title: Failing our Most Vulnerable: COVID-19 and Long-Term Care Facilities in Ontario

text: Background: The COVID-19 epidemic has taken a fearsome toll on individuals residing in long-term care facilities (LTC). As of April 10, 2020 half COVID-19 deaths in Canada had occurred in LTC. We sought to better understand trends and risk factors for COVID-19 death in LTC in Ontario. Methods: We analyzed a COVID-19 outbreak database created by the Ontario Ministry of Health, for the period March 29-April 7, 2020. Mortality incidence rate ratios for LTC were calculated with community living Ontarians aged > 69 used as the comparator group. Count-based regression methods were used to model temporal trends and identify associations between infection risk in staff and residents, and subsequent LTC resident death. Results: Confirmed or suspected cases of COVID-19 were identified in 272/627 LTC by April 7, 2020. The incidence rate ratio for COVID-19 death was 13.1 (9.9-17.3) relative to community living adults over 69. Incidence rate ratio increased over time and was 87.28 (90% CrI 9.98 to 557.08) by April 7, 2020. Lagged infection in staff was a strong predictor of death in residents (e.g., adjusted IRR for death per infected staff member 1.17, 95% CI 1.11 to 1.26 at a 6-day lag). Interpretation: Mortality risk in elders in Ontario is currently concentrated in LTC, and this risk has increased sharply over a short period of time. Early identification of risk requires a focus on testing and provision of personal protective equipment to staff, and restructuring the LTC workforce to prevent movement of COVID-19 between LTC.


title: Impact of shelter-in-place order for COVID-19 on trauma activations: Santa Clara County, California, March 2020

text: INTRODUCTION: The shelter-in-place order for Santa Clara County, California on 16 March was the first of its kind in the USA. It was unknown what impact this order would have on trauma activations. METHODS: We performed a retrospective analysis of institutional trauma registries among the two American College of Surgeons Level 1 trauma centers serving Santa Clara County, California. Trauma activation volumes at the trauma centers from January to March 2020 were compared with month-matched historical cohorts from 2018 to 2019. RESULTS: Only 81 (3%) patients were trauma activations at the trauma centers in the 15 days after the shelter-in-place order went into effect on 16 March 2020, compared with 389 activations during the same time period in 2018 and 2019 (p<0.0001). There were no other statistically significant changes to the epidemiology of trauma activations. Only one trauma activation had a positive COVID-19 test. DISCUSSION: Overall trauma activations decreased 4.8-fold after the shelter-in-place order went into effect in Santa Clara County on 16 March 2020, with no other effect on the epidemiology of persons presenting after traumatic injury. CONCLUSION: Shelter-in-place orders may reduce strain on healthcare systems by diminishing hospital admissions from trauma, in addition to reducing virus transmission.


title: Estimating the burden of SARS-CoV-2 in France

text: France has been heavily affected by the SARS-CoV-2 epidemic and went into lockdown on the 17th March 2020. Using models applied to hospital and death data, we estimate the impact of the lockdown and current population immunity. We find 2.6% of infected individuals are hospitalized and 0.53% die, ranging from 0.001% in those <20y to 8.3% in those >80y. Across all ages, men are more likely to be hospitalized, enter intensive care, and die than women. The lockdown reduced the reproductive number from 3.3 to 0.5 (84% reduction). By 11 May, when interventions are scheduled to be eased, we project 3.7 million (range: 2.3-6.7) people, 5.7% of the population, will have been infected. Population immunity appears insufficient to avoid a second wave if all control measures are released at the end of the lockdown.


title: Risk prediction for poor outcome and death in hospital in-patients with COVID-19: derivation in Wuhan, China and external validation in London, UK

text: Background Accurate risk prediction of clinical outcome would usefully inform clinical decisions and intervention targeting in COVID-19. The aim of this study was to derive and validate risk prediction models for poor outcome and death in adult inpatients with COVID-19. Methods Model derivation using data from Wuhan, China used logistic regression with death and poor outcome (death or severe disease) as outcomes. Predictors were demographic, comorbidity, symptom and laboratory test variables. The best performing models were externally validated in data from London, UK. Findings 4.3% of the derivation cohort (n=775) died and 9.7% had a poor outcome, compared to 34.1% and 42.9% of the validation cohort (n=226). In derivation, prediction models based on age, sex, neutrophil count, lymphocyte count, platelet count, C-reactive protein and creatinine had excellent discrimination (death c-index=0.91, poor outcome c-index=0.88), with good-to-excellent calibration. Using two cut-offs to define low, high and very-high risk groups, derivation patients were stratified in groups with observed death rates of 0.34%, 15.0% and 28.3% and poor outcome rates 0.63%, 8.9% and 58.5%. External validation discrimination was good (c-index death=0.74, poor outcome=0.72) as was calibration. However, observed rates of death were 16.5%, 42.9% and 58.4% and poor outcome 26.3%, 28.4% and 64.8% in predicted low, high and very-high risk groups. Interpretation Our prediction model using demography and routinely-available laboratory tests performed very well in internal validation in the lower-risk derivation population, but less well in the much higher-risk external validation population. Further external validation is needed. Collaboration to create larger derivation datasets, and to rapidly externally validate all proposed prediction models in a range of populations is needed, before routine implementation of any risk prediction tool in clinical care.


title: Smoking behavior and psychological dynamics during COVID-19 social distancing and stay-at-home policies: A survey

text: During the COVID-19 pandemic, about 60 million of Italians stayed at home. These circumstances may generate exceptional challenges and stress for people who regularly use cigarettes, ecigarettes, heated tobacco products, dual users, former smokers and never smokers. Here, we present results from a study that was aimed at surveying smoking behaviour and psychological dynamics during the Italian COVID-19 social distancing and stay-at-home policies. Participants living in Italy were invited to complete an online brief questionnaire. A questionnaire was prepared and uploaded in an online survey tool. They were asked to participate regardless of their current smoking status and were divided in seven subgroups. In total, 1825 participants were included in the analysis. Exclusive cigarette smokers; Dual users of cigarette and ecigarettes; Dual users of cigarette and heated tobacco products; Former smokers; Exclusive users of e-cigarette; Exclusive users of heated tobacco products; never smoker. Dual users of cigarette and e-cigarette and exclusive cigarette smokers perceived that their daily consumption has slightly decreased. Exclusive cigarette smokers and exclusive e-cigarette users changed the way of purchasing products. Most exclusive cigarette smokers have considered quitting but most exclusive e-cigarette users have not considered stopping the use of e-cigarettes. In former smokers’ group, about one third of participants declared thoughts about starting to smoke again and in never smokers’ group few participants declared intention to start smoking. The COVID-19 era could be considered a “transition” phase and as such requires a search for a new balance. These changes in everyday habits can be a significant moment to use established and emerging strategies to create a definitive smoke-free world.


title: Application of Blockchain and Internet of Things to Ensure Tamper-Proof Data Availability for Food Safety

text: Food supply chain plays a vital role in human health and food prices. Food supply chain inefficiencies in terms of unfair competition and lack of regulations directly affect the quality of human life and increase food safety risks. This work merges Hyperledger Fabric, an enterprise-ready blockchain platform with existing conventional infrastructure, to trace a food package from farm to fork using an identity unique for each food package while keeping it uncomplicated. It keeps the records of business transactions that are secured and accessible to stakeholders according to the agreed set of policies and rules without involving any centralized authority. This paper focuses on exploring and building an uncomplicated, low-cost solution to quickly link the existing food industry at different geographical locations in a chain to track and trace the food in the market.


title: Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters

text: Animal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease. One Sentence Summary An antibody targeting the spike protein of SARS-CoV-2 limits infection in immunosuppressed Syrian hamster models.


title: SARS-CoV-2 envelope protein topology in eukaryotic membranes

text: Coronavirus E protein is a small membrane protein found in the virus envelope. Different coronavirus E proteins share striking biochemical and functional similarities, but sequence conservation is limited. In this report, we studied the E protein topology from the new SARS-CoV-2 virus both in microsomal membranes and in mammalian cells. Experimental data reveal that E protein is a single-spanning membrane protein with the N-terminus being translocated across the membrane, while the C-terminus is exposed to the cytoplasmic side (Ntlum/Ctcyt). The defined membrane protein topology of SARS-CoV-2 E protein may provide a useful framework to understand its interaction with other viral and host components and establish the basis to tackle the pathogenesis of SARS-CoV-2.


title: When Darkness Becomes a Ray of Light in the Dark Times: Understanding the COVID-19 via the Comparative Analysis of the Dark Proteomes of SARS-CoV-2, Human SARS and Bat SARS-Like Coronaviruses

text: Recently emerged coronavirus designated as SARS-CoV-2 (also known as 2019 novel coronavirus (2019-nCoV) or Wuhan coronavirus) is a causative agent of coronavirus disease 2019 (COVID-19), which is rapidly spreading throughout the world now. More than 9,00,000 cases of SARS-CoV-2 infection and more than 47,000 COVID-19-associated mortalities have been reported worldwide till the writing of this article, and these numbers are increasing every passing hour. World Health Organization (WHO) has declared the SARS-CoV-2 spread as a global public health emergency and admitted that the COVID-19 is a pandemic now. The multiple sequence alignment data correlated with the already published reports on the SARS-CoV-2 evolution and indicated that this virus is closely related to the bat Severe Acute Respiratory Syndrome-like coronavirus (bat SARS-like CoV) and the well-studied Human SARS coronavirus (SARS CoV). The disordered regions in viral proteins are associated with the viral infectivity and pathogenicity. Therefore, in this study, we have exploited a set of complementary computational approaches to examine the dark proteomes of SARS-CoV-2, bat SARS-like, and human SARS CoVs by analysing the prevalence of intrinsic disorder in their proteins. According to our findings, SARS-CoV-2 proteome contains very significant levels of structural order. In fact, except for Nucleocapsid, Nsp8, and ORF6, the vast majority of SARS-CoV-2 proteins are mostly ordered proteins containing less intrinsically disordered protein regions (IDPRs). However, IDPRs found in SARS-CoV-2 proteins are functionally important. For example, cleavage sites in its replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins were shown to contain molecular recognition features (MoRFs), which are intrinsic disorder-based protein-protein interaction sites that are commonly utilized by proteins for interaction with specific partners. The results of our extensive investigation of the dark side of the SARS-CoV-2 proteome will have important implications for the structural and non-structural biology of SARS or SARS-like coronaviruses. Significance The infection caused by a novel coronavirus (SARS-CoV-2) that causes severe respiratory disease with pneumonia-like symptoms in humans is responsible for the current COVID-19 pandemic. No in-depth information on structures and functions of SARS-CoV-2 proteins is currently available in the public domain, and no effective anti-viral drugs and/or vaccines are designed for the treatment of this infection. Our study provides the first comparative analysis of the order- and disorder-based features of the SARS-CoV-2 proteome relative to human SARS and bat CoV that may be useful for structure-based drug discovery.


