Showing papers by "University of Texas Health Science Center at Houston published in 2020"
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NewYork–Presbyterian Hospital1, University of Insubria2, University of Texas Health Science Center at Houston3, Chinese PLA General Hospital4, University of Vermont Medical Center5, Harvard University6, Beth Israel Deaconess Medical Center7, Loyola University Medical Center8, University of Chicago9, University of Milan10, Auckland City Hospital11, St Thomas' Hospital12, Hofstra University13, University of Michigan14, Population Health Research Institute15, Hamilton Health Sciences16, Ottawa Hospital Research Institute17, Brigham and Women's Hospital18, Vanderbilt University19, Universidad Católica San Antonio de Murcia20, University of Mainz21, McMaster University22, University of Liverpool23, Aalborg University24
TL;DR: The current understanding of the pathogenesis, epidemiology, management and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, and of those with preexistingThrombotic disease who develop CO VID-19 are reviewed.
2,222 citations
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Emory University1, United States Public Health Service2, Rutgers University3, Harvard University4, Central Michigan University5, Westchester Medical Center6, Icahn School of Medicine at Mount Sinai7, New York University8, Saint Barnabas Medical Center9, University of Pennsylvania10, SUNY Downstate Medical Center11, Yale University12, University of Colorado Denver13, Boston Children's Hospital14, Case Western Reserve University15, Louisiana State University16, University of Washington17, Johns Hopkins University18, University of Texas Health Science Center at Houston19, University of Mississippi20, Tufts University21, Vanderbilt University22
TL;DR: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents.
Abstract: Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19)...
1,887 citations
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Francis Crick Institute1, Fox Chase Cancer Center2, Washington University in St. Louis3, Cold Spring Harbor Laboratory4, Salk Institute for Biological Studies5, Howard Hughes Medical Institute6, Cornell University7, Goethe University Frankfurt8, Fred Hutchinson Cancer Research Center9, Massachusetts Institute of Technology10, Harvard University11, University of Manchester12, New York University13, University of Texas Health Science Center at Houston14, University of Pennsylvania15, Stony Brook University16, Hofstra University17, Weizmann Institute of Science18, Oregon Health & Science University19, University of California, San Francisco20, King's College London21, Johns Hopkins University22
TL;DR: This Consensus Statement issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance the understanding of this important cell type in the tumour microenvironment.
Abstract: Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
1,616 citations
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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
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TL;DR: Coronavirus disease 2019 is associated with a high inflammatory burden that can induce vascular inflammation, myocarditis, and cardiac arrhythmias and should be judiciously controlled per evidence-based guidelines.
Abstract: Importance Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) has reached a pandemic level. Coronaviruses are known to affect the cardiovascular system. We review the basics of coronaviruses, with a focus on COVID-19, along with their effects on the cardiovascular system. Observations Coronavirus disease 2019 can cause a viral pneumonia with additional extrapulmonary manifestations and complications. A large proportion of patients have underlying cardiovascular disease and/or cardiac risk factors. Factors associated with mortality include male sex, advanced age, and presence of comorbidities including hypertension, diabetes mellitus, cardiovascular diseases, and cerebrovascular diseases. Acute cardiac injury determined by elevated high-sensitivity troponin levels is commonly observed in severe cases and is strongly associated with mortality. Acute respiratory distress syndrome is also strongly associated with mortality. Conclusions and Relevance Coronavirus disease 2019 is associated with a high inflammatory burden that can induce vascular inflammation, myocarditis, and cardiac arrhythmias. Extensive efforts are underway to find specific vaccines and antivirals against SARS-CoV-2. Meanwhile, cardiovascular risk factors and conditions should be judiciously controlled per evidence-based guidelines.
