Showing papers by "University of Pennsylvania published in 2016"
Harvard University1, Broad Institute2, Boston Children's Hospital3, University of Washington4, University of Arizona5, Cardiff University6, Google7, Icahn School of Medicine at Mount Sinai8, Samsung Medical Center9, Vertex Pharmaceuticals10, University of Michigan11, University of Cambridge12, State University of New York Upstate Medical University13, Karolinska Institutet14, University of Eastern Finland15, Wellcome Trust Centre for Human Genetics16, University of Oxford17, Cedars-Sinai Medical Center18, University of Ottawa19, University of Pennsylvania20, University of North Carolina at Chapel Hill21, University of Helsinki22, University of California, San Diego23, University of Mississippi Medical Center24
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Abstract: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
8,758 citations
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.
5,050 citations
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.
4,804 citations
Columbia University1, Scott & White Hospital2, Cedars-Sinai Medical Center3, Cleveland Clinic4, Emory University5, Stanford University6, University of Pennsylvania7, MedStar Washington Hospital Center8, Hospital Corporation of America9, New York University10, Advocate Lutheran General Hospital11, Mayo Clinic12, Primary Children's Hospital13, Laval University14, University of British Columbia15
TL;DR: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke; surgery resulted in fewer major vascular complications and less paravalvular aorta regurgitation.
Abstract: BackgroundPrevious trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. MethodsWe randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. ResultsThe rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event...
3,744 citations
TL;DR: Improvements to imputation machinery are described that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools.
Abstract: Christian Fuchsberger, Goncalo Abecasis and colleagues describe a new web-based imputation service that enables rapid imputation of large numbers of samples and allows convenient access to large reference panels of sequenced individuals. Their state space reduction provides a computationally efficient solution for genotype imputation with no loss in imputation accuracy.
2,556 citations
Erasmus University Rotterdam1, University of Pennsylvania2, Bethel University3, McMaster Children's Hospital4, National Institutes of Health5, Children's Hospital at Westmead6, University of California, San Francisco7, Kaiser Permanente Oakland Medical Center8, Claude Bernard University Lyon 19, Medical University of Vienna10, Kitasato University11, John Radcliffe Hospital12, Charité13, Cleveland Clinic14, Innsbruck Medical University15, Witten/Herdecke University16, Johns Hopkins University School of Medicine17, Catalan Institution for Research and Advanced Studies18
TL;DR: Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
Abstract: Summary Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
2,391 citations
University of Alabama at Birmingham1, University of Michigan2, University of Wisconsin-Madison3, University of Pittsburgh4, Johns Hopkins University School of Medicine5, University of Texas Health Science Center at Houston6, Rowan University7, University of Pennsylvania8, Georgia Regents University9, Cornell University10, Boston Children's Hospital11, Wayne State University12
TL;DR: IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
2,367 citations
TL;DR: The Prostate Imaging - Reporting and Data System Version 2 (PI-RADS™ v2) simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management.
2,210 citations
Wellcome Trust Sanger Institute1, University of Michigan2, University of Oxford3, University of Geneva4, University of Exeter5, Greifswald University Hospital6, National Research Council7, University of Bristol8, University of Colorado Boulder9, Fred Hutchinson Cancer Research Center10, University of Washington11, SUNY Downstate Medical Center12, Erasmus University Rotterdam13, University of Trieste14, VU University Amsterdam15, South London and Maudsley NHS Foundation Trust16, King's College London17, University of Edinburgh18, Harvard University19, National Institutes of Health20, Harokopio University21, Innsbruck Medical University22, Broad Institute23, University of Helsinki24, Lund University25, Norwegian University of Science and Technology26, University of Cambridge27, University of Minnesota28, Technische Universität München29, University of North Carolina at Chapel Hill30, University of Toronto31, McGill University32, Leiden University33, University of Pennsylvania34, University of Groningen35, Utrecht University36, Churchill Hospital37
TL;DR: A reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies.
