Showing papers by "University of Colorado Boulder published in 2018"
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 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
TL;DR: Recommendations regarding the use of the EEO concept, including the upscaling of laboratory results, were derived from an extensive analysis of studies reported in the peer-reviewed literature enabling a critical comparison of various established and emerging AOPs based on electrical energy per order (EEO) values.
1,677 citations
University of Minnesota1, University of Colorado Boulder2, VU University Amsterdam3, Harvard University4, University of Southern California5, University of Tartu6, University of Queensland7, Erasmus University Rotterdam8, Hospital for Special Surgery9, University of Copenhagen10, Statens Serum Institut11, Broad Institute12, University of Essex13, University of Edinburgh14, University of Cambridge15, University Hospital of Lausanne16, Geisinger Health System17, Wenzhou Medical College18, Stanford University19, University of North Carolina at Chapel Hill20, University of Wisconsin-Madison21, Hofstra University22, The Feinstein Institute for Medical Research23, University of Dundee24, University of Toronto25, Princeton University26, National Bureau of Economic Research27, New York University Shanghai28, Queen's University29, Karolinska Institutet30, Uppsala University31, University of Lausanne32, New York University33, Stockholm School of Economics34
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
1,658 citations
TL;DR: This study narrows down the immense number of bacterial taxa to a “most wanted” list that will be fruitful targets for genomic and cultivation-based efforts aimed at improving the understanding of soil microbes and their contributions to ecosystem functioning.
Abstract: The immense diversity of soil bacterial communities has stymied efforts to characterize individual taxa and document their global distributions. We analyzed soils from 237 locations across six continents and found that only 2% of bacterial phylotypes (~500 phylotypes) consistently accounted for almost half of the soil bacterial communities worldwide. Despite the overwhelming diversity of bacterial communities, relatively few bacterial taxa are abundant in soils globally. We clustered these dominant taxa into ecological groups to build the first global atlas of soil bacterial taxa. Our study narrows down the immense number of bacterial taxa to a “most wanted” list that will be fruitful targets for genomic and cultivation-based efforts aimed at improving our understanding of soil microbes and their contributions to ecosystem functioning.
1,204 citations
TL;DR: A hierarchically nanostructured gel (HNG) based on polyvinyl alcohol (PVA) and polypyrrole (PPy) that serves as an independent solar vapour generator that enables highly efficient solar vapours generation.
Abstract: Solar vapour generation is an efficient way of harvesting solar energy for the purification of polluted or saline water. However, water evaporation suffers from either inefficient utilization of solar energy or relies on complex and expensive light-concentration accessories. Here, we demonstrate a hierarchically nanostructured gel (HNG) based on polyvinyl alcohol (PVA) and polypyrrole (PPy) that serves as an independent solar vapour generator. The converted energy can be utilized in situ to power the vaporization of water contained in the molecular meshes of the PVA network, where water evaporation is facilitated by the skeleton of the hydrogel. A floating HNG sample evaporated water with a record high rate of 3.2 kg m−2 h−1 via 94% solar energy from 1 sun irradiation, and 18–23 litres of water per square metre of HNG was delivered daily when purifying brine water. These values were achievable due to the reduced latent heat of water evaporation in the molecular mesh under natural sunlight. Effective energy confinement via tailored water transport in hierarchical nanostructured gels enables highly efficient solar vapour generation.
1,174 citations
TL;DR: Recent progress in addressing stability, how to allow mass production, and how to maintain uniformity of large-area films are reviewed, and the remaining challenges along the pathway to their commercialization are discussed.
