Showing papers by "Vanderbilt University published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
Centers for Disease Control and Prevention1, University of North Carolina at Chapel Hill2, Vanderbilt University3, University of Arizona4, Rutgers University5, University of Colorado Denver6, Colorado Department of Public Health and Environment7, University of Wisconsin-Madison8, United States Department of Energy9, Johns Hopkins University10, University of Arkansas for Medical Sciences11, Washington University in St. Louis12, University of Minnesota13
TL;DR: This report provides updated ASD prevalence estimates for children aged 8 years during the 2014 surveillance year, on the basis of DSM-IV-TR criteria, and describes characteristics of the population of children with ASD.
Abstract: Problem/condition Autism spectrum disorder (ASD). Period covered 2014. Description of system The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence of autism spectrum disorder (ASD) among children aged 8 years whose parents or guardians reside within 11 ADDM sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). ADDM surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by professional service providers in the community. Staff completing record review and abstraction receive extensive training and supervision and are evaluated according to strict reliability standards to certify effective initial training, identify ongoing training needs, and ensure adherence to the prescribed methodology. Record review and abstraction occurs in a variety of data sources ranging from general pediatric health clinics to specialized programs serving children with developmental disabilities. In addition, most of the ADDM sites also review records for children who have received special education services in public schools. In the second phase of the study, all abstracted information is reviewed systematically by experienced clinicians to determine ASD case status. A child is considered to meet the surveillance case definition for ASD if he or she displays behaviors, as described on one or more comprehensive evaluations completed by community-based professional providers, consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autistic disorder; pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism); or Asperger disorder. This report provides updated ASD prevalence estimates for children aged 8 years during the 2014 surveillance year, on the basis of DSM-IV-TR criteria, and describes characteristics of the population of children with ASD. In 2013, the American Psychiatric Association published the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which made considerable changes to ASD diagnostic criteria. The change in ASD diagnostic criteria might influence ADDM ASD prevalence estimates; therefore, most (85%) of the records used to determine prevalence estimates based on DSM-IV-TR criteria underwent additional review under a newly operationalized surveillance case definition for ASD consistent with the DSM-5 diagnostic criteria. Children meeting this new surveillance case definition could qualify on the basis of one or both of the following criteria, as documented in abstracted comprehensive evaluations: 1) behaviors consistent with the DSM-5 diagnostic features; and/or 2) an ASD diagnosis, whether based on DSM-IV-TR or DSM-5 diagnostic criteria. Stratified comparisons of the number of children meeting either of these two case definitions also are reported. Results For 2014, the overall prevalence of ASD among the 11 ADDM sites was 16.8 per 1,000 (one in 59) children aged 8 years. Overall ASD prevalence estimates varied among sites, from 13.1-29.3 per 1,000 children aged 8 years. ASD prevalence estimates also varied by sex and race/ethnicity. Males were four times more likely than females to be identified with ASD. Prevalence estimates were higher for non-Hispanic white (henceforth, white) children compared with non-Hispanic black (henceforth, black) children, and both groups were more likely to be identified with ASD compared with Hispanic children. Among the nine sites with sufficient data on intellectual ability, 31% of children with ASD were classified in the range of intellectual disability (intelligence quotient [IQ] 85). The distribution of intellectual ability varied by sex and race/ethnicity. Although mention of developmental concerns by age 36 months was documented for 85% of children with ASD, only 42% had a comprehensive evaluation on record by age 36 months. The median age of earliest known ASD diagnosis was 52 months and did not differ significantly by sex or race/ethnicity. For the targeted comparison of DSM-IV-TR and DSM-5 results, the number and characteristics of children meeting the newly operationalized DSM-5 case definition for ASD were similar to those meeting the DSM-IV-TR case definition, with DSM-IV-TR case counts exceeding DSM-5 counts by less than 5% and approximately 86% overlap between the two case definitions (kappa = 0.85). Interpretation Findings from the ADDM Network, on the basis of 2014 data reported from 11 sites, provide updated population-based estimates of the prevalence of ASD among children aged 8 years in