Showing papers by "Université de Montréal published in 2021"
Daniel J. Klionsky1, Amal Kamal Abdel-Aziz2, Sara Abdelfatah3, Mahmoud Abdellatif4 +2980 more•Institutions (777)
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
1,129 citations
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Mainz3, Peking University4, Japanese Foundation for Cancer Research5, Medical University of Lublin6, Fudan University7, University of La Frontera8, Université de Montréal9, National and Kapodistrian University of Athens10, St John of God Murdoch Hospital11, Harvard University12, Bristol-Myers Squibb13, University of Texas MD Anderson Cancer Center14
TL;DR: The CheckMate 649 trial as discussed by the authors evaluated first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophage alogaryal adenocarcinoma.
858 citations
Ben-Gurion University of the Negev1, McMaster University2, Population Health Research Institute3, University of North Carolina at Chapel Hill4, Sanjay Gandhi Post Graduate Institute of Medical Sciences5, University of Gothenburg6, Katholieke Universiteit Leuven7, Iuliu Hațieganu University of Medicine and Pharmacy8, Peking Union Medical College Hospital9, Tohoku University10, University of Sydney11, University of Jos12, Cornell University13, National Autonomous University of Mexico14, University of Manchester15, University of Ghana16, Isfahan University of Medical Sciences17, University of Amsterdam18, Ege University19, Wonkwang University20, Universidade Federal do Rio Grande do Sul21, Pontifical Xavierian University22, Moscow State University of Medicine and Dentistry23, Universiti Sains Malaysia24, Wrocław Medical University25, Dhaka Medical College and Hospital26, Autonomous University of Barcelona27, University of Cape Town28, University of Indonesia29, Queen's University30, National University of Singapore31, Rabin Medical Center32, University of Alberta33, Mazandaran University of Medical Sciences34, Université de Montréal35
TL;DR: It is found that more than 40% of persons worldwide have FGIDs, which affect quality of life and healthcare use, and similar trends and relative distributions were found in people who completed internet vs personal interviews.
763 citations
TL;DR: The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org) is an open‐access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, and human.
Abstract: The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org) is an open-access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, and human. The ~1.93 million curated interactions in BioGRID can be used to build complex networks to facilitate biomedical discoveries, particularly as related to human health and disease. All BioGRID content is curated from primary experimental evidence in the biomedical literature, and includes both focused low-throughput studies and large high-throughput datasets. BioGRID also captures protein post-translational modifications and protein or gene interactions with bioactive small molecules including many known drugs. A built-in network visualization tool combines all annotations and allows users to generate network graphs of protein, genetic and chemical interactions. In addition to general curation across species, BioGRID undertakes themed curation projects in specific aspects of cellular regulation, for example the ubiquitin-proteasome system, as well as specific disease areas, such as for the SARS-CoV-2 virus that causes COVID-19 severe acute respiratory syndrome. A recent extension of BioGRID, named the Open Repository of CRISPR Screens (ORCS, orcs.thebiogrid.org), captures single mutant phenotypes and genetic interactions from published high throughput genome-wide CRISPR/Cas9-based genetic screens. BioGRID-ORCS contains datasets for over 1,042 CRISPR screens carried out to date in human, mouse and fly cell lines. The biomedical research community can freely access all BioGRID data through the web interface, standardized file downloads, or via model organism databases and partner meta-databases.
565 citations
TL;DR: In this article, the population of 47 compact binary mergers detected with a false-alarm rate of 0.614 were dynamically assembled, and the authors found that the BBH rate likely increases with redshift, but not faster than the star formation rate.
Abstract: We report on the population of 47 compact binary mergers detected with a false-alarm rate of 0.01 are dynamically assembled. Third, we estimate merger rates, finding RBBH = 23.9-+8.614.3 Gpc-3 yr-1 for BBHs and RBNS = 320-+240490 Gpc-3 yr-1 for binary neutron stars. We find that the BBH rate likely increases with redshift (85% credibility) but not faster than the star formation rate (86% credibility). Additionally, we examine recent exceptional events in the context of our population models, finding that the asymmetric masses of GW190412 and the high component masses of GW190521 are consistent with our models, but the low secondary mass of GW190814 makes it an outlier.
468 citations
TL;DR: A survey of machine learning and combinatorial optimization problems can be found in this paper, where the main point is to see generic optimization problems as data points and inquire what is the relevant distribution of problems to use for learning on a given task.
464 citations
TL;DR: In this article, the authors examined whether sera from recovered and naive donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants.