title: G6PD Deficiency Overrepresented Among Pediatric COVID-19 Cases in One Saudi Children Hospital

text: Fluorescent spot test for glucose-6-phosphate dehydrogenase (G6PD) deficiency was performed in 5 boys and 14 girls who had confirmed COVID-19. Out of those, 4 (80%) boys and 5 (36%) girls were found to be G6PD deficient.


title: Grierson, D. (Ed.): Developmental Regulation of Plant Gene Expression. Series: PlantBiotechnology, Vol. 2. 226 S., zahlr. Abb. u. Tab. Blackie, Glasgow and London; publishedin the USA by Chapman and Hall, New York. Preis: £ 55

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title: Chinese Society of Interventional Radiology Expert Consensus on the prevention and control of COVID-19 in interventional radiology procedures (first edition).

text: The COVID-19 pandemic seriously threatens the lives of the general public and poses momentous challenges to all medical workers, including those engaged in interventional radiology, who play an important role in the diagnosis and treatment of various diseases. To further standardize the prevention and control of nosocomial infections and ensure the safety of doctors and patients, the Chinese Society of Interventional Radiology (CSIR) organized multidisciplinary experts in the field of interventional radiology in China to prepare an "Expert Consensus" elaborating and summarizing the protective strategies and suggestions for medical workers in the field of interventional radiology when they engage in interventional diagnosis and treatment activities against the background of novel coronavirus infection control. The aim is to provide a reference for interventional procedures in hospitals and other medical institutions at all levels in China and worldwide. The key points include the following: (I) non-emergency interventional diagnosis and treatment should be suspended while work is ongoing to prevent and control the spread of COVID-19; (II) protective measures should be taken according to the appropriate level designated for COVID-19 infection prevention and control; (III) patients should take measures to protect themselves when they want to see a doctor, including accessing outpatient services online and other relevant channels of consultation.


title: Who is lonely in lockdown? Cross-cohort analyses of predictors of loneliness before and during the COVID-19 pandemic

text: Background: There are concerns internationally that lockdown measures taken during the COVID-19 pandemic could lead to a rise in loneliness. As loneliness is recognised as a major public health concern, it is therefore vital that research considers the impact of the current COVID-19 pandemic on loneliness in order to provide necessary support. But it remains unclear who is lonely in lockdown? Methods: This study compared socio-demographic predictors of loneliness before and during the COVID-19 pandemic using cross-cohort analyses of data from UK adults captured before the pandemic (UK Household Longitudinal Study, n=31,064) and during the pandemic (UCL COVID-19 Social Study, n=60,341). Results: Risk factors for loneliness were near identical prior to and during the pandemic. Young adults, women, people with lower education or income, the economically inactive, people living alone, and urban residents had a higher odds of being lonely. Some people who were already at risk for being lonely (e.g. young adults aged 18-30, people with low household income, and adults living alone) experienced a heightened risk during the COVID-19 pandemic compared to usual (indicated by higher coefficients). Further, being a student emerged as a higher risk factor during lockdown than usual. Conclusions: Findings suggest that interventions to reduce or prevent loneliness during COVID-19 should be targeted at those socio-demographic groups already identified as high-risk in previous research. These groups are likely not just to experience loneliness during the pandemic but to have an even higher odds than normal of experiencing loneliness relative to low-risk groups.


title: How many are at increased risk of severe COVID-19 disease? Rapid global, regional and national estimates for 2020

text: Background The risk of severe COVID-19 disease is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 illness, and how this varies between countries may inform the design of possible strategies to shield those at highest risk. Methods We estimated the number of individuals at increased risk of severe COVID-19 disease by age (5-year age groups), sex and country (n=188) based on prevalence data from the Global Burden of Disease (GBD) study for 2017 and United Nations population estimates for 2020. We also calculated the number of individuals without an underlying condition that could be considered at-risk because of their age, using thresholds from 50-70 years. The list of underlying conditions relevant to COVID-19 disease was determined by mapping conditions listed in GBD to the guidelines published by WHO and public health agencies in the UK and US. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. Results We estimate that 1.7 (1.0 - 2.4) billion individuals (22% [15-28%] of the global population) are at increased risk of severe COVID-19 disease. The share of the population at increased risk ranges from 16% in Africa to 31% in Europe. Chronic kidney disease (CKD), cardiovascular disease (CVD), diabetes and chronic respiratory disease (CRD) were the most prevalent conditions in males and females aged 50+ years. African countries with a high prevalence of HIV/AIDS and Island countries with a high prevalence of diabetes, also had a high share of the population at increased risk. The prevalence of multimorbidity (>1 underlying conditions) was three times higher in Europe than in Africa (10% vs 3%). Conclusion Based on current guidelines and prevalence data from GBD, we estimate that one in five individuals worldwide has a condition that is on the list of those at increased risk of severe COVID-19 disease. However, for many of these individuals the underlying condition will be undiagnosed or not severe enough to be captured in health systems, and in some cases the increase in risk may be quite modest. There is an urgent need for robust analyses of the risks associated with different underlying conditions so that countries can identify the highest risk groups and develop targeted shielding policies to mitigate the effects of the COVID-19 pandemic.


title: Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

text: Zika virus (ZIKV) specific neutralizing antibodies hold a great promise for antibody-based interventions and vaccine design against ZIKV infection. However, their development in infected patients remain unknown. Here, we report on the dynamic development of a potent and protective ZIKV-specific human antibody ZK2B10 initially isolated from a ZIKV convalescent individual using next-generation sequencing (NGS). The unbiased repertoire analysis showed dramatic changes in many families of heavy and light chain variable regions. However, lineage tracing of ZK2B10 revealed limited somatic hypermutation throughout the 12 months since the onset of symptom. In particular, NGS-derived germline-like somatic variants neutralized and protected mice from lethal challenge of ZIKV without detectable cross-reactivity with Dengue virus (DENV). Site-directed mutagenesis identified two residues within λ chain, N31 and S91 that are essential to the functional maturation. The dynamic features unveiled here will assist us to better understand the pathogenesis of ZIKV infection and inform rational design of vaccines. Author summary Recently emerged ZIKV is associated with severe neurological complications such as Guillain–Barré syndrome in adults and congenital microcephaly in newborns. No ZIKV-specific therapeutics or vaccines are currently available. We and others have identified a number of neutralizing antibodies capable of protecting experimental animals from ZIKV infection. However, the development of these potent antibodies during ZIKV natural infection remains unknown. Here, we report on the longitudinal analysis of one such antibody ZK2B10 using next-generation sequencing (NGS), bioinformatics and functional analysis. We found that the ZK2B10 germline-like antibodies possess strong neutralizing activity in vitro and impressive protectivity against lethal ZIKV infection in vivo. These findings suggest that the potent and protective antibody response against ZIKV can be generated within relative short term with high germline identity which provide great hope and promise for successful vaccine development against ZIKV.


title: A post-COVID future: tourism community re-imagined and enabled

text: The urgent demands of the present necessitate an interrogation–a re-exploration and a re-envisioning of the future of tourism–of what has to change (and remain constant). Despite the crippling effects of COVID-19, new forms of solidarity are emerging that challenge the prevailing competitiveness ethic. While a transactional economic revival has to remain a top priority, progress will advance, so long as tourism becomes more transformational and transcendent. Discoveries of new methodologies for achieving the Sustainable Development Goals and versions of a Green New Deal, for example, are generating interest, notably ‘mass flourishing’ introduced in ‘anti-fragile’ ways. Utilizing a ‘future-back’ paradigm that demands deep-dive assessments and articulation of purpose, the gaps between ‘what is’ and ‘what could or should be’ are bound to close. Such undertakings represent a ‘coming together’ of all stakeholders, a role that academicians are urged to embrace, especially through action research, curriculum change and creation of ‘daring classrooms’.