Abstract: We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
2,149 citations
Cornell University1, Boston University2, Johns Hopkins University3, University of Miami4, University of California, San Francisco5, Texas A&M Health Science Center College of Medicine6, Centers for Disease Control and Prevention7, University of Washington8, Case Western Reserve University9, University of Pennsylvania10, Denver Health Medical Center11, University of Michigan12, University of California, Davis13, University of California, Los Angeles14, United States Department of Veterans Affairs15, Washington University in St. Louis16, Wake Forest University17, University of Utah18, Memorial Sloan Kettering Cancer Center19
TL;DR: These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics.
Abstract: Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics.
University of Verona1, University of Duisburg-Essen2, Icahn School of Medicine at Mount Sinai3, University of Milan4, New York University5, University of Padua6, St. Jude Children's Research Hospital7, Louisiana State University8, University of Maryland, Baltimore County9, Georgia Regents University10, University of Eastern Piedmont11, Heidelberg University12, German Cancer Research Center13, University of Pennsylvania14, Wistar Institute15
TL;DR: The authors identify the challenges and proposed set of minimal reporting guidelines for mouse and human MDSC are a heterogeneous population expanded in cancer and other chronic inflammatory conditions.
Abstract: Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
TL;DR: The algorithms of machine learning, which can sift through vast numbers of variables looking for combinations that reliably predict outcomes, will improve prognosis, displace much of the work of radiologists and anatomical pathologists, and improve diagnostic accuracy.
Abstract: The algorithms of machine learning, which can sift through vast numbers of variables looking for combinations that reliably predict outcomes, will improve prognosis, displace much of the work of radiologists and anatomical pathologists, and improve diagnostic accuracy.
TL;DR: Aasld Guidelines for Treatment of Chronic Hepatitis B Norah Terrault;Natalie Bzowej;Kyong-Mi Chang;Jessica Hwang;Maureen Jonas;Hassan Murad; Hepatology
Nicholas J Kassebaum1, Megha Arora1, Ryan M Barber1, Zulfiqar A Bhutta2 +679 more•Institutions (268)
TL;DR: In this paper, the authors used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.
TL;DR: An updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo is provided, and the recent potential applications of basic science discoveries in the clinical setting are explored.
Abstract: The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.
TL;DR: This study aimed to confirm the earlier findings with this extended follow-up and show the results for subgroup and biomarker analyses, and assesses endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline.
Abstract: Summary Background In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. Methods In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients—ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0–1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy—were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Findings Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7–9·2). Median progression-free survival was 9·5 months (95% CI 9·2–11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5–5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36–0·59, p PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response. Interpretation Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Funding Pfizer.
TL;DR: Hydrogels are introduced to those who may be unfamiliar with procedures to culture and study cells with these systems, with a particular focus on commercially available hydrogels.
Abstract: There is growing appreciation of the role that the extracellular environment plays in regulating cell behavior. Mechanical, structural, and compositional cues, either alone or in concert, can drastically alter cell function. Biomaterials, and particularly hydrogels, have been developed and implemented to present defined subsets of these cues for investigating countless cellular processes as a means of understanding morphogenesis, aging, and disease. Although most scientists concede that standard cell culture materials (tissue culture plastic and glass) do a poor job of recapitulating native cellular milieus, there is currently a knowledge barrier for many researchers in regard to the application of hydrogels for cell culture. Here, we introduce hydrogels to those who may be unfamiliar with procedures to culture and study cells with these systems, with a particular focus on commercially available hydrogels.
TL;DR: Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma, and endoscopic surveillance intervals are attenuated, based on recent level 1 evidence.
Centers for Disease Control and Prevention1, University of Utah2, University of California, San Francisco3, University of Minnesota4, Northeast Ohio Medical University5, Boston Children's Hospital6, University of Pennsylvania7, The Pew Charitable Trusts8, Brigham and Women's Hospital9, University of California, Davis10, Georgetown University Medical Center11, Harvard University12, Washington University in St. Louis13, University of Illinois at Chicago14, Pacific Lutheran University15
TL;DR: In the United States in 2010-2011, there was an estimated annual antibiotic prescription rate per 1000 population of 506, but only an estimated 353 antibiotic prescriptions were likely appropriate, supporting the need for establishing a goal for outpatient antibiotic stewardship.
