social Study (a panel study collecting data weekly during the Covid-19 pandemic) were analysed from 01/04/2020-28/04/2020. The sample was well-stratified and weighted to population proportions of gender, age, ethnicity, education and geographical location. Fixed effects regression was used to explore within-person variation over time. Results: Cumulative number of worries and experience of adversities were both related to higher levels of anxiety and depression. Number of worries were associated more with anxiety than depression, but number of experiences were equally related to anxiety and depression. Individuals of lower socio-economic position were more negatively affected psychologically by adverse experiences. Conclusions: Measures over the first few weeks of lockdown in the UK appear to have been insufficient at reassuring people given we are still seeing clear associations with poor mental health both for cumulative worries and also for a range of specific worries relating to finance, access to essentials, personal safety and COVID-19. Interventions are required that both seek to prevent adverse events (e.g. redundancies) and that reassure individuals and support adaptive coping strategies.


title: The Potential role of Particulate Matter in the Spreading of COVID-19 in Northern Italy: First Evidence-based Research Hypotheses

text: Background: An epidemic model based only on respiratory droplets and close contact could not fully explain the regional differences in the spread of the recent severe acute respiratory syndrome COVID-19 in Italy, which was fast and dramatic only in Lombardy and Po Valley. On March 16th 2020, we presented a Position Paper proposing a research hypothesis concerning the association between higher mortality rates due to COVID-19 observed in Northern Italy and the peaks of particulate matter concentrations, frequently exceeding the legal limit of 50 micrograms/m3 as PM10 daily average Methods: To assess environmental factors related to the spread of the COVID-19 in Italy from February 24th to March 13th (the date when the lockdown has been imposed over Italy), official daily data relevant to ambient PM10 levels were collected from all Italian Provinces between February 9th and February 29th , taking into account the average time (estimated in 17 days) elapsed between the initial infection and the recorded COVID positivity. In addition to the number of exceedances of PM10 daily limit value, we considered also population data and daily travelling information per each Province. Results. PM10 daily limit value exceedances appear to be a significant predictor (p <0.001) of infection in univariate analyses. Less polluted Provinces had a median of 0.03 infection cases over 1000 residents, while most polluted Provinces had a median of 0.26 cases over 1000 residents. Thirty-nine out of 41 Northern Italian Provinces resulted in the category with highest PM10 levels, while 62 out of 66 Southern Provinces presented low PM10 concentrations (p<0.001). In Milan, the average growth rate before the lockdown was significantly higher than Rome (0.34 vs. 0.27 per day, with a doubling time of 2.0 days vs. 2.6), suggesting a basic reproductive number R0>6.0, comparable with the highest values estimated for China.


title: CoViD-19 Immunopathology and Immunotherapy

text: New evidence on the T-cell immuno-pathology in patient’s with Corona Virus Disease 2019 (CoViD-19) was reported by Diao et al. in MedRxiv (doi: 10.1101/2020.02.18.20024364) [1]. It reports observations on 522 patients with confirmed CoViD-19 symptomatology, compared to 40 control subjects. In brief, notable T cytopoenia was recorded by flow cytometry in the CD4+ and the CD8+ populations, which were significantly yet inversely correlated with remarkably increased serum levels of the pro-inflammatory cytokines IL-6, IL-10 and TNF-a. Flow cytometry established a progressive increase in the expression of programmed cell death marker-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) as patients (n=14) deteriorated from prodromal to symptomatic CoViD-19 requiring intensive care. Here, we interpret these observations of Diao et al from our current understanding of T cell immunophysiology and immunopathology following an immune challenge in the form of sustained viral infection, as is the case in CoViD-19, with emphasis on exhausted T cells (Tex). Recent clinical trials to rescue Tex show promising outcomes. The relevance of these interventions for the prevention and treatment of CoViD-19 is discussed. Taken together, the data of Diao et al could proffer the first glimpse of immunopathology and possible immunotherapy for patients with CoViD-19.


title: Emergence of Low-density Inflammatory Neutrophils Correlates with Hypercoagulable State and Disease Severity in COVID-19 Patients

text: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Approximately 20% of infected patients experience a severe manifestation of the disease, causing bilateral pneumonia and acute respiratory distress syndrome. Severe COVID-19 patients also have a pronounced coagulopathy with approximately 30% of patients experiencing thromboembolic complications. However, the etiology driving the coagulopathy remains unknown. Here, we explore whether the prominent neutrophilia seen in severe COVID-19 patients contributes to inflammation-associated coagulation. We found in severe patients the emergence of a CD16IntCD44lowCD11bInt low-density inflammatory band (LDIB) neutrophil population that trends over time with changes in disease status. These cells demonstrated spontaneous neutrophil extracellular trap (NET) formation, phagocytic capacity, enhanced cytokine production, and associated clinically with D-dimer and systemic IL-6 and TNF- levels, particularly for CD40+ LDIBs. We conclude that the LDIB subset contributes to COVID-19-associated coagulopathy (CAC) and could be used as an adjunct clinical marker to monitor disease status and progression. Identifying patients who are trending towards LDIB crisis and implementing early, appropriate treatment could improve all-cause mortality rates for severe COVID-19 patients.