What to D.O.: ‘I'm Scared of the Coronavirus Too’


title: The timing of contact restrictions and pro-active testing balances the socio-economic impact of a lockdown with the control of infections

text: During the SARS-CoV-2 pandemic, numerous mathematical models have been developed. Reporting artefacts and missing data about asymptomatic spreaders, imply considerable margins of uncertainty for model-based predictions. Epidemiological models can however also be used to investigate the consequences of measures to control the pandemic, reflected in changes to parameter values. We present a SIR-based, SUIR model in which the influence of testing and a reduction of contacts is studied by distinguishing 'Unidentified' and 'Identified' spreaders of infections. The model uses four ordinary differential equations and is kept deliberately simple to investigate general patterns occurring from testing and contact restrictions. The model goes beyond other efforts, by introducing time dependent parameter curves that represent different strategies in controlling the pandemic. Our analysis reveals the effect of 'pro-active' testing for the design of contact restriction measures. By pro-active testing we mean testing beyond those people who show symptoms. The simulations can explain why the timing of contract restrictions and pro-active testing is important. The model can also be used to study the consequence of different strategies to exit from lockdown. Our SUIR model is implemented in Python and is made available through a Juypter Notebooks. This an extensive documentation of the derivation and implementation of the model, as well as transparent and reproducible simulation studies. Our model should contribute to a better understanding of the role of testing and contact restrictions.


title: Early Spread of SARS-Cov-2 in the Icelandic Population

text: BACKGROUND Limited data exist on how SARS-CoV-2 enters and spreads in the general population. METHODS We used two strategies for SARS-CoV-2 testing: targeted testing of high-risk individuals (n=4,551) and a population screening (n=5,502). We sequenced SARS-CoV-2 from 340 individuals. RESULTS On March 22 2020, 528 had tested positive for SARS-CoV-2 in the targeted testing (11.6%) and 50 in the population screening (0.9%); approximately 0.2% of the Icelandic population. Large fractions of positives had travelled outside Iceland (38.4% and 34.0%). Fewer under 10 years old were positive than those older: 2.8% vs. 12.3% for targeted testing (P=1.6e-9) and 0.0% vs. 1.0% for population screening (P=0.031). Fewer females were positive in the targeted testing than males (9.5% vs. 14.6%, P=6.8e-9). SARS-CoV-2 came from eight clades, seven A clades and one B clade. The clade composition differed between the testing groups and changed with time. In the early targeted testing, 65.0% of clades were A2a1 and A2a2 derived from Italian and Austrian skiing areas, but in the later targeted testing went down to 30.6% and were overtaken by A1a and A2a, the most common clades in the population screening. CONCLUSION SARS-CoV-2 has spread widely in Iceland outside of the high-risk groups. Several strains cause these infections and their relative contribution changed rapidly. Children and females are less vulnerable than adults and males. To contain the pandemic we must increase the scope of the testing.


title: The Current COVID-19 Spread Pattern in India

text: In this article, we are going to show how to find out short term forecasts of the total number of COVID-19 cases in India in an easy way. Initially the spread of the disease was observably slow in India. Since the first week of May a highly nonlinear pattern has started to take shape. It can be observed that currently in India the spread pattern is nearly exponential. It can be seen further that the number of cases is still continuing to grow very fast. Therefore, instead of going for rigorous time series analysis, we may opt for looking at the data from a recent date downwards, and short term forecasts based on simple numerical analytical methods can be made accordingly.


title: Elementary time-delay dynamics of COVID-19 disease

text: An elementary model of COVID-19 dynamics, based on time-delay differential equations with a step-like survival function, is shown to be in good agreement with data from China and South Korea. The time-delal approach overcomes the major limitation of standard Susceptible-Exposed-Infected-Recovered (SEIR) models based on ordinary differential equations, namely their inability to predict the observed curve of infected individuals as a function of time. The model is also applied to countries where the epidemic is in earlier stages, such as Italy and Spain, to obtain estimates of the total number of cases and peak number of infected people that might be observed.


title: CoV2ID: Detection and Therapeutics Oligo Database for SARS-CoV-2

text: The ability to detect the SARS-CoV-2 in a widespread epidemic is crucial for screening of carriers and for the success of quarantine efforts. Methods based on real-time reverse transcription polymerase chain reaction (RT-qPCR) and sequencing are being used for virus detection and characterization. However, RNA viruses are known for their high genetic diversity which poses a challenge for the design of efficient nucleic acid-based assays. The first SARS-CoV-2 genomic sequences already showed novel mutations, which may affect the efficiency of available screening tests leading to false-negative diagnosis or inefficient therapeutics. Here we describe the CoV2ID (http://covid.portugene.com/), a free database built to facilitate the evaluation of molecular methods for detection of SARS-CoV-2 and treatment of COVID-19. The database evaluates the available oligonucleotide sequences (PCR primers, RT-qPCR probes, etc.) considering the genetic diversity of the virus. Updated sequences alignments are used to constantly verify the theoretical efficiency of available testing methods. Detailed information on available detection protocols are also available to help laboratories implementing SARS-CoV-2 testing.


title: Estimating the ascertainment rate of SARS-CoV-2 infection in Wuhan, China: implications for management of the global outbreak

text: We sought to estimate the ascertainment ratio of SARS-CoV-2 infection in Wuhan, China, using a modified Bayesian SEIR model with publicly reported case data. We estimated it at 0.465% (95%CI: 0.464-0.466%), implying that the outbreak in Wuhan was abated by depletion of susceptibles, rather than public health action alone. This suggests a high-transmissibility/low-severity profile for the current pandemic and raises doubt about whether suppression, rather than mitigation, is a feasible goal.


title: Hydroxychloroquine Versus COVID-19: A Rapid Systematic Review and Meta-Analysis

text: Background: Coronavirus Disease 2019 (COVID-19) has become a major global issue with rising the number of infected individuals and mortality in recent months. Among all therapeutic approaches, arguments have raised about hydroxychloroquine efficacy in treatment of COVID-19. We aimed to overcome the controversies regarding effectiveness of hydroxychloroquine in treatment of COVID-19, using a systematic review and meta-analysis. Methods: A systematic search was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, Google Scholar and medRxiv pre-print database using all available MeSH terms for COVID-19 and hydroxychloroquine. Two authors selected and assessed the quality of studies independently using related checklists. Data have been extracted from included studies and analyzed using CMA v. 2.2.064. heterogeneity was also assessed using I-squared test. Results: Seven studies including four clinical trials and three observational studies have entered into the study. The results of meta-analysis of clinical trials showed that there were no significant differences between patients who received the standard treatment with HCQ regimen and the patients that received the standard treatment without HCQ (RR: 1.44, 95% CI, 0.80-2.59). CT-Scan findings improved in 59% (95% CI 0.15-0.92) and nasopharyngeal culture following RT-PCR resulted negative in 76% (95% CI 0.56-0.89) of patients received hydroxychloroquine. Meta-analysis of observational studies showed 75% (95% CI, 0.54-0.88) of patients were discharged from the hospital, 34% (95% CI, 0.07-0.14) admitted to intensive care unit and 1.5% (95% CI, 0.03-0.83) have expired. Conclusion: This study indicated no clinical benefits regarding HCQ for treatment of COVID-19 patients. However, further large clinical trials should be taken into account in order to achieve more reliable findings.


title: Study protocol for COvid-19 Vascular sERvice (COVER) study: The impact of the COVID-19 pandemic on the provision, practice and outcomes of vascular surgery

text: Background: The novel Coronavirus Disease 2019 (COVID-19) pandemic is having a profound impact on global healthcare. Shortages in staff, operating theatre space and intensive care beds has led to a significant reduction in the provision of surgical care. Even vascular surgery, often insulated from resource scarcity due to its status as an urgent specialty, has limited capacity due to the pandemic. Furthermore, many vascular surgical patients are elderly with multiple comorbidities putting them at increased risk of COVID-19 and its complications. There is an urgent need to investigate the impact on patients presenting to vascular surgeons during the COVID-19 pandemic. Methods and Analysis: The COvid-19 Vascular sERvice (COVER) study has been designed to investigate the worldwide impact of the COVID-19 pandemic on vascular surgery, at both service provision and individual patient level. COVER is running as a collaborative study through the Vascular and Endovascular Research Network (VERN) with the support of numerous national (Vascular Society of Great Britain and Ireland, British Society of Endovascular Therapy, British Society of Interventional Radiology, Rouleaux Club) and an evolving number of international organisations (Vascupedia, SingVasc, Audible Bleeding (USA), Australian and New Zealand Vascular Trials Network (ANZVTN)). The study has 3 Tiers: Tier 1 is a survey of vascular surgeons to capture longitudinal changes to the provision of vascular services within their hospital; Tier 2 captures data on vascular and endovascular procedures performed during the pandemic; and Tier 3 will capture any deviations to patient management strategies from pre-pandemic best practice. Data submission and collection will be electronic using online survey tools (Tier 1: SurveyMonkey for service provision data) and encrypted data capture forms (Tiers 2 and 3: REDCap for patient level data). Tier 1 data will undergo real-time serial analysis to determine longitudinal changes in practice, with country-specific analyses also performed. The analysis of Tier 2 and Tier 3 data will occur on completion of the study as per the pre-specified statistical analysis plan. Ethical Approval: Ethical approval from the UK Health Research Authority has been obtained for Tiers 2 and 3 (20/NW/0196 Liverpool Central). Participating centres in the UK will be required to seek local research and development approval. Non-UK centres will need to obtain a research ethics committee or institutional review board approvals in accordance with national and/or local requirements. ISRCTN: 80453162 (https://doi.org/10.1186/ISRCTN80453162) Ethical Approval: 20/NW/0196 Liverpool Central, IRAS: 282224


title: Deep Sentiment Classification and Topic Discovery on Novel Coronavirus or COVID-19 Online Discussions: NLP Using LSTM Recurrent Neural Network Approach

text: Internet forums and public social media, such as online healthcare forums, provide a convenient channel for users (people/patients) concerned about health issues to discuss and share information with each other. In late December 2019, an outbreak of a novel coronavirus (infection from which results in the disease named COVID-19) was reported, and, due to the rapid spread of the virus in other parts of the world, the World Health Organization declared a state of emergency. In this paper, we used automated extraction of COVID-19–related discussions from social media and a natural language process (NLP) method based on topic modeling to uncover various issues related to COVID-19 from public opinions. Moreover, we also investigate how to use LSTM recurrent neural network for sentiment classification of COVID-19 comments. Our findings shed light on the importance of using public opinions and suitable computational techniques to understand issues surrounding COVID-19 and to guide related decision-making.


