Showing papers by "University of Copenhagen published in 2020"
TL;DR: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates, and there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries.
5,802 citations
Book•
23 Feb 2020
TL;DR: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper, where a brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.
Abstract: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.
3,111 citations
Christopher J L Murray1, Christopher J L Murray2, Christopher J L Murray3, Aleksandr Y. Aravkin2 +2269 more•Institutions (286)
TL;DR: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure.
3,059 citations
TL;DR: Research evaluating the direct neuropsychiatric consequences and the indirect effects on mental health is highly needed to improve treatment, mental health care planning and for preventive measures during potential subsequent pandemics.
Abstract: Background
During the COVID-19 pandemic general medical complications have received the most attention, whereas only few studies address the potential direct effect on mental health of SARS-CoV-2 and the neurotropic potential. Furthermore, the indirect effects of the pandemic on general mental health are of increasing concern, particularly since the SARS-CoV-1 epidemic (2002–2003) was associated with psychiatric complications.
2,018 citations
University of Bristol1, University of British Columbia2, World Health Organization3, University of Toronto4, Carlos III Health Institute5, University of Pittsburgh6, Université Paris-Saclay7, French Institute of Health and Medical Research8, François Rabelais University9, Peking Union Medical College Hospital10, University of Oxford11, University College London12, Imperial College London13, University of Copenhagen14, Monash University15, University Hospitals Bristol NHS Foundation Trust16, Nottingham University Hospitals NHS Trust17, Federal University of São Paulo18, Auckland City Hospital19, University of São Paulo20
TL;DR: A prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19 found that low-dose dexamethasone reduced mortality in hospitalized patients with Cohen's disease who required respiratory support.
Abstract: Importance Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using theI2statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. Exposures Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82];P Conclusions and Relevance In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
1,764 citations
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
University of Sydney1, University of Michigan2, Duke University3, University of Alabama at Birmingham4, University of Pittsburgh5, University of Florida6, Centers for Disease Control and Prevention7, University of Münster8, University of Udine9, Ankara University10, University of Wisconsin-Madison11, Paris Diderot University12, University of Arkansas for Medical Sciences13, University of Paris14, University of Lausanne15, Brown University16, Istituto Giannina Gaslini17, Carlos III Health Institute18, Uniformed Services University of the Health Sciences19, National Institutes of Health20, University of Pennsylvania21, St George's, University of London22, Heidelberg University23, University of Copenhagen24, University College London25, University of Texas MD Anderson Cancer Center26, Katholieke Universiteit Leuven27, Goethe University Frankfurt28, University of Würzburg29, Johns Hopkins University30, Monash University31, Federal University of Rio de Janeiro32, Catholic University of the Sacred Heart33, University of Texas Health Science Center at San Antonio34, Masaryk University35, RMIT University36, Radboud University Nijmegen37, University of Melbourne38, Stanford University39, University of California, Davis40, Georgia Regents University41, Cornell University42, University of Aberdeen43, University Hospital of Wales44
TL;DR: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.
Abstract: BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.
1,211 citations
Leicester General Hospital1, University of Leicester2, Duke University3, National Institutes of Health4, Yale University5, Katholieke Universiteit Leuven6, King's College London7, The Catholic University of America8, University of Copenhagen9, Steno Diabetes Center10, Harvard University11, University of North Carolina at Chapel Hill12
TL;DR: A panel to update the prior position statements on the management of type 2 diabetes in adults includes additional focus on lifestyle management and diabetes self-management education and support and efforts targeting weight loss.
Abstract: The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium–glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.
1,192 citations
F. Kyle Satterstrom1, F. Kyle Satterstrom2, Jack A. Kosmicki, Jiebiao Wang3 +198 more•Institutions (53)
TL;DR: The largest exome sequencing study of autism spectrum disorder (ASD) to date, using an enhanced analytical framework to integrate de novo and case-control rare variation, identifies 102 risk genes at a false discovery rate of 0.1 or less, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
1,169 citations
Technical University of Denmark1, University of Paris2, University of Washington3, Free University of Berlin4, Paris Descartes University5, Novo Nordisk Foundation6, Robert Koch Institute7, Federal Institute for Risk Assessment8, University of Antwerp9, Hvidovre Hospital10, University of Copenhagen11, Animal and Plant Health Agency12, ANSES13
TL;DR: WGS-based AST using ResFinder 4.0 provides in silico antibiograms as reliable as those obtained by phenotypic AST at least for the bacterial species/antimicrobial agents of major public health relevance considered.