Abstract: Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naive donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold. Neutralization was due to antibodies targeting the receptor binding domain and was not boosted by a second immunization. Immunization of naive donors also elicited cross-neutralizing responses, but at lower titers. Our study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.
405 citations
TL;DR: This review categorizes the leading deep learning-based medical and non-medical image segmentation solutions into six main groups of deep architectural, data synthesis- based, loss function-based, sequenced models, weakly supervised, and multi-task methods.
Abstract: The semantic image segmentation task consists of classifying each pixel of an image into an instance, where each instance corresponds to a class. This task is a part of the concept of scene understanding or better explaining the global context of an image. In the medical image analysis domain, image segmentation can be used for image-guided interventions, radiotherapy, or improved radiological diagnostics. In this review, we categorize the leading deep learning-based medical and non-medical image segmentation solutions into six main groups of deep architectural, data synthesis-based, loss function-based, sequenced models, weakly supervised, and multi-task methods and provide a comprehensive review of the contributions in each of these groups. Further, for each group, we analyze each variant of these groups and discuss the limitations of the current approaches and present potential future research directions for semantic image segmentation.
398 citations
TL;DR: In this paper, the authors conducted a systematic review and meta-analysis of observational studies with comparison data on SARS-CoV-2 infection and severity of COVID-19 during pregnancy.
Abstract: BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) on maternal and newborn health is unclear. We aimed to evaluate the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and adverse pregnancy outcomes. METHODS: We conducted a systematic review and meta-analysis of observational studies with comparison data on SARS-CoV-2 infection and severity of COVID-19 during pregnancy. We searched for eligible studies in MEDLINE, Embase, ClinicalTrials.gov, medRxiv and Cochrane databases up to Jan. 29, 2021, using Medical Subject Headings terms and keywords for "severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR coronavirus disease 2019 OR COVID-19" AND "pregnancy." We evaluated the methodologic quality of all included studies using the Newcastle-Ottawa Scale. Our primary outcomes were preeclampsia and preterm birth. Secondary outcomes included stillbirth, gestational diabetes and other pregnancy outcomes. We calculated summary odds ratios (ORs) or weighted mean differences with 95% confidence intervals (CI) using random-effects meta-analysis. RESULTS: We included 42 studies involving 438 548 people who were pregnant. Compared with no SARS-CoV-2 infection in pregnancy, COVID-19 was associated with preeclampsia (OR 1.33, 95% CI 1.03 to 1.73), preterm birth (OR 1.82, 95% CI 1.38 to 2.39) and stillbirth (OR 2.11, 95% CI 1.14 to 3.90). Compared with mild COVID-19, severe COVID-19 was strongly associated with preeclampsia (OR 4.16, 95% CI 1.55 to 11.15), preterm birth (OR 4.29, 95% CI 2.41 to 7.63), gestational diabetes (OR 1.99, 95% CI 1.09 to 3.64) and low birth weight (OR 1.89, 95% CI 1.14 to 3.12). INTERPRETATION: COVID-19 may be associated with increased risks of preeclampsia, preterm birth and other adverse pregnancy outcomes.
350 citations
University of California1, Duke University2, University of Glasgow3, University of Brescia4, Harvard University5, University of North Carolina at Chapel Hill6, University of Minnesota7, University of Copenhagen8, Saarland University9, Medical University of Vienna10, Imperial College London11, Pontifical Catholic University of Chile12, Linköping University13, University of Utah14, National and Kapodistrian University of Athens15, Nova Southeastern University16, Comenius University in Bratislava17, Sofia Medical University18, Henry Ford Hospital19, Peking Union Medical College20, Middlemore Hospital21, St. Vincent's Health System22, Moscow State University23, Université de Montréal24, Wrocław Medical University25, University of São Paulo26, Vilnius University27, University of Cape Town28, Masaryk University29, University Hospital of Bern30, St John of God Health Care31, Carol Davila University of Medicine and Pharmacy32, University of Groningen33, Dokuz Eylül University34, University of Lorraine35, Amgen36
TL;DR: Among patients with heart failure and a reduced ejection, patients who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo.
Abstract: Background The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect ...
341 citations
TL;DR: In this article, the authors use an interrupted time series to study the political effect of the enforcement of a strict confinement policy in response to the COVID-19 pandemic, and find that lockdowns have increased vote intentions for the party of the prime minister/president, trust in government and satisfaction with democracy.