title: Which animals are at risk? Predicting species susceptibility to Covid-19

text: In only a few months, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, leaving physicians, scientists, and public health officials racing to understand, treat, and contain this zoonotic disease. SARS-CoV-2 has made the leap from animals to humans, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. While there is evidence that certain species, such as cats, are susceptible, the vast majority of animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict their infection risk are urgently needed. SARS-CoV-2 spike protein binding to angiotensin converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we identified key ACE2 residues that distinguish susceptible from resistant species using in-depth sequence and structural analyses of ACE2 and its binding to SARS-CoV-2. Our findings have important implications for identification of ACE2 and SARS-CoV-2 residues for therapeutic targeting and identification of animal species with increased susceptibility for infection on which to focus research and protection measures for environmental and public health.


title: Effectiveness of Intravenous Immunoglobulin for Children with Severe COVID-19: A Rapid Review

text: Background: Intravenous immunoglobulin (IVIG) is usually used as supportive therapy, but the treatment of COVID-19 by IVIG is controversial. This rapid review aims to explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19. Methods: We systematically searched the literature on the use of IVIG in patients with COVID-19, Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS), including both adults and children. We assessed the risk of bias and quality of evidence and reported the main findings descriptively. Results: A total of 1519 articles were identified by initial literature search, and finally six studies, included one randomized controlled trial (RCT), four case series and one case report involving 198 patients. One case series showed the survival of COVID-19 patients with acute respiratory distress syndrome (ARDS) was not improved by IVIG. One case report showed high-dose IVIG could improve the outcome of COVID-19 adults. Three observational studies showed inconsistent results of the effect of IVIG on SARS patients. One RCT showed that IVIG did not reduce mortality or the incidence of nosocomial infection in adults with severe SARS. The quality of evidence was between low and very low. Conclusions: The existing evidence is insufficient to support the efficacy or safety of IVIG in the treatment of COVID-19. Keywords: COVID-19; children; intravenous immunoglobulin; rapid review.


title: Projection of hospitalization by COVID-19 in Brazilfollowing different social distances policies

text: Following the first infections in the Wuhan City, COVID-19 became a global pandemic as declared by the World Health Organization (WHO). Since it is an airborne disease transmitted between humans, many countries adopted a quarantine on their own population as well as closing borders measures. In Brazil many are discussing the best way to manage the opening of the quarantine under the constraints of hospitals infrastructure. In this work we implement a forecast of the demand for hospital beds for the next 30 days for every state in Brazil for different quarantine flexibilization scenarios and analyse how long it would take for the demand to exceed current available hospital beds.


title: Phylogenetic Analysis of SARS-CoV-2 Genomes in Turkey

text: COVID-19 has effectively spread worldwide. As of May 2020, Turkey is among the top ten countries with the most cases. A comprehensive genomic characterization of the virus isolates in Turkey is yet to be carried out. Here, we built a phylogenetic tree with globally obtained 15,277 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes. We identified the subtypes based on the phylogenetic clustering in comparison with the previously annotated classifications. We performed a phylogenetic analysis of the first thirty SARS-CoV-2 genomes isolated and sequenced in Turkey. We suggest that the first introduction of the virus to the country is earlier than the first reported case of infection. Virus genomes isolated from Turkey are dispersed among most types in the phylogenetic tree. We find two of the seventeen sub-clusters enriched with the isolates of Turkey, which likely have spread expansively in the country. Finally, we traced virus genomes based on their phylogenetic placements. This analysis suggested multiple independent international introductions of the virus and revealed a hub for the inland transmission. We released a web application to track the global and interprovincial virus spread of the isolates from Turkey in comparison to thousands of genomes worldwide.


title: Epidemiological Characteristics of COVID-19: A Systemic Review and Meta-Analysis

text: Background: Our understanding of the corona virus disease 2019 (COVID-19) continues to evolve. However, there are many unknowns about its epidemiology. Purpose: To synthesize the number of deaths from confirmed COVID-19 cases, incubation period, as well as time from onset of COVID-19 symptoms to first medical visit, ICU admission, recovery and death of COVID-19. Data Sources: MEDLINE, Embase, and Google Scholar from December 01, 2019 through to March 11, 2020 without language restrictions as well as bibliographies of relevant articles. Study Selection: Quantitative studies that recruited people living with or died due to COVID-19. Data Extraction: Two independent reviewers extracted the data. Conflicts were resolved through discussion with a senior author. Data Synthesis: Out of 1675 non-duplicate studies identified, 57 were included. Pooled mean incubation period was 5.84 (99% CI: 4.83, 6.85) days. Pooled mean number of days from the onset of COVID-19 symptoms to first clinical visit was 4.82 (95% CI: 3.48, 6.15), ICU admission was 10.48 (95% CI: 9.80, 11.16), recovery was 17.76 (95% CI: 12.64, 22.87), and until death was 15.93 (95% CI: 13.07, 18.79). Pooled probability of COVID-19-related death was 0.02 (95% CI: 0.02, 0.03). Limitations: Studies are observational and findings are mainly based on studies that recruited patient from clinics and hospitals and so may be biased toward more severe cases. Conclusion: We found that the incubation period and lag between the onset of symptoms and diagnosis of COVID-19 is longer than other respiratory viral infections including MERS and SARS; however, the current policy of 14 days of mandatory quarantine for everyone might be too conservative. Longer quarantine periods might be more justified for extreme cases.


title: Depression and loneliness during COVID-19 restrictions in the United States, and their associations with frequency of social and sexual connections

text: Purpose: To estimate the prevalence of depression and loneliness during the US COVID-19 response, and examine their associations with frequency of social and sexual connections. Methods: We conducted an online cross-sectional survey of a nationally representative sample of American adults (n=1010), aged 18-94, running from April 10-20, 2020. We assessed depressive symptoms (CES-D-10 scale), loneliness (UCLA 3-Item Loneliness scale), and frequency of in-person and remote social connections (4 items, e.g. hugging family member, video chats) and sexual connections (4 items, e.g. partnered sexual activity, dating app use). Results: One-third of participants (32%) reported depressive symptoms, and loneliness was high [mean (SD): 4.4 (1.7)]. Those with depressive symptoms were more likely to be women, age 20-29, unmarried, and low-income. Frequent in-person connections were associated with lower depression and loneliness; frequent remote connections were not. Conclusions: Depression and loneliness were elevated during the early US COVID-19 response. Those who maintained frequent in-person, but not remote, social and sexual connections had better mental health outcomes. While COVID-19 social restrictions remain necessary, it will be critical to expand mental health services to serve those most at-risk and identify effective ways of maintaining social and sexual connections from a distance.


title: Protecting parliamentary democracy in “plague” times: Accountability and democratic institutions during the pandemic

text: The spread of COVID-19 has not only placed strains on public health and the economy. It has presented challenges to the constitutional structure and the continuing requirement that parliaments within the Westminister system of government be able to operate. In such systems, the continued legitimacy of government action and accountability for those actions rests and must remain with the elected chamber of Parliament. At the same time, COVID-19 precludes normal gatherings of parliamentarians for proceedings. This article briefly explores the constitutional necessity for continued parliamentary scrutiny, the various forms such proceedings have taken to date and the application of parliamentary privilege to such proceedings.


title: Differential COVID-19-attributable mortality and BCG vaccine use in countries

text: While mortality attributable to COVID-19 has devastated global health systems and economies, striking regional differences have been observed. The Bacille Calmette Guerin (BCG) vaccine has previously been shown to have non-specific protective effects on infections, as well as long-term efficacy against tuberculosis. Using publicly available data we built a simple log-linear regression model to assess the association of BCG use and COVID-19-attributable mortality per 1 million population after adjusting for confounders including country economic status (GDP per capita), and proportion of elderly among the population. The timing of country entry into the pandemic epidemiological trajectory was aligned by plotting time since the 100th reported case. Countries with economies classified as lower-middle-income, upper-middle-income and high-income countries (LMIC, UMIC, HIC) had median crude COVID-19 log-mortality of 0.4 (Interquartile Range (IQR) 0.1, 0.4), 0.7 (IQR 0.2, 2.2) and 5.5 (IQR 1.6, 13.9), respectively. COVID-19-attributable mortality among BCG-using countries was 5.8 times lower [95% CI 1.8-19.0] than in non BCG-using countries. Notwithstanding limitations due to testing constraints in LMICs, case ascertainment bias and a plausible rise of cases as countries progress along the epidemiological trajectory, these analyses provide intriguing observations that urgently warrant mobilization of resources for prospective randomized interventional studies and institution of systematic disease surveillance, particularly in LMICs.


title: Appendix I Aspects of Clinical Relevance in Donkeys

text: Unknown


title: Clinical Characteristics of Coronavirus Pneumonia 2019 (COVID-19): An Updated Systematic Review

text: OBJECTIVE Clinical characteristics of novel coronavirus pneumonia (COVID-19) have been described in numerous studies but yielded varying results. We aimed to conduct a systematic review on scientific literatures and to synthesize critical data on clinical traits of COVID-19 from its initial outbreak to pandemic. METHODS Systematic searches were conducted to identify retrospective observational study that contained clinical characteristics on COVID-19 through multiple databases. Two reviewers independently evaluated eligible publications. Data on clinical characteristics of COVID-19 were extracted and analyzed. RESULTS Seventy-two retrospective studies demonstrating the clinical characteristics of COVID-19 were included. A total of 3470 COVID-19 patients were synthesized to the final analysis in an unbiased manner. The most common symptom was fever (2878 [83.0%]), and 63.4% of the patients presented fever as onset symptom. There were 2528 [88.2%] of 2866 cases had abnormal lung findings on chest CT scan. Laboratory findings showed that 1498 [62.8%] of 2387 cases had lymphopenia, and 1354 [64.8%] of 2091 cases had an increased level of C-reactive protein (CRP). A total of 185 [11.5%] patients were admitted to intensive care unit (ICU) while the overall case fatality rate (CFR) was 3.7%. Compared to patients admitted outside of Hubei, China, those from Hubei had a significant higher ICU admission rate (21.9% vs. 2.5%, p<0.001). Also, CFR attributed to COVID-19 was significantly higher in Hubei than that of non-Hubei admissions (10.4% vs. 0.6%, p<0.001). INTERPRETATION This large patient-based systematic review presents a more precise profiling of the COVID-19 from its outbreak to current pandemic. Dynamic evolvements of COVID-19 are needed to be characterized in future studies.