Abstract: BACKGROUND Perovskite solar cells (PSCs) have attracted intensive attention because of their ever-increasing power conversion efficiency (PCE), low-cost materials constituents, and simple solution fabrication process. Initiated in 2009 with an efficiency of 3.8%, PSCs have now achieved a lab-scale power conversion efficiency of 23.3%, rivaling the performance of commercial multicrystalline silicon solar cells, as well as copper indium gallium selenide (CIGS) and cadmium telluride (CdTe) thin-film solar cells. Thousands of articles related to PSCs have been published each year since 2015, highlighting PSCs as a topic of intense interest in photovoltaics (PV) research. With high efficiencies achieved in lab devices, stability and remaining challenges in upscaling the manufacture of PSCs are two critical concerns that must be addressed on the path to PSC commercialization. ADVANCES We review recent progress in PSCs and discuss the remaining challenges along the pathway to their commercialization. Device configurations of PSCs (see the figure) include mesoscopic formal (n-i-p) and inverted (p-i-n) structures, planar formal and inverted structures, and the printable triple mesoscopic structures. PCEs of devices that use these structures have advanced rapidly in the case of small-area devices (~0.1 cm 2 ). PSCs are also attracting attention as top cells for the construction of tandem solar cells with existing mature PV technologies to increase efficiency beyond the Shockley-Queisser limit of single-junction devices. The stability of PSCs has attracted much well-deserved attention of late, and notable progress has been made in the past few years. PSCs have recently achieved exhibited lifetimes of 10,000 hours under 1 sun (1 kW/m 2 ) illumination with an ultraviolet filter at a stabilized temperature of 55°C and at short-circuit conditions for a printable triple mesoscopic PSCs. This irradiation is equivalent to the total irradiation of 10 years of outdoor use in most of Europe. However, within the PSC community, standard testing protocols require further development. In addition, transparency in reporting standards on stability tests needs to be improved; this can be achieved by providing both initial photovoltaic performance and normalization parameters. The upscaling of PSCs has also progressed steadily, leading to PSC mini-modules, standard-sized modules, and power systems. PV companies have set out to manufacture large-area PSC modules (see the figure), and a 110-m 2 perovskite PV system with screen-printed triple mesoscopic PSC modules was recently debuted. Studies of these increased-area modules and systems will promote the development of PSCs toward commercialization. PSC research is expanding to cover fundamental topics on materials and lab-sized cells, as well as to address issues of industrial-scale manufacturing and deployment. OUTLOOK The PV market has been continuously expanding in recent years, bringing opportunities for new PV technologies of which PSCs are promising candidates. It is imperative to achieve a low cost per watt, which means that both efficiency and lifetime need improvement relative to current parameters. The efficiency gap between lab cells and industrial modules has seen impressive reductions in crystalline silicon; PSCs must similarly enlarge module areas to the panel level and need to achieve lifetimes comparable to those of legacy PV technologies. Other improvements will need to include industry-scale electronic-grade films, recycling methods to address concerns regarding lead toxicity, and the adoption of standardized testing protocols to predict the operation lifetime of PSCs. Modules will need to endure light-induced degradation, potential-induced degradation, partial-shade stress, and mechanical shock. The field can benefit from lessons learned during the development of mature PV technologies as it strives to define, and overcome, the hurdles to PSC commercial impact.
1,160 citations
Cornell University1, Yale University2, Washington University in St. Louis3, University of Michigan4, University of Vermont5, University of Colorado Boulder6, Florida International University7, Virginia Commonwealth University8, University of Minnesota9, University of California, San Diego10, Harvard University11
TL;DR: An overview of the imaging procedures of the ABCD study is provided, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature are provided.
1,114 citations
TL;DR: The capabilities and design philosophy of the current version of the PySCF package are document, which is as efficient as the best existing C or Fortran‐based quantum chemistry programs.
