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1.
Elife ; 112022 07 07.
Article in English | MEDLINE | ID: covidwho-1924599

ABSTRACT

The National Institute on Minority Health and Health Disparities (NIMHD) has developed a framework to guide and orient research into health disparities and minority health. The framework depicts different domains of influence (such as biological and behavioral) and different levels of influence (such as individual and interpersonal). Here, influenced by the "One Health" approach, we propose adding two new levels of influence - interspecies and planetary - to this framework to reflect the interconnected nature of human, animal, and environmental health. Extending the framework in this way will help researchers to create new avenues of inquiry and encourage multidisciplinary collaborations. We then use the One Health approach to discuss how the COVID-19 pandemic has exacerbated health disparities, and show how the expanded framework can be applied to research into health disparities related to antimicrobial resistance and obesity.


Subject(s)
COVID-19 , Minority Health , COVID-19/epidemiology , Humans , Minority Groups , Pandemics , United States
2.
Elife ; 112022 03 16.
Article in English | MEDLINE | ID: covidwho-1766127

ABSTRACT

Publications are essential for a successful academic career, and there is evidence that the COVID-19 pandemic has amplified existing gender disparities in the publishing process. We used longitudinal publication data on 431,207 authors in four disciplines - basic medicine, biology, chemistry and clinical medicine - to quantify the differential impact of COVID-19 on the annual publishing rates of men and women. In a difference-in-differences analysis, we estimated that the average gender difference in publication productivity increased from -0.26 in 2019 to -0.35 in 2020; this corresponds to the output of women being 17% lower than the output of men in 2109, and 24% lower in 2020. An age-group comparison showed a widening gender gap for both early-career and mid-career scientists. The increasing gender gap was most pronounced among highly productive authors and in biology and clinical medicine. Our study demonstrates the importance of reinforcing institutional commitments to diversity through policies that support the inclusion and retention of women in research.


Subject(s)
COVID-19 , Efficiency , Female , Humans , Male , Pandemics , Publishing , Sex Factors
3.
Elife ; 102021 12 20.
Article in English | MEDLINE | ID: covidwho-1662832

ABSTRACT

Employing concepts from physics, chemistry and bioengineering, 'learning-by-building' approaches are becoming increasingly popular in the life sciences, especially with researchers who are attempting to engineer cellular life from scratch. The SynCell2020/21 conference brought together researchers from different disciplines to highlight progress in this field, including areas where synthetic cells are having socioeconomic and technological impact. Conference participants also identified the challenges involved in designing, manipulating and creating synthetic cells with hierarchical organization and function. A key conclusion is the need to build an international and interdisciplinary research community through enhanced communication, resource-sharing, and educational initiatives.


Subject(s)
Artificial Cells , Bioengineering/methods , Bioengineering/statistics & numerical data , Bioengineering/trends , Intersectoral Collaboration , Organelles/physiology , Synthetic Biology/trends , Forecasting , Humans
4.
Elife ; 102021 11 23.
Article in English | MEDLINE | ID: covidwho-1622815

ABSTRACT

Background: Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. Methods: Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO. Results: Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy. Conclusions: We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness. Funding: GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.


Subject(s)
Antihypertensive Agents/adverse effects , COVID-19/complications , Data Mining/methods , Drug-Related Side Effects and Adverse Reactions , Hypertension/drug therapy , Pharmacovigilance , Adverse Drug Reaction Reporting Systems , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/therapeutic use , Bayes Theorem , Calcium Channel Blockers/adverse effects , Fibrinolytic Agents/adverse effects , Humans , Hypertension/complications , SARS-CoV-2
5.
Elife ; 102021 11 25.
Article in English | MEDLINE | ID: covidwho-1534521

ABSTRACT

Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings. Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings. Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made. Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions. Funding: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).