Abstract: WGS-based antimicrobial susceptibility testing (AST) is as reliable as phenotypic AST for several antimicrobial/bacterial species combinations. However, routine use of WGS-based AST is hindered by the need for bioinformatics skills and knowledge of antimicrobial resistance (AMR) determinants to operate the vast majority of tools developed to date. By leveraging on ResFinder and PointFinder, two freely accessible tools that can also assist users without bioinformatics skills, we aimed at increasing their speed and providing an easily interpretable antibiogram as output.
1,155 citations
National Institutes of Health1, Delft University of Technology2, Humboldt University of Berlin3, DuPont4, Laval University5, University of Alicante6, University of Copenhagen7, Vilnius University8, University of Georgia9, University of St Andrews10, Bangor University11, University of Toronto12, University of Freiburg13, Wageningen University and Research Centre14, North Carolina State University15
TL;DR: An updated evolutionary classification of CRISPR–Cas systems and cas genes is provided, with an emphasis on the major developments that have occurred since the publication of the latest classification, in 2015, which includes 2 classes, 6 types and 33 subtypes.
Abstract: The number and diversity of known CRISPR-Cas systems have substantially increased in recent years. Here, we provide an updated evolutionary classification of CRISPR-Cas systems and cas genes, with an emphasis on the major developments that have occurred since the publication of the latest classification, in 2015. The new classification includes 2 classes, 6 types and 33 subtypes, compared with 5 types and 16 subtypes in 2015. A key development is the ongoing discovery of multiple, novel class 2 CRISPR-Cas systems, which now include 3 types and 17 subtypes. A second major novelty is the discovery of numerous derived CRISPR-Cas variants, often associated with mobile genetic elements that lack the nucleases required for interference. Some of these variants are involved in RNA-guided transposition, whereas others are predicted to perform functions distinct from adaptive immunity that remain to be characterized experimentally. The third highlight is the discovery of numerous families of ancillary CRISPR-linked genes, often implicated in signal transduction. Together, these findings substantially clarify the functional diversity and evolutionary history of CRISPR-Cas.
Hospital General Universitario Gregorio Marañón1, King's College London2, South London and Maudsley NHS Foundation Trust3, Seconda Università degli Studi di Napoli4, University of Copenhagen5, Pontifical Catholic University of Chile6, University of South Florida7, Royal College of Surgeons in Ireland8, Charité9, Hofstra University10, RMIT University11, Yale University12, University of Birmingham13, University of Hong Kong14, University of Paris15, University College London16, Nanyang Technological University17, Columbia University18, University of Antioquia19, Katholieke Universiteit Leuven20, Shanghai Jiao Tong University21, Keio University22, University of Barcelona23, University of Brescia24
TL;DR: The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery.
University of the Basque Country1, Ikerbasque2, Carlos III Health Institute3, University of Salamanca4, University of Manchester5, National Health Service6, Imperial College London7, Mayo Clinic8, Sapienza University of Rome9, University of Copenhagen10, University of Glasgow11, University of Regensburg12, University of Padua13, Yale University14, University of Edinburgh15, University of Minnesota16, Marche Polytechnic University17, University of Rennes18, University of Paris19, University of Florence20, University of Milano-Bicocca21, University of Zurich22, Erasmus University Rotterdam23, University of Barcelona24
TL;DR: This expert Consensus Statement, endorsed by the ENS-CCA, summarizes the latest advances in CCA, including classification, genetics and treatment, and provides recommendations for CCA management and priorities across basic, translational and clinical research.
Abstract: Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted
TL;DR: The extent of the trait data compiled in TRY is evaluated and emerging patterns of data coverage and representativeness are analyzed to conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements.
