Showing papers by "Yale University published in 2019"
University of Glasgow1, Brigham and Women's Hospital2, Yale University3, University of Copenhagen4, University of Missouri–Kansas City5, National University of Cordoba6, Wrocław Medical University7, Harvard University8, University of Minnesota9, Charles University in Prague10, Saarland University11, National Yang-Ming University12, Taipei Veterans General Hospital13, Slovak Medical University14, Fudan University15, University of Calgary16, Libin Cardiovascular Institute of Alberta17, Sofia Medical University18, University of Gothenburg19, Semmelweis University20, University of São Paulo21, Montreal Heart Institute22, University of Toronto23, Uppsala University24, University of Wisconsin-Madison25, AstraZeneca26
TL;DR: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than amongThose who received placebo, regardless of the presence or absence of diabetes.
Abstract: Background In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-ind...
3,541 citations
Harvard University1, University of Michigan2, PinnacleHealth System3, St. Luke's Hospital4, Spectrum Health5, Mount Sinai Hospital6, Scripps Research Institute7, University of Kansas8, Yale University9, Johns Hopkins University10, Alfred Hospital11, McGill University12, Saint Francis University13, University of Pittsburgh14, Mayo Clinic15, Medtronic plc16, Paradigm17
TL;DR: In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self‐expanding supraannular bioprosthesis was noninferior to surgery with respect to the composite end point of death or disabling stroke at 24 months.
Abstract: Background Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is know...
2,240 citations
European Bioinformatics Institute1, University of California, Santa Cruz2, University of Lausanne3, University of Bern4, Massachusetts Institute of Technology5, Broad Institute6, Brunel University London7, Yale University8, University of Warsaw9, Ohio State University10, Pompeu Fabra University11, King's College London12
TL;DR: This work generates primary data, creates bioinformatics tools and provides analysis to support the work of expert manual gene annotators and automated gene annotation pipelines to identify and characterise gene loci to the highest standard.
Abstract: The accurate identification and description of the genes in the human and mouse genomes is a fundamental requirement for high quality analysis of data informing both genome biology and clinical genomics. Over the last 15 years, the GENCODE consortium has been producing reference quality gene annotations to provide this foundational resource. The GENCODE consortium includes both experimental and computational biology groups who work together to improve and extend the GENCODE gene annotation. Specifically, we generate primary data, create bioinformatics tools and provide analysis to support the work of expert manual gene annotators and automated gene annotation pipelines. In addition, manual and computational annotation workflows use any and all publicly available data and analysis, along with the research literature to identify and characterise gene loci to the highest standard. GENCODE gene annotations are accessible via the Ensembl and UCSC Genome Browsers, the Ensembl FTP site, Ensembl Biomart, Ensembl Perl and REST APIs as well as https://www.gencodegenes.org.
2,095 citations
Ljubljana University Medical Centre1, King's College London2, Vita-Salute San Raffaele University3, Stanford University4, American Diabetes Association5, University of Padua6, Harvard University7, University of Amsterdam8, University of Sydney9, University of Colorado Denver10, University of Sheffield11, University of Washington12, University of Cambridge13, Shanghai Jiao Tong University14, University of Virginia15, JDRF16, Katholieke Universiteit Leuven17, University of East Anglia18, San Antonio River Authority19, Steno Diabetes Center20, University of Montpellier21, University of Florida22, Nihon University23, Yale University24, Tel Aviv University25
TL;DR: This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
Abstract: Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
1,776 citations
TL;DR: The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
Abstract: The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.
1,691 citations
Barbara Burtness1, Kevin J. Harrington2, Richard Greil, Denis Soulières3 +202 more•Institutions (18)
TL;DR: A randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries finds that pembrolizumab alone improved overall survival and progression-free survival and cetuximab with chemotherapy improved Overall survival in the total population.
1,490 citations
Lundbeck1, Aarhus University2, Harvard University3, Broad Institute4, Karolinska Institutet5, Cardiff University6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, University of Iceland9, deCODE genetics10, Mental Health Services11, Charité12, Semel Institute for Neuroscience and Human Behavior13, University of California, Los Angeles14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Yale University21, Veterans Health Administration22, Children's Hospital of Philadelphia23, Haukeland University Hospital24, University of Bergen25, University of Pennsylvania26, I.M. Sechenov First Moscow State Medical University27, University of Würzburg28, Maastricht University29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
TL;DR: Among patients with HER2‐positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T‐DM1 than with trastuzumab alone.