Infectious diseases, particularly those caused by airborne pathogens like SARS-CoV-2, spread by social contact, and understanding how people mix is critical in controlling outbreaks. To explore these patterns, researchers typically carry out large contact surveys. Participants are asked for personal information (such as gender, age and occupation), as well as details of recent social contacts, usually those that happened in the last 24 hours. This information includes, the age and gender of the contact, where the interaction happened, how long it lasted, and whether it involved physical touch. These kinds of surveys help scientists to predict how infectious diseases might spread. But there is a problem: most of the data come from high-income countries, and there is evidence to suggest that social contact patterns differ between places. Therefore, data from these countries might not be useful for predicting how infections spread in lower-income regions. Here, Mousa et al. have collected and combined data from 27 contact surveys carried out before the COVID-19 pandemic to see how baseline social interactions vary between high- and lower-income settings. The comparison revealed that, in higher-income countries, the number of daily contacts people made decreased with age. But, in lower-income countries, younger and older individuals made similar numbers of contacts and mixed with all age groups. In higher-income countries, more contacts happened at work or school, while in low-income settings, more interactions happened at home and people were also more likely to live in larger, intergenerational households. Mousa et al. also found that gender affected how long contacts lasted and whether they involved physical contact, both of which are key risk factors for transmitting airborne pathogens. These findings can help researchers to predict how infectious diseases might spread in different settings. They can also be used to assess how effective non-medical restrictions, like shielding of the elderly and workplace closures, will be at reducing transmissions in different parts of the world.


Subject(s)
COVID-19/transmission , Disease Transmission, Infectious , Adolescent , Adult , Aged , COVID-19/virology , Female , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Young Adult
6.
Elife ; 102021 06 01.
Article in English | MEDLINE | ID: covidwho-1513078

ABSTRACT

A voucher is a permanently preserved specimen that is maintained in an accessible collection. In genomics, vouchers serve as the physical evidence for the taxonomic identification of genome assemblies. Unfortunately, the vast majority of vertebrate genomes stored in the GenBank database do not refer to voucher specimens. Here, we urge researchers generating new genome assemblies to deposit voucher specimens in accessible, permanent research collections, and to link these vouchers to publications, public databases, and repositories. We also encourage scientists to deposit voucher specimens in order to recognize the work of local field biologists and promote a diverse and inclusive knowledge base, and we recommend best practices for voucher deposition to prevent taxonomic errors and ensure reproducibility and legality in genetic studies.


Subject(s)
Biological Specimen Banks , Databases, Genetic , Genomics , Specimen Handling , Animals , Data Accuracy , Humans , Phylogeny , Reproducibility of Results
7.
Elife ; 102021 08 20.
Article in English | MEDLINE | ID: covidwho-1513067

ABSTRACT

Identifying the key vector and host species that drive the transmission of zoonotic pathogens is notoriously difficult but critical for disease control. We present a nested approach for quantifying the importance of host and vectors that integrates species' physiological competence with their ecological traits. We apply this framework to a medically important arbovirus, Ross River virus (RRV), in Brisbane, Australia. We find that vertebrate hosts with high physiological competence are not the most important for community transmission; interactions between hosts and vectors largely underpin the importance of host species. For vectors, physiological competence is highly important. Our results identify primary and secondary vectors of RRV and suggest two potential transmission cycles in Brisbane: an enzootic cycle involving birds and an urban cycle involving humans. The framework accounts for uncertainty from each fitted statistical model in estimates of species' contributions to transmission and has has direct application to other zoonotic pathogens.


Subject(s)
Alphavirus Infections/virology , Birds/virology , Culicidae/virology , Disease Reservoirs/virology , Disease Vectors , Ross River virus/pathogenicity , Viral Zoonoses , Alphavirus Infections/transmission , Animals , Host-Pathogen Interactions , Humans , Models, Biological , Queensland , Virulence
8.
Elife ; 102021 08 04.
Article in English | MEDLINE | ID: covidwho-1513060

ABSTRACT

Cilia are hairlike organelles involved in both sensory functions and motility. We discuss the question of whether the location of chemical receptors on cilia provides an advantage in terms of sensitivity and whether motile sensory cilia have a further advantage. Using a simple advection-diffusion model, we compute the capture rates of diffusive molecules on a cilium. Because of its geometry, a non-motile cilium in a quiescent fluid has a capture rate equivalent to a circular absorbing region with ∼4× its surface area. When the cilium is exposed to an external shear flow, the equivalent surface area increases to ∼6×. Alternatively, if the cilium beats in a non-reciprocal way in an otherwise quiescent fluid, its capture rate increases with the beating frequency to the power of 1/3. Altogether, our results show that the protruding geometry of a cilium could be one of the reasons why so many receptors are located on cilia. They also point to the advantage of combining motility with chemical reception.