Abstract: Major crises can act as critical junctures or reinforce the political status quo, depending on how citizens view the performance of central institutions. We use an interrupted time series to study the political effect of the enforcement of a strict confinement policy in response to the COVID-19 pandemic. Specifically, we take advantage of a unique representative web-based survey that was fielded in March and April 2020 in Western Europe to compare the political support of those who took the survey right before and right after the start of the lockdown in their country. We find that lockdowns have increased vote intentions for the party of the Prime Minister/President, trust in government and satisfaction with democracy. Furthermore, we find that, while rallying individuals around current leaders and institutions, they have had no effect on traditional left–right attitudes.
TL;DR: The data recorded by these instruments during their first and second observing runs are described, including the gravitational-wave strain arrays, released as time series sampled at 16384 Hz.
University of Utah1, University of Colorado Denver2, Oregon Health & Science University3, Harvard University4, University of California, San Diego5, University of Texas Health Science Center at Houston6, Medical College of Wisconsin7, Medical University of South Carolina8, Northwestern University9, Emory University10, University of Pennsylvania11, University of São Paulo12, Sun Yat-sen University13, Ghent University14, Karolinska Institutet15, University of Chicago16, Rush University Medical Center17, University of Barcelona18, University of California, Los Angeles19, Vanderbilt University20, University of Arizona21, University of Kansas22, Université de Montréal23, University of Auckland24, Rutgers University25, University of Amsterdam26, Columbia University27, Eastern Virginia Medical School28, University of New South Wales29, Katholieke Universiteit Leuven30, Guy's Hospital31, Stanford University32, University of British Columbia33, Mayo Clinic34, Johns Hopkins University35, Korea University36, Uniformed Services University of the Health Sciences37, Jikei University School of Medicine38, University of Washington39, University of Siena40, University of East Anglia41, University of Adelaide42, Pusan National University43, University of Calgary44, University of Cincinnati45, University of North Carolina at Chapel Hill46, Cleveland Clinic47, University of Winnipeg48, Chulalongkorn University49, Cornell University50, National University of Singapore51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in the understanding and treatment of rhinologic disease.
Abstract: I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.
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TL;DR: In this paper, neural networks are used to learn the rich internal representations required for difficult tasks such as recognizing objects or understanding language, which can be used to classify objects or understand language.
Abstract: How can neural networks learn the rich internal representations required for difficult tasks such as recognizing objects or understanding language?
Stephen P.H. Alexander1, Arthur Christopoulos2, Anthony P. Davenport3, Eamonn Kelly4 +151 more•Institutions (85)
TL;DR: The Concise Guide to PHARMACOLOGY 2021/22 as mentioned in this paper provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands.
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
TL;DR: NeuroKit2 as discussed by the authors is an open-source, community-driven, and user-centered Python package for neurophysiological signal processing, which includes high-level functions that enable data processing in a few lines of code using validated pipelines.
Abstract: NeuroKit2 is an open-source, community-driven, and user-centered Python package for neurophysiological signal processing. It provides a comprehensive suite of processing routines for a variety of bodily signals (e.g., ECG, PPG, EDA, EMG, RSP). These processing routines include high-level functions that enable data processing in a few lines of code using validated pipelines, which we illustrate in two examples covering the most typical scenarios, such as an event-related paradigm and an interval-related analysis. The package also includes tools for specific processing steps such as rate extraction and filtering methods, offering a trade-off between high-level convenience and fine-tuned control. Its goal is to improve transparency and reproducibility in neurophysiological research, as well as foster exploration and innovation. Its design philosophy is centred on user-experience and accessibility to both novice and advanced users.
University of Toronto1, University of São Paulo2, King Saud University3, Medical College of Wisconsin4, Mater Misericordiae University Hospital5, University College Dublin6, Université de Sherbrooke7, Libin Cardiovascular Institute of Alberta8, Ottawa Hospital Research Institute9, Queen's University10, University of Vermont11, University of Vermont Medical Center12, Université de Montréal13, University of Alberta14, Radboud University Nijmegen15, University of British Columbia16, University of Bern17
TL;DR: In this paper, the authors evaluated the effects of therapeutic heparin compared with prophylactic hepharmin among moderately ill patients with covid-19 admitted to hospital wards.
Abstract: Objective To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. Design Randomised controlled, adaptive, open label clinical trial. Setting 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. Participants 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). Interventions Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. Main outcome measures The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. Results The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). Conclusions In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. Trial registration ClinicalTrials.gov NCT04362085.