title: Bradycardia, Renal Failure, Atrioventricular Nodal Blockade, Shock, and Hyperkalemia (BRASH) Syndrome as a Presentation of Coronavirus Disease 2019

text: The novel coronavirus disease 2019 (COVID-19) has led to a global pandemic. While acute respiratory failure has been the predominant concern, there have been reports of other end-organ damage such as renal failure. We report a case of an elderly woman who presented with BRASH syndrome, a constellation of bradycardia, renal failure, atrioventricular (AV) nodal blockade, shock, and hyperkalemia (BRASH), which was likely triggered by COVID-19.


title: Current Status of Treatment Options, Clinical Trials, and Vaccine Development for SARS-CoV-2 Infection

text: The severe acute respiratory syndrome virus (SARS-CoV-2), a novel coronavirus first discovered in Wuhan, China in December 2019 causes the Coronavirus Disease 19 (COVID-19), which presents with a wide range of clinical symptoms from mild or moderate to severe and critical illnesses With the continuing transmission of the virus worldwide and the rapidly evolving situation globally, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic in March Currently, there is no proven specific treatment for this potentially deadly disease beyond supportive care However, a massive effort has been put globally into the investigation of medications and other interventional measures to fight COVID-19 Convalescent plasma therapy from recovered patients has recently drawn considerable interest Several alternative medical treatments, although evidence of their efficacy still lacking, have also gained popularity, especially in countries with such traditions such as India and China Rapid repurposing of drugs for COVID-19 has revealed a few promising candidate antiviral agents, but further research, especially high quality randomized controlled trials, will be needed to prove their efficacy and safety in the clinical use to treat COVID-19 Vaccine development has been the imperative task in the battle against SARS-CoV-2 While clinical trials have been launched for several candidate vaccines, research on COVID-19 vaccines is still at an early stage So far, optimized supportive care remains the best practice against COVID-19


title: Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients

text: Abstract Background: Since December 2019, more than 100,000 coronavirus disease 2019 (COVID-19) patients have been confirmed globally based on positive viral nucleic acids with real-time reverse transcriptase-polymerase chain reaction (RT-PCR). However, the association between clinical, laboratory and CT characteristics and RT-PCR results is still unclear. We sought to examine this association in detail, especially in recovered patients. Methods: We analysed data from 52 confirmed patients who had been discharged with COVID-19. The clinical, laboratory, and radiological data were dynamically recorded and compared with the admission and follow-up RT-PCR results. Results: In this cohort, 52 admitted COVID-19 patients who had confirmed positive RT-PCR results were discharged after 2 rounds of consecutively negative RT-PCR results. Compared with admission levels, CRP levels (median 4.93 mg/L [IQR: 1.78-10.20]) decreased significantly (p<0.001). and lymphocyte counts (median 1.50×109/L [IQR: 1.11-1.88]) increased obviously after obtaining negative RT-PCR results (p<0.001). Additionally, substantially improved inflammatory exudation was observed on chest CT except for 2 progressed patients. At the two-week follow-up after discharge, 7 patients had re-positive RT-PCR results, including the abovementioned 2 progressed patients. Among the 7 patients, new GGO was demonstrated in 2 patients. There were no significant differences in CPR levels or lymphocyte counts when comparing the negative and re-positive PCT results (all p >0.05). Conclusion: Heterogeneity between CT features and RT-PCR results was found in COVID-19, especially in some recovered patients with negative RT-PCR results. Our study highlights that both RT-PCR and chest CT should be considered as the key determinants for the diagnosis and management of COVID-19 patients.


title: Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

text: Remdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung. One Sentence Summary We developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.