multiple communities in the United States. The overall ASD prevalence estimate of 16.8 per 1,000 children aged 8 years in 2014 is higher than previously reported estimates from the ADDM Network. Because the ADDM sites do not provide a representative sample of the entire United States, the combined prevalence estimates presented in this report cannot be generalized to all children aged 8 years in the United States. Consistent with reports from previous ADDM surveillance years, findings from 2014 were marked by variation in ASD prevalence when stratified by geographic area, sex, and level of intellectual ability. Differences in prevalence estimates between black and white children have diminished in most sites, but remained notable for Hispanic children. For 2014, results from application of the DSM-IV-TR and DSM-5 case definitions were similar, overall and when stratified by sex, race/ethnicity, DSM-IV-TR diagnostic subtype, or level of intellectual ability. Public health action Beginning with surveillance year 2016, the DSM-5 case definition will serve as the basis for ADDM estimates of ASD prevalence in future surveillance reports. Although the DSM-IV-TR case definition will eventually be phased out, it will be applied in a limited geographic area to offer additional data for comparison. Future analyses will examine trends in the continued use of DSM-IV-TR diagnoses, such as autistic disorder, PDD-NOS, and Asperger disorder in health and education records, documentation of symptoms consistent with DSM-5 terminology, and how these trends might influence estimates of ASD prevalence over time. The latest findings from the ADDM Network provide evidence that the prevalence of ASD is higher than previously reported estimates and continues to vary among certain racial/ethnic groups and communities. With prevalence of ASD ranging from 13.1 to 29.3 per 1,000 children aged 8 years in different communities throughout the United States, the need for behavioral, educational, residential, and occupational services remains high, as does the need for increased research on both genetic and nongenetic risk factors for ASD.
3,967 citations
TL;DR: In this paper, a Monte Carlo sampler (The Joker) is used to perform a search for companions to 96,231 red-giant stars observed in the APOGEE survey (DR14) with $ ≥ 3$ spectroscopic epochs.
Abstract: Multi-epoch radial velocity measurements of stars can be used to identify stellar, sub-stellar, and planetary-mass companions. Even a small number of observation epochs can be informative about companions, though there can be multiple qualitatively different orbital solutions that fit the data. We have custom-built a Monte Carlo sampler (The Joker) that delivers reliable (and often highly multi-modal) posterior samplings for companion orbital parameters given sparse radial-velocity data. Here we use The Joker to perform a search for companions to 96,231 red-giant stars observed in the APOGEE survey (DR14) with $\\geq 3$ spectroscopic epochs. We select stars with probable companions by making a cut on our posterior belief about the amplitude of the stellar radial-velocity variation induced by the orbit. We provide (1) a catalog of 320 companions for which the stellar companion properties can be confidently determined, (2) a catalog of 4,898 stars that likely have companions, but would require more observations to uniquely determine the orbital properties, and (3) posterior samplings for the full orbital parameters for all stars in the parent sample. We show the characteristics of systems with confidently determined companion properties and highlight interesting systems with candidate compact object companions.
2,564 citations
University of Texas Southwestern Medical Center1, Stanford University2, University of Southern California3, University of California, Los Angeles4, West Virginia University5, Harvard University6, University of Colorado Boulder7, Vanderbilt University8, Case Western Reserve University9, Cincinnati Children's Hospital Medical Center10, Cleveland Clinic11, Fox Chase Cancer Center12, University of Pennsylvania13, University of Washington14, Seattle Children's15, University of Texas MD Anderson Cancer Center16, Nemours Foundation17, International University, Cambodia18, Oregon Health & Science University19
TL;DR: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.
Abstract: Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. Results A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence ...
1,773 citations
Columbia University Medical Center1, Vanderbilt University2, Ohio State University3, Cedars-Sinai Medical Center4, University of Virginia5, Intermountain Medical Center6, Baylor University Medical Center7, Carolinas Medical Center8, Piedmont Hospital9, University of Colorado Hospital10, University of Missouri–Kansas City11, MedStar Health12, Scott & White Hospital13
TL;DR: Among patients with heart failure and moderate‐to‐severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline‐directed medical therapy, transcatheter mitral‐valve repair resulted in a lower rate of hospitalization forHeart failure and lower all‐cause mortality within 24 months of follow‐up than medical therapy alone.