Abstract: Background Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy have a worse pro...
1,365 citations
TL;DR: Using an improved human mutation rate model, human protein-coding genes are classified along a spectrum representing tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
Abstract: Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
1,128 citations
TL;DR: Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with type 1 diabetes in the United States achieve ADA goals for HbA1c, and racial differences were evident in use of pumps and CGM and Hb a1c levels.
Abstract: Objective To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. Research design and methods Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants. Results Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of 10-fold in children Conclusions Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c.
1,082 citations
New York University1, Lunenfeld-Tanenbaum Research Institute2, Northwood University3, Ghent University Hospital4, Johns Hopkins University School of Medicine5, Brigham and Women's Hospital6, Paris Descartes University7, Cornell University8, University of Fribourg9, University of Cincinnati Academic Health Center10, Yale University11
TL;DR: The PI-RADS Steering Committee, using a consensus-based process, has recommended several modifications to PI- RADS v2, maintaining the framework of assigning scores to individual sequences and using these scores to derive an overall assessment category.
TL;DR: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s as mentioned in this paper.
Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
University of California, San Diego1, Université de Montréal2, Versailles Saint-Quentin-en-Yvelines University3, Curie Institute4, French Institute of Health and Medical Research5, Instituto Português de Oncologia Francisco Gentil6, University of Milan7, Samsung8, Cliniques Universitaires Saint-Luc9, Université catholique de Louvain10, Fox Chase Cancer Center11, Yale University12, Merck & Co.13, Institute of Cancer Research14, The Royal Marsden NHS Foundation Trust15
TL;DR: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of p embrolizUMab as a monotherapy and as part of combination therapy in earlier stages of disease.
TL;DR: The Large Synoptic Survey Telescope (LSST) as discussed by the authors is a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachon in northern Chile.
Abstract: We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the solar system, exploring the transient optical sky, and mapping the Milky Way. LSST will be a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachon in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg2 field of view, a 3.2-gigapixel camera, and six filters (ugrizy) covering the wavelength range 320–1050 nm. The project is in the construction phase and will begin regular survey operations by 2022. About 90% of the observing time will be devoted to a deep-wide-fast survey mode that will uniformly observe a 18,000 deg2 region about 800 times (summed over all six bands) during the anticipated 10 yr of operations and will yield a co-added map to r ~ 27.5. These data will result in databases including about 32 trillion observations of 20 billion galaxies and a similar number of stars, and they will serve the majority of the primary science programs. The remaining 10% of the observing time will be allocated to special projects such as Very Deep and Very Fast time domain surveys, whose details are currently under discussion. We illustrate how the LSST science drivers led to these choices of system parameters, and we describe the expected data products and their characteristics.
Shanghai Jiao Tong University1, University of Ottawa2, AmeriCorps VISTA3, Nagasaki University4, Seoul National University5, National Taiwan University6, Yale University7, Czech University of Life Sciences Prague8, University of Tartu9, Huazhong University of Science and Technology10, University of Washington11, Health Effects Institute12
TL;DR: The data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe, and reinforce the evidence of a link between mortality and PM concentration established in regional and local studies.
Abstract: BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias.METHODS: We evaluated the assoc ...
TL;DR: Evidently, rare viable hybrid offspring between the release strain and the Jacobina population are sufficiently robust to be able to reproduce in nature and highlight the importance of having in place a genetic monitoring program during releases to detect un-anticipated outcomes.
Abstract: In an attempt to control the mosquito-borne diseases yellow fever, dengue, chikungunya, and Zika fevers, a strain of transgenically modified Aedes aegypti mosquitoes containing a dominant lethal gene has been developed by a commercial company, Oxitec Ltd. If lethality is complete, releasing this strain should only reduce population size and not affect the genetics of the target populations. Approximately 450 thousand males of this strain were released each week for 27 months in Jacobina, Bahia, Brazil. We genotyped the release strain and the target Jacobina population before releases began for >21,000 single nucleotide polymorphisms (SNPs). Genetic sampling from the target population six, 12, and 27–30 months after releases commenced provides clear evidence that portions of the transgenic strain genome have been incorporated into the target population. Evidently, rare viable hybrid offspring between the release strain and the Jacobina population are sufficiently robust to be able to reproduce in nature. The release strain was developed using a strain originally from Cuba, then outcrossed to a Mexican population. Thus, Jacobina Ae. aegypti are now a mix of three populations. It is unclear how this may affect disease transmission or affect other efforts to control these dangerous vectors. These results highlight the importance of having in place a genetic monitoring program during such releases to detect un-anticipated outcomes.
