Showing papers by "McGill University published in 2019"
University of Bristol1, University Hospitals Bristol NHS Foundation Trust2, Monash University3, French Institute of Health and Medical Research4, Paris Descartes University5, Cochrane Collaboration6, St George's, University of London7, University of York8, Queen Mary University of London9, Clinical Trial Service Unit10, Harvard University11, University of Oxford12, University of Southern Denmark13, Odense University Hospital14, University of Alberta15, University of Toronto16, University of Manchester17, Johns Hopkins University18, McGill University19, University College London20
TL;DR: The Cochrane risk-of-bias tool has been updated to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Abstract: Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
9,228 citations
TL;DR: In this article, the Event Horizon Telescope was used to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87.
Abstract: When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 +/- 3 mu as, which is circular and encompasses a central depression in brightness with a flux ratio greater than or similar to 10: 1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M = (6.5 +/- 0.7) x 10(9) M-circle dot. Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.
2,589 citations
Harvard University1, University of Michigan2, PinnacleHealth System3, St. Luke's Hospital4, Spectrum Health5, Mount Sinai Hospital6, Scripps Research Institute7, University of Kansas8, Yale University9, Johns Hopkins University10, Alfred Hospital11, McGill University12, Saint Francis University13, University of Pittsburgh14, Mayo Clinic15, Medtronic plc16, Paradigm17
TL;DR: In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self‐expanding supraannular bioprosthesis was noninferior to surgery with respect to the composite end point of death or disabling stroke at 24 months.
Abstract: Background Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is know...
2,240 citations
Memorial Sloan Kettering Cancer Center1, Netherlands Cancer Institute2, Cleveland Clinic3, Institut Gustave Roussy4, University of Texas MD Anderson Cancer Center5, University of Glasgow6, University of British Columbia7, University of Lyon8, Osaka University9, University of Ulsan10, Russian Railways11, McGill University12, Medical University of Vienna13, The Royal Marsden NHS Foundation Trust14, Georgetown University15, University of Tübingen16, Pfizer17, Harvard University18
TL;DR: Progression‐free survival was significantly longer with avelumab plus axitinib than with sunit inib among patients who received these agents as first‐line treatment for advanced renal‐cell carcinoma.
Abstract: Background In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously...
1,597 citations
TL;DR: An overview of the main functional modules and the general workflow of MetaboAnalyst 4.0 is provided, followed by 12 detailed protocols: © 2019 by John Wiley & Sons, Inc.
Abstract: MetaboAnalyst (https://www.metaboanalyst.ca) is an easy-to-use web-based tool suite for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since its first release in 2009, MetaboAnalyst has evolved significantly to meet the ever-expanding bioinformatics demands from the rapidly growing metabolomics community. In addition to providing a variety of data processing and normalization procedures, MetaboAnalyst supports a wide array of functions for statistical, functional, as well as data visualization tasks. Some of the most widely used approaches include PCA (principal component analysis), PLS-DA (partial least squares discriminant analysis), clustering analysis and visualization, MSEA (metabolite set enrichment analysis), MetPA (metabolic pathway analysis), biomarker selection via ROC (receiver operating characteristic) curve analysis, as well as time series and power analysis. The current version of MetaboAnalyst (4.0) features a complete overhaul of the user interface and significantly expanded underlying knowledge bases (compound database, pathway libraries, and metabolite sets). Three new modules have been added to support pathway activity prediction directly from mass peaks, biomarker meta-analysis, and network-based multi-omics data integration. To enable more transparent and reproducible analysis of metabolomic data, we have released a companion R package (MetaboAnalystR) to complement the web-based application. This article provides an overview of the main functional modules and the general workflow of MetaboAnalyst 4.0, followed by 12 detailed protocols: © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Data uploading, processing, and normalization Basic Protocol 2: Identification of significant variables Basic Protocol 3: Multivariate exploratory data analysis Basic Protocol 4: Functional interpretation of metabolomic data Basic Protocol 5: Biomarker analysis based on receiver operating characteristic (ROC) curves Basic Protocol 6: Time-series and two-factor data analysis Basic Protocol 7: Sample size estimation and power analysis Basic Protocol 8: Joint pathway analysis Basic Protocol 9: MS peaks to pathway activities Basic Protocol 10: Biomarker meta-analysis Basic Protocol 11: Knowledge-based network exploration of multi-omics data Basic Protocol 12: MetaboAnalystR introduction.