Subject(s)
Cilia/physiology , Inorganic Chemicals/metabolism , Organic Chemicals/metabolism , Models, Theoretical , Organelles/physiology
9.
Elife ; 102021 01 26.
Article in English | MEDLINE | ID: covidwho-1513022

ABSTRACT

Humans have relied on sourdough starter microbial communities to make leavened bread for thousands of years, but only a small fraction of global sourdough biodiversity has been characterized. Working with a community-scientist network of bread bakers, we determined the microbial diversity of 500 sourdough starters from four continents. In sharp contrast with widespread assumptions, we found little evidence for biogeographic patterns in starter communities. Strong co-occurrence patterns observed in situ and recreated in vitro demonstrate that microbial interactions shape sourdough community structure. Variation in dough rise rates and aromas were largely explained by acetic acid bacteria, a mostly overlooked group of sourdough microbes. Our study reveals the extent of microbial diversity in an ancient fermented food across diverse cultural and geographic backgrounds.


Sourdough bread is an ancient fermented food that has sustained humans around the world for thousands of years. It is made from a sourdough 'starter culture' which is maintained, portioned, and shared among bread bakers around the world. The starter culture contains a community of microbes made up of yeasts and bacteria, which ferment the carbohydrates in flour and produce the carbon dioxide gas that makes the bread dough rise before baking. The different acids and enzymes produced by the microbial culture affect the bread's flavor, texture and shelf life. However, for such a dependable staple, sourdough bread cultures and the mixture of microbes they contain have scarcely been characterized. Previous studies have looked at the composition of starter cultures from regions within Europe. But there has never been a comprehensive study of how the microbial diversity of sourdough starters varies across and between continents. To investigate this, Landis, Oliverio et al. used genetic sequencing to characterize the microbial communities of sourdough starters from the homes of 500 bread bakers in North America, Europe and Australasia. Bread makers often think their bread's unique qualities are due to the local environment of where the sourdough starter was made. However, Landis, Oliverio et al. found that geographical location did not correlate with the diversity of the starter cultures studied. The data revealed that a group of microbes called acetic acid bacteria, which had been overlooked in past research, were relatively common in starter cultures. Moreover, starters with a greater abundance of this group of bacteria produced bread with a strong vinegar aroma and caused dough to rise at a slower rate. This research demonstrates which species of bacteria and yeast are most commonly found in sourdough starters, and suggests geographical location has little influence on the microbial diversity of these cultures. Instead, the diversity of microbes likely depends more on how the starter culture was made and how it is maintained over time.


Subject(s)
Bacteria/metabolism , Bread/microbiology , Food Microbiology , Microbiota , Acetic Acid/metabolism
10.
Elife ; 102021 10 18.
Article in English | MEDLINE | ID: covidwho-1478421

ABSTRACT

An early-warning model to predict in-hospital mortality on admission of COVID-19 patients at an emergency department (ED) was developed and validated using a machine-learning model. In total, 2782 patients were enrolled between March 2020 and December 2020, including 2106 patients (first wave) and 676 patients (second wave) in the COVID-19 outbreak in Italy. The first-wave patients were divided into two groups with 1474 patients used to train the model, and 632 to validate it. The 676 patients in the second wave were used to test the model. Age, 17 blood analytes, and Brescia chest X-ray score were the variables processed using a random forests classification algorithm to build and validate the model. Receiver operating characteristic (ROC) analysis was used to assess the model performances. A web-based death-risk calculator was implemented and integrated within the Laboratory Information System of the hospital. The final score was constructed by age (the most powerful predictor), blood analytes (the strongest predictors were lactate dehydrogenase, D-dimer, neutrophil/lymphocyte ratio, C-reactive protein, lymphocyte %, ferritin std, and monocyte %), and Brescia chest X-ray score (https://bdbiomed.shinyapps.io/covid19score/). The areas under the ROC curve obtained for the three groups (training, validating, and testing) were 0.98, 0.83, and 0.78, respectively. The model predicts in-hospital mortality on the basis of data that can be obtained in a short time, directly at the ED on admission. It functions as a web-based calculator, providing a risk score which is easy to interpret. It can be used in the triage process to support the decision on patient allocation.