TL;DR: The authors explore the potential of the 16S gene for discriminating bacterial taxa and show that full-length sequencing combined with appropriate clustering of intragenomic sequence variation can provide accurate representation of bacterial species in microbiome datasets.
Abstract: The 16S rRNA gene has been a mainstay of sequence-based bacterial analysis for decades. However, high-throughput sequencing of the full gene has only recently become a realistic prospect. Here, we use in silico and sequence-based experiments to critically re-evaluate the potential of the 16S gene to provide taxonomic resolution at species and strain level. We demonstrate that targeting of 16S variable regions with short-read sequencing platforms cannot achieve the taxonomic resolution afforded by sequencing the entire (~1500 bp) gene. We further demonstrate that full-length sequencing platforms are sufficiently accurate to resolve subtle nucleotide substitutions (but not insertions/deletions) that exist between intragenomic copies of the 16S gene. In consequence, we argue that modern analysis approaches must necessarily account for intragenomic variation between 16S gene copies. In particular, we demonstrate that appropriate treatment of full-length 16S intragenomic copy variants has the potential to provide taxonomic resolution of bacterial communities at species and strain level.
University of Texas MD Anderson Cancer Center1, American College of Radiology2, University of Michigan3, University of Wisconsin Hospital and Clinics4, Cleveland Clinic5, University of California, San Francisco6, The Ohio State University Wexner Medical Center7, Yale University8, Fox Chase Cancer Center9, Princess Margaret Cancer Centre10, University Hospitals of Cleveland11, Ohio State University12, University of Oklahoma Health Sciences Center13, Stanford University14, Emory University15, University of Louisville16, Kaiser Permanente17, University of Alabama at Birmingham18, University of Chicago19
TL;DR: After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years).
University College London1, International Institute for Applied Systems Analysis2, University of Reading3, Brighton and Sussex Medical School4, University of London5, Cooperative Institute for Research in Environmental Sciences6, Umeå University7, Tsinghua University8, Cardiff University9, University of Geneva10, University of New England (United States)11, University of Birmingham12, Yale University13, University of Washington14, Northeastern University15, Virginia Tech16, University of York17, Cayetano Heredia University18, University of Sussex19, Nelson Marlborough Institute of Technology20, Emory University21, Columbia University22, Centre for Environment, Fisheries and Aquaculture Science23, Babson College24, Iran University of Medical Sciences25, University of Exeter26, Imperial College London27, University of Colorado Boulder28, Griffith University29, University of Aberdeen30, European Centre for Disease Prevention and Control31, Universiti Teknologi MARA32, Atlantic Oceanographic and Meteorological Laboratory33
TL;DR: The 2019 report of The Lancet Countdown on health and climate change : ensuring that the health of a child born today is not defined by a changing climate is ensured.
TL;DR: Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril–valsartan therapy led to a greater reduction in the N‐terminal pro–B‐type natriuretic peptide concentration than enalapril therapy.
Abstract: Background Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril–valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown. Methods We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. Results Of the 881 patients wh...
Harvard University1, University of Chicago2, Columbia University3, University of Colorado Boulder4, Duke University5, Baptist Health6, Washington University in St. Louis7, University of Minnesota8, Houston Methodist Hospital9, University of Nebraska Medical Center10, Yale University11, MedStar Washington Hospital Center12, University of Michigan13, Advocate Lutheran General Hospital14, St Thomas' Hospital15, University of North Carolina at Chapel Hill16, Piedmont Hospital17, Abbott Laboratories18
TL;DR: Among patients with advanced heart failure, a fully magnetically levitated centrifugal‐flow left ventricular assist device was associated with less frequent need for pump replacement than an axial‐flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device.
Abstract: Background In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device ...
TL;DR: This article found that cognitive reflection test performance is negatively correlated with perceived accuracy of fake news, and positively correlated with the ability to distinguish fake news from real news, even for headlines that align with individuals' political ideology.