title: Did Japan miss its chance to keep the coronavirus in check?

text: He has become known in Japan as the “80% uncle ” Over the past several weeks, Hokkaido University epidemiologist Hiroshi Nishiura has given innumerable TV and newspaper interviews urging the public to reduce social contact by 80% in order to reverse the suddenly explosive growth of Japan’s COVID-19 epidemic “Cooperate to reduce contacts immediately in a drastic manner,” Nishiura keeps saying He often points to a graph showing results from his modeling indicating that Japan’s outbreak can only be contained if people drastically and immediately limit their interactions with others If they used to have contact with 10 people a day, they have to cut that to two, he says Japan’s government is hoping people will listen Confirmed case numbers remain relatively low, but are rising at an alarming rate On 15 March, Japan had an official cumulative total of 780 cases;as of 19 April, that number had soared to more than 10,700, 3000 of them in Tokyo “Tokyo and other big cities are already entering an explosive phase and other areas in Japan are also following that path,” says Kenji Shibuya, a global health scholar at King’s College London He and others blame a containment strategy that focused on known infection clusters but limited access to testing, allowing individual cases to escape surveillance


title: The Lifelines COVID-19 Cohort: a questionnaire-based study to investigate COVID-19 infection and its health and societal impacts in a Dutch population-based cohort

text: The COVID-19 pandemic has affected billions of people around the world not only through the infection itself but also through its wider impact on public health and daily life. To assess the effects of the pandemic, a team of researchers across a wide range of disciplines developed and implemented the Lifelines COVID-19 questionnaire, leading to the development of the Lifelines COVID-19 cohort. This cohort is recruited from participants of the Lifelines prospective population cohort and the Lifelines NEXT birth cohort, and participants were asked to fill out detailed questionnaires about their physical and mental health and experiences on a weekly basis starting in late March of 2020 and on a bi-weekly basis staring in June 2020. The Lifelines region covers the three Northern provinces of the Netherlands-Drenthe, Groningen and Friesland-which together account for about 10% of the Dutch population. To date, >70,000 people have responded to the questionnaires at least once, and the questionnaire program is still ongoing. Data collected by the questionnaires will be used to address four aspects of the outbreak: (1) how the COVID-19 pandemic developed in the three northern provinces of the Netherlands, (2) which environmental risk factors predict disease susceptibility and severity, (3) which genetic risk factors predict disease susceptibility and severity and (4) what are the psychological and societal impacts of the crisis.


title: The impact of thermal pasteurization on viral load in human milk and other matrices: A rapid review

text: Holder pasteurization (62.5{degrees}C, 30 min) of human milk (HM) is thought to reduce the risk of transmitting viruses to an infant. Some viruses may be secreted into milk- others may be contaminants. The effect of thermal pasteurization on viruses in HM has yet to be rigorously reviewed. The objective of this study is to characterize the effect of commonly used pasteurization techniques on viruses in HM and non-HM matrices. Databases (MEDLINE, Embase, Web of Science) were searched from inception to April 20th, 2020 for primary research articles assessing the impact of pasteurization on viral load or detection of live virus. Reviews were excluded, as were studies lacking quantitative measurements or those assessing pasteurization as a component of a larger process. Overall, 65,131 reports were identified, and 108 studies included. Pasteurization of HM at a minimum temperature of 56{degrees}C-60{degrees}C is effective at reducing detectable live virus. In cell culture media or plasma, coronaviruses (e.g., SARS-CoV, SARS-CoV-2, MERS) are highly susceptible to heating at [≥]56{degrees}C. Although pasteurization parameters and matrices reported vary, all viruses studied, with the exception of parvoviruses, were susceptible to thermal killing. Future research important for the study of novel viruses should standardize pasteurization protocols and should test viral inactivation using a human milk matrix.


Stepping Out of Isolation: Autistic People and COVID-19


title: Differential Antibody Recognition by Novel SARS-CoV-2 and SARS-CoV Spike Protein Receptor Binding Domains: Mechanistic Insights and Implications for the Design of Diagnostics and Therapeutics

text: The appearance of the novel betacoronavirus SARS-CoV-2 represents a major threat to human health, and its diffusion around the world is causing dramatic consequences. The knowledge of the 3D structures of SARS-CoV-2 proteins can facilitate the development of therapeutic and diagnostic molecules. Specifically, comparative analyses of the structures of SARS-CoV-2 proteins and homologous proteins from previously characterized viruses, such as SARS-CoV, can reveal the common and/or distinctive traits that underlie the mechanisms of recognition of cell receptors and of molecules of the immune system. Herein, we apply our recently developed energy-based methods for the prediction of antibody-binding epitopes and protein-protein interaction regions to the Receptor Binding Domain (RBD) of the Spike proteins from SARS-CoV-2 and SARS-CoV. Our analysis focusses only on the study of the structure of RBDs in isolation, without making use of any previous knowledge of binding properties. Importantly, our results highlight structural and sequence differences among the regions that are predicted to be immunoreactive and bind/elicit antibodies. These results provide a rational basis to the observation that several SARS-CoV RDB-specific monoclonal antibodies fail to appreciably bind the SARS-CoV-2 counterpart. Furthermore, we correctly identify the region of SARS-CoV-2 RBD that is engaged by the cell receptor ACE2 during viral entry into host cells. The data, sequences and structures we present here can be useful for the development of novel therapeutic and diagnostic interventions.


Aim Kidney impairment is observed in patients with COVID-19. We aimed to demonstrate the effect of anti-COVID-19 agent remdesivir on renal fibrosis. Methods Remdesivir and its active nucleoside metabolite GS-441524 were used to treat TGF-β stimulated renal fibroblasts (NRK-49F) and human renal epithelial cells (HK2). Cell viability was determined by CCK8 assay, and fibrotic markers were measured by Western blotting. Vehicle or remdesivir were given by intraperitoneal injection or renal injection through the left ureter in unilateral ureteral obstruction (UUO) mice. Serum and kidneys were harvested. The concentrations of remdesivir and GS-441524 were measured using LC-MS/MS. Renal and liver function were assessed. Renal fibrosis was evaluated by Masson’s trichrome staining and Western blotting. Results Remdesivir and GS-441524 inhibited cell proliferation and the expression of fibrotic markers (fibronectin, pSmad3, and aSMA) in NRK-49F and HK2 cells. Intraperitoneal injection or renal injection of remdesivir attenuated renal fibrosis of UUO kidneys. Renal and liver function were not changed in remdesivir treated UUO mice. Remdesivir can not be detected, but two remdesivir metabolites were detected after injection. Conclusion Remdesivir inhibits renal fibrosis in obstructed kidneys.


title: The estimations of the COVID-19 incubation period: a systematic review of the literature

text: Objective: to undertake a review and critical appraisal of all published/preprint reports that offer an estimation of incubation periods for novel coronavirus (COVID-19). Design: a rapid and systematic review/critical appraisal Data sources: COVID-19 Open Research Dataset supplied by Georgetown's Centre for Security and Emerging Technology as well as PubMed and Embase via Arxiv, medRxiv, and bioRxiv. Results: screening was undertaken 44,000 articles with a final selection of 25 studies referring to 18 different experimental projects related to the estimation of the incubation period of COVID-19. Findings: The majority of extant published estimates offer empirical evidence showing that the incubation period for the virus is a mean of 7.8 days, with a median of 5.01 days, which falls into the ranges proposed by the WHO (0 to 14 days) and the ECDC (2 to 12 days). Nevertheless, a number of authors proposed that quarantine time should be a minimum of 14 days and that for estimates of mortality risks a median time delay of 13 days between illness and mortality should be under consideration. It is unclear as to whether any correlation exists between the age of patients and the length of time they incubate the virus. Finally, it is generally agreed that robust precautions must be put in place for the prevention and/or mitigation of asymptomatic transmission to high-risk patients caused by those incubating the virus.


title: TOWARD A COVID-19 SCORE-RISK ASSESSMENTS AND REGISTRY

text: ABSTRACT Importance Critical care resources like ventilators, used to manage the current COVID-19 pandemic, are potentially inadequate. Established triage standards and guidelines may not contain the most appropriate severity assessment and outcome prediction models. Objectives Develop a draft pandemic specific triage assessment score for the current COVID-19 pandemic. Design a website where initial Toward a COVID-19 Scores (TACS) can be quickly calculated and used to compare various treatment strategies. Create a TACS Registry where data and outcomes for suspected and confirmed COVID-19 patients can be recorded. Use the TACS Registry to develop an influenza epidemic specific database and score for use in future respiratory based epidemics. Design, Setting, Participants Retrospective analysis of 3,301 ICU admissions with respiratory failure admitted to 41 U.S. Intensive Care Units from 2015-19. Independent external validation on 1,175 similar ICU Admissions using identical entry criteria from Barnes Jewish Hospital (BJH), Washington University from 2016-2019. Main Outcomes TACS was created with 16 readily available predictive variables for risk assessment of hospital mortality 24 hours after ICU Admission and the need for prolonged assisted mechanical ventilation (PAMV) ( >>96 hours) at 24- and 48-hours post ICU admission. Results TACS achieved an Area Under the Curve (AUC) for hospital mortality after 24 hours of 0.80 in the development dataset; 0.81 in the internal validation dataset. At a probability of 50% hospital mortality, positive predictive value (PPV) was 0.55, negative predictive value (NPV) 0.89; sensitivity 22%, specificity 97%. For PAMV after 24 hours, the AUC was 0.84 in the development dataset, 0.81 in the validation dataset. For PAMV after 48 hours, the AUC was 0.82 in the development dataset, 0.78 in the validation dataset. In the external validation the AUC for TACS was 0.76 +/- 0.024. We launched a website that is scaled for mobile device use ( https://covid19score.azurewebsites.net/) that provides open access to a user-friendly TACS Calculator for all predictions. We also designed a voluntary TACS Registry for collection of data and outcomes on ICU Admissions with COVID-19. Conclusions and Relevance Toward a COVID-19 score is a starting point for an epidemic specific triage assessment that could be used to evaluate various approaches to treatment. The TACS Registry provides the ability to establish a respiratory specific outcomes database that can be used to create a triage approach for future such pandemics.


title: Fitting SIR model to COVID-19 pandemic data and comparative forecasting with machine learning

text: In this work, we use a classical SIR model to study COVID-19 pandemic. We aim to deal with the SIR model fitting to COVID-19 data by using different technics and tools. We particularly use two ways: the first one start by fitting the total number of the confirmed cases and the second use a parametric solver tool. Finally a comparative forecasting, machine learning tools, is given.


title: Mechanism and inhibition of SARS-CoV-2 PLpro

text: Coronaviruses, including SARS-CoV-2, encode multifunctional proteases that are essential for viral replication and evasion of host innate immune mechanisms. The papain-like protease PLpro cleaves the viral polyprotein, and reverses inflammatory ubiquitin and anti-viral ubiquitin-like ISG15 protein modifications1,2. Drugs that target SARS-CoV-2 PLpro (hereafter, SARS2 PLpro) may hence be effective as treatments or prophylaxis for COVID-19, reducing viral load and reinstating innate immune responses3. We here characterise SARS2 PLpro in molecular and biochemical detail. SARS2 PLpro cleaves Lys48-linked polyubiquitin and ISG15 modifications with high activity. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. We further exploit two strategies to target PLpro. A repurposing approach, screening 3727 unique approved drugs and clinical compounds against SARS2 PLpro, identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors were able to inhibit SARS2 PLpro with high potency and excellent antiviral activity in SARS-CoV-2 infection models.


title: Theoretical basis and effect characteristics of andrographolide against COVID-19/ 穿心莲内酯类制剂抗新型冠状病毒肺炎的相关理论依据和作用特点

text: Since December 2019, coronavirus disease 2019 (COVID-19) has spread rapidly in China. National Health Commission of the People’s Republic of China and local departments have released a number of diagnosis and treatment plans for COVID-19. Some plans recommend Xiyanping Injection for the clinical treatment of COVID-19. The active component of the drug is the total sulfonate of andrographolide, which is a derivative of andrographolide. This paper summarized the pharmacological action and clinical application of andrographolide, and proposed that it has the functions of clearing heat and detoxification, anti-bacterial and anti-inflammatory, and definite therapeutic effect on respiratory system diseases including viral pneumonia and upper respiratory tract infection, and a large number of clinical data have been accumulated. Andrographolide has a potential antiviral effect on the treatment of COVID-19, and can reduce the level of inflammation in patients, improve respiratory symptoms, inhibit concurrent bacterial infection, and improve the body immunity. At the same time, it will not bring the immunosuppressive effect of hormone drugs, and the incidence of adverse reactions is low. In addition, Andrographolide has certain hepatoprotective effects and clinical value for treating cardiovascular diseases in clinical experience, suggesting that it may have some protective effects on drug-induced liver injury, heart injury and liver injury caused by durgs against COVID-19, but further clinical verification is needed. The pharmacological action and clinical application of andrographolide are summarized. This paper also analyzes the etiology, pathogenesis and dialectical treatment of COVID-19 from the perspective of traditional Chinese medicine, and points out that the treatment of COVID-19 with andrographolide is consistent with the theory of traditional Chinese medicine.


title: Monitoring the propagation of COVID-19-pandemic first waves

text: A phenomenological approach is proposed to monitor the propagation of the COVID-19-pandemic first waves. A large set of data collected at a worldwide scale during the first months of 2020 is compiled into series of semi-logarithmic plots, for a selection of thirty-two countries from the five continents. Three regimes are identified in the propagation of an epidemic wave: a pre-epidemic regime 1, an exponential-growth regime 2, and a resorption regime 3. A two-parameters scaling of the first-wave death variation reported in China is used to fit those reported in other countries. Comparison is made between the propagation of the pandemic in different countries, which are classified in four groups, from group A where the pandemic first waves were contained efficiently, to group D where the pandemic first waves widely spread. Group A is mainly composed of Asian countries, where fast and efficient measures have been applied. Group D is composed of Western-Europe countries and the United States of America, where late decisions and confused political communication (pandemic seriousness, protection masks, herd immunity etc.) led to significant death tolls. The threat of large resurging epidemic waves after a hasty lockdown lift is discussed, in particular for the countries from group D, where the number of contagious people remained high in the beginning of May 2020. The situation is opposite in Asian countries from group A, where the number of contagious people was successfully maintained to a low level. In particular, the results obtained by Hong Kong and South Korea are highlighted, and the measures taken there are presented as virtuous examples that other countries may follow.


title: Cognitive impairment is a common comorbidity in COVID-19 deceased patients. A hospital-based retrospective cohort study.

text: Introduction: Little is known about the relation of cognitive impairment (CI) to COVID-19 mortality. Here, we analyse the frequency of CI in deceased COVID-19 patients. Methods: We included 477 adult cases that died after admission from March 1 to March 31, 2020: 281 with confirmed COVID-19, 58 probable COVID-19, and 138 who died of other causes. Results: The number of comorbidities was high in the confirmed COVID-19, and CI was common (30%: 21.1% dementia; 8.9% mild cognitive impairment). Subjects with CI were older, more lived in nursing homes and had shorter times from symptom onset to death than those without CI. COVID-19 patients with CI were rarely admitted to the ICU and fewer received non-invasive mechanical ventilation, but palliative care was provided more often. Conclusions: Dementia is a frequent comorbidity in COVID-19 deceased patients. The burden of COVID-19 in the dementia community will be high.


title: Development and External Validation of a Prognostic Tool for COVID-19 Critical Disease

text: Background: The rapid spread of coronavirus disease 2019 (COVID-19) revealed significant constraints in critical care capacity. In anticipation of subsequent waves, reliable prediction of disease severity is essential for critical care capacity management and may enable earlier targeted interventions to improve patient outcomes. The purpose of this study is to develop and externally validate a prognostic model/clinical tool for predicting COVID-19 critical disease at presentation to medical care. Methods: This is a retrospective study of a prognostic model for the prediction of COVID-19 critical disease where critical disease was defined as ICU admission, ventilation, and/or death. The derivation cohort was used to develop a multivariable logistic regression model. Covariates included patient comorbidities, presenting vital signs, and laboratory values. Model performance was assessed on the validation cohort by concordance statistics. The model was developed with consecutive patients with COVID-19 who presented to University of California Irvine Medical Center in Orange County, California. External validation was performed with a random sample of patients with COVID-19 at Emory Healthcare in Atlanta, Georgia. Results: Of a total 3208 patients tested in the derivation cohort, 9% (299/3028) were positive for COVID-19. Clinical data including past medical history and presenting laboratory values were available for 29% (87/299) of patients (median age, 48 years [range, 21-88 years]; 64% [36/55] male). The most common comorbidities included obesity (37%, 31/87), hypertension (37%, 32/87), and diabetes (24%, 24/87). Critical disease was present in 24% (21/87). After backward stepwise selection, the following factors were associated with greatest increased risk of critical disease: number of comorbidities, body mass index, respiratory rate, white blood cell count, % lymphocytes, serum creatinine, lactate dehydrogenase, high sensitivity troponin I, ferritin, procalcitonin, and C-reactive protein. Of a total of 40 patients in the validation cohort (median age, 60 years [range, 27-88 years]; 55% [22/40] male), critical disease was present in 65% (26/40). Model discrimination in the validation cohort was high (concordance statistic: 0.94, 95% confidence interval 0.87-1.01). A web-based tool was developed to enable clinicians to input patient data and view likelihood of critical disease. Conclusions and Relevance: We present a model which accurately predicted COVID-19 critical disease risk using comorbidities and presenting vital signs and laboratory values, on derivation and validation cohorts from two different institutions. If further validated on additional cohorts of patients, this model/clinical tool may provide useful prognostication of critical care needs.


title: Excess cases of Influenza like illnesses in France synchronous with COVID19 invasion.

text: Several French regions where COVID19 has been reported currently show a renewed increase in ILI cases in the general practice based Sentinelles network. Here we computed the number of excess cases by region and found correlation with the number of reported COVID19 cases so far. These data suggest larger circulation of SARS-CoV-2 in the French population than apparent from confirmed cases.


Breaking News: Brace for Chloroquine Poisonings Because of the Coronavirus Pandemic


Cystic Fibrosis: Fighting Together Against Coronavirus Infection


title: Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures

text: SARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome of ∼30 kb, whose outbreak caused the still ongoing COVID-19 pandemic. The ability of coronaviruses to rapidly evolve, adapt, and cross species barriers makes the development of effective and durable therapeutic strategies a challenging and urgent need. As for other RNA viruses, genomic RNA structures are expected to play crucial roles in several steps of the coronavirus replication cycle. Despite this, only a handful of functionally conserved structural elements within coronavirus RNA genomes have been identified to date. Here, we performed RNA structure probing by SHAPE-MaP to obtain a single-base resolution secondary structure map of the full SARS-CoV-2 coronavirus genome. The SHAPE-MaP probing data recapitulate the previously described coronavirus RNA elements (5′ UTR, ribosomal frameshifting element, and 3′ UTR), and reveal new structures. Secondary structure-restrained 3D modeling of highly-structured regions across the SARS-CoV-2 genome allowed for the identification of several putative druggable pockets. Furthermore, ∼8% of the identified structure elements show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. In addition, we identify a set of persistently single-stranded regions having high sequence conservation, suitable for the development of antisense oligonucleotide therapeutics. Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-related infections.


title: Enhancing Intelligent Cross-Domain Fault Diagnosis Performance on Rotating Machines with Noisy Health Labels

text: Abstract In the recent years, the intelligent data-driven fault diagnosis methods on the rotating machines have been popularly developed. Especially, deep learning algorithms have been adopted in several studies and promising results have been obtained. However, the cross-domain fault diagnostic problem still remains a challenging issue, where the training and testing data are collected from different operating conditions of the machine. To bridge the domain gap in the training and testing data and increase the model generalization ability, a domain adaptation approach is proposed in this paper within the deep learning framework. Multiple convolutional operations are employed for automatic feature extraction. The maximum mean discrepancy is used to optimize the distributions of the learned features for accurate diagnosis. To further enhance the model generalization ability, the health condition labels of the data are injected with additional noise during model training. Experiments on a bearing fault diagnosis dataset are carried out for validation. The results show that, compared with the popular transfer learning algorithms, the proposed method with noisy health labels can successfully improve the cross-domain diagnosis performance on rotating machines.


title: Afterword

text: Unknown


title: Preface to the Third Edition

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title: Mapping the Immunodominance Landscape of SARS-CoV-2 Spike Protein for the Design of Vaccines against COVID-19

text: The ongoing coronavirus disease 2019 (COVID-19) pandemic is a serious threat to global public health, and imposes severe burdens on the entire human society. The severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) can cause severe respiratory illness and death. Currently, there are no specific antiviral drugs that can treat COVID-19. Several vaccines against SARS-CoV-2 are being actively developed by research groups around the world. The surface S (spike) protein and the highly expressed internal N (nucleocapsid) protein of SARS-CoV-2 are widely considered as promising candidates for vaccines. In order to guide the design of an effective vaccine, we need experimental data on these potential epitope candidates. In this study, we mapped the immunodominant (ID) sites of S protein using sera samples collected from recently discharged COVID-19 patients. The SARS-CoV-2 S protein-specific antibody levels in the sera of recovered COVID-19 patients were strongly correlated with the neutralising antibody titres. We used epitope mapping to determine the landscape of ID sites of S protein, which identified nine linearized B cell ID sites. Four out of the nine ID sites were found in the receptor-binding domain (RBD). Further analysis showed that these ID sites are potential high-affinity SARS-CoV-2 antibody binding sites. Peptides containing two out of the nine sites were tested as vaccine candidates against SARS-CoV-2 in a mouse model. We detected epitope-specific antibodies and SARS-CoV-2-neutralising activity in the immunised mice. This study for the first time provides human serological data for the design of vaccines against COVID-19.


title: National Smoking Rates Correlate Inversely with COVID-19 Mortality

text: ABSTRACT Introduction: Recent studies show cigarette smokers are markedly under-represented among patients hospitalized for COVID-19 in over a dozen countries. It is unclear if this may be related to confounding factors such as age distribution, access to care, and inaccurate records. We hypothesized that these concerns could be avoided by studying smoking prevalence in relation to COVID-19 mortality. Since climate has been identified as a factor in COVID-19, we studied groups of countries with relatively comparable temperatures. Methods: The 20 hottest and 20 coldest countries in the Johns Hopkins Mortality Analysis database with a minimum mortality rate of .3 deaths/100,000 were selected on the basis of the average temperatures of their largest city. Mortality rates were determined as of May 1, 2020 and correlated with national smoking rate adjusting for sex ratio, obesity, temperature, and elderly population. Results: A highly significant inverse correlation between current daily smoking prevalence and COVID-19 mortality rate was noted for the group of hot countries (R=-.718, p = .0002), cold countries (R=-.567, p=.0046), and the combined group (R=-.324, p=.0207). However, after adjustments only the regression for hot countries and the combined group remained significant. In hot countries, for each percentage point increase in smoking rate mortality decreased by .147 per 100,000 population (95% CI .102- 192, p=.0066). This resulted in mortality rates several-fold elevated in the countries with the lowest smoking rates relative to the highest smoking rates. In the combined group, mortality decreased by .257 per 100,000 population (95% CI .175-.339, p=.0034). Discussion: These findings add support to the finding of an inverse relationship between current smoking and seriously symptomatic COVID-19. However, we conclude that the difference in mortality between the highest and lowest smoking countries appears too large to be due primarily to the effects of smoking per se. A potentially beneficial effect of smoking is surprising, but compatible with a number of hypothetical mechanisms which deserve exploration: 1) Studies show smoking alters ACE2 expression which may affect COVID-19 infection or its progression to serious lung pathology. 2) Nicotine has anti-inflammatory activity and also appears to alter ACE2 expression. 3) Nitric oxide in cigarette smoke is known to be effective in treating pulmonary hypertension and has shown in vitro antiviral effects including against SARS-CoV-2. 4) Smoking has complicated effects on the immune system involving both up and down regulation, any of which might alone or in concert antagonize progression of COVID-19. 5) Smokers are exposed to hot vapors which may stimulate immunity in the respiratory tract by various heat-related mechanisms (e.g. heat shock proteins). Studies of steam and sauna treatments have shown efficacy in other viral respiratory conditions. At this time there is no clear evidence that smoking is protective against COVID-19, so the established recommendations to avoid smoking should be emphasized. The interaction of smoking and COVID-19 will only be reliably determined by carefully designed prospective study, and there is reason to believe that there are unknown confounds that may be spuriously suggesting a protective effect of smoking. However, the magnitude of the apparent inverse association of COVID-19 and smoking and its myriad clinical implications suggest the importance of further investigation.


title: Extracorporeal Membrane Oxygenation as Treatment of Severe COVID-19 Infection: A Case Report

text: Novel coronavirus 2019 (COVID-19) is a severe respiratory infection leading to acute respiratory distress syndrome (ARDS) accounting for thousands of cases and deaths across the world. Several alternatives in treatment options have been assessed and used in this patient population. However, when mechanical ventilation and prone positioning are unsuccessful, venovenous extracorporeal membrane oxygenation (VV-ECMO) may be used. We present a case of a 41-year-old female, with no significant medical history and no recent history of exposure to sick contacts, presented to the emergency department (ED) with fever, severe shortness of breath, and flu-like symptoms with a positive COVID-19 test. Ultimately, she worsened on mechanical ventilation and prone positioning and required VV-ECMO. The use of VV-ECMO in COVID-19 infected patients is still controversial. While some studies have shown a high mortality rate despite aggressive treatment, such as in our case, the lack of large sample size studies and treatment alternatives places healthcare providers against a wall without options in patients with severe refractory ARDS due to COVID-19.


title: Simple Mathematics on Covid-19 Expansion

text: We review the Kermack and McKendrick model of epidemics and apply it to Covid-19. Despite the simplicity of this model, solid conclusions are extracted that can assist potential decisions on the strategy to combat the outbreak, essentially configuring a scenario ranging from short-term suppression to long-term mitigation depending on the achieved reduction in the contact number.


Psychiatry in the age of COVID-19


title: Clinical Characteristics of Children with COVID-19: A Rapid Review and Meta-Analysis

text: Abstract Background: Most guidelines on COVID-19 published so far include recommendations for patients regardless of age. Clinicians need a more accurate understanding of the clinical characteristics of children with COVID-19. Methods: We searched studies reporting clinical characteristics in children with COVID-19 published until March 31, 2020. We screened the literature, extracted the data and evaluated the risk of bias and quality of evidence of the included studies. We combined some of the outcomes (symptoms) in a single-arm meta-analysis using a random-effects model. Results: Our search retrieved 49 studies, including 25 case reports, 23 case series and one cohort study, with a total of 1667 patients. Our meta-analysis showed that most children with COVID-19 have mild symptoms. Eighty-three percent of the children were within family clusters of cases, and 19% had no symptoms. At least 7% with digestive symptoms. The main symptoms of children were fever (48%, 95% confidence interval [CI]: 39%, 56%) and cough (39%, 95% CI: 30%, 48%). The lymphocyte count was below normal level in only 15% [95% CI: 8%, 22%] of children which is different from adult patients. 66% [95% CI: 55%, 77%] of children had abnormal findings in CT imaging. Conclusions: Most children with COVID-19 have only mild symptoms, and many children are asymptomatic. Fever and cough are the most common symptoms in children. Vomiting and diarrhea were not common in children. The lymphocyte count is usually within the normal range in children.


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title: A thermostable, closed, SARS-CoV-2 spike protein trimer

text: The spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. S exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor binding site, and subsequently from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S which allow production of thermostable, crosslinked, S protein trimers that are trapped in the closed, pre-fusion, state. We have determined the structures of crosslinked and non-crosslinked proteins, identifying two distinct closed conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen.