1,467 citations
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Tulane University1, Cedars-Sinai Medical Center2, National Institutes of Health3, University of Arizona4, Karolinska Institutet5, Brigham and Women's Hospital6, Georgia State University7, University of Colorado Denver8, Washington University in St. Louis9, Johns Hopkins University10, University of Modena and Reggio Emilia11, University of Illinois at Chicago12, University of Texas Health Science Center at Houston13, University of Zurich14, Charité15, Georgetown University16, Duke University17, Veterans Health Administration18
TL;DR: Clinicians and researchers are guided to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
781 citations
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Baylor College of Medicine1, Northwestern University2, Johns Hopkins University3, Harvard University4, Baystate Medical Center5, Wayne State University6, Rutgers University7, Columbia University8, Ohio State University9, University of Pennsylvania10, University of Washington11, University of Texas Health Science Center at Houston12, Children's National Medical Center13
TL;DR: The burden of COVID-19 infection in North American PICUs is described and confirmed that severe illness in children is significant but far less frequent than in adults and prehospital comorbidities appear to be an important factor in children.
Abstract: Importance The recent and ongoing coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented toll on adults critically ill with COVID-19 infection. While there is evidence that the burden of COVID-19 infection in hospitalized children is lesser than in their adult counterparts, to date, there are only limited reports describing COVID-19 in pediatric intensive care units (PICUs). Objective To provide an early description and characterization of COVID-19 infection in North American PICUs, focusing on mode of presentation, presence of comorbidities, severity of disease, therapeutic interventions, clinical trajectory, and early outcomes. Design, Setting, and Participants This cross-sectional study included children positive for COVID-19 admitted to 46 North American PICUs between March 14 and April 3, 2020. with follow-up to April 10, 2020. Main Outcomes and Measures Prehospital characteristics, clinical trajectory, and hospital outcomes of children admitted to PICUs with confirmed COVID-19 infection. Results Of the 48 children with COVID-19 admitted to participating PICUs, 25 (52%) were male, and the median (range) age was 13 (4.2-16.6) years. Forty patients (83%) had significant preexisting comorbidities; 35 (73%) presented with respiratory symptoms and 18 (38%) required invasive ventilation. Eleven patients (23%) had failure of 2 or more organ systems. Extracorporeal membrane oxygenation was required for 1 patient (2%). Targeted therapies were used in 28 patients (61%), with hydroxychloroquine being the most commonly used agent either alone (11 patients) or in combination (10 patients). At the completion of the follow-up period, 2 patients (4%) had died and 15 (31%) were still hospitalized, with 3 still requiring ventilatory support and 1 receiving extracorporeal membrane oxygenation. The median (range) PICU and hospital lengths of stay for those who had been discharged were 5 (3-9) days and 7 (4-13) days, respectively. Conclusions and Relevance This early report describes the burden of COVID-19 infection in North American PICUs and confirms that severe illness in children is significant but far less frequent than in adults. Prehospital comorbidities appear to be an important factor in children. These preliminary observations provide an important platform for larger and more extensive studies of children with COVID-19 infection.
758 citations
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TL;DR: The multitude of potential vulnerabilities and risks for people experiencing homelessness in becoming infected, needing care, and transmitting COVID-19 cannot be ignored and must be planned for.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is infecting people throughout the world. It is probable that coronavirus disease (COVID-19) will be transmitted to people experiencing homelessness, which will become a major problem in particular in North America where there are sizable populations of people experiencing homelessness in nearly every metropolitan city in the USA and Canada. In the USA, more than 500 000 people were reported to be experiencing homelessness on any given night over the past decade (2007–19). The State of Homelessness in Canada 2016 report estimated 35 000 people are experiencing homelessness on any given night in Canada. People experiencing homelessness live in environments that are conducive to a disease epidemic. Many people experiencing homelessness live in congregate living settings—be it formal (ie, shelters or halfway houses) or informal (ie, encampments or abandoned buildings)—and might not have regular access to basic hygiene supplies or showering facilities, all of which could facilitate virus transmission. People experiencing homelessness are a vulnerable group, and their potential exposure to COVID-19 might negatively affect their ability to be housed, and their mental and physical health. People experiencing homelessness aged younger than 65 years have all-cause mortality that is 5–10 times higher than that of the general population. COVID-19 infection might further increase this mortality disparity. Many people experiencing homelessness have chronic mental and physical conditions, engage in high rates of substance abuse (including sharing of needles), and have often less access to health care, all of which could lead to potential problems with screening, quarantining, and treating people who might have COVID-19. Such problems have occurred as recently as last year, when outbreaks of typhus, hepatitis A, tuberculosis, trench fever, and