1,522 citations
University of Auckland1, Deakin University2, Virginia Tech3, Commonwealth Scientific and Industrial Research Organisation4, Catholic University of Leuven5, Public Health Foundation of India6, Imperial College London7, Australian National University8, Washington University in St. Louis9, Brookings Institution10, University of Stirling11, University of London12, Harvard University13, University of Hertfordshire14, McGill University15, Drexel University16, Tehran University of Medical Sciences17, George Washington University18, Newcastle University19, Wellington Management Company20, Huazhong University of Science and Technology21, World Bank22, University of Cape Town23, University of Amsterdam24, University of Newcastle25
TL;DR: This work aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about concrete mechanical properties such as E-modulus and compressive strength.
1,480 citations
Griffith University1, University of Glasgow2, University of Pittsburgh3, Trinity College, Dublin4, University College London5, Public Health Foundation of India6, Heidelberg University7, Radboud University Nijmegen8, Universidade Federal do Rio Grande do Sul9, National University of Colombia10, University of California, San Francisco11, New York University12, McGill University13
TL;DR: The extent and consequences of oral diseases, their social and commercial determinants, and their ongoing neglect in global health policy are described to highlight the urgent need to address oral diseases among other NCDs as a global health priority.
1,349 citations
Mike A. Nalls1, Cornelis Blauwendraat1, Costanza L. Vallerga2, Karl Heilbron +245 more•Institutions (23)
TL;DR: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified.
Abstract: Summary Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).
1,152 citations
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
1,090 citations
TL;DR: An overview of the global impact and burden of frailty, the usefulness of the frailty concept in clinical practice, potential targets for frailty prevention, and directions that need to be explored in the future are provided.
1,075 citations
McGill University1, WWF-India2, University of Basel3, WWF-Canada4, The Nature Conservancy5, University of Nevada, Reno6, Delft University of Technology7, Konstanz University of Applied Sciences8, King's College London9, Umeå University10, Swedish University of Agricultural Sciences11, University of Washington12, Harvard University13, University of Wisconsin-Madison14, Michigan Technological University15, Conservation International16, Stanford University17, Free University of Berlin18, Leibniz Association19, University of Tübingen20
TL;DR: A comprehensive assessment of the world’s rivers and their connectivity shows that only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length.
Abstract: Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them. A comprehensive assessment of the world’s rivers and their connectivity shows that only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length.
TL;DR: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s as mentioned in this paper.
Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
TL;DR: The growing application of gene expression profiling demands powerful yet user-friendly bioinformatics tools to support systems-level data understanding and NetworkAnalyst was first released in 2014 to address the key need for interpreting gene expression data within the context of protein-protein interaction networks.
Abstract: The growing application of gene expression profiling demands powerful yet user-friendly bioinformatics tools to support systems-level data understanding. NetworkAnalyst was first released in 2014 to address the key need for interpreting gene expression data within the context of protein-protein interaction (PPI) networks. It was soon updated for gene expression meta-analysis with improved workflow and performance. Over the years, NetworkAnalyst has been continuously updated based on community feedback and technology progresses. Users can now perform gene expression profiling for 17 different species. In addition to generic PPI networks, users can now create cell-type or tissue specific PPI networks, gene regulatory networks, gene co-expression networks as well as networks for toxicogenomics and pharmacogenomics studies. The resulting networks can be customized and explored in 2D, 3D as well as Virtual Reality (VR) space. For meta-analysis, users can now visually compare multiple gene lists through interactive heatmaps, enrichment networks, Venn diagrams or chord diagrams. In addition, users have the option to create their own data analysis projects, which can be saved and resumed at a later time. These new features are released together as NetworkAnalyst 3.0, freely available at https://www.networkanalyst.ca.