Abstract: Importance The National Action Plan for Combating Antibiotic-Resistant Bacteria set a goal of reducing inappropriate outpatient antibiotic use by 50% by 2020, but the extent of inappropriate outpatient antibiotic use is unknown. Objective To estimate the rates of outpatient oral antibiotic prescribing by age and diagnosis, and the estimated portions of antibiotic use that may be inappropriate in adults and children in the United States. Design, Setting, and Participants Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, annual numbers and population-adjusted rates with 95% confidence intervals of ambulatory visits with oral antibiotic prescriptions by age, region, and diagnosis in the United States were estimated. Exposures Ambulatory care visits. Main Outcomes and Measures Based on national guidelines and regional variation in prescribing, diagnosis-specific prevalence and rates of total and appropriate antibiotic prescriptions were determined. These rates were combined to calculate an estimate of the appropriate annual rate of antibiotic prescriptions per 1000 population. Results Of the 184 032 sampled visits, 12.6% of visits (95% CI, 12.0%-13.3%) resulted in antibiotic prescriptions. Sinusitis was the single diagnosis associated with the most antibiotic prescriptions per 1000 population (56 antibiotic prescriptions [95% CI, 48-64]), followed by suppurative otitis media (47 antibiotic prescriptions [95% CI, 41-54]), and pharyngitis (43 antibiotic prescriptions [95% CI, 38-49]). Collectively, acute respiratory conditions per 1000 population led to 221 antibiotic prescriptions (95% CI, 198-245) annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1000 population, among all conditions and ages combined in 2010-2011, an estimated 506 antibiotic prescriptions (95% CI, 458-554) were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate antibiotic prescriptions. Conclusions and Relevance In the United States in 2010-2011, there was an estimated annual antibiotic prescription rate per 1000 population of 506, but only an estimated 353 antibiotic prescriptions were likely appropriate, supporting the need for establishing a goal for outpatient antibiotic stewardship.
University of Pennsylvania1, Wayne State University2, Fox Chase Cancer Center3, University of Texas MD Anderson Cancer Center4, University of Virginia5, Seattle Cancer Care Alliance6, Cleveland Clinic7, Indiana University8, National Taiwan University9, University of California, San Francisco10, Harvard University11, Merck & Co.12, New York University13
TL;DR: This trial assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC, and the proportion of patients who achieved an objective response.
Abstract: Summary Background Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. Methods In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score ( 2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p Findings Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Interpretation Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Funding Merck & Co.
Howard Hughes Medical Institute1, Harvard University2, Broad Institute3, University of California, Berkeley4, University of California, Los Angeles5, Chinese Academy of Sciences6, Max Planck Society7, Columbia University8, Massachusetts Institute of Technology9, Cayetano Heredia University10, University of Pennsylvania11, University College London12, University of Bern13, Leiden University14, Nanyang Technological University15, University of Chicago16, Estonian Biocentre17, National University of La Plata18, University of Oxford19, University of Bergen20, Novosibirsk State University21, Moscow Institute of Physics and Technology22, Sofia Medical University23, Armenian National Academy of Sciences24, Wellcome Trust Sanger Institute25, Raja Isteri Pengiran Anak Saleha Hospital26, Case Western Reserve University27, University of Tartu28, Estonian Academy of Sciences29, Stony Brook University30, Illumina31, Gladstone Institutes32, University of Helsinki33, University of Washington34, Bashkir State University35, Jaramogi Oginga Odinga University of Science and Technology36, Pompeu Fabra University37, University of Arizona38, University of Cambridge39, Leidos40, Université de Montréal41, University of Utah42, Altai State University43, Council of Scientific and Industrial Research44
TL;DR: It is demonstrated that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.