title: COVID-19 outbreak in Italy: estimation of reproduction numbers over two months toward the Phase 2

text: After two months from the first case in COVID-19 outbreak, Italy counts more than 190,000 confirmed positive cases. From the beginning of April 2020, the nationwide lockdown started to show early effects by reducing the total cumulative incidence reached by the epidemic wave. This allows the government to program the measures to loosen lockdown restrictions for the so called "Phase 2". Here we provided the reproduction number estimation both in space and in time from February 24th to April 24th, 2020 across two months into the epidemic. Our estimates suggest basic reproduction number averaged over all the regions of 3.29, confirming that epidemiological figures of the SARS-CoV-2 epidemic in Italy are higher than those observed at the early stage of Wuhan (China) outbreak. Based on the SARS-CoV-2 transmission dynamics reported here, we gave a quantitative evaluation of the efficiency of the government measures to low the reproduction number under the unity (control regime). We estimated that among the worst hit regions in Italy, Lombardy reached the control regime on March 22nd followed by Emilia-Romagna (March 23th), Veneto (March 25th) and Piemonte (March 26th). Overall, we found that the mean value of time to reach the control regime in all the country is about 31 days from the February 24th and about 14 days from the first day of nationwide lockdown (March 12th). Finally, we highlighted the interplay between the reproduction number and two demographic indices in order to probe the "state of activity" of the epidemic for each Italian region in the control regime. We believe that this approach can provide a tool in the management of "Phase 2", potentially helping in challenging decision to continue, ease or tighten up restrictions.


title: Transmission dynamics of the COVID-19 epidemic in India, and evaluating the impact of asymptomatic carriers and role of expanded testing in the lockdown exit strategy: a modelling approach

text: Background: The coronavirus disease 2019 (COVID-19) has caused over 3 200 000 cases and 230 000 deaths as on 2 May 2020, and has quickly become an unprecedented global health threat. India, with its unique challenges in fighting this pandemic, imposed one of the worlds strictest and largest population-wide lockdown on 25 March 2020. Here, we estimated key epidemiological parameters and evaluated the effect of control measures on the COVID-19 epidemic in India and its states. Through a modeling approach that accounted for asymptomatics, we assessed the impact of lockdown relaxation and increased testing. Methods: We estimated the basic reproduction number and effective reproduction number at a national and state level in India after adjusting for imported cases and reporting lag using established statistical methods, using time-series data from 4 March to 25 April 2020. Using a dynamic SEIR-QDPA model fitted to data from India, we forecasted the size and temporality of the ongoing first wave while accounting for the interventions in place. We used the model to simulate lockdown relaxation under various scenarios to evaluate its effect on the size and temporality of the second wave. We also evaluated the feasibility of increased testing as a containment strategy after restrictions are relaxed and its impact on the epidemic size and resumption of socio-economic activities, while taking into account the changes in transmission dynamics brought about by asymptomatic carriers. Findings: The median delay from symptom onset to detection (reporting lag) was estimated to be 2{middle dot}68 days (95% CI 2{middle dot}00-3{middle dot}00) with an IQR of 2{middle dot}03 days (95% CI 1{middle dot}00-3{middle dot}00). The R0 for India was estimated to be 2{middle dot}083 (95% CI 2{middle dot}044-2{middle dot}122 ; R2 = 0{middle dot}972), while the Rt gradually down trended from 1{middle dot}665 (95%CI 1{middle dot}539-1{middle dot}789) on 30 March to 1{middle dot}159 (95% CI 1{middle dot}128-1{middle dot}189) on 21 April. 60{middle dot}7% of confirmed COVID-19 cases in our sample were found to be asymptomatic. We observed that delaying the lockdown relaxation increases the time to new rise in active cases after the relaxation in a linear fashion. If lockdown was reintroduced after a fixed relaxation period, the magnitude of the second peak could be reduced by delaying the relaxation and decreasing the duration of relaxation. These benefits were greater in case of a gradual relaxation as compared to a sudden lifting of lockdown. We found that detecting a higher proportion of cases through testing significantly decreases the total infections. This positive impact of testing progressively increased at higher transmission rates when restrictions were relaxed. We found that similar containment targets could be achieved by both, a combination of high testing and less social restrictions, and a combination of lower testing with intensive social distancing. Interpretation: The nationwide social distancing interventions in India since 25 March have reduced the effective transmission levels, though sub-threshold Rt remains to be achieved. If lockdown is to be extended, additional benefits for mitigating the second wave can be achieved if it is extended farther after the peak of active cases has passed. Intensive social distancing is inherently enough to contain the epidemic, however, testing will play a pivotal role in the lockdown exit strategy by impeding the epidemic growth enough to allow for a greater resumption of socio-economic activities, thus minimizing the social and economic fallout resulting from severe restrictions. Considering that asymptomatics play an undeniable role in the transmission of COVID-19, dependence on presence of symptoms for control strategies, behavioural changes and testing should be reduced.