Proceedings Article•
24 May 2019TL;DR: This paper introduces a novel class of off-policy algorithms, batch-constrained reinforcement learning, which restricts the action space in order to force the agent towards behaving close to on-policy with respect to a subset of the given data.
Abstract: Many practical applications of reinforcement learning constrain agents to learn from a fixed batch of data which has already been gathered, without offering further possibility for data collection. In this paper, we demonstrate that due to errors introduced by extrapolation, standard off-policy deep reinforcement learning algorithms, such as DQN and DDPG, are incapable of learning with data uncorrelated to the distribution under the current policy, making them ineffective for this fixed batch setting. We introduce a novel class of off-policy algorithms, batch-constrained reinforcement learning, which restricts the action space in order to force the agent towards behaving close to on-policy with respect to a subset of the given data. We present the first continuous control deep reinforcement learning algorithm which can learn effectively from arbitrary, fixed batch data, and empirically demonstrate the quality of its behavior in several tasks.
Carlos III Health Institute1, University of Cologne2, University of Sydney3, Paris Descartes University4, Universidade Federal de Ciências da Saúde de Porto Alegre5, Pontifícia Universidade Católica do Rio Grande do Sul6, Medical University of Graz7, University of California, San Diego8, University of Copenhagen9, Katholieke Universiteit Leuven10, University of Bologna11, University of the Witwatersrand12, RMIT University13, McGill University14, Hacettepe University15, University of Paris16, Utrecht University17, Mazandaran University of Medical Sciences18, Tel Aviv University19, Hospital General de México20, Istituto Giannina Gaslini21, Mahidol University22, Federal University of São Paulo23, King's College, Aberdeen24, Comenius University in Bratislava25, Boston Children's Hospital26, Complutense University of Madrid27, Hospital General Universitario Gregorio Marañón28, University Hospital Heidelberg29, University of California, Los Angeles30, American University of Beirut31, Innsbruck Medical University32, University of Lausanne33, Catholic University of Korea34, Goethe University Frankfurt35, Erasmus University Rotterdam36, National and Kapodistrian University of Athens37, Monash University38, Federal University of Rio de Janeiro39, Catholic University of the Sacred Heart40, University of Health Sciences Antigua41, National Institutes of Health42, Amrita Institute of Medical Sciences and Research Centre43, University of Pittsburgh44, Peter MacCallum Cancer Centre45, University of Melbourne46, P. D. Hinduja Hospital and Medical Research Centre47, University of Southern California48, Duke University49, Singapore General Hospital50, NewYork–Presbyterian Hospital51, Cardiff University52, University of Texas Health Science Center at San Antonio53, Children's Hospital of Philadelphia54, Post Graduate Institute of Medical Education and Research55
TL;DR: Management of mucormycosis depends on recognising disease patterns and on early diagnosis, and limited availability of contemporary treatments burdens patients in low and middle income settings.
Abstract: Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
TL;DR: In this article, a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by GRS was constructed and compared with the observed visibilities.
Abstract: The Event Horizon Telescope (EHT) has mapped the central compact radio source of the elliptical galaxy M87 at 1.3 mm with unprecedented angular resolution. Here we consider the physical implications of the asymmetric ring seen in the 2017 EHT data. To this end, we construct a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by general relativistic ray tracing. We compare the observed visibilities with this library and confirm that the asymmetric ring is consistent with earlier predictions of strong gravitational lensing of synchrotron emission from a hot plasma orbiting near the black hole event horizon. The ring radius and ring asymmetry depend on black hole mass and spin, respectively, and both are therefore expected to be stable when observed in future EHT campaigns. Overall, the observed image is consistent with expectations for the shadow of a spinning Kerr black hole as predicted by general relativity. If the black hole spin and M87's large scale jet are aligned, then the black hole spin vector is pointed away from Earth. Models in our library of non-spinning black holes are inconsistent with the observations as they do not produce sufficiently powerful jets. At the same time, in those models that produce a sufficiently powerful jet, the latter is powered by extraction of black hole spin energy through mechanisms akin to the Blandford-Znajek process. We briefly consider alternatives to a black hole for the central compact object. Analysis of existing EHT polarization data and data taken simultaneously at other wavelengths will soon enable new tests of the GRMHD models, as will future EHT campaigns at 230 and 345 GHz.