Abstract: Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.
University of Alabama at Birmingham1, University of Michigan2, University of Wisconsin-Madison3, University of Pittsburgh4, Johns Hopkins University School of Medicine5, University of Texas Health Science Center at Houston6, Rowan University7, University of Pennsylvania8, Georgia Regents University9, Cornell University10, Boston Children's Hospital11, Wayne State University12
TL;DR: IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Lars G. Fritsche1, Wilmar Igl2, Jessica N. Cooke Bailey3, Felix Grassmann2 +182 more•Institutions (58)
TL;DR: The results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
TL;DR: In this article, a computational screening study of 2D layered transition metal carbides, MXenes, was performed for the hydrogen evolution reaction (HER) and the results showed that the basal planes of Mo2CTx are catalytically active toward the HER, unlike in the case of widely studied MoS2.
Abstract: The hydrogen evolution reaction (HER) is an important energy conversion process that underpins many clean energy technologies including water splitting. Herein, we report for the first time the application of two-dimensional (2D) layered transition metal carbides, MXenes, as electrocatalysts for the HER. Our computational screening study of 2D layered M2XTx (M = metal; X = (C, N); and Tx = surface functional groups) predicts Mo2CTx to be an active catalyst candidate for the HER. We synthesized both Mo2CTx and Ti2CTx MXenes, and in agreement with our theoretical predictions, Mo2CTx was found to exhibit far higher HER activity than Ti2CTx. Theory suggests that the basal planes of Mo2CTx are catalytically active toward the HER, unlike in the case of widely studied MoS2, in which only the edge sites of the 2H phase are active. This work paves the way for the development of novel 2D layered materials that can be applied in a multitude of other clean energy reactions for a sustainable energy future.
Boston Children's Hospital1, Harvard University2, University of Calgary3, University of Manchester4, University of Edinburgh5, University of Alabama at Birmingham6, Rotunda Hospital7, Rutgers University8, Wayne State University9, University of Toronto10, University of Pennsylvania11, Oregon Health & Science University12, Utrecht University13, University of Pittsburgh14, Case Western Reserve University15, University College London16, University of Oslo17, VU University Amsterdam18, University of Groningen19
TL;DR: The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria for placental lesions, which will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.
Abstract: Context.—The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. Objective.—To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. Data Sources.—Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. Conclusions.—The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous m...
Journal Article•
TL;DR: A second-order ordinary differential equation is derived, which is the limit of Nesterov's accelerated gradient method, and it is shown that the continuous time ODE allows for a better understanding of Nestersov's scheme.
Abstract: We derive a second-order ordinary differential equation (ODE) which is the limit of Nesterov's accelerated gradient method. This ODE exhibits approximate equivalence to Nesterov's scheme and thus can serve as a tool for analysis. We show that the continuous time ODE allows for a better understanding of Nesterov's scheme. As a byproduct, we obtain a family of schemes with similar convergence rates. The ODE interpretation also suggests restarting Nesterov's scheme leading to an algorithm, which can be rigorously proven to converge at a linear rate whenever the objective is strongly convex.
TL;DR: Recent progress in tailoring and combining quantum dots to build electronic and optoelectronic devices and new ligand chemistries and matrix materials have been reported that provide freedom to control the dynamics of excitons and charge carriers and to design device interfaces are reviewed.