title: COVID-19: A Medical Student’s Perspective

text: As a 3rd year medical student who was on the inpatient medicine wards when the pandemic broke out, my life is jarringly discontinuous with what it was before. While I know many students have returned to their education in some form online, there is no replacement educational experience for being on the wards. One week I was waking up before sunrise to pre-round on patients, managing aspiration pneumonia and alcohol withdrawal, and feeling like a member of the medical team. The next week, I was at home in my pajamas, wishing my team good luck and hoping for some kind of news, some kind of certainty.


title: Physical activity and coronavirus disease 2019 (COVID-19): specific recommendations for home-based physical training

text: The novel coronavirus disease 2019 (COVID-19) seems to be having a major impact on physical activity behaviours globally. The pandemic has forced many people around the world to stay at home and self-isolate for a period of time. WHO recommends 60 min/day of moderate-to-vigorous physical activity for 6–17-yr-olds, and 75 min/wk of vigorous or 150 min/wk of moderate physical activity for adults and elderly, including 3 and 2 days/wk, respectively, with muscle and bone strengthening. Practical recommendations for staying active at home, with aerobic exercise training on a bike or rowing ergometer, bodyweight training, dance and active video gaming, can aid to counteract the detrimental physical and mental side-effects of the COVID-19 protective lifestyle regulations. This commentary provides useful information on home-based physical activity for sedentary people across the lifespan, including children and adolescence, that can be undertaken during the present pandemic or other outbreaks of infectious disease.


title: Pns108 Deadoption of Routine Chest X-rays in the Icu: a Brazilian Choosing Wisely Experience

text: Objectives: Daily chest radiographs (CXRs) have long been a routine part of care in the intensive care units (ICU). We sought to reduce overutilisation of CXRs obtained in this setting, using a multifaceted intervention to eliminate automated daily studies. Methods: Within a 45-bed multidisciplinary ICU of a tertiary teaching hospital in Brazil, we prospectively applied a three-step intervention from May 2017 to April 2018. Firstly, a partnership formed by physician champions from both ICU and Radiology and marketing coordinators advertised Choosing Wisely recommendations for Critical Care as emails and banners. The aforementioned team educated ICU staff physicians and residents about the low diagnostic yield of automated daily CXRs through didactic sections. Then, formal discussions about CXR need for each patient during morning ICU rounds was adopted. Finally, the programmed daily order option from the electronic health records system was removed. A reeducation lecture was held in August 2018 and partial audit data was shown. Results: From May to October 2018, all CXR images were urgently acquired, and their average time was 43 minutes from order to availability. Before intervention, the median number of CXRs per patient per day was 0.38 (0.36 - 0.40). After, this amount decreased to 0.30 (0.28 - 0.32) [p= 0.0013], representing a 22% reduction on CXR request. Mean length of ICU stay before and after campaign was, respectively, 8.14 (7.79 - 8.71) and 8.45 (8.24 - 9.74) days [p= 0.35]. Mean mortality rate before and after intervention was, respectively, 18.45% (± 3.87%) and 21.58% (± 2.23%) [p = 0.12]. Conclusions: This was the first report of a Choosing Wisely initiative in a Brazilian ICU of a public hospital. Transition to a high value on-demand CXR strategy in ICUs is safe and particularly noteworthy in a low resource public health system.


Knowledge about COVID-19 and patients beliefs about and use of herbal products during the COVID-19 pandemic: a cross-sectional study in Saudi Arabia


title: The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15

text: Steroid compounds, which are expected to have dual functions in blocking host inflammation and MERS-CoV replication, were screened from a chemical library. Within this library, ciclesonide, an inhaled corticosteroid, suppressed human coronavirus replication in cultured cells, but did not suppress replication of respiratory syncytial virus or influenza virus. The effective concentration of ciclesonide to block SARS-CoV-2 (the cause of COVID-19) replication (EC90) was 6.3 μM. After the eleventh consecutive MERS-CoV passage in the presence of ciclesonide, a resistant mutation was generated, which resulted in an amino acid substitution (A25V) in nonstructural protein (NSP) 15, as identified using reverse genetics. A recombinant virus with the mutation was also resistant to ciclesonide suppression of viral replication. These observations suggest that the effect of ciclesonide was specific to coronavirus, suggesting this is a candidate drug for treatment of patients suffering MERS or COVID-19.


title: Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

text: Objective To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. Design Retrospective cohort study. Setting An analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. Participants All adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. Intervention Patients were further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measures The primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. Results A total of 4,642 patients (mean age: 66.1 +/- 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving "HCQ alone" or "HCQ plus AZI" were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the "HCQ" and "Neither drug" groups for 28-day mortality: AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the "HCQ" group: AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the "HCQ+AZI" vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). Conclusions Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials.