Abstract: Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
Joan B. Soriano1, Parkes J Kendrick2, Katherine R. Paulson2, Vinay Gupta2 +311 more•Institutions (178)
TL;DR: It is shown that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.
TL;DR: A model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2 is suggested, in which Manipulation of hepara sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.
TL;DR: The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe, and is detailed in this paper.
Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.
Sahlgrenska University Hospital1, National Institutes of Health2, University of Paris3, Children's Hospital Oakland Research Institute4, University of Glasgow5, Aarhus University6, Centro Nacional de Investigaciones Cardiovasculares7, Medical University of Vienna8, University of Amsterdam9, University of California, Los Angeles10, University of Western Ontario11, Monash University12, University of Copenhagen13, Royal Perth Hospital14, University of Western Australia15, French Institute of Health and Medical Research16, Oregon Health & Science University17, University of Bristol18, University of Cambridge19, Trinity College, Dublin20, University of Texas Southwestern Medical Center21, Charité22, Utrecht University23, University of the Witwatersrand24, Imperial College London25, Technische Universität München26, University of Helsinki27, University of Groningen28, Hacettepe University29, University of Milan30, Columbia University31
TL;DR: In this paper, the authors proposed a method to solve the problem of the problem: this paper ] of "uniformity" of the distribution of data points in the data set.
Abstract: Abstract
TL;DR: The future of public health is likely to become increasingly digital, and the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases is reviewed.
Abstract: Digital technologies are being harnessed to support the public-health response to COVID-19 worldwide, including population surveillance, case identification, contact tracing and evaluation of interventions on the basis of mobility data and communication with the public. These rapid responses leverage billions of mobile phones, large online datasets, connected devices, relatively low-cost computing resources and advances in machine learning and natural language processing. This Review aims to capture the breadth of digital innovations for the public-health response to COVID-19 worldwide and their limitations, and barriers to their implementation, including legal, ethical and privacy barriers, as well as organizational and workforce barriers. The future of public health is likely to become increasingly digital, and we review the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases.
Posted Content•
TL;DR: This paper is the first survey of over 150 studies of the popular BERT model, reviewing the current state of knowledge about how BERT works, what kind of information it learns and how it is represented, common modifications to its training objectives and architecture, the overparameterization issue, and approaches to compression.
Abstract: Transformer-based models have pushed state of the art in many areas of NLP, but our understanding of what is behind their success is still limited. This paper is the first survey of over 150 studies of the popular BERT model. We review the current state of knowledge about how BERT works, what kind of information it learns and how it is represented, common modifications to its training objectives and architecture, the overparameterization issue and approaches to compression. We then outline directions for future research.
National Institutes of Health1, Wellcome Trust Sanger Institute2, Rockefeller University3, University of California, Davis4, European Bioinformatics Institute5, Seoul National University6, Max Planck Society7, Durham University8, University of Massachusetts Amherst9, University of Adelaide10, University of Missouri11, East Carolina University12, University of Queensland13, Queen Mary University of London14, Wellington Management Company15, University of Arizona16, Natural History Museum17, Bangor University18, University of Konstanz19, Northeastern University20, Naturalis21, University of Graz22, Florida Museum of Natural History23, University of California, Santa Cruz24, Pacific Biosciences25, University of Maryland, College Park26, Harbin Institute of Technology27, University of Chicago28, Oregon Health & Science University29, Monash University Malaysia Campus30, University of Milan31, University of Copenhagen32, Pennsylvania State University33, University of Los Andes34, Agency for Science, Technology and Research35, Royal Ontario Museum36, Smithsonian Conservation Biology Institute37, University of East Anglia38, Pompeu Fabra University39, University College Dublin40, University of Illinois at Urbana–Champaign41, La Trobe University42, University of California, San Diego43, UPRRP College of Natural Sciences44, Dresden University of Technology45
TL;DR: The Vertebrate Genomes Project is embarked on, an effort to generate high-quality, complete reference genomes for all ~70,000 extant vertebrate species and help enable a new era of discovery across the life sciences.