University of Pennsylvania1, University of Texas MD Anderson Cancer Center2, University of Marburg3, Memorial Sloan Kettering Cancer Center4, University of Bologna5, Carlos III Health Institute6, University of Maryland, Baltimore7, University of Chicago8, University of Minnesota9, University of Alabama at Birmingham10, Medical University of South Carolina11, University of California, San Francisco12, Thomas Jefferson University13, National Taiwan University14, Yale University15, Centre Hospitalier Universitaire de Toulouse16, University of Fukui17, Seoul National University18, University of Ulsan19, Wake Forest University20, Harvard University21, Astellas Pharma22, Johns Hopkins University23
TL;DR: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.
Abstract: Background Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemothera...
TL;DR: A broad framework is provided for incorporating AI and machine learning tools into clinical oncology, with an emphasis on biomarker development, and some of the challenges relating to the use of AI are discussed, including the need for well-curated validation datasets, regulatory approval and fair reimbursement strategies.
Abstract: In the past decade, advances in precision oncology have resulted in an increased demand for predictive assays that enable the selection and stratification of patients for treatment. The enormous divergence of signalling and transcriptional networks mediating the crosstalk between cancer, stromal and immune cells complicates the development of functionally relevant biomarkers based on a single gene or protein. However, the result of these complex processes can be uniquely captured in the morphometric features of stained tissue specimens. The possibility of digitizing whole-slide images of tissue has led to the advent of artificial intelligence (AI) and machine learning tools in digital pathology, which enable mining of subvisual morphometric phenotypes and might, ultimately, improve patient management. In this Perspective, we critically evaluate various AI-based computational approaches for digital pathology, focusing on deep neural networks and 'hand-crafted' feature-based methodologies. We aim to provide a broad framework for incorporating AI and machine learning tools into clinical oncology, with an emphasis on biomarker development. We discuss some of the challenges relating to the use of AI, including the need for well-curated validation datasets, regulatory approval and fair reimbursement strategies. Finally, we present potential future opportunities for precision oncology.
TL;DR: Transcriptional adaptation, a genetic compensation process by which organisms respond to mutations by upregulating related genes, is triggered by mRNA decay and involves a sequence-dependent mechanism.
Abstract: Genetic robustness, or the ability of an organism to maintain fitness in the presence of harmful mutations, can be achieved via protein feedback loops. Previous work has suggested that organisms may also respond to mutations by transcriptional adaptation, a process by which related gene(s) are upregulated independently of protein feedback loops. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analysing several models of transcriptional adaptation in zebrafish and mouse, we uncover a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. These findings have implications for our understanding of disease-causing mutations, and will help in the design of mutant alleles with minimal transcriptional adaptation-derived compensation.
TL;DR: In this article, the authors reviewed recent progress in the development of AlGaN-based deep-ultraviolet light-emitting devices and described the key obstacles to enhancing their efficiency and how to improve their performance.
Abstract: By alloying GaN with AlN the emission of AlGaN light-emitting diodes can be tuned to cover almost the entire ultraviolet spectral range (210–400 nm), making ultraviolet light-emitting diodes perfectly suited to applications across a wide number of fields, whether biological, environmental, industrial or medical. However, technical developments notwithstanding, deep-ultraviolet light-emitting diodes still exhibit relatively low external quantum efficiencies because of properties intrinsic to aluminium-rich group III nitride materials. Here, we review recent progress in the development of AlGaN-based deep-ultraviolet light-emitting devices. We also describe the key obstacles to enhancing their efficiency and how to improve their performance in terms of defect density, carrier-injection efficiency, light extraction efficiency and heat dissipation. This Review covers recent progress in AlGaN-based deep-ultraviolet light-emitting devices. The key technologies of how to improve their performance, carrier-injection efficiency, light extraction efficiency and heat dissipation are discussed.
TL;DR: Conformal field theories have been long known to describe the universal physics of scale invariant critical points as discussed by the authors, and they describe continuous phase transitions in fluids, magnets, and numerous other materials, while at the same time sit at the heart of our modern understanding of quantum field theory.