Abstract: Background Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor Transcatheter mitral-valve repair may improve their clinical outcomes Methods At 78 sites in the United States and Canada, we enrolled patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group) The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 880% Results Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 t
1,758 citations
University of Alabama at Birmingham1, University of South Florida2, Vanderbilt University3, City of Hope National Medical Center4, Fox Chase Cancer Center5, University Of Tennessee System6, Brigham and Women's Hospital7, Seattle Cancer Care Alliance8, Case Western Reserve University9, Roswell Park Cancer Institute10, Northwestern University11, Harvard University12, University of Nebraska Medical Center13, University of Utah14, Memorial Sloan Kettering Cancer Center15
TL;DR: This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
Abstract: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
1,545 citations
University of Hawaii at Manoa1, University of Pennsylvania2, University of Michigan3, Harvard University4, GlaxoSmithKline5, Imperial College London6, Princess Margaret Cancer Centre7, University of Toronto8, Vanderbilt University9, Drexel University10, Carnegie Mellon University11, Stanford University12, University of Virginia13, Broad Institute14, Toyota Technological Institute at Chicago15, Princeton University16, Trinity University17, National Institutes of Health18, Howard Hughes Medical Institute19, University of Florida20, University of Colorado Denver21, University of Münster22, Georgetown University Medical Center23, Washington University in St. Louis24, Brown University25, Morgridge Institute for Research26, University of Wisconsin-Madison27
TL;DR: It is found that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art.
Abstract: Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine.
1,491 citations
Yeshiva University1, Harvard University2, University of Toronto3, Loyola University New Orleans4, University of Michigan5, Virginia Commonwealth University6, University of North Carolina at Chapel Hill7, Mayo Clinic8, Duke University9, National Institutes of Health10, Indiana University11, Northwestern University12, McMaster University13, Washington University in St. Louis14, Emory University15, University of Texas at San Antonio16, Vanderbilt University17, University of Pittsburgh18, Rutgers University19, Indiana University – Purdue University Indianapolis20
TL;DR: In this paper, the authors performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer.
Abstract: Background The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free surv...
1,337 citations
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
Bela Abolfathi1, D. S. Aguado2, Gabriela Aguilar3, Carlos Allende Prieto2 +361 more•Institutions (94)
TL;DR: SDSS-IV is the fourth generation of the Sloan Digital Sky Survey and has been in operation since 2014 July. as discussed by the authors describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14).
Abstract: The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
965 citations
Posted Content•
TL;DR: In this paper, the authors consider identification, estimation, and inference procedures for treatment effect parameters using Difference-in-Differences (DiD) with multiple time periods, variation in treatment timing, and when the "parallel trends assumption" holds potentially only after conditioning on observed covariates.
Abstract: In this article, we consider identification, estimation, and inference procedures for treatment effect parameters using Difference-in-Differences (DiD) with (i) multiple time periods, (ii) variation in treatment timing, and (iii) when the "parallel trends assumption" holds potentially only after conditioning on observed covariates. We show that a family of causal effect parameters are identified in staggered DiD setups, even if differences in observed characteristics create non-parallel outcome dynamics between groups. Our identification results allow one to use outcome regression, inverse probability weighting, or doubly-robust estimands. We also propose different aggregation schemes that can be used to highlight treatment effect heterogeneity across different dimensions as well as to summarize the overall effect of participating in the treatment. We establish the asymptotic properties of the proposed estimators and prove the validity of a computationally convenient bootstrap procedure to conduct asymptotically valid simultaneous (instead of pointwise) inference. Finally, we illustrate the relevance of our proposed tools by analyzing the effect of the minimum wage on teen employment from 2001--2007. Open-source software is available for implementing the proposed methods.
Washington University in St. Louis1, Northwestern University2, University of Padua3, University of Bordeaux4, Claude Bernard University Lyon 15, University of Lyon6, University of Amsterdam7, Vanderbilt University8, Queen Mary University of London9, Mayo Clinic10, University of Bern11, Katholieke Universiteit Leuven12
TL;DR: Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of refux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations.
Abstract: Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET
Sandia National Laboratories1, University of California, Davis2, Massachusetts Institute of Technology3, Cornell University4, United States Army Research Laboratory5, Ohio State University6, University of California, Santa Barbara7, Boston University8, North Carolina State University9, Purdue University10, Georgia Institute of Technology11, Michigan State University12, Air Force Research Laboratory13, National Institute of Information and Communications Technology14, University of South Carolina15, United States Naval Research Laboratory16, Arizona State University17, University of Illinois at Urbana–Champaign18, Vanderbilt University19
TL;DR: The UWBG semiconductor materials, such as high Al‐content AlGaN, diamond and Ga2O3, advanced in maturity to the point where realizing some of their tantalizing advantages is a relatively near‐term possibility.
Abstract: J. Y. Tsao,* S. Chowdhury, M. A. Hollis,* D. Jena, N. M. Johnson, K. A. Jones, R. J. Kaplar,* S. Rajan, C. G. Van de Walle, E. Bellotti, C. L. Chua, R. Collazo, M. E. Coltrin, J. A. Cooper, K. R. Evans, S. Graham, T. A. Grotjohn, E. R. Heller, M. Higashiwaki, M. S. Islam, P. W. Juodawlkis, M. A. Khan, A. D. Koehler, J. H. Leach, U. K. Mishra, R. J. Nemanich, R. C. N. Pilawa-Podgurski, J. B. Shealy, Z. Sitar, M. J. Tadjer, A. F. Witulski, M. Wraback, and J. A. Simmons
TL;DR: SAIGE is a scalable and accurate generalized mixed model association test that can efficiently analyze large data sets while controlling for unbalanced case-control ratios and sample relatedness, as shown by applying SAIGE to the UK Biobank data for > 1,400 binary phenotypes.
Abstract: In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.
Evangelos Evangelou1, Evangelos Evangelou2, Helen R. Warren3, Helen R. Warren4 +338 more•Institutions (93)
TL;DR: In this article, the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry was conducted.
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future
TL;DR: In this article, the authors examine the key challenges facing membrane distillation and explore the opportunities for improving membrane membranes and system design, highlighting the outlook for MD desalination, highlighting challenges and key areas for future research and development.
Abstract: Energy-efficient desalination and water treatment technologies play a critical role in augmenting freshwater resources without placing an excessive strain on limited energy supplies. By desalinating high-salinity waters using low-grade or waste heat, membrane distillation (MD) has the potential to increase sustainable water production, a key facet of the water-energy nexus. However, despite advances in membrane technology and the development of novel process configurations, the viability of MD as an energy-efficient desalination process remains uncertain. In this review, we examine the key challenges facing MD and explore the opportunities for improving MD membranes and system design. We begin by exploring how the energy efficiency of MD is limited by the thermal separation of water and dissolved solutes. We then assess the performance of MD relative to other desalination processes, including reverse osmosis and multi-effect distillation, comparing various metrics including energy efficiency, energy quality, and susceptibility to fouling. By analyzing the impact of membrane properties on the energy efficiency of an MD desalination system, we demonstrate the importance of maximizing porosity and optimizing thickness to minimize energy consumption. We also show how ineffective heat recovery and temperature polarization can limit the energetic performance of MD and how novel process variants seek to reduce these inefficiencies. Fouling, scaling, and wetting can have a significant detrimental impact on MD performance. We outline how novel membrane designs with special surface wettability and process-based fouling control strategies may bolster membrane and process robustness. Finally, we explore applications where MD may be able to outperform established desalination technologies, increasing water production without consuming large amounts of electrical or high-grade thermal energy. We conclude by discussing the outlook for MD desalination, highlighting challenges and key areas for future research and development.