TL;DR: PHQ-9 sensitivity compared with semistructured diagnostic interviews was greater than in previous conventional meta-analyses that combined reference standards, and a cut-off score of 10 or above maximized combined sensitivity and specificity overall and for subgroups.
Abstract: Objective To determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression. Design Individual participant data meta-analysis. Data sources Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-February 2015). Inclusion criteria Eligible studies compared PHQ-9 scores with major depression diagnoses from validated diagnostic interviews. Primary study data and study level data extracted from primary reports were synthesized. For PHQ-9 cut-off scores 5-15, bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, among studies that used semistructured diagnostic interviews, which are designed for administration by clinicians; fully structured interviews, which are designed for lay administration; and the Mini International Neuropsychiatric (MINI) diagnostic interviews, a brief fully structured interview. Sensitivity and specificity were examined among participant subgroups and, separately, using meta-regression, considering all subgroup variables in a single model. Results Data were obtained for 58 of 72 eligible studies (total n=17 357; major depression cases n=2312). Combined sensitivity and specificity was maximized at a cut-off score of 10 or above among studies using a semistructured interview (29 studies, 6725 participants; sensitivity 0.88, 95% confidence interval 0.83 to 0.92; specificity 0.85, 0.82 to 0.88). Across cut-off scores 5-15, sensitivity with semistructured interviews was 5-22% higher than for fully structured interviews (MINI excluded; 14 studies, 7680 participants) and 2-15% higher than for the MINI (15 studies, 2952 participants). Specificity was similar across diagnostic interviews. The PHQ-9 seems to be similarly sensitive but may be less specific for younger patients than for older patients; a cut-off score of 10 or above can be used regardless of age.. Conclusions PHQ-9 sensitivity compared with semistructured diagnostic interviews was greater than in previous conventional meta-analyses that combined reference standards. A cut-off score of 10 or above maximized combined sensitivity and specificity overall and for subgroups. Registration PROSPERO CRD42014010673.
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson3 +191 more•Institutions (61)
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
Nasim Mavaddat1, Kyriaki Michailidou1, Kyriaki Michailidou2, Joe Dennis1 +307 more•Institutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
University College London1, Canadian Institute for Advanced Research2, Université de Montréal3, University of Oxford4, Stanford University5, Imperial College London6, University of Bristol7, University of Bern8, Google9, University of Toronto10, Cold Spring Harbor Laboratory11, Columbia University12, University of Ottawa13, McGill University14, Foundation for Research & Technology – Hellas15, Netherlands Institute for Neuroscience16, University of Zurich17, University of Pennsylvania18, Friedrich Miescher Institute for Biomedical Research19, York University20
TL;DR: It is argued that a deep network is best understood in terms of components used to design it—objective functions, architecture and learning rules—rather than unit-by-unit computation.
Abstract: Systems neuroscience seeks explanations for how the brain implements a wide variety of perceptual, cognitive and motor tasks. Conversely, artificial intelligence attempts to design computational systems based on the tasks they will have to solve. In artificial neural networks, the three components specified by design are the objective functions, the learning rules and the architectures. With the growing success of deep learning, which utilizes brain-inspired architectures, these three designed components have increasingly become central to how we model, engineer and optimize complex artificial learning systems. Here we argue that a greater focus on these components would also benefit systems neuroscience. We give examples of how this optimization-based framework can drive theoretical and experimental progress in neuroscience. We contend that this principled perspective on systems neuroscience will help to generate more rapid progress.