Subject(s)
COVID-19/mortality , Hospital Mortality , Machine Learning , Aged , Aged, 80 and over , Algorithms , COVID-19/diagnostic imaging , Emergency Service, Hospital , Female , Hospitals , Humans , Italy/epidemiology , Male , Middle Aged , ROC Curve , Risk Factors , SARS-CoV-2/isolation & purification , X-Rays
11.
Elife ; 102021 08 20.
Article in English | MEDLINE | ID: covidwho-1368024

ABSTRACT

Background: Previously, we conducted a systematic review and analyzed the respiratory kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Chen et al., 2021). How age, sex, and coronavirus disease 2019 (COVID-19) severity interplay to influence the shedding dynamics of SARS-CoV-2, however, remains poorly understood. Methods: We updated our systematic dataset, collected individual case characteristics, and conducted stratified analyses of SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) across COVID-19 severity, sex, and age groups (aged 0-17 years, 18-59 years, and 60 years or older). Results: The systematic dataset included 1266 adults and 136 children with COVID-19. Our analyses indicated that high, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. Severe cases tended to show slightly higher URT shedding post-symptom onset, but similar rates of viral clearance, when compared to nonsevere infections. After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of respiratory shedding. The estimated accuracy for using LRT shedding as a prognostic indicator for COVID-19 severity was up to 81%, whereas it was up to 65% for URT shedding. Conclusions: Virological factors, especially in the LRT, facilitate the pathogenesis of severe COVID-19. Disease severity, rather than sex or age, predicts SARS-CoV-2 kinetics. LRT viral load may prognosticate COVID-19 severity in patients before the timing of deterioration and should do so more accurately than URT viral load. Funding: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair, and the Toronto COVID-19 Action Fund.


Subject(s)
COVID-19/physiopathology , Respiratory System/physiopathology , SARS-CoV-2/physiology , Virus Shedding , Adult , COVID-19/diagnosis , COVID-19/virology , Child , Female , Humans , Male , Prognosis , Respiratory System/virology , Severity of Illness Index , Viral Load
12.
Elife ; 102021 08 20.
Article in English | MEDLINE | ID: covidwho-1368023

ABSTRACT

SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD-ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD-ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , Cell Line , Humans , Protein Binding , Spike Glycoprotein, Coronavirus/genetics
13.
Elife ; 102021 06 11.
Article in English | MEDLINE | ID: covidwho-1266916

ABSTRACT

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Pneumonia, Viral/drug therapy , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/drug therapy , Aged , Aged, 80 and over , Doxazosin/therapeutic use , Humans , Male , Middle Aged , Pneumonia, Viral/mortality , Respiratory Distress Syndrome/mortality , Retrospective Studies , Sweden/epidemiology , Tamsulosin/therapeutic use , United States/epidemiology
14.
Elife ; 102021 04 16.
Article in English | MEDLINE | ID: covidwho-1190616