Abstract: Python-based simulations of chemistry framework (PySCF) is a general-purpose electronic structure platform designed from the ground up to emphasize code simplicity, so as to facilitate new method development and enable flexible computational workflows. The package provides a wide range of tools to support simulations of finite-size systems, extended systems with periodic boundary conditions, low-dimensional periodic systems, and custom Hamiltonians, using mean-field and post-mean-field methods with standard Gaussian basis functions. To ensure ease of extensibility, PySCF uses the Python language to implement almost all of its features, while computationally critical paths are implemented with heavily optimized C routines. Using this combined Python/C implementation, the package is as efficient as the best existing C or Fortran-based quantum chemistry programs. In this paper, we document the capabilities and design philosophy of the current version of the PySCF package. WIREs Comput Mol Sci 2018, 8:e1340. doi: 10.1002/wcms.1340
This article is categorized under:
Structure and Mechanism > Computational Materials Science
Electronic Structure Theory > Ab Initio Electronic Structure Methods
Software > Quantum Chemistry
1,042 citations
TL;DR: It is reported that diverse ADs form phase- separated condensates with the Mediator coactivator, suggesting that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensate with Mediation is involved in gene activation.
1,040 citations
Newcastle University1, Baylor College of Medicine2, Broad Institute3, University of Colorado Boulder4, Pacific Northwest Diabetes Research Institute5, Turku University Hospital6, University of Turku7, Technische Universität München8, Georgia Regents University9, National Institutes of Health10, Lund University11, University of Tampere12, University of South Florida13
TL;DR: Analysis of stool samples from 903 children as part of the TEDDY study shows that breastfeeding was the most important factor associated with microbiome structure, and the cessation of breast milk resulted in faster maturation of the gut microbiome.
Abstract: The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial–immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1–9 such as persistent islet autoimmunity and type 1 diabetes10–12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3–14), a transitional phase (months 15–30), and a stable phase (months 31–46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case–control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial–immune crosstalk for long-term health.
TL;DR: The detection of a flattened absorption profile in the sky-averaged radio spectrum that is largely consistent with expectations for the 21-centimetre signal induced by early stars; however, the best-fitting amplitude of the profile is more than a factor of two greater than the largest predictions.
Abstract: The 21-cm absorption profile is detected in the sky-averaged radio spectrum, but is much stronger than predicted, suggesting that the primordial gas might have been cooler than predicted. As the first stars heated hydrogen in the early Universe, the 21-cm hyperfine line—an astronomical standard that represents the spin-flip transition in the ground state of atomic hydrogen—was altered, causing the hydrogen gas to absorb photons from the microwave background. This should produce an observable absorption signal at frequencies of less than 200 megahertz (MHz). Judd Bowman and colleagues report the observation of an absorption profile centred at a frequency of 78 MHz that is about 19 MHz wide and 0.5 kelvin deep. The profile is generally in line with expectations, although it is deeper than predicted. An accompanying paper by Rennan Barkana suggests that baryons were interacting with cold dark-matter particles in the early Universe, cooling the gas more than had been expected. After stars formed in the early Universe, their ultraviolet light is expected, eventually, to have penetrated the primordial hydrogen gas and altered the excitation state of its 21-centimetre hyperfine line. This alteration would cause the gas to absorb photons from the cosmic microwave background, producing a spectral distortion that should be observable today at radio frequencies of less than 200 megahertz1. Here we report the detection of a flattened absorption profile in the sky-averaged radio spectrum, which is centred at a frequency of 78 megahertz and has a best-fitting full-width at half-maximum of 19 megahertz and an amplitude of 0.5 kelvin. The profile is largely consistent with expectations for the 21-centimetre signal induced by early stars; however, the best-fitting amplitude of the profile is more than a factor of two greater than the largest predictions2. This discrepancy suggests that either the primordial gas was much colder than expected or the background radiation temperature was hotter than expected. Astrophysical phenomena (such as radiation from stars and stellar remnants) are unlikely to account for this discrepancy; of the proposed extensions to the standard model of cosmology and particle physics, only cooling of the gas as a result of interactions between dark matter and baryons seems to explain the observed amplitude3. The low-frequency edge of the observed profile indicates that stars existed and had produced a background of Lyman-α photons by 180 million years after the Big Bang. The high-frequency edge indicates that the gas was heated to above the radiation temperature less than 100 million years later.
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.
Institute for Health Metrics and Evaluation1, University of Louisville2, