bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study identifies risk variants for sporadic Creutzfeldt-Jakob disease in STX6 and GAL3ST1
Authors: Jones Emma , Hummerich Holger , Viré Emmanuelle , Uphill James , Dimitriadis Athanasios , Speedy Helen , Campbell Tracy , Norsworthy Penny , Quinn Liam , Whitfield Jerome , Linehan Jacqueline , Jaunmuktane Zane , Brandner Sebastian , Jat Parmjit , Nihat Akin , Mok Tze How , Ahmed Parvin , Collins Steven , Stehmann Christiane , Sarros Shannon , Kovacs Gabor , Geschwind Michael , Golubjatnikov Aili , Fronztek Karl , Budka Herbert , Aguzzi Adriano , Karamujić-Čomić Hata , van der Lee Sven , Ibrahim-Verbaas Carla A , Van Duijn Cornelia , Sikorska Beata , Golanska Ewa , Liberski Pawel , Calero Miguel , Calero Olga , Juan Pascual Sanchez , Salas Antonio , Martinón-Torres Federico , Bouaziz-Amar Elodie , Haik Stephane , Laplanche Jean-Louis , Brandel Jean-Phillipe , Amouyel Phillipe , Lambert Jean-Charles , Parchi Piero , Bartoletti-Stella Anna , Capellari Sabina , Poleggi Anna , Ladogana Anna , Pocchiari Maurizio , Aneli Serena , Matullo Giuseppe , Knight Richard , Zafar Saima , Zerr Inga , Booth Stephanie , Coulthart Michael B , Jansen Gerard H , Glisic Katie , Blevins Janis , Gambetti Pierluigi , Safar Jiri , Appleby Brian , Collinge John , Mead Simon
Published: April 2020

Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.
Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor
Authors: Chen Xiangyu , Li Ren , Pan Zhiwei , Qian Chunfang , Yang Yang , You Renrong , Zhao Jing , Liu Pinghuang , Gao Leiqiong , Li Zhirong , Huang Qizhao , Xu Lifan , Tang Jianfang , Tian Qin , Yao Wei , Hu Li , Yan Xiaofeng , Zhou Xinyuan , Wu Yuzhang , Deng Kai , Zhang Zheng , Qian Zhaohui , Chen Yaokai , Ye Lilin
Published: April 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). To date, no prophylactic vaccines or approved therapeutic agents are available for preventing and treating this highly transmittable disease. Here we report two monoclonal antibodies (mAbs) cloned from memory B cells of patients recently recovered from COVID-19, and both mAbs specifically bind to the spike (S) protein of SARS-CoV-2, block the binding of receptor binding domain (RBD) of SARS-CoV-2 to human angiotensin converting enzyme 2 (hACE2), and effectively neutralize S protein-pseudotyped virus infection. These human mAbs hold the promise for the prevention and treatment of the ongoing pandemic of COVID-19.
Epigenome-wide analyses identify DNA methylation signatures of dementia risk
Authors: Walker Rosie M. , Bermingham Mairead L. , Vaher Kadi , Morris Stewart W. , Clarke Toni-Kim , Bretherick Andrew D. , Zeng Yanni , Amador Carmen , Rawlik Konrad , Pandya Kalyani , Hayward Caroline , Campbell Archie , Porteous David J. , McIntosh Andrew M. , Marioni Riccardo E. , Evans Kathryn L.
Published: April 2020

INTRODUCTION

Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here, we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer’s disease (AD)-free participants.

METHODS

Associations between dementia risk measures (family history, genetic risk score (GRS), and dementia risk scores (combining lifestyle, demographic and genetic factors) and whole-blood DNA methylation were assessed in discovery and replication samples (n=∼400 – ∼5,000) from Generation Scotland.

RESULTS

AD genetic risk and two risk scores were associated with differential methylation. The GRS predominantly associated with methylation differences in cis but also identified a genomic region implicated in Parkinson’s disease. Loci associated with the risk scores were enriched for those previously associated with body mass index and alcohol consumption.

DISCUSSION

Dementia risk measures show widespread association with blood-based methylation, which indicates differences in the processes affected by genetic and demographic/lifestyle risk factors.
To mask or not to mask: Modeling the potential for face mask use by the general public to curtail the COVID-19 pandemic
Authors: Eikenberry Steffen E. , Mancuso Marina , Iboi Enahoro , Phan Tin , Eikenberry Keenan , Kuang Yang , Kostelich Eric , Gumel Abba B.
Published: April 2020

Face mask use by the general public for limiting the spread of the COVID-19 pandemic is controversial, though increasingly recommended, and the potential of this intervention is not well understood. We develop a compartmental model for assessing the community-wide impact of mask use by the general, asymptomatic public, a portion of which may be asymptomatically infectious. Model simulations, using data relevant to COVID-19 dynamics in the US states of New York and Washington, suggest that broad adoption of even relatively ineffective face masks may meaningfully reduce community transmission of COVID-19 and decrease peak hospitalizations and deaths. Moreover, mask use decreases the effective transmission rate in nearly linear proportion to the product of mask effectiveness (as a fraction of potentially infectious contacts blocked) and coverage rate (as a fraction of the general population), while the impact on epidemiologic outcomes (death, hospitalizations) is highly nonlinear, indicating masks could synergize with other non-pharmaceutical measures. Notably, masks are found to be useful with respect to both preventing illness in healthy persons and preventing asymptomatic transmission. Hypothetical mask adoption scenarios, for Washington and New York state, suggest that immediate near universal (80%) adoption of moderately (50%) effective masks could prevent on the order of 17–45% of projected deaths over two months in New York, while decreasing the peak daily death rate by 34–58%, absent other changes in epidemic dynamics. Even very weak masks (20% effective) can still be useful if the underlying transmission rate is relatively low or decreasing: In Washington, where baseline transmission is much less intense, 80% adoption of such masks could reduce mortality by 24–65% (and peak deaths 15–69%), compared to 2–9% mortality reduction in New York (peak death reduction 9–18%). Our results suggest use of face masks by the general public is potentially of high value in curtailing community transmission and the burden of the pandemic. The community-wide benefits are likely to be greatest when face masks are used in conjunction with other non-pharmaceutical practices (such as social-distancing), and when adoption is nearly universal (nation-wide) and compliance is high.
Infoveillance based on Social Sensors to Analyze the impact of Covid19 in South American Population
Authors: Saire Josimar E. Chire
Published: April 2020

Infoveillance is an application from Infodemiology field with the aim to monitor public health and create public policies. Social sensor is the people providing thought, ideas through electronic communication channels(i.e. Internet). The actual scenario is related to tackle the covid19 impact over the world, many countries have the infrastructure, scientists to help the growth and countries took actions to decrease the impact. South American countries have a different context about Economy, Health and Research, so Infoveillance can be a useful tool to monitor and improve the decisions and be more strategical. The motivation of this work is analyze the capital of Spanish Speakers Countries in South America using a Text Mining Approach with Twitter as data source. The preliminary results helps to understand what happens two weeks ago and opens the analysis from different perspectives i.e. Economics, Social.
Oxygen needs in austere environment : French military health service experience
Authors: Cungi Pierre-Julien , Mathais Quentin , D’Aranda Erwan , Cardinale Mickael , Goutorbe Philippe , Bordes Julien , Meaudre Eric
Published: April 2020

INTRODUCTION

Management of Oxygen supplies is a recurring problem for the intensivists and anesthesiologists working in an austere environment. The French military health service has chosen oxygen concentrators (OC) as the primary source of oxygen.

OBJECTIVES

The main objective was to evaluate the feasibility of using OC as the main source of 02for intensive care patients. We assess the need to use pressurized 02during the ICU hospitalization. The secondary objectives were to identify the causes of the use of pressurized 02.

MATERIAL AND METHOD

We realize an interventional cohort study at the French role 3 hospitals located in the Republic of Djibouti. The criteria of inclusion were all patients aged over 18 years, requiring oxygen and admitted to intensive care.

RESULTS

We include 35 patients over 6-month period for 251 days of oxygenation, including 142 days of invasive mechanical ventilation. The population include 21 (60%) men, aged of 35 (30 - 49) years. Twenty-eight (80%) patients benefits of invasive ventilation. Median 02administration duration was 6 (3-10) days, and the median duration of mechanical ventilation was 3 (1-5) days. Nineteen pressurized O2 treatments were required over 251 days of oxygen therapy, or 7.5% of the total oxygen therapy time. The causes of recourse were in 10 cases (52.6%) severe ARDS, in 6 cases (31.6%) an emergency orotracheal intubation and in 3 cases (15.8%) a transfer. Only one OC dysfunction occurred during the study.

CONCLUSION

OC can be used as a primary source for intensive care patients in an austere environment. The use of pressurized 02remains imperative in the event of an electrical failure and the need to use high Fi02over 60%.
The efficiency in the ordinary hospital bed management in Italy: an in-depth analysis of intensive care unit in the areas affected by COVID-19 before the outbreak
Authors: Pecoraro Fabrizio , Clemente Fabrizio , Luzi Daniela
Published: April 2020

In the first months of 2020 an increasing number of individuals worldwide are infected by the coronavirus disease 2019 (COVID-19). A particularly severe diffusion of the virus has affected Italy and in particular its northern regions. This is resulting in a high demand of hospitalization with a particular attention on the intensive care units (ICUs). Hospitals are suffering the high degree of patients to be treated for respiratory diseases and the majority of the structures located in the north of Italy are or are going to be saturated. This has led the actual and past national and regional governments to be heavily criticized for reducing in the past years the number of beds, in particular those located in the ICUs across the country. Aim of this study is to analyse the availability of hospital beds across the country as well as to determine their management in terms of complexity and performance of cases treated at regional level. The results of this study underlines that, despite the reduction of beds for the majority of the hospital wards, ICUs availabilities did not change between 2010 and 2017. Moreover, this study confirms that the majority of the Italian regions efficiently manage these structural facilities allowing hospitals to treat patients without the risk of having an overabundance of patients and a scarcity of beds. In fact, this analysis shows that, in normal situations, the management of hospital and intensive care beds has no critical levels.
Outbreak dynamics of COVID-19 in China and the United States
Authors: Peirlinck Mathias , Linka Kevin , Costabal Francisco Sahli , Kuhl Ellen
Published: April 2020

On March 11, 2020, the World Health Organization declared the coronavirus disease 2019, COVID19, a global pandemic. In an unprecedented collective effort, massive amounts of data are now being collected worldwide to estimate the immediate and long-term impact of this pandemic on the health system and the global economy. However, the precise timeline of the disease, its transmissibility, and the effect of mitigation strategies remain incompletely understood. Here we integrate a global network model with a local epidemic SEIR model to quantify the outbreak dynamics of COVID-19 in China and the United States. For the outbreak in China, in n = 30 provinces, we found a latent period of 2.56±0.72 days, a contact period of 1.47±0.32 days, and an infectious period of 17.82±2.95 days. We postulate that the latent and infectious periods are disease-specific, whereas the contact period is behavior-specific and can vary between different provinces, states, or countries. For the early stages of the outbreak in the United States, in n = 50 states, we adopted the disease-specific values from China, and found a contact period of 3.38±0.69 days. Our network model predicts that–without the massive political mitigation strategies that are in place today–the United states would have faced a basic reproduction number of 5.3±0.95 and a nationwide peak of the outbreak on May 10, 2020 with 3 million infections. Our results demonstrate how mathematical modeling can help estimate outbreak dynamics and provide decision guidelines for successful outbreak control. We anticipate that our model will become a valuable tool to estimate the potential of vaccination and quantify the effect of relaxing political measures including total lock down, shelter in place, and travel restrictions for low-risk subgroups of the population or for the population as a whole.
Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility
Authors: Stawiski Eric W. , Diwanji Devan , Suryamohan Kushal , Gupta Ravi , Fellouse Frederic A. , Sathirapongsasuti J. Fah , Liu Jiang , Jiang Ying-Ping , Ratan Aakrosh , Mis Monika , Santhosh Devi , Somasekar Sneha , Mohan Sangeetha , Phalke Sameer , Kuriakose Boney , Antony Aju , Junutula Jagath R. , Schuster Stephan C. , Jura Natalia , Seshagiri Somasekar
Published: April 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in ∼3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting enzyme2 (ACE2) cell surface protein to invade the host cell. The SARS-CoV-2 S-protein has acquired mutations that increase its affinity to human ACE2 by ∼10-15-fold compared to SARS-CoV S-protein, making it highly infectious. In this study, we assessed if ACE2 polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein interaction. Our comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. Using recently reported structural data and a recent S-protein-interacting synthetic mutant map of ACE2, we have identified natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Overall, ACE2 variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV epidemics, however, are likely to play an important role in altering susceptibility to CoVs.
Currently available intravenous immunoglobulin (Gamunex®-C and Flebogamma®DIF) contains antibodies reacting against SARS-CoV-2 antigens
Authors: Díez José-María , Romero Carolina , Gajardo Rodrigo
Published: April 2020

Background

There is a critical need for effective therapies that are immediately available to control the spread of COVID-19 disease. In this study, we assessed currently marketed intravenous immunoglobulin (IVIG) products for antibodies against human common coronaviruses that may cross-react with the SARS-CoV-2 virus.

Methods

Gamunex®-C and Flebogamma®DIF (Grifols) IVIG were tested against several betacoronaviruses antigens using ELISA techniques: HCoV (undetermined antigen), HCoV-HKU1 (N protein), SARS-CoV (culture lysate), MERS-CoV (N protein; S1 protein/RBD; S protein), and SARS-CoV-2 (S1 protein).

Results

Both IVIG products showed consistent reactivity to components of the tested viruses. Positive cross-reactivity was seen in SARS-CoV, MERS-CoV, and SARS-CoV-2. For SARS-CoV-2, positive reactivity was observed at IVIG concentrations ranging from 100 μg/mL with Gamunex-C to 1 mg/mL with Flebogamma 5% DIF.