title: Telemedicine for the Spine Surgeon in the Age of COVID-19: Multicenter Experiences of Feasibility and Implementation Strategies

text: Study design: Multicenter study. Objectives: The COVID-19 pandemic has obligated physicians to recur to additional resources and make drastic changes regarding the standard physician-patient encounter. In the last century, there has been a substantial improvement in technology, which over the years has opened the door to a new form of medical practicing known as telemedicine. Methods: Healthcare workers from three hospitals involved in the care for COVID-19 patients in the united states were invited to share their experience using telemedicine to deliver clinical care to their patients. Results: Since the appearance of this worldwide outbreak, social distancing has been a key factor in preventing the spread of the virus, for which measures have been taken to limit physical contact. Because of the ongoing situation, telemedicine has been progressively incorporated into the physician-patient encounters and quickly has become an essential component in the day-today medical practice. Conclusions: It is feasible to deliver viable spine practice with the use of telemedicine. A proper patient selection of patients requiring virtual treatment versus those requiring in-person visits should be considered.


title: ROBOCOV: An affordable open-source robotic platform for SARS-CoV-2 testing by RT-qPCR

text: Current global pandemic due to the SARS-CoV-2 has struggled and pushed the limits of global health systems. Supply chain disruptions and scarce availability of commercial laboratory reagents have motivated worldwide actors to search for alternative workflows to cope with the demand. We have used the OT-2 open-source liquid-handling robots (Opentrons, NY), RNA extraction and RT-qPCR reagents to set-up a reproducible workflow for RT-qPCR SARS-CoV-2 testing. We developed a framework with a template and several functions and classes that allow the creation of customized RT-qPCR automated circuits. As a proof of concept, we provide data obtained by a fully-functional tested code using the MagMax™ Pathogen RNA/DNA kit and the MagMax™ Viral/Pathogen II kit (Thermo Fisher Scientific, MA) on the Kingfisher™ Flex instrument (Thermo Fisher Scientific, MA). With these codes available is easy to create new stations or circuits from scratch, adapt existing ones to changes in the experimental protocol, or perform fine adjustments to fulfil special needs. The affordability of this platform makes it accessible for most laboratories and hospitals with a bioinformatician, democratising automated SARS-CoV-2 PCR testing and increasing, temporarily or not, the capacity of carrying out tests. It also confers flexibility, as this platform is not dependant on any particular commercial kit and can be quickly adapted to protocol changes or other special needs.


title: Genomic diversity and hotspot mutations in 30,983 SARS-CoV-2 genomes: moving toward a universal vaccine for the “confined virus”?

text: The Coronavirus disease 19 (COVID-19) pandemic has been ongoing since its onset in late November 2019 in Wuhan, China. To date, the SARS-CoV-2 virus has infected more than 8 million people worldwide and killed over 5% of them. Efforts are being made all over the world to control the spread of the disease and most importantly to develop a vaccine. Understanding the genetic evolution of the virus, its geographic characteristics and stability is particularly important for developing a universal vaccine covering all circulating strains of SARS-CoV-2 and for predicting its efficacy. In this perspective, we analyzed the sequences of 30,983 complete genomes from 80 countries located in six geographical zones (Africa, Asia, Europe, North & South America, and Oceania) isolated from December 24, 2019 to May 13, 2020, and compared them to the reference genome. Our in-depth analysis revealed the presence of 3,206 variant sites compared to the reference Wuhan-Hu-1 genome, with a distribution that is largely uniform over all continents. Remarkably, a low frequency of recurrent mutations was observed; only 182 mutations (5.67%) had a prevalence greater than 1%. Nevertheless, fourteen hotspot mutations (> 10%) were identified at different locations, seven at the ORF1ab gene (in regions coding for nsp2, nsp3, nsp6, nsp12, nsp13, nsp14 and nsp15), three in the nucleocapsid protein, one in the spike protein, one in orf3a, and one in orf8. Moreover, 35 non-synonymous mutations were identified in the receptor-binding domain (RBD) of the spike protein with a low prevalence (<1%) across all genomes, of which only four could potentially enhance the binding of the SARS-CoV-2 spike protein to the human receptor ACE2. These results along with the phylogenetic analysis demonstrate that the virus does not have a significant divergence at the protein level compared to the reference both among and within different geographical areas. Unlike the influenza virus or HIV viruses, the slow rate of mutation of SARS-CoV-2 makes the potential of developing an effective global vaccine very likely.