ABSTRACT

Background: Which virological factors mediate overdispersion in the transmissibility of emerging viruses remains a long-standing question in infectious disease epidemiology. Methods: Here, we use systematic review to develop a comprehensive dataset of respiratory viral loads (rVLs) of SARS-CoV-2, SARS-CoV-1 and influenza A(H1N1)pdm09. We then comparatively meta-analyze the data and model individual infectiousness by shedding viable virus via respiratory droplets and aerosols. Results: The analyses indicate heterogeneity in rVL as an intrinsic virological factor facilitating greater overdispersion for SARS-CoV-2 in the COVID-19 pandemic than A(H1N1)pdm09 in the 2009 influenza pandemic. For COVID-19, case heterogeneity remains broad throughout the infectious period, including for pediatric and asymptomatic infections. Hence, many COVID-19 cases inherently present minimal transmission risk, whereas highly infectious individuals shed tens to thousands of SARS-CoV-2 virions/min via droplets and aerosols while breathing, talking and singing. Coughing increases the contagiousness, especially in close contact, of symptomatic cases relative to asymptomatic ones. Infectiousness tends to be elevated between 1 and 5 days post-symptom onset. Conclusions: Intrinsic case variation in rVL facilitates overdispersion in the transmissibility of emerging respiratory viruses. Our findings present considerations for disease control in the COVID-19 pandemic as well as future outbreaks of novel viruses. Funding: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant program, NSERC Senior Industrial Research Chair program and the Toronto COVID-19 Action Fund.


To understand how viruses spread scientists look at two things. One is ­ on average ­ how many other people each infected person spreads the virus to. The other is how much variability there is in the number of people each person with the virus infects. Some viruses like the 2009 influenza H1N1, a new strain of influenza that caused a pandemic beginning in 2009, spread pretty uniformly, with many people with the virus infecting around two other people. Other viruses like SARS-CoV-2, the one that causes COVID-19, are more variable. About 10 to 20% of people with COVID-19 cause 80% of subsequent infections ­ which may lead to so-called superspreading events ­ while 60-75% of people with COVID-19 infect no one else. Learning more about these differences can help public health officials create better ways to curb the spread of the virus. Chen et al. show that differences in the concentration of virus particles in the respiratory tract may help to explain why superspreaders play such a big role in transmitting SARS-CoV-2, but not the 2009 influenza H1N1 virus. Chen et al. reviewed and extracted data from studies that have collected how much virus is present in people infected with either SARS-CoV-2, a similar virus called SARS-CoV-1 that caused the SARS outbreak in 2003, or with 2009 influenza H1N1. Chen et al. found that as the variability in the concentration of the virus in the airways increased, so did the variability in the number of people each person with the virus infects. Chen et al. further used mathematical models to estimate how many virus particles individuals with each infection would expel via droplets or aerosols, based on the differences in virus concentrations from their analyses. The models showed that most people with COVID-19 infect no one because they expel little ­ if any ­ infectious SARS-CoV-2 when they talk, breathe, sing or cough. Highly infectious individuals on the other hand have high concentrations of the virus in their airways, particularly the first few days after developing symptoms, and can expel tens to thousands of infectious virus particles per minute. By contrast, a greater proportion of people with 2009 influenza H1N1 were potentially infectious but tended to expel relatively little infectious virus when the talk, sing, breathe or cough. These results help explain why superspreaders play such a key role in the ongoing pandemic. This information suggests that to stop this virus from spreading it is important to limit crowd sizes, shorten the duration of visits or gatherings, maintain social distancing, talk in low volumes around others, wear masks, and hold gatherings in well-ventilated settings. In addition, contact tracing can prioritize the contacts of people with high concentrations of virus in their airways.


Subject(s)
Aerosols , COVID-19/transmission , Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/transmission , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/transmission , Virus Shedding , Disease Transmission, Infectious , Humans , Viral Load
15.
Elife ; 102021 03 05.
Article in English | MEDLINE | ID: covidwho-1119624

ABSTRACT

Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions.


Subject(s)
COVID-19/epidemiology , Adolescent , Adult , Age Factors , Aged , Bayes Theorem , COVID-19/diagnosis , COVID-19 Serological Testing , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Middle Aged , Pandemics , SARS-CoV-2/isolation & purification , Seroepidemiologic Studies , Uncertainty , Young Adult
16.
Elife ; 92020 11 23.
Article in English | MEDLINE | ID: covidwho-1042987

ABSTRACT

An eLife survey explores the experiences of those in the research community who support colleagues struggling with their mental health.