TL;DR: The COLCORONA trial as mentioned in this paper investigated the effect of colchicine on the composite of COVID-19-related death or hospital admission and found that colchics led to a lower rate of the composite adverse events than placebo.
TL;DR: This paper conducted a meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
TL;DR: In this article, the authors present a clinical practice guideline for the management of Clostridioides difficile infection (CDI) in adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI.
Abstract: This clinical practice guideline is a focused update on management of Clostridioides difficile infection (CDI) in adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI. This guideline was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). This guideline is intended for use by healthcare professionals who care for adults with CDI, including specialists in infectious diseases, gastroenterologists, hospitalists, pharmacists, and any clinicians and healthcare providers caring for these patients. The panel's recommendations for the management CDI are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the management of CDI in adults. The panel followed a systematic process which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.
Utrecht University1, Netherlands Cancer Institute2, University of Sydney3, Princess Alexandra Hospital4, Alfred Hospital5, Edith Cowan University6, Peter MacCallum Cancer Centre7, The Royal Marsden NHS Foundation Trust8, Carlos III Health Institute9, Radboud University Nijmegen10, Washington University in St. Louis11, University of Amsterdam12, Aix-Marseille University13, Hannover Medical School14, Université de Montréal15, Merck & Co.16, European Organisation for Research and Treatment of Cancer17, Institut Gustave Roussy18
TL;DR: In this paper, the authors compared pembrolizumab versus placebo in patients with resected high-risk stage III melanoma, and showed that penglizumaab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median followup.
Abstract: Summary Background The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p Methods This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov , NCT02362594 , and EudraCT, 2014-004944-37. Findings Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p Interpretation Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. Funding Merck Sharp & Dohme.
François-Xavier Lescure1, Hitoshi Honda, Robert A. Fowler2, Jennifer Sloane Lazar +294 more•Institutions (7)
TL;DR: In this article, the authors evaluated the safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical(requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.
Columbia University1, University of Glasgow2, National Institutes of Health3, Sahlgrenska University Hospital4, Monterrey Institute of Technology and Higher Education5, University of Palermo6, University of Cambridge7, Université de Montréal8, University of Western Ontario9, Wageningen University and Research Centre10, University of Toronto11, Tufts University12, French Institute of Health and Medical Research13, University of Copenhagen14, Copenhagen University Hospital15, Pasteur Institute16, University of Helsinki17, Hacettepe University18, University of Milan19
TL;DR: In this paper, a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, and challenges in defining, quantifying, and assessing the atherogenic properties of remnant particles.
Abstract: Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.
University of Toronto1, University of California, San Francisco2, Université de Montréal3, University of North Carolina at Chapel Hill4, Medical College of Wisconsin5, Oregon Health & Science University6, University of Utah7, Harvard University8, Washington University in St. Louis9, St. Michael's GAA, Sligo10, Phillips University11, Georgia Regents University12, Cincinnati Children's Hospital Medical Center13, Oslo University Hospital14, Yale University15, Mayo Clinic16, Odense University Hospital17, University of California, Los Angeles18, University of Arkansas for Medical Sciences19, Tel Aviv University20, University of Edinburgh21, Utrecht University22, Toronto Western Hospital23, University of Colorado Hospital24, University of Bari25, Hospital Italiano de Buenos Aires26, Hammersmith Hospital27, Royal Melbourne Hospital28
TL;DR: The expert panel generated and approved 6 new recommendations that highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery.
Abstract: Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.
TL;DR: In this article, the first and second observing runs of the Advanced LIGO and Virgo detector network were used to obtain the first standard-siren measurement of the Hubble constant (H 0).
Abstract: This paper presents the gravitational-wave measurement of the Hubble constant (H 0) using the detections from the first and second observing runs of the Advanced LIGO and Virgo detector network. The presence of the transient electromagnetic counterpart of the binary neutron star GW170817 led to the first standard-siren measurement of H 0. Here we additionally use binary black hole detections in conjunction with galaxy catalogs and report a joint measurement. Our updated measurement is H 0 = km s−1 Mpc−1 (68.3% of the highest density posterior interval with a flat-in-log prior) which is an improvement by a factor of 1.04 (about 4%) over the GW170817-only value of km s−1 Mpc−1. A significant additional contribution currently comes from GW170814, a loud and well-localized detection from a part of the sky thoroughly covered by the Dark Energy Survey. With numerous detections anticipated over the upcoming years, an exhaustive understanding of other systematic effects are also going to become increasingly important. These results establish the path to cosmology using gravitational-wave observations with and without transient electromagnetic counterparts.