Shigella bacteria were reported among people experiencing homelessness in US cities with large homeless populations. There are some additional issues, which are unique to people experiencing homelessness, to consider with regards to COVID-19. Homeless populations might be more transient and geographically mobile than individuals in the general population, making it difficult to track and prevent transmission and to treat those who need care. COVID-19 was recently found to be transmittable via the oral–faecal route. Some major US cities with large homeless populations, like San Francisco, have experienced issues with public defecation, which might pose an additional transmission risk for people experiencing homelessness and other individuals. Together, the multitude of potential vulnerabilities and risks for people experiencing homelessness in becoming infected, needing care, and transmitting COVID-19 cannot be ignored and must be planned for. Some lessons can be learned from the response to severe acute respiratory syndrome among homeless service providers nearly two decades ago. Testing kits and training on how to recognise COVID-19 should be widely disseminated to homeless service providers and deployed in shelters, encampments, and street outreach. Alternative spaces might be needed to quarantine and treat people experiencing homelessness. If cities impose a lockdown to prevent COVID-19 transmission, there are few emergency preparedness plans to transport and provide shelter for the large number of people experiencing homelessness. In lockdowns, public spaces are closed, movement outside homes are restricted, and major roads of transport might be closed, all of which might negatively affect people experiencing homelessness. It is unclear how and where unsheltered people experiencing homelessness will be moved to if quarantines and lockdowns are implemented. In such a scenario, closures of shelters and other high-density communal settings (eg, drop-in centres and soup kitchens) are possible, which could increase the number of unsheltered people experiencing homelessness and reduce their access to needed services. Lockdowns and disease containment procedures might also be deleterious to the mental health of people experiencing homelessness, many of whom have fears around involuntary hospitalisation and incarceration. In response to COVID-19, the State of Washington has declared a state of emergency, allowing cities to take Lancet Public Health 2020
475 citations
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Katrina L. Grasby1, Neda Jahanshad2, Jodie N. Painter1, Lucía Colodro-Conde3 +356 more•Institutions (115)
TL;DR: Results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness and find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
436 citations
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TL;DR: Local weather condition with low temperature, mild diurnal temperature range and low humidity likely favor the transmission of novel coronavirus disease 2019 and meteorological factors play an independent role in the COVID-19 transmission after controlling population migration.
434 citations
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TL;DR: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors.
Abstract: Background Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. Methods We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. Results Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. Conclusions Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.
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TL;DR: Lipidomics across the bilayer membrane plus biophysical and fluorescence approaches find asymmetry in phospholipid unsaturation and localization of protein transmembrane domains based on their ability to pack within the different membrane leaflets.
Abstract: A fundamental feature of cellular plasma membranes (PMs) is an asymmetric lipid distribution between the bilayer leaflets. However, neither the detailed, comprehensive compositions of individual PM leaflets nor how these contribute to structural membrane asymmetries have been defined. We report the distinct lipidomes and biophysical properties of both monolayers in living mammalian PMs. Phospholipid unsaturation is dramatically asymmetric, with the cytoplasmic leaflet being approximately twofold more unsaturated than the exoplasmic leaflet. Atomistic simulations and spectroscopy of leaflet-selective fluorescent probes reveal that the outer PM leaflet is more packed and less diffusive than the inner leaflet, with this biophysical asymmetry maintained in the endocytic system. The structural asymmetry of the PM is reflected in the asymmetric structures of protein transmembrane domains. These structural asymmetries are conserved throughout Eukaryota, suggesting fundamental cellular design principles.
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TL;DR: The autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy.
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TL;DR: To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—the authors estimated additional population equivalents with UHC effective coverage from 2018 to 2023, and quantified frontiers of U HC effective coverage performance on the basis of pooled health spending per capita.
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TL;DR: A Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis is uncovered and it is proposed that in lungs fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.
Abstract: The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.
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Alexander G. Bick, Joshua S. Weinstock1, Satish K. Nandakumar2, Satish K. Nandakumar3 +162 more•Institutions (49)
TL;DR: Analysis of high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine programme enables simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells.
Abstract: Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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TL;DR: In this exploratory analysis, low levels of national preparedness, scale of testing and population characteristics were associated with increased national case load and overall mortality.
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TL;DR: The conceptual underpinnings of the raft hypothesis are reviewed and critically discuss the supporting and contradicting evidence in cells, focusing on why controversies about the composition, properties, and even the very existence of lipid rafts remain unresolved.
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Boston University1, Canadian Blood Services2, Montreal Children's Hospital3, New York University4, Albany Medical College5, University of Chicago6, Dartmouth College7, University of Washington8, Hacettepe University9, University of Tennessee Health Science Center10, University of Pittsburgh11, Northwestern University12, University of Milano-Bicocca13, Universidad del Desarrollo14, University of Sydney15, Southmead Hospital16, University of Florida17, William Mitchell College of Law18, University of Melbourne19, University of Cape Town20, Dubai Hospital21, University of Valencia22, University of Toronto23, The Queen's Medical Center24, University of Texas Health Science Center at Houston25, Seoul National University Bundang Hospital26, Sir Charles Gairdner Hospital27, Texas A&M University28, Kagawa University29, Capital Medical University30, Tribhuvan University31, Indiana University – Purdue University Indianapolis32, Montreal Neurological Institute and Hospital33, Ruby Hall Clinic34, University of Southern California35
TL;DR: Recommendations are provided for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances and have widespread international society endorsement.
Abstract: Importance There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries. Objective To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel. Process Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery. Evidence Synthesis Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed. Recommendations Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH Conclusions and Relevance This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.
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Cooper University Hospital1, Duke University2, Foothills Medical Centre3, Hospital of the University of Pennsylvania4, University of Alabama at Birmingham5, University of Texas Health Science Center at Houston6, University of Pittsburgh7, University of Michigan8, Emory University9, New York University10, University of Colorado Denver11
TL;DR: This Society for Vascular Surgery/Society of Thoracic Surgeons (SVS/STS) document illustrates and defines the overall nomenclature associated with type B aortic dissection and describes a new classification system for practical use and reporting that includes the aorti arch.
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TL;DR: Deep learning has not yet fully penetrated clinical NLP and is growing rapidly, but growing acceptance of deep learning as a baseline for NLP research, and of DL-based NLP in the medical community is shown.
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University of Copenhagen1, Baylor College of Medicine2, University of Texas at Austin3, University of Texas Health Science Center at Houston4, University of Alabama at Birmingham5, University of California, Berkeley6, Population Health Research Institute7, Tufts University8, Ohio State University9, University of California, San Francisco10
TL;DR: Whole-fat dairy, unprocessed meat, eggs and dark chocolate are SFA-rich foods with a complex matrix that are not associated with increased risk of CVD, and the totality of available evidence does not support further limiting the intake of such foods.
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TL;DR: It is concluded that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.
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TL;DR: In this article, the authors provide a general review of the epidemiology, pathophysiology and medical management of adult patients with Traumatic Brain Injury (TBI) for providers practicing outside the field of physical medicine and rehabilitation.
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TL;DR: Transcriptome profiling of 21,422 single cells—including cardiomyocytes and neighbouring cells from healthy adults and patients with heart failure and in recovery, and delineate their cellular compositions and interaction networks provides insights into cell-type-targeted intervention of heart diseases.
Abstract: Owing to the prevalence and high mortality rates of cardiac diseases, a more detailed characterization of the human heart is necessary; however, this has been largely impeded by the cellular diversity of cardiac tissue and limited access to samples. Here, we show transcriptome profiling of 21,422 single cells-including cardiomyocytes (CMs) and non-CMs (NCMs)-from normal, failed and partially recovered (left ventricular assist device treatment) adult human hearts. Comparative analysis of atrial and ventricular cells revealed pronounced inter- and intracompartmental CM heterogeneity as well as compartment-specific utilization of NCM cell types as major cell-communication hubs. Systematic analysis of cellular compositions and cell-cell interaction networks showed that CM contractility and metabolism are the most prominent aspects that are correlated with changes in heart function. We also uncovered active engagement of NCMs in regulating the behaviour of CMs, exemplified by ACKR1+-endothelial cells, injection of which preserved cardiac function after injury. Beyond serving as a rich resource, our study provides insights into cell-type-targeted intervention of heart diseases.