Subject(s)
Mental Health , Social Support , Data Collection , Humans
17.
Elife ; 92020 11 04.
Article in English | MEDLINE | ID: covidwho-994185

ABSTRACT

Scientific conferences have an important role in the exchange of ideas and knowledge within the scientific community. Conferences also provide early-career researchers with opportunities to make themselves known within their field of research. Although the COVID-19 pandemic has brought traditional in-person conferences to a halt for the foreseeable future, the growth of virtual conferences has highlighted many of the disadvantages associated with the in-person format and demonstrated the advantages of moving these events online. Here, based on data from in-person and virtual conferences in a range of subjects, we describe how virtual conferences are more inclusive, more affordable, less time-consuming and more accessible worldwide, especially for early-career researchers. Making conferences more open and inclusive will provide both immediate and long-term benefits to the scientific community.


Subject(s)
Access to Information , Congresses as Topic , Coronavirus Infections , Information Dissemination , Interprofessional Relations , Pandemics , Pneumonia, Viral , Social Isolation , Virtual Reality , COVID-19 , Congresses as Topic/economics , Cooperative Behavior , Diffusion of Innovation , Humans , International Cooperation
18.
Elife ; 92020 11 23.
Article in English | MEDLINE | ID: covidwho-940328

ABSTRACT

Bruton's tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here, we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including large-scale shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.


Treatments for blood cancers, such as leukemia and lymphoma, rely heavily on chemotherapy, using drugs that target a vulnerable aspect of the cancer cells. B-cells, a type of white blood cell that produces antibodies, require a protein called Bruton's tyrosine kinase, or BTK for short, to survive. The drug ibrutinib (Imbruvica) is used to treat B-cell cancers by blocking BTK. The BTK protein consists of several regions. One of them, known as the kinase domain, is responsible for its activity as an enzyme (which allows it to modify other proteins by adding a 'tag' known as a phosphate group). The other regions of BTK, known as regulatory modules, control this activity. In BTK's inactive form, the regulatory modules attach to the kinase domain, blocking the regulatory modules from interacting with other proteins. When BTK is activated, it changes its conformation so the regulatory regions detach and become available for interactions with other proteins, at the same time exposing the active kinase domain. Ibrutinib and other BTK drugs in development bind to the kinase domain to block its activity. However, it is not known how this binding affects the regulatory modules. Previous efforts to study how drugs bind to BTK have used a version of the protein that only had the kinase domain, instead of the full-length protein. Now, Joseph et al. have studied full-length BTK and how it binds to five different drugs. The results reveal that ibrutinib and another drug called dasatinib both indirectly disrupt the normal position of the regulatory domains pushing BTK toward a conformation that resembles the activated state. By contrast, the three other compounds studied do not affect the inactive structure. Joseph et al. also examined a mutation in BTK that confers resistance against ibrutinib. This mutation increases the activity of BTK by disrupting the inactive structure, leading to B cells surviving better. Understanding how drug resistance mechanisms can work will lead to better drug treatment strategies for cancer. BTK is also a target in other diseases such as allergies or asthma and even COVID-19. If interactions between partner proteins and the regulatory domain are important in these diseases, then they may be better treated with drugs that maintain the regulatory modules in their inactive state. This research will help to design drugs that are better able to control BTK activity.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Catalytic Domain , Protein Conformation/drug effects , Protein Kinase Inhibitors/pharmacology , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/metabolism , Adenine/pharmacology , Agammaglobulinaemia Tyrosine Kinase/chemistry , Agammaglobulinaemia Tyrosine Kinase/genetics , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Dasatinib/chemistry , Dasatinib/metabolism , Dasatinib/pharmacology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/prevention & control , Models, Molecular , Molecular Structure , Mutation , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , SARS-CoV-2/physiology , src Homology Domains/genetics
19.
J Cardiovasc Electrophysiol ; 31(11): 2812-2813, 2020 11.
Article in English | MEDLINE | ID: covidwho-732125
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