Abstract: High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are only available for a few non-microbial species. To address this issue, the international Genome 10K (G10K) consortium has worked over a five-year period to evaluate and develop cost-effective methods for assembling the most accurate and complete reference genomes to date. Here we summarize these developments, introduce a set of quality standards, and present lessons learned from sequencing and assembling 16 species representing major vertebrate lineages (mammals, birds, reptiles, amphibians, teleost fishes and cartilaginous fishes). We confirm that long-read sequencing technologies are essential for maximizing genome quality and that unresolved complex repeats and haplotype heterozygosity are major sources of error in assemblies. Our new assemblies identify and correct substantial errors in some of the best historical reference genomes. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an effort to generate high-quality, complete reference genomes for all ~70,000 extant vertebrate species and help enable a new era of discovery across the life sciences.
Humanitas University1, University College Dublin2, Autonomous University of Madrid3, Cambridge University Hospitals NHS Foundation Trust4, Winterthur Museum, Garden and Library5, University of Basel6, Catholic University of the Sacred Heart7, Aarhus University Hospital8, University of Copenhagen9, Royal Liverpool University Hospital10, Aalborg University11, Mater Dei Hospital12, University of Bologna13, Barts Health NHS Trust14, Comenius University in Bratislava15, Sheba Medical Center16, University of Porto17, McMaster University18, Linköping University19, Seconda Università degli Studi di Napoli20, Katholieke Universiteit Leuven21, University of Padua22, Maastricht University Medical Centre23, Beaujon Hospital24, University of Zurich25, Imperial College London26
TL;DR: The present article addresses surgical management, including preoperative aspects and drug management before surgery, and provides technical advice for a variety of common clinical situations.
Abstract: This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines.
University of Texas MD Anderson Cancer Center1, Harvard University2, Stanford University3, University of Washington4, University of Copenhagen5, German Cancer Research Center6, Heidelberg University7, Nemours Foundation8, Vanderbilt University Medical Center9, University of California, Los Angeles10, University of Southern California11, Université Paris-Saclay12, University Hospitals of Cleveland13, St. Jude Children's Research Hospital14, Paris Descartes University15, University of Chicago16, Thomas Jefferson University17, Memorial Sloan Kettering Cancer Center18, Seattle Children's19, Bayer HealthCare Pharmaceuticals20, University of Texas Southwestern Medical Center21, Cornell University22
TL;DR: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active and indicate that long-term administration of larot rectinib are feasible.
Abstract: Summary Background The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. Methods Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov , NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). Findings Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72–85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [ Interpretation These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. Funding Bayer and Loxo Oncology.
TL;DR: Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.
Abstract: A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1-7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
TL;DR: Two bioinformatic tools enable sequence similarity network and phylogenetic analysis of gene clusters and their families across hundreds of strains and in large datasets, leading to the discovery of new natural products.
Abstract: Genome mining has become a key technology to exploit natural product diversity. Although initially performed on a single-genome basis, the process is now being scaled up to mine entire genera, strain collections and microbiomes. However, no bioinformatic framework is currently available for effectively analyzing datasets of this size and complexity. In the present study, a streamlined computational workflow is provided, consisting of two new software tools: the ‘biosynthetic gene similarity clustering and prospecting engine’ (BiG-SCAPE), which facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families; and the ‘core analysis of syntenic orthologues to prioritize natural product gene clusters’ (CORASON), which elucidates phylogenetic relationships within and across these families. BiG-SCAPE is validated by correlating its output to metabolomic data across 363 actinobacterial strains and the discovery potential of CORASON is demonstrated by comprehensively mapping biosynthetic diversity across a range of detoxin/rimosamide-related gene cluster families, culminating in the characterization of seven detoxin analogues. Two bioinformatic tools, BiG-SCAPE and CORASON, enable sequence similarity network and phylogenetic analysis of gene clusters and their families across hundreds of strains and in large datasets, leading to the discovery of new natural products.
TL;DR: The latest findings from methodologies for profiling and testing transcriptional regulatory elements at scale are discussed, and how the data support an updated, nuanced model that accounts for the numerous overlapping molecular properties of promoters and enhancers are explained.
Abstract: The proper activities of enhancers and gene promoters are essential for coordinated transcription within a cell. Although diverse methodologies have been developed to identify enhancers and promoters, most have tacitly assumed that these elements are distinct. However, studies have unexpectedly shown that regulatory elements may have both enhancer and promoter functions. Here we review these results, focusing on the factors that determine the promoter and/or enhancer activity of regulatory elements. We discuss emerging models that define regulatory elements by accessible DNA and their non-mutually-exclusive abilities to drive transcription initiation (promoter activity) and/or to enhance transcription at other such regions (enhancer activity).
McMaster University1, University of Pennsylvania2, University of Adelaide3, University of Copenhagen4, Population Health Research Institute5, University of Miyazaki6, University of Queensland7, University of Birmingham8, University of Toronto9, University of Calgary10, University of British Columbia11, University of Brescia12, University of Western Ontario13, Charles University in Prague14, Kyoto Prefectural University of Medicine15, Kyoto University16, Imperial College London17, University of Cambridge18
TL;DR: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD, and a reduced-dose regimen of glucocorticoids was noninferior to a standard- dose regimen with respect to death orESKD.
Abstract: Background More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Methods We conducted a randomized trial with a 2-by-2 factor...
TL;DR: This review discusses how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease, and how the compartmentalized pH microenvironment favors cancer development.
Abstract: Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
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Federal University of Paraíba1, University of North Carolina at Chapel Hill2, University of Bonn3, Merck & Co.4, University of Gothenburg5, University of New Mexico6, University of Copenhagen7, Moscow State University8, University of Strasbourg9, University of Florida10, Duke University11, North Carolina State University12, University of California, Los Angeles13, University of Toronto14, Novartis15, University of British Columbia16
TL;DR: This Perspective summarizes recent technological advances in QSAR modeling but it also highlights the applicability of algorithms, modeling methods, and validation practices developed inQSAR to a wide range of research areas outside of traditional QSar boundaries including synthesis planning, nanotechnology, materials science, biomaterials, and clinical informatics.
Abstract: Prediction of chemical bioactivity and physical properties has been one of the most important applications of statistical and more recently, machine learning and artificial intelligence methods in chemical sciences. This field of research, broadly known as quantitative structure–activity relationships (QSAR) modeling, has developed many important algorithms and has found a broad range of applications in physical organic and medicinal chemistry in the past 55+ years. This Perspective summarizes recent technological advances in QSAR modeling but it also highlights the applicability of algorithms, modeling methods, and validation practices developed in QSAR to a wide range of research areas outside of traditional QSAR boundaries including synthesis planning, nanotechnology, materials science, biomaterials, and clinical informatics. As modern research methods generate rapidly increasing amounts of data, the knowledge of robust data-driven modelling methods professed within the QSAR field can become essential for scientists working both within and outside of chemical research. We hope that this contribution highlighting the generalizable components of QSAR modeling will serve to address this challenge.
TL;DR: This work predicts that use of (single-cell) transcriptomics, genetic screens, genetic engineering of cellular glycosylation capacities and custom design of glycoprotein therapeutics are advancements that will ignite wider integration of gly cosylation in general cell biology.
Abstract: Glycosylation is the most abundant and diverse form of post-translational modification of proteins that is common to all eukaryotic cells. Enzymatic glycosylation of proteins involves a complex metabolic network and different types of glycosylation pathways that orchestrate enormous amplification of the proteome in producing diversity of proteoforms and its biological functions. The tremendous structural diversity of glycans attached to proteins poses analytical challenges that limit exploration of specific functions of glycosylation. Major advances in quantitative transcriptomics, proteomics and nuclease-based gene editing are now opening new global ways to explore protein glycosylation through analysing and targeting enzymes involved in glycosylation processes. In silico models predicting cellular glycosylation capacities and glycosylation outcomes are emerging, and refined maps of the glycosylation pathways facilitate genetic approaches to address functions of the vast glycoproteome. These approaches apply commonly available cell biology tools, and we predict that use of (single-cell) transcriptomics, genetic screens, genetic engineering of cellular glycosylation capacities and custom design of glycoprotein therapeutics are advancements that will ignite wider integration of glycosylation in general cell biology.