TL;DR: This work advocates change towards individually tailored interventions that preserve an individual's independence, physical function, and cognition by promoting the recognition of frailty, furthering advancements in evidence-based treatment options, and identifying cost-effective care delivery strategies.
International Agency for Research on Cancer1, University of Leicester2, Karolinska Institutet3, Cancer Institute of New South Wales4, Cancer Council Victoria5, Alberta Health Services6, St. John's University7, Nova Scotia Health Authority8, Cancer Care Ontario9, McGill University10, Public Health England11, Queen's University Belfast12, Cardiff University13, Canadian Partnership Against Cancer14, The Royal Marsden NHS Foundation Trust15, University of Oxford16, King's College London17
TL;DR: Progress in cancer control over the study period was evident for stomach, colon, lung (in males), and ovarian cancer, and the impact of comorbidity are likely the main determinants of patient outcomes.
Abstract: Summary Background Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.
McGill University1, University of Oxford2, Innsbruck Medical University3, Mayo Clinic4, University of Marburg5, University of Paris6, Vita-Salute San Raffaele University7, University of Cagliari8, University of Bologna9, University of Montpellier10, University of Genoa11, University of Göttingen12, Harvard University13, First Faculty of Medicine, Charles University in Prague14, Seoul National University Hospital15, Charité16, French Institute of Health and Medical Research17, University of Sydney18, Brigham and Women's Hospital19, Université du Québec à Montréal20
TL;DR: In a prospective multicentre study involving 1280 patients with idiopathic RBD, Postuma et al. test the predictive power of 21 prodromal markers of neurodegeneration, providing a template for planning neuroprotective trials.
Abstract: Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
Katholieke Universiteit Leuven1, University of Pisa2, University of California, San Francisco3, McGill University4, Tufts University5, VU University Medical Center6, University of Sydney7, Children's Hospital at Westmead8, Federal University of São Paulo9, Vita-Salute San Raffaele University10, Columbia University11
TL;DR: There is a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health, and what is plausible regarding the health effects of vitamin D.
Abstract: The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
University of Wisconsin-Madison1, Philippines National Collegiate Athletic Association2, Western University of Health Sciences3, George Washington University4, International Olympic Committee5, University of São Paulo6, McGill University7, Stanford University8, University of Portsmouth9, University of Amsterdam10, University of Arizona11, Chung-Ang University12, University of Maryland, Baltimore13, McMaster University14, Kocaeli University15, Rutgers University16, Princeton University17, Vanderbilt University Medical Center18, University of Nebraska–Lincoln19, Stellenbosch University20
TL;DR: To advance a more standardised, evidence based approach to mental health symptoms and disorders in elite athletes, an International Olympic Committee Consensus Work Group critically evaluated the current state of science and provided recommendations.
Abstract: Mental health symptoms and disorders are common among elite athletes, may have sport related manifestations within this population and impair performance. Mental health cannot be separated from physical health, as evidenced by mental health symptoms and disorders increasing the risk of physical injury and delaying subsequent recovery. There are no evidence or consensus based guidelines for diagnosis and management of mental health symptoms and disorders in elite athletes. Diagnosis must differentiate character traits particular to elite athletes from psychosocial maladaptations.Management strategies should address all contributors to mental health symptoms and consider biopsychosocial factors relevant to athletes to maximise benefit and minimise harm. Management must involve both treatment of affected individual athletes and optimising environments in which all elite athletes train and compete. To advance a more standardised, evidence based approach to mental health symptoms and disorders in elite athletes, an International Olympic Committee Consensus Work Group critically evaluated the current state of science and provided recommendations.
TL;DR: It is shown that steeping a single plastic teabag at brewing temperature (95 °C) releases approximately 11.6 billion microplastics and 3.1 billion nanoplastics into a single cup of the beverage.