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Icahn School of Medicine at Mount Sinai1, Mount Sinai Hospital2, Boston University3, Ohio State University4, Veterans Health Administration5, University of Alabama at Birmingham6, Harborview Medical Center7, Harvard University8, Northwestern University9, Providence Health & Services10, University of Texas Health Science Center at San Antonio11, Brigham and Women's Hospital12, American Association of Clinical Endocrinologists13, University of Arizona14, Mayo Clinic15, Gundersen Health System16, University of Texas Health Science Center at Houston17, Geisinger Health System18
TL;DR: Bariatric procedures remain a safe and effective intervention for higher-risk patients with obesity and clinical decision-making should be evidence-based within the context of a chronic disease.
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Memorial Sloan Kettering Cancer Center1, Barwon Health2, University of Chicago3, University of Liège4, Mayo Clinic5, Boston Children's Hospital6, Curie Institute7, University of Texas Health Science Center at Houston8, Institut Gustave Roussy9, Fred Hutchinson Cancer Research Center10, University of Minnesota11, University of California, San Francisco12, Sarah Cannon Research Institute13
TL;DR: In this prospective, genomics-driven study of rucaparib in mCRPC, limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2 are found, however, patients with alteration in other DDR-associated genes (e.g., PALB2) may benefit from ParP inhibition.
Abstract: Purpose: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. Patients and Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). Results: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition. See related commentary by Sokolova et al., p. 2439
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TL;DR: It is argued that targeting IL-17 is immunologically plausible as a strategy to prevent acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) and that existing anti-IL-17 therapies should be considered for the treatment of severe CO VID-19.
Abstract: IL-17 and IL-17 receptor inhibitors boast an impressive safety history and are widely available. Here, we argue that targeting IL-17 is immunologically plausible as a strategy to prevent acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) and discuss why we think that a clinical trial of a drug in this class could be a logical addition to the effort to find effective therapies. Levels of the cytokine IL-17 positively correlate with disease severity in COVID-19. Here, the authors argue that existing anti-IL-17 therapies should be considered for the treatment of severe COVID-19.
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University of Massachusetts Amherst1, University of North Carolina at Chapel Hill2, University of Oxford3, The Chinese University of Hong Kong4, Kyoto University5, Seoul National University Hospital6, Vanderbilt University Medical Center7, National University of Singapore8, Academia Sinica9, Nagoya University10, Los Angeles Biomedical Research Institute11, University of California, Los Angeles12, Hallym University13, University of Texas Health Science Center at Houston14, University of Michigan15, Wake Forest University16, Genentech17, Imperial College London18, London North West Healthcare NHS Trust19, University of Manchester20, University of Liverpool21, Kyushu University22, Peking Union Medical College23, National Taiwan University24, University of Minnesota25, Chinese National Human Genome Center26, National Defense Medical Center27, Tri-Service General Hospital28, Taipei Veterans General Hospital29, National Yang-Ming University30, Jichi Medical University31, Heidelberg University32, University of Tokyo33, Osaka University34, Agency for Science, Technology and Research35, University of the Ryukyus36, Ehime University37, Samsung Medical Center38, Yonsei University39, University of San Carlos40, Peking University41, Macau University of Science and Technology42, China Medical University (Taiwan)43, Shanghai Jiao Tong University44, Kurume University45, University of Pittsburgh46, Capital Medical University47, New Generation University College48, Seoul National University49
TL;DR: A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2abetes in both East Asian and European populations.
Abstract: Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
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Harvard University1, Memorial Sloan Kettering Cancer Center2, University of Texas Health Science Center at Houston3, Mayo Clinic4, Yale University5, University of Toronto6, Columbia University7, Washington University in St. Louis8, University of Virginia9, Duke University10, University of Alabama at Birmingham11, University of Washington12, University of Pennsylvania13, University of California, Los Angeles14, Johns Hopkins University15, University of Miami16, Vanderbilt University17
TL;DR: Insight is identified into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.
Abstract: Background Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. Methods We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. Results Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. Conclusions This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.