Abstract: Conformal field theories have been long known to describe the fascinating universal physics of scale invariant critical points. They describe continuous phase transitions in fluids, magnets, and numerous other materials, while at the same time sit at the heart of our modern understanding of quantum field theory. For decades it has been a dream to study these intricate strongly coupled theories nonperturbatively using symmetries and other consistency conditions. This idea, called the conformal bootstrap, saw some successes in two dimensions but it is only in the last ten years that it has been fully realized in three, four, and other dimensions of interest. This renaissance has been possible both due to significant analytical progress in understanding how to set up the bootstrap equations and the development of numerical techniques for finding or constraining their solutions. These developments have led to a number of groundbreaking results, including world record determinations of critical exponents and correlation function coefficients in the Ising and $O(N)$ models in three dimensions. This article will review these exciting developments for newcomers to the bootstrap, giving an introduction to conformal field theories and the theory of conformal blocks, describing numerical techniques for the bootstrap based on convex optimization, and summarizing in detail their applications to fixed points in three and four dimensions with no or minimal supersymmetry.
TL;DR: This review aims to present consensus recommendations for the optimal perioperative management of patients undergoing thoracic surgery (principally lung resection) using meta-analyses, randomized controlled trials, large non-randomized studies and reviews.
Abstract: Enhanced recovery after surgery is well established in specialties such as colorectal surgery. It is achieved through the introduction of multiple evidence-based perioperative measures that aim to diminish postoperative organ dysfunction while facilitating recovery. This review aims to present consensus recommendations for the optimal perioperative management of patients undergoing thoracic surgery (principally lung resection). A systematic review of meta-analyses, randomized controlled trials, large non-randomized studies and reviews was conducted for each protocol element. Smaller prospective and retrospective cohort studies were considered only when higher-level evidence was unavailable. The quality of the evidence base was graded by the authors and used to form consensus recommendations for each topic. Development of these recommendations was endorsed by the Enhanced Recovery after Surgery Society and the European Society for Thoracic Surgery. Recommendations were developed for a total of 45 enhanced recovery items covering topics related to preadmission, admission, intraoperative care and postoperative care. Most are based on good-quality studies. In some instances, good-quality data were not available, and subsequent recommendations are generic or based on data extrapolated from other specialties. In other cases, no recommendation can currently be made because either equipoise exists or there is a lack of available evidence. Recommendations are based not only on the quality of the evidence but also on the balance between desirable and undesirable effects. Key recommendations include preoperative counselling, nutritional screening, smoking cessation, prehabilitation for high-risk patients, avoidance of fasting, carbohydrate loading, avoidance of preoperative sedatives, venous thromboembolism prophylaxis, prevention of hypothermia, short-acting anaesthetics to facilitate early emergence, regional anaesthesia, nausea and vomiting control, opioid-sparing analgesia, euvolemic fluid management, minimally invasive surgery, early chest drain removal, avoidance of urinary catheters and early mobilization after surgery. These guidelines outline recommendations for the perioperative management of patients undergoing lung surgery based on the best available evidence. As the recommendation grade for most of the elements is strong, the use of a systematic perioperative care pathway has the potential to improve outcomes after surgery.
University of California, Los Angeles1, Memorial Sloan Kettering Cancer Center2, Columbia University Medical Center3, Princess Margaret Cancer Centre4, Samsung Medical Center5, Yale University6, University of Pennsylvania7, Vanderbilt University8, University of California, San Francisco9, Emory University10, Hebron University11, Merck & Co.12, University of Sydney13
TL;DR: Pembrolizumab monotherapy provided durable antitumor activity and high 5-year OS rates in patients with treatment-naive or previously treated advanced NSCLC and had a tolerable long-term safety profile with little evidence of late-onset or new toxicity.
Abstract: PURPOSEPembrolizumab monotherapy has demonstrated durable antitumor activity in advanced programmed death ligand 1 (PD-L1)–expressing non‒small-cell lung cancer (NSCLC). We report 5-year outcomes f...
Ghent University1, University of California, San Diego2, Leiden University3, Dresden University of Technology4, Stanford University5, University of Maryland, College Park6, Indiana University7, University of Cambridge8, Cardiff University9, University of Western Ontario10, Monash University, Clayton campus11, University of Toronto12, University of Vermont13, University of Oregon14, University of Tasmania15, University of Oslo16, Utrecht University17, Katholieke Universiteit Leuven18, Yale University19, Vanderbilt University20, University of Amsterdam21, Anglia Ruskin University22, Indian Institute of Science23, Queen's University24, King's College London25, Michigan State University26, University of Iowa27, Trinity College, Dublin28
TL;DR: The goal is to facilitate a more accurate use of the stop-signal task and provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
Abstract: Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.