Université de Montréal1, McMaster University2, University of Waterloo3, Canadian Blood Services4, University of Ottawa5, Ottawa Hospital Research Institute6, Gulf Coast Regional Blood Center7, Héma-Québec8, Cornell University9, Sunnybrook Health Sciences Centre10, University of British Columbia11, Laval University12, University of Calgary13, University of Toronto14, New York Blood Center15, Mount Sinai Hospital, Toronto16, Public Health Agency of Canada17, University of Manitoba18
TL;DR: In this paper, the authors conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ).
Abstract: The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
TL;DR: An epidemic-induced telework adjustment model derived from the theory of Work Adjustment and the Interactional Model of Individual Adjustment is developed and tested on a sample of 1574 teleworkers in France, demonstrating the superiority of the influence of crisis-specific variables that are professional isolation, telework environment, work increase and stress.
Abstract: The covid-19 pandemic crisis presents unprecedented challenges and has profound implications for the way people live and work. Information and communication technologies have been playing a crucial...
TL;DR: In this article, a two-sample Mendelian randomization (MR) study was conducted to identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding.
Abstract: To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.
University of Pennsylvania1, Royal Melbourne Hospital2, Medical University of Vienna3, University of Kansas4, Oslo University Hospital5, Emory University6, Ohio State University7, University of Chicago8, University of California, San Francisco9, McMaster University10, University of Texas MD Anderson Cancer Center11, Université de Montréal12, Royal Prince Alfred Hospital13, Karolinska Institutet14, University of Würzburg15, Hokkaido University16, University of Minnesota17, NewYork–Presbyterian Hospital18, University of Amsterdam19, University of Michigan20, Johns Hopkins University21, Kyushu University22, University of Milan23, Novartis24, Oregon Health & Science University25
TL;DR: Tisagenlecleucel showed durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas in the pivotal JULIET trial.
Abstract: Summary Background In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. Methods In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov , NCT02445248 , and is ongoing. Findings Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Interpretation Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Funding Novartis Pharmaceuticals.
Texas A&M University1, University of Exeter2, University of Helsinki3, Université du Québec à Montréal4, Tanjungpura University5, University of Hawaii at Manoa6, University of Bristol7, Bowdoin College8, Chulalongkorn University9, University of California, Los Angeles10, Max Planck Society11, University of Nottingham12, University of Magallanes13, Oeschger Centre for Climate Change Research14, Université de Montréal15, Lehigh University16, Northeast Normal University17, Mount Holyoke College18, McGill University19, Stockholm University20, University of Leicester21, Katholieke Universiteit Leuven22, University of St Andrews23, Florida State University24, Aarhus University25, University of Toronto26, University of New Hampshire27, University of Łódź28, Centre national de la recherche scientifique29, Cranfield University30, University of Alberta31, Stockholm Environment Institute32, Lawrence Berkeley National Laboratory33, United States Geological Survey34, Texas A&M University at Galveston35, University of Victoria36, Adam Mickiewicz University in Poznań37, Finnish Meteorological Institute38, Royal Holloway, University of London39, University of Queensland40, Lamont–Doherty Earth Observatory41, National Park Service42, University of York43, Hope College44, University of Reading45, Uva Wellassa University46, Queen's University Belfast47, University of California, Berkeley48, Memorial University of Newfoundland49
TL;DR: In this article, the authors define and quantify the leading drivers of change that have impacted peatland carbon stocks during the Holocene and predict their effect during this century and in the far future.
Abstract: The carbon balance of peatlands is predicted to shift from a sink to a source this century. However, peatland ecosystems are still omitted from the main Earth system models that are used for future climate change projections, and they are not considered in integrated assessment models that are used in impact and mitigation studies. By using evidence synthesized from the literature and an expert elicitation, we define and quantify the leading drivers of change that have impacted peatland carbon stocks during the Holocene and predict their effect during this century and in the far future. We also identify uncertainties and knowledge gaps in the scientific community and provide insight towards better integration of peatlands into modelling frameworks. Given the importance of the contribution by peatlands to the global carbon cycle, this study shows that peatland science is a critical research area and that we still have a long way to go to fully understand the peatland–carbon–climate nexus. Peatlands are impacted by climate and land-use changes, with feedback to warming by acting as either sources or sinks of carbon. Expert elicitation combined with literature review reveals key drivers of change that alter peatland carbon dynamics, with implications for improving models.