Abstract: The increasing presence of micro- and nano-sized plastics in the environment and food chain is of growing concern. Although mindful consumers are promoting the reduction of single-use plastics, some manufacturers are creating new plastic packaging to replace traditional paper uses, such as plastic teabags. The objective of this study was to determine whether plastic teabags could release microplastics and/or nanoplastics during a typical steeping process. We show that steeping a single plastic teabag at brewing temperature (95 °C) releases approximately 11.6 billion microplastics and 3.1 billion nanoplastics into a single cup of the beverage. The composition of the released particles is matched to the original teabags (nylon and polyethylene terephthalate) using Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The levels of nylon and polyethylene terephthalate particles released from the teabag packaging are several orders of magnitude higher than plastic loads pr...
TL;DR: Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide and can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Abstract: Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Günter Blöschl1, Marc F. P. Bierkens2, António Chambel3, Christophe Cudennec4 +209 more•Institutions (124)
TL;DR: In this article, a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts is described. But despite the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work.
Abstract: This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come.
McGill University1, University of Bristol2, University of Queensland3, Garvan Institute of Medical Research4, Imperial College London5, New York University6, McGill University Health Centre7, Erasmus University Rotterdam8, University of Rochester9, Anschutz Medical Campus10, University of Cambridge11, University Hospital Southampton NHS Foundation Trust12, University of Southampton13, University of Oxford14, University of Ioannina15, Brown University16, University of Gothenburg17, Children's Mercy Hospital18, Wellcome Trust Sanger Institute19
TL;DR: This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
Abstract: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
TL;DR: Although individual-level risk remains moderate to low and results from this study should be confirmed in future adequately powered prospective studies, the high prevalence of adolescents consuming cannabis generates a large number of young people who could develop depression and suicidality attributable to cannabis.
Abstract: Importance Cannabis is the most commonly used drug of abuse by adolescents in the world. While the impact of adolescent cannabis use on the development of psychosis has been investigated in depth, little is known about the impact of cannabis use on mood and suicidality in young adulthood. Objective To provide a summary estimate of the extent to which cannabis use during adolescence is associated with the risk of developing subsequent major depression, anxiety, and suicidal behavior. Data Sources Medline, Embase, CINAHL, PsycInfo, and Proquest Dissertations and Theses were searched from inception to January 2017. Study Selection Longitudinal and prospective studies, assessing cannabis use in adolescents younger than 18 years (at least 1 assessment point) and then ascertaining development of depression in young adulthood (age 18 to 32 years) were selected, and odds ratios (OR) adjusted for the presence of baseline depression and/or anxiety and/or suicidality were extracted. Data Extraction and Synthesis Study quality was assessed using the Research Triangle Institute item bank on risk of bias and precision of observational studies. Two reviewers conducted all review stages independently. Selected data were pooled using random-effects meta-analysis. Main Outcomes and Measures The studies assessing cannabis use and depression at different points from adolescence to young adulthood and reporting the corresponding OR were included. In the studies selected, depression was diagnosed according to the third or fourth editions ofDiagnostic and Statistical Manual of Mental Disordersor by using scales with predetermined cutoff points. Results After screening 3142 articles, 269 articles were selected for full-text review, 35 were selected for further review, and 11 studies comprising 23 317 individuals were included in the quantitative analysis. The OR of developing depression for cannabis users in young adulthood compared with nonusers was 1.37 (95% CI, 1.16-1.62;I2 = 0%). The pooled OR for anxiety was not statistically significant: 1.18 (95% CI, 0.84-1.67;I2 = 42%). The pooled OR for suicidal ideation was 1.50 (95% CI, 1.11-2.03;I2 = 0%), and for suicidal attempt was 3.46 (95% CI, 1.53-7.84,I2 = 61.3%). Conclusions and Relevance Although individual-level risk remains moderate to low and results from this study should be confirmed in future adequately powered prospective studies, the high prevalence of adolescents consuming cannabis generates a large number of young people who could develop depression and suicidality attributable to cannabis. This is an important public health problem and concern, which should be properly addressed by health care policy.