TL;DR: It is shown that ComBat removes unwanted sources of scan variability while simultaneously increasing the power and reproducibility of subsequent statistical analyses, and is useful for combining imaging data with the goal of studying life‐span trajectories in the brain.
Alvaro N. Barbeira1, Scott P. Dickinson1, Rodrigo Bonazzola1, Jiamao Zheng1 +260 more•Institutions (43)
TL;DR: A mathematical expression is derived to compute PrediXcan results using summary data, and the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes are investigated.
Abstract: Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
Northwestern University1, University of California, San Francisco2, University of Michigan3, University of California, San Diego4, City of Hope National Medical Center5, Vanderbilt University6, Seattle Cancer Care Alliance7, Fox Chase Cancer Center8, University of Wisconsin-Madison9, Mayo Clinic10, Yale University11, University of South Florida12, Washington University in St. Louis13, University of Alabama at Birmingham14, Stanford University15, Case Western Reserve University16, University of Colorado Boulder17, Harvard University18, Roswell Park Cancer Institute19, Memorial Sloan Kettering Cancer Center20, University of Utah21, University of Tennessee Health Science Center22, University of Texas MD Anderson Cancer Center23, Johns Hopkins University24, Duke University25, Ohio State University26
TL;DR: The NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer.
Abstract: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection
Northwestern University1, University of California, San Francisco2, University of Michigan3, University of California, San Diego4, City of Hope National Medical Center5, Vanderbilt University6, Seattle Cancer Care Alliance7, Fox Chase Cancer Center8, University of Wisconsin-Madison9, University of Utah10, Mayo Clinic11, Yale Cancer Center12, University of South Florida13, Washington University in St. Louis14, University of Alabama at Birmingham15, Stanford University16, Case Western Reserve University17, University of Colorado Boulder18, Brigham and Women's Hospital19, Ohio State University20, Roswell Park Cancer Institute21, Memorial Sloan Kettering Cancer Center22, University of Tennessee Health Science Center23, University of Texas MD Anderson Cancer Center24, Johns Hopkins University25, Duke University26, National Comprehensive Cancer Network27
TL;DR: The NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib are summarized.
Abstract: The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib.
University of North Carolina at Chapel Hill1, University of Pennsylvania2, University of Colorado Denver3, Tel Aviv University4, Baylor University Medical Center5, Durham University6, University of California, San Diego7, Mayo Clinic8, Northwestern University9, Nestlé10, Tufts University11, Boston Children's Hospital12, Icahn School of Medicine at Mount Sinai13, University of Texas Southwestern Medical Center14, Cincinnati Children's Hospital Medical Center15, Baylor College of Medicine16, Nationwide Children's Hospital17, University of Paris18, University of Health Sciences Antigua19, University of Illinois at Urbana–Champaign20, Shimane University21, University Hospitals Coventry and Warwickshire NHS Trust22, Harvard University23, Juntendo University24, University of Ljubljana25, National and Kapodistrian University of Athens26, University of Utah27, University of Adelaide28, University of South Florida29, University of Lausanne30, University College London31, Kaiser Permanente32, University of Newcastle33, Vanderbilt University34, Vrije Universiteit Brussel35, Federal University of Paraná36, Children's Memorial Hospital37, University of Amsterdam38
TL;DR: An updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement, and the evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EOE than as a diagnostic criterion.
University of South Florida1, Washington University in St. Louis2, University of Texas MD Anderson Cancer Center3, Oregon Health & Science University4, University of Kansas5, Cornell University6, Medical University of South Carolina7, Vanderbilt University8, Northside Hospital9, Harvard University10, University of Michigan11, University of California, Los Angeles12, University of California, San Diego13, University of Rochester14, Fred Hutchinson Cancer Research Center15, Stanford University16
TL;DR: CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML, and improved outcomes were observed across age-groups and AML subtypes.
Abstract: Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML) Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen The primary end point was overall survival Results CPX-351 significantly improved median overall survival versus 7+3 (956 v 595 months; hazard ratio, 069; 95% CI, 052 to 090; one-sided P = 003) Overall remission rate was also significantly higher with CPX-351 versus 7+3 (477% v 333%; two-sided P = 016) Improved outcomes were observed across age-groups and AML subtypes The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351 Early mortality rates with CPX-351 and 7+3 were 59% and 106% (two-sided P = 149) through day 30 and 137% and 212% (two-sided P = 097) through day 60 Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML The safety profile of CPX-351 was similar to that of conventional 7+3 therapy
Vanderbilt University1, Van Andel Institute2, University of North Carolina at Chapel Hill3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Massachusetts Institute of Technology6, Harvard University7, Baylor College of Medicine8, University of Kansas9, Brigham and Women's Hospital10, Washington University in St. Louis11, Mayo Clinic12, Leidos13, Yale University14, Oregon Health & Science University15
TL;DR: Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers.
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
TL;DR: It is demonstrated experimentally that intelligent control of an autonomous vehicle is able to dampen stop-and-go waves that can arise even in the absence of geometric or lane changing triggers, suggesting a paradigm shift in traffic management.
Abstract: Traffic waves are phenomena that emerge when the vehicular density exceeds a critical threshold. Considering the presence of increasingly automated vehicles in the traffic stream, a number of research activities have focused on the influence of automated vehicles on the bulk traffic flow. In the present article, we demonstrate experimentally that intelligent control of an autonomous vehicle is able to dampen stop-and-go waves that can arise even in the absence of geometric or lane changing triggers. Precisely, our experiments on a circular track with more than 20 vehicles show that traffic waves emerge consistently, and that they can be dampened by controlling the velocity of a single vehicle in the flow. We compare metrics for velocity, braking events, and fuel economy across experiments. These experimental findings suggest a paradigm shift in traffic management: flow control will be possible via a few mobile actuators (less than 5%) long before a majority of vehicles have autonomous capabilities.
University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
TL;DR: This study demonstrates how a molecularly driven clinical trial can be used to refine the biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
Abstract: Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
TL;DR: The fabrication of a TFC NF membrane with a crumpled polyamide (PA) layer via interfacial polymerization on a single-walled carbon nanotubes/polyether sulfone composite support loaded with nanoparticles as a sacrificial templating material is reported, yielding an overall desalination performance superior to state-of-the-art NF membranes reported so far.
Abstract: Nanofiltration (NF) membranes with ultrahigh permeance and high rejection are highly beneficial for efficient desalination and wastewater treatment. Improving water permeance while maintaining the high rejection of state-of-the-art thin film composite (TFC) NF membranes remains a great challenge. Herein, we report the fabrication of a TFC NF membrane with a crumpled polyamide (PA) layer via interfacial polymerization on a single-walled carbon nanotubes/polyether sulfone composite support loaded with nanoparticles as a sacrificial templating material, using metal-organic framework nanoparticles (ZIF-8) as an example. The nanoparticles, which can be removed by water dissolution after interfacial polymerization, facilitate the formation of a rough PA active layer with crumpled nanostructure. The NF membrane obtained thereby exhibits high permeance up to 53.5 l m−2h−1 bar−1 with a rejection above 95% for Na2SO4, yielding an overall desalination performance superior to state-of-the-art NF membranes reported so far. Our work provides a simple avenue to fabricate advanced PA NF membranes with outstanding performance. Nanofiltration membranes are important for water desalination technologies, but designing membranes that achieve both high permeance and high salt rejection remains challenging. Here, the authors use sacrificial nanoparticles in the membrane fabrication process, leading to crumpled structures with ultrahigh permeance.
TL;DR: Nivolumab treatment resulted in long-term OS and durable responses in a proportion of patients with pretreated advanced NSCLC and 12 5-year survivors received no subsequent therapy and were without evidence of progressive disease at last follow-up.
Abstract: PurposeIn two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non–small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors.Patients and MethodsPatients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method.ResultsThe estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Crite...
TL;DR: This Review consolidates the key information on the currently available animal models of obesity and diabetes and highlights the advantages, limitations and important caveats of each of these models.
Abstract: More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.