The psychology behind response of people in wake of the COVID-19 pandemic in India


title: Rethinking Residency Conferences in the Era of COVID-19

text: The COVID-19 pandemic requires a substantial change to the traditional approach to conference didactics. Switching to a virtual medium for conference sessions presents several challenges, particularly with regard to aspects that rely heavily on in-person components (e.g., simulation, ultrasound). This paper will discuss the challenges and strategies to address them for conference planning in the era of COVID-19.


title: Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry

text: The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.


title: The clinical characteristics of COVID-19: a retrospective analysis of 104 patients from the outbreak on board the Diamond Princess cruise ship in Japan

text: Background: The ongoing outbreak of the coronavirus disease 2019 (COVID-19) is a global threat. Identification of markers for symptom onset and disease progression is a pressing issue. We compared the clinical features on admission among patients who were diagnosed with asymptomatic, mild, and severe COVID-19 at the end of observation. Methods: This retrospective, single-center study included 104 patients with laboratory-confirmed COVID-19 from the mass infection on the Diamond Princess cruise ship from February 11 to February 25, 2020. Clinical records, laboratory data, and radiological findings were analyzed. Clinical outcomes were followed up until February 26, 2020. Clinical features on admission were compared among those with different disease severity at the end of observation. Univariate analysis identified factors associated with symptom onset and disease progression. Findings: The median age was 68 years, and 54 patients were male. Briefly, 43, 41, and 20 patients on admission and 33, 43, and 28 patients at the end of observation had asymptomatic, mild, and severe COVID-19, respectively. Serum lactate hydrogenase levels were significantly higher in 10 patients who were asymptomatic on admission but developed symptomatic COVID-19 compared with 33 patients who remained asymptomatic throughout the observation period. Older age, consolidation on chest computed tomography, and lymphopenia on admission were more frequent in patients with severe COVID-19 than those with mild COVID-19 at the end of observation. Interpretation: Lactate dehydrogenase level is a potential predictor of symptom onset in COVID-19. Older age, consolidation on chest CT images, and lymphopenia might be risk factors for disease progression of COVID-19 and contribute to the clinical management. Funding: Not applicable.


title: A Novel Box for Aerosol and Droplet Guarding and Evacuation in Respiratory Infection (BADGER): A Potential Mitigating Strategy for the COVID-19 Pandemic and Future Outbreaks

text: The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions and killed hundreds of thousands of people worldwide as of May 2020. Healthcare providers are at increased risks of infection when caring for patients with COVID-19. The mechanism of transmission of SARS-CoV-2 is still not fully understood. However, there is growing evidence for airborne transmission of SARS-CoV-2, in addition to direct droplet spread and indirect contact. Here, we report on the design, construction, and testing of the BADGER (Box for Aerosol and Droplet Guarding and Evacuation in Respiratory Infection), an affordable, scalable device that can contain droplets and aerosol particles. The BADGER has multiple hand-ports for healthcare providers to perform essential tasks on a patient's airway and head. A semi-sealed environment is created inside the BADGER, which maintains at least twelve-air changes per hour using in-wall vacuum suction. Qualitative testing demonstrates that under conditions typical of non-invasive supplemental oxygen treatment, the BADGER can contain nebulized denatonium benzoate and smoke. Quantitative aerosol testing shows more than 90% containment of sub-micrometer aerosolized particles. Overall, the BADGER has the potential to contain large droplets and small airborne particles, and to provide an additional layer of protection for healthcare providers treating COVID-19 patients.


title: Estimating pre-symptomatic transmission of COVID-19: a secondary analysis using published data

text: Background: Understanding the extent of virus transmission that can occur before symptom onset is vital for targeting control measures against the global pandemic of COVID-19. Objective: Estimation of (1) the proportion of pre-symptomatic transmission of COVID-19 that can occur and (2) timing of transmission relative to symptom onset. Design: Secondary analysis of published data Data sources: Meta-analysis of COVID-19 incubation period and a rapid systematic review of serial interval and generation time, which are published separately. Methods: Simulations were generated of incubation period and of serial interval or generation time. From these, transmission times relative to symptom onset were calculated and the proportion of pre-symptomatic transmission was estimated. Results: A total of 23 estimates of serial interval and five estimates of generation time from 17 publications were included. These came from nine different data source categories (presented here in descending order of the proportion of pre-symptomatic transmission): Hong Kong, Tianjin, pooled data from Hong Kong and Shenzhen, Singapore, Mainland China excluding Hubei, mixed sources, Shenzhen, northern Italy and Wuhan. Transmission time relative to symptom onset ranged from a mean of 2.05 days before symptom onset for Hong Kong to 1.72 days after symptom onset for Wuhan. Proportion of pre-symptomatic transmission ranged from 33.7% in Wuhan to 72.7% in Hong Kong. Based on individual estimates, transmission time relative to symptom onset ranged from mean of 2.95 days before symptom onset to 1.72 days after symptom onset and proportion of pre-symptomatic transmission ranged from 33.7% to 79.9%. Simple unweighted pooling of estimates based on serial intervals resulted in a mean time of transmission of 0.67 days before symptoms, and an estimated 56.1% of transmission occurring in the pre-symptomatic period. Conclusions: Contact rates between symptomatic infectious and susceptible people are likely to influence the proportion of pre-symptomatic transmission. There is substantial potential for pre-symptomatic transmission of COVID-19 in a range of different contexts. Our work suggests that transmission of SARS-CoV-2 is most likely in the day before symptom onset whereas estimates suggesting most pre-symptomatic transmission highlighted a mean transmission times almost 3 days before symptom onset. These findings highlight the urgent need for extremely rapid and effective case detection, contact tracing and quarantine measures if strict social distancing measures are to be eased.


title: Digesting the crisis: autophagy and coronaviruses

text: Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions.


title: How does the outbreak of 2019-nCoV spread in mainland China? A retrospective analysis of the dynamic transmission routes

text: The fourth outbreak of the Coronaviruses, known as the 2019-nCoV, has occurred in Wuhan city of Hubei province in China in December 2019. We propose a time-varying sparse vector autoregressive (VAR) model to retrospectively analyze and visualize the dyamic transmission routes of this outbreak in mainland China over January 31 - February 19, 2020. Our results demonstrate that the influential inter-province routes from Hubei have become unidentifiable since February 4, whereas the self-transmission in each province was accelerating over February 4-15. From February 16, all routes became less detectable, and no influential transmissions could be identified on February 18 and 19. Such evidence supports the effectiveness of government interventions, including the travel restrictions in Hubei. Implications of our results suggest that in addition to the origin of the outbreak, virus preventions are of crucial importance in provinces with the largest migrant workers percentages (e.g., Jiangxi, Henan and Anhui) to controlling the spread of 2019-nCoV.


title: Presenting features of COVID-19 in older people: relationships with frailty, inflammation and mortality

text: Purpose To describe the clinical features of COVID-19 in older adults, and relate these to outcomes. Methods Cohort study of 217 individuals ([≥]70 years) hospitalised with COVID-19, followed up for allcause mortality. Secondary outcomes included cognitive and physical function at discharge. C-reactive protein and neutrophil : lymphocyte ratio were used as measures of immune activity. Results Cardinal COVID-19 symptoms (fever, dyspnoea, cough) were common but not universal. Inflammation on hospitalisation was lower in frail older adults. Fever, dyspnoea, delirium and inflammation were associated with mortality. Delirium at presentation was an independent risk factor for cognitive decline at discharge. Conclusions COVID-19 may present without cardinal symptoms as well as implicate a possible role for agerelated changes in immunity in mediating the relationship between frailty and mortality.


title: Identification of a critical horseshoe-shaped region in the nsp5 (Mpro, 3CLpro) protease interdomain loop (IDL) of coronavirus mouse hepatitis virus (MHV)

text: Human coronaviruses are enveloped, positive-strand RNA viruses which cause respiratory diseases ranging in severity from the seasonal common cold to SARS and COVID-19. Of the 7 human coronaviruses discovered to date, 3 emergent and severe human coronavirus strains (SARS-CoV, MERS-CoV, and SARS-CoV-2) have recently jumped to humans in the last 20 years. The COVID-19 pandemic spawned by the emergence of SARS-CoV-2 in late 2019 has highlighted the importance for development of effective therapeutics to target emerging coronaviruses. Upon entry, the replicase genes of coronaviruses are translated and subsequently proteolytically processed by virus-encoded proteases. Of these proteases, nonstructural protein 5 (nsp5, Mpro, or 3CLpro), mediates the majority of these cleavages and remains a key drug target for therapeutic inhibitors. Efforts to develop nsp5 active-site inhibitors for human coronaviruses have thus far been unsuccessful, establishing the need for identification of other critical and conserved non-active-site regions of the protease. In this study, we describe the identification of an essential, conserved horseshoe-shaped region in the nsp5 interdomain loop (IDL) of mouse hepatitis virus (MHV), a common coronavirus replication model. Using site-directed mutagenesis and replication studies, we show that several residues comprising this horseshoe-shaped region either fail to tolerate mutagenesis or were associated with viral temperature-sensitivity. Structural modeling and sequence analysis of these sites in other coronaviruses, including all 7 human coronaviruses, suggests that the identified structure and sequence of this horseshoe regions is highly conserved and may represent a new, non-active-site regulatory region of the nsp5 (3CLpro) protease to target with coronavirus inhibitors. Importance In December 2019, a novel coronavirus (SARS-CoV-2) emerged in humans and triggered a pandemic which has to date resulted in over 8 million confirmed cases of COVID-19 across more than 180 countries and territories (June 2020). SARS-CoV-2 represents the third emergent coronavirus in the past 20 years and the future emergence of new coronaviruses in humans remains certain. Critically, there remains no vaccine nor established therapeutics to treat cases of COVID-19. The coronavirus nsp5 protease is a conserved and indispensable virus-encoded enzyme which remains a key target for therapeutic design. However, past attempts to target the active site of nsp5 with inhibitors have failed stressing the need to identify new conserved non-active-site targets for therapeutic development. This study describes the discovery of a novel conserved structural region of the nsp5 protease of coronavirus mouse hepatitis virus (MHV) which may provide a new target for coronavirus drug development.