Conclusion

Gamunex-C and Flebogamma DIF IVIG contain antibodies reacting against SARS-CoV-2 antigens. These preparations may be useful for immediate treatment of COVID-19 disease.
ESTIMATION OF COVID-19 CASES IN FRANCE AND IN DIFFERENT COUNTRIES: HOMOGENEISATION BASED ON MORTALITY
Authors: Dhenain Marc
Published: April 2020

Every day the authorities of different countries provide an estimate of the number of persons affected by Covid-19 and a count of fatality. We propose to use the fatality reported in each country to provide a better estimate (Ct0-estimated) of the number of cases at a given time t0.

With Ft0: number of actual fatalities reported in a country at time t0; Fr-est: estimated fatality rate; C(est-d): estimated fatalities 18 days before t0; C(est-3d): estimated fatalities 21 days before t0.

Based on Ct0-estimated calculated using a fatality rate of 2%, we assessed the number of cases April 10th, 2020 in Belgium, China, France, Germany, Iran, Italy, South Korea, Netherlands, Spain, United Kingdom and USA. This number reached 2,872,097 in France and 924,892 persons in Germany. The proposed formulas also make it possible to evaluate the impact of policies to prevent the spread of epidemic on the appearance of new cases.
Modelling the impact of COVID-19 in Australia to inform transmission reducing measures and health system preparedness
Authors: Moss R , Wood J , Brown D , Shearer F , Black AJ , Cheng AC , McCaw JM , McVernon J
Published: April 2020

Background

The ability of global health systems to cope with increasing numbers of COVID-19 cases is of major concern. In readiness for this challenge, Australia has drawn on clinical pathway models developed over many years in preparation for influenza pandemics. These models have been used to estimate health care requirements for COVID-19 patients, in the context of broader public health measures.

Methods

An age and risk stratified transmission model of COVID-19 infection was used to simulate an unmitigated epidemic with parameter ranges reflecting uncertainty in current estimates of transmissibility and severity. Overlaid public health measures included case isolation and quarantine of contacts, and broadly applied social distancing. Clinical presentations and patient flows through the Australian health care system were simulated, including expansion of available intensive care capacity and alternative clinical assessment pathways.

Findings

An unmitigated COVID-19 epidemic would dramatically exceed the capacity of the Australian health system, over a prolonged period. Case isolation and contact quarantine alone will be insufficient to constrain case presentations within a feasible level of expansion of health sector capacity. Overlaid social restrictions will need to be applied at some level over the course of the epidemic to ensure that systems do not become overwhelmed, and that essential health sector functions, including care of COVID-19 patients, can be maintained. Attention to the full pathway of clinical care is needed to ensure access to critical care.

Interpretation

Reducing COVID-19 morbidity and mortality will rely on a combination of measures to strengthen and extend public health and clinical capacity, along with reduction of overall infection transmission in the community. Ongoing attention to maintaining and strengthening the capacity of health care systems and workers to manage cases is needed.

Funding

Australian Government Department of Health Office of Health Protection, Australian Government National Health and Medical Research Council
Simplified model of the number of Covid-19 patients in the ICU: update April 6, 2020
Authors: Cividjian A. , Wallet F , Guichon C. , Martin O. , Couray-Targe S. , Rimmelé T , Wey PF
Published: April 2020

INTRODUCTION

Predicting the number of Covid-19 patients in the Intensive Care Units (ICU) could be useful to avoid the breaking point. We attempted to deduce a formula in order to model the number of the ICU patients in France from the official data and patient turnover in the ICU.

METHODS

The Covid-19 ICU patient turnover was calculated using a recurrence relation from the internal data provided by Hospices Civils de Lyon. The number of new Covid-19 cases detected daily was modelized to fit with the last known data in France and extrapolated for the coming days using two scenarios following the existing data in China (best scenario) and Italy (worst scenario). The number of daily admissions in ICU was calculated as the sum of 13.7% of the new Covid-19 cases detected on a given day and 7.8% of the average of the total new Covid-19 cases recorded in the last week. Approximately 39.7% of patients admitted to the ICU were non-intubated with an average ICU length of stay of 4 days. Conversely, 60.3% of patients were intubated and for those who died among them (14.44%) the ICU length of stay was of 4 days for 78.3% of them and of 15 days for 21.7% of them. For the intubated patients that were discharged alive, the ICU length of stay was of 6 days for 44.4% of them and of 20 days for 55.6% of them.

RESULTS

We predict a peak of 7072 – 8043 patients for the overall French territory.