Abstract: BACKGROUND The Information Age was founded on the semiconductor revolution, marked by the growth of high-purity semiconductor single crystals. The resultant design and fabrication of electronic devices exploits our ability to control the concentration, motion, and dynamics of charge carriers in the bulk semiconductor solid state. Our desire to introduce electronics everywhere is fueled by opportunities to create intelligent and enabling devices for the information, communication, consumer product, health, and energy sectors. This demand for ubiquitous electronics is spurring the design of materials that exhibit engineered physical properties and that can enable new fabrication methods for low-cost, large-area, and flexible devices. Semiconductors, which are at the heart of electronics and optoelectronics, come with high demands on chemical purity and structural perfection. Alternatives to silicon technology are expected to combine the electronic and optical properties of inorganic semiconductors (high charge carrier mobility, precise n- and p-type doping, and the ability to engineer the band gap energy) with the benefits of additive device manufacturing: low cost, large area, and the use of solution-based fabrication techniques. Along these lines, colloidal semiconductor quantum dots (QDs), which are nanoscale crystals of analogous bulk semiconductor crystals, offer a powerful platform for device engineers. Colloidal QDs may be tailored in size, shape, and composition and their surfaces functionalized with molecular ligands of diverse chemistry. At the nanoscale (typically 2 to 20 nm), quantum and dielectric confinement effects give rise to the prized size-, shape-, and composition-tunable electronic and optical properties of QDs. Surface ligands enable the stabilization of QDs in the form of colloids, allowing their bottom-up assembly into QD solids. The physical properties of QD solids can be designed by selecting the characteristics of the individual QD building blocks and by controlling the electronic communication between the QDs in the solid state. These QD solids can be engineered with application-specific electronic and optoelectronic properties for the large-area, solution-based assembly of devices. ADVANCES The large surface-to-volume ratio of QDs places a substantial importance on the composition and structure of the surface in defining the physical properties that govern the concentration, motion, and dynamics of excitations and charge carriers in QD solids. Recent studies have shown pathways to passivate uncoordinated atoms at the QD surface that act to trap and scatter charge carriers. Surface atoms, ligands, and ions can serve as dopants to control the electron affinity of QD solids. Surface ligands and surrounding matrices control the barriers to electronic, excitonic, and thermal transport between QDs and between QDs and matrices. New ligand chemistries and matrix materials have been reported that provide freedom to control the dynamics of excitons and charge carriers and to design device interfaces. These advances in engineering the chemical and physical properties of the QD surface have been translated into recent achievements of high-mobility transistors and circuits, high-quantum-yield photodetectors and light-emitting devices, and high-efficiency photovoltaic devices. OUTLOOK The dominant role and dynamic nature of the QD surface, and the strong motive to build novel QD devices, will drive the exploration of new surface chemistries and matrix materials, processes for their assembly and integration with other materials in devices, and measurements and simulations with which to map the relationship between surface chemistry and materials and device properties. Challenges remain to achieve full control over the carrier type, concentration, and mobility in the QD channel and the barriers and traps at device interfaces that limit the gain and speed of QD electronics. Surface chemistries that allow for both long carrier lifetime and high carrier mobility and the freedom to engineer the bandgap and band alignment of QDs and other device layers are needed to exploit physics particular to QDs and to advance device architectures that contribute to improving the performance of QD optoelectronics. The importance of thermal transport in QD solids and their devices is an essential emerging topic that promises to become of greater importance as we develop QD devices.
University of Pennsylvania1, Medical Research Council2, Wellcome Trust Sanger Institute3, European Bioinformatics Institute4, Medical University of Vienna5, Hospital for Sick Children6, University of California, Davis7, National Research Council8, Harvard University9, Baylor College of Medicine10, Nanjing University11, Broad Institute12, University of Strasbourg13, Children's Hospital Oakland Research Institute14, Technische Universität München15, Francis Crick Institute16
TL;DR: It is shown that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts and reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background.
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
Penn State Milton S. Hershey Medical Center1, Kaiser Permanente2, Northwestern University3, University of Cincinnati4, NewYork–Presbyterian Hospital5, Cornell University6, Boston University7, University of Alabama at Birmingham8, Johns Hopkins University9, University of Miami10, University of Pennsylvania11, Harvard University12, Mount Sinai Health System13, Henry Ford Health System14, Mayo Clinic15, Emory University16, Swedish Covenant Hospital17, American Academy of Dermatology18
TL;DR: Issues from grading of acne to the topical and systemic management of the disease are reviewed and suggestions on use are provided based on available evidence.
Abstract: Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.