CONCUSION

Despite a simplified mathematical model, the strength of our study is a narrow possible range of predicted total number of ICU patients.
A pragmatic model to forecast the COVID-19 epidemic in different countries and allowing for daily updates
Authors: Nordt Carlos , Herdener Marcus
Published: April 2020

Due to high infections rates and a high death toll of the COVID-19 pandemic, it is important to have daily updated forecasted estimates for the next weeks in order to allocate the scare resources as good as possible. We propose a pragmatic model to forecast the COVID-19 epidemic by applying a mixture normal distribution to open accessible WHO data. We specified a simple joint model on data from 20 countries with number of confirmed COVID-19 infections and number of COVID-19 deaths. We found that the duration of an epidemic wave (99% of total size) was usually between 45 – 48 days. Using data up to April 6, 2020, we found in six of 20 counties two waves, spaced between 21 and 47 days. In China and Korea the first wave was bigger, and in Denmark, Iran, Japan, and Sweden the second wave was stronger. Lag time between time trends in confirmed infections and time trends in deaths varied between 3.1 and 9.5 days. We obtained a good fit between observed and modelled data in almost all countries. In about halve of the countries the highest peak of the COVID-19 epidemic had been reached until April 6, 2020. Among the 20 countries, it is predicted that the USA will reach the highest numbers of confirmed infections (653 683 – 802 205) and number of deaths (36 591 – 53 286). Taken together, for many countries reasonable and up-to-date forecasting seems to be feasible. This method therefore bears a high potential for assisting decision makers to adjust the measures aiming at reducing the spread of the virus appropriately.
Potential dissemination of epidemics based on Brazilian mobile geolocation data. Part I: Population dynamics and future spreading of infection in the states of São Paulo and Rio de Janeiro during the pandemic of COVID-19
Authors: Peixoto Pedro S. , Marcondes Diego , Peixoto Cláudia , Queiroz Lucas , Gouveia Rafael , Delgado Afonso , Oliva Sérgio M.
Published: April 2020

Mobile geolocation data is a valuable asset in the assessment of movement patterns of a population. Once a highly contagious disease takes place in a location the movement patterns aid in predicting the potential spatial spreading of the disease, hence mobile data becomes a crucial tool to epidemic models. In this work, based on millions of anonymized mobile visits data in Brazil, we investigate the most probable spreading patterns of the COVID-19 within states of Brazil. The study is intended to help public administrators in action plans and resources allocation, whilst studying how mobile geolocation data may be employed as a measure of population mobility during an epidemic. The first part of the study focus on the states of São Paulo and Rio de Janeiro during the period of March 2020, when the disease first started to spread in these states. Metapopulation models for the disease spread were simulated in order to evaluate the risk of infection of each city within the states, by ranking them according to the time the disease will take to infect each city. We observed that, although the high risk regions are those closer to the capital cities, where the outbreak has started, there are also cities in the countryside with great risk.
ACE-inhibitors and Angiotensin-2 Receptor Blockers are not associated with severe SARS-COVID19 infection in a multi-site UK acute Hospital Trust
Authors: Bean Daniel M , Kraljevic Zeljko , Searle Thomas , Bendayan Rebecca , O’Gallagher Kevin , Pickles Andrew , Folarin Amos , Roguski Lukasz , Noor Kawsar , Shek Anthony , Zakeri Rosita , Shah Ajay M , Teo James TH , Dobson Richard JB
Published: April 2020

Aims

The SARS-Cov2 virus binds to the ACE2 receptor for cell entry. It has been suggested that ACE-inhibitors (ACEi) and Angiotensin-2 Blockers (ARB), which are commonly used in patients with hypertension or diabetes and may raise ACE2 levels, could increase the risk of severe COVID19 infection.

Methods and Results

We evaluated this hypothesis in a consecutive cohort of 1200 acute inpatients with COVID19 at two hospitals with a multi-ethnic catchment population in London (UK). The mean age was 68±17 years (57% male) and 74% of patients had at least 1 comorbidity. 415 patients (34.6%) reached the primary endpoint of death or transfer to a critical care unit for organ support within 21-days of symptom onset. 399 patients (33.3 %) were taking ACEi or ARB. Patients on ACEi/ARB were significantly older and had more comorbidities. The odds ratio (OR) for the primary endpoint in patients on ACEi and ARB, after adjustment for age, sex and co-morbidities, was 0.63 (CI 0.47-0.84, p<0.01).

Conclusions

There was no evidence for increased severity of COVID19 disease in hospitalised patients on chronic treatment with ACEi or ARB. A trend towards a beneficial effect of ACEi/ARB requires further evaluation in larger meta-analyses and randomised clinical trials.
Non-specific Primers Reveal False-negative Risk in Detection of COVID-19
Authors: Liu Wei
Published: April 2020

Background

A novel coronavirus disease 2019 (COVID-19) broke out in Wuhan of Hubei province and had spread throughout the world since December 2019. Because the clinically diagnosed cases in Hubei province were reported for the first time on February 13, 2020, a very high peak of new cases in China was observed. The reason why so many clinically diagnosed cases appeared was not clear.

Methods

All data of new cases in China were acquired from WHO situation reports. Linear fitting was used to infer the ability to detect COVID-19 infections. Primer-BLAST and nucleotide blast were applied to check the specificity of primers. Expression data of human mRNA in different tissues was obtained from Human Protein Atlas.

Findings

Based on the data and analysis of changes of new laboratory-confirmed cases and new clinically diagnosed cases, it was inferred that there were many false-negative results in all clinically diagnosed cases in Hubei province. There were eight non-specific primers in dozens of primers used in clinical or research detection of COVID-19. Among them, a pair of primer for the ORF1ab regions of SARS-CoV-2 genome well matched some human mRNAs such as Cathepsin C transcripts. Compared to other transcripts, Cathepsin C mRNA had a high abundance in tonsil, lung and small intestine.

Interpretation

Some non-specific RT-PCR primers could cause the serious interference during RT-PCR amplification so as to increase the risk of false-negative diagnoses for COVID-19 infections.

Funding

Key Research Project of the Higher Education of Henan Province

Research in context

Evidence before this study

The author searched PubMed on April 15, 2020, for papers that describe false-negative RT-PCR detection of COVID-19 by using the search terms “COVID-19”, “false-negative” and “RT-PCR”, with no language or time restrictions. Eleven investigations only presented the rate of false-negative detection or the importance of positive chest CT finding. There were no reports referring the primer problems of false-negative detection in COVID-19 infections.

Added value of this study

The author had found that some primers could amplify the human mRNA in specimens, which mixed SARS-CoV-2 viral particles and other tissue cells. A pair of primer provided by China CDC could vastly match the sequences of human CTSC transcripts with high abundance. That could lead to false-negative results in detection of COVID-19 infections.

Implications of all the available evidence

Although there were so many false-negative results in detection of COVID-19 infections in China, the exact reason was not clear. Problems in sampling and test condition were discussed thoroughly, but conclusions were usually contradictory. Therefore, the work could promote the verification of the false-negative detection of COVID-19 infections in China.
SARS-CoV-2 and human milk: what is the evidence?
Authors: Lackey Kimberly A. , Pace Ryan M. , Williams Janet E. , Bode Lars , Donovan Sharon M. , Järvinen Kirsi M. , Seppo Antti E. , Raiten Daniel J. , Meehan Courtney L. , McGuire Mark A. , McGuire Michelle K.
Published: April 2020

The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling and concerning public health challenges of our time. To address the myriad issues generated by this pandemic, an interdisciplinary breadth of research, clinical, and public health communities has rapidly engaged to collectively find answers and solutions. One area of active inquiry is understanding the mode(s) of SARS-CoV-2 transmission. While respiratory droplets are a known mechanism of transmission, other mechanisms are likely. Of particular importance to global health is the possibility of vertical transmission from infected mothers to infants through breastfeeding or consumption of human milk. However, there is limited published literature related to vertical transmission of any human coronaviruses (including SARS-CoV-2) via human milk and/or breastfeeding. Results of the literature search reported here (finalized on April 17, 2020) revealed a single study providing some evidence of vertical transmission of human coronavirus 229E; a single study evaluating presence of SARS-CoV in human milk (it was negative); and no published data on MERS-CoV and human milk. We identified 12 studies reporting human milk tested for SARS-CoV-2; one study detected the virus in one milk sample, and another study detected SARS-CoV-2 specific IgG in milk. Importantly, none of the studies on coronaviruses and human milk report validation of their collection and analytical methods for use in human milk. These reports are evaluated here, and their implications related to the possibility of vertical transmission of coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.
HOW THE COVID-19 PANDEMIA IS SPREADING IN ITALY
Authors: Salvatoni Alessandro
Published: April 2020

In this short paper we describe a simple technique aimed to forecast the course of the spreading of Covid-19 virus infection in Italy. Data released every day by the Italian “Protezione Civile” organization have been processed with reference of the the SIR classical mathematical model by Kermack and McKendrick. The model provides a rough estimate of the time needed to completely block virus spread. The above assumptions will be valid if Covid-19 will not be recognized as capable of establishing a chronic productive infection in significant fraction of the population.
Modeling the COVID-19 pandemic - parameter identification and reliability of predictions
Authors: Hackl Klaus
Published: April 2020

In this paper, we try to identify the parameters for two elementary epidemic models, the so-called SI- and SIS-models, via non-linear regression using data of the COVID-19 pandemic. This is done based on the data for the number of daily infections. Studying the history of predictions made, we attempt to estimate their reliability concerning the future course of the epidemic. We validate this procedure using data for the case numbers in China and South Korea. Then we apply it in order to find predictions for Germany, Italy and the United States. The results are encouraging, but no final judgment on the validity of the procedure can yet be made.
A model to predict COVID-19 epidemics with applications to South Korea, Italy, and Spain
Authors: Liu Z. , Magal P. , Seydi Ousmane , Webb Glenn
Published: April 2020

1

In this work, our team develops a differential equations model of COVID-19 epidemics. Our goal is to predict forward in time the future number of cases from early reported case data in regions throughout the world. Our model incorporates the following important elements of COVID-19 epidemics: (1) the number of asymptomatic infectious individuals (with very mild or no symptoms), (2) the number of symptomatic reported infectious individuals (with severe symptoms) and (3) the number of symptomatic unreported infectious individuals (with less severe symptoms). We apply our model to COVID-!9 epidemics in South Korea, Italy and Spain.
On Biases of Attention in Scientific Discovery
Authors: Singer Uriel , Radinsky Kira , Horvitz Eric
Published: April 2020

How do nuances of scientists’ attention influence what they discover? We pursue an understanding of the influences of patterns of attention on discovery with a case study about confirmations of protein-protein interactions over time. We find that modeling and accounting for attention can help us to recognize and interpret biases in databases of confirmed interactions and to better understand missing data and unknowns in our fund of knowledge.
LabWAS: novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks
Authors: Goldstein Jeffery A. , Weinstock Joshua S. , Bastarache Lisa A. , Larach Daniel B. , Fritsche Lars G. , Schmidt Ellen M. , Brummett Chad M. , Kheterpal Sachin , Abecasis Goncalo R. , Denny Joshua C. , Zawistowski Matthew
Published: April 2020

Phenotypes extracted from Electronic Health Records (EHRs) are increasingly prevalent in genetic studies. EHRs contain hundreds of distinct clinical laboratory test results, providing a trove of health data beyond diagnoses. Such lab data is complex and lacks a ubiquitous coding scheme, making it more challenging than diagnosis data. Here we describe the first large-scale cross-health system genome-wide association study (GWAS) of EHR-based quantitative lab measurements. We meta-analyzed 70 labs matched between the BioVU cohort from the Vanderbilt University Health System and the Michigan Genomics Initiative (MGI) cohort from Michigan Medicine. We show high replication of known association for these labs, validating EHR-based measurements as high-quality phenotypes for genetic analysis. Notably, our analysis provides the first replication for 700 previous GWAS associations across 46 different labs. We discovered 31 novel associations at genome-wide significance for 22 distinct labs, including the first reported associations for two labs. We replicated 22 of these novel associations in an independent tranche of BioVU samples. The summary statistics for all association tests are available through an interactive webtool to benefit other researchers. Finally, we performed mirrored analyses in BioVU and MGI to assess competing analytic practices for lab data. We find that using the mean of all available lab measurements provides a robust summary value, but alternate summarizations can improve power in certain labs. This study provides a proof-of-principle for cross health system GWAS and is a framework for future studies of quantitative traits in EHRs.
Prediction on Covid-19 epidemic for different countries: Focusing on South Asia under various precautionary measures
Authors: Paul Abhijit , Chatterjee Samrat , Bairagi Nandadulal
Published: April 2020

The coronavirus disease 2019 (COVID-19), which emerged from Wuhan, China, is now a pandemic, affecting across the globe. Government of different countries have developed and adopted various policies to contain this epidemic and the most common were the social distancing and lockdown. We proposed a SEIR epidemic model that accommodates the effects of lockdown and individual based precautionary measures and used it to estimate model parameters from the epidemic data up to 2nd April, 2020, freely available in GitHub repository for COVID-19, for nine developed and developing countries. We used the estimated parameters to predict the disease burden in these countries with special emphasis on India, Bangladesh and Pakistan. Our analysis revealed that the lockdown and recommended individual hygiene can slow down the outbreak but unable to eradicate the disease from the society. With the current human-to-human transmission rate and existing level of personal precautionary, the number of infected individuals in India will be increasing at least for the next 3 months and the peak will come in 5 months. We can, however, reduce the epidemic size and prolong the time to arrive epidemic peak by seriously following the measures suggested by the authorities. We need to wait for another one month to obtain more data and epidemiological parameters for giving a better prediction about the pandemic. It is to be mentioned that research community is working for drugs and/ or vaccines against COVID19 and the presence of such pharmaceutical interventions will significantly alter the results.
Exercising caution in correlating COVID-19 incidence and mortality rates with BCG vaccination policies due to variable rates of SARS CoV-2 testing
Authors: Hensel Janine , McAndrews Kathleen M. , McGrail Daniel J. , Dowlatshahi Dara P. , LeBleu Valerie S. , Kalluri Raghu
Published: April 2020

The Bacillus Calmette-Guerin (BCG) vaccine provides protection against tuberculosis (TB), and is proposed to provide protection to non-TB infectious diseases. The COVID-19 outbreak results from infection with the novel coronavirus SARS-CoV-2 (CoV-2) and was declared a pandemic on March 11th, 2020. We queried whether the BCG vaccine offers protection against CoV-2 infection. We observed that countries with a current universal BCG vaccination policy have a significantly lower COVID-19 incidence than countries which never had a universal BCG policy or had one in the past. However, population density, median age, TB incidence, urban population, and, most significantly, CoV-2 testing rate, were also connected with BCG policy and could potentially confound the analysis. By limiting the analysis to countries with high CoV-2 testing rates, defined as greater than 2,500 tests per million inhabitants, these parameters were no longer statistically associated with BCG policy. When analyzing only countries with high testing rates, there was no longer a significant association between the number of COVID-19 cases per million inhabitants and the BCG vaccination policy. Although preliminary, our analyses indicate that the BCG vaccination may not offer protection against CoV-2 infection. While reporting biases may confound our observations, our findings support exercising caution in determining potential correlation between BCG vaccination and COVID-19 incidence, in part due significantly lower rates of CoV-2 testing per million inhabitants in countries with current universal BCG vaccination policy.
Prognostic factors for severity and mortality in patients infected with COVID-19: A living systematic review protocol
Authors: Izcovich Ariel , Ragusa Martín , Sanguine Verónica , Tortosa Fernando , Espinosa Federico , Agnoletti Camila , Lavena Marzio María Andrea , Ceirano Agustina , Bengolea Agustín , Saavedra Ezequiel , Catalano Hugo N. , Rada Gabriel ,   COVID-19 L·OVE Working Group
Published: April 2020

Objective

The objective of our systematic review is to identify prognostic factors that can potentially be used in decision-making related to the care of patients infected with COVID-19.

Design

This is the protocol of a living systematic review.

Data sources

We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence covered and customised to group all COVID-19 evidence in one place. The search will continue until the day before submission to a journal.

Eligibility criteria for selecting studies and methods

We will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation).

We will include studies that assess patients with confirmed or suspected SARS-CoV-2 infection and inform the relation between potential prognostic factors and death or disease severity. Two groups of two reviewers will independently screen studies for eligibility, extract data and assess the risk of bias. We will perform meta-analyses and use GRADE to assess the certainty of evidence for each prognostic factor and outcome.

A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates.

Ethics and dissemination

No ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.

PROSPERO Registration

Submitted to PROSPERO (awaiting ID allocation).
Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic
Authors: Riccardo Flavia , Ajelli Marco , Andrianou Xanthi D , Bella Antonino , Del Manso Martina , Fabiani Massimo , Bellino Stefania , Boros Stefano , Urdiales Alberto Mateo , Marziano Valentina , Rota Maria Cristina , Filia Antonietta , D’Ancona Fortunato Paolo , Siddu Andrea , Punzo Ornella , Trentini Filippo , Guzzetta Giorgio , Poletti Piero , Stefanelli Paola , Castrucci Maria Rita , Ciervo Alessandra , Di Benedetto Corrado , Tallon Marco , Piccioli Andrea , Brusaferro Silvio , Rezza Giovanni , Merler Stefano , Pezzotti Patrizio ,   for the COVID-19 working group
Published: April 2020

Background

In February 2020, a locally-acquired COVID-19 case was detected in Lombardia, Italy. This was the first signal of ongoing transmission of SARS-CoV-2 in the country. The outbreak rapidly escalated to a national level epidemic, amid the WHO declaration of a pandemic.

Methods

We analysed data from the national case-based integrated surveillance system of all RT-PCR confirmed COVID-19 infections as of March 24th 2020, collected from all Italian regions and autonomous provinces. Here we provide a descriptive epidemiological summary on the first 62,843 COVID-19 cases in Italy as well as estimates of the basic and net reproductive numbers by region.

Findings

Of the 62,843 cases of COVID-19 analysed, 71.6% were reported from three Regions (Lombardia, Veneto and Emilia-Romagna). All cases reported after February 20th were locally acquired. Estimates of R0 varied between 2.5 (95%CI: 2.18-2.83) in Toscana and 3 (95%CI: 2.68-3.33) in Lazio, with epidemic doubling time of 3.2 days (95%CI: 2.3-5.2) and 2.9 days (95%CI: 2.2-4.3), respectively. The net reproduction number showed a decreasing trend starting around February 20-25, 2020 in Northern regions. Notably, 5,760 cases were reported among health care workers. Of the 5,541 reported COVID-19 associated deaths, 49% occurred in people aged 80 years or above with an overall crude CFR of 8.8%. Male sex and age were independent risk factors for COVID-19 death.

Interpretation

The COVID-19 infection in Italy emerged with a clustering onset similar to the one described in Wuhan, China and likewise showed worse outcomes in older males with comorbidities. Initial R0 at 2.96 in Lombardia, explains the high case-load and rapid geographical spread observed. Overall Rt in Italian regions is currently decreasing albeit with large diversities across the country, supporting the importance of combined non-pharmacological control measures.

Funding

routine institutional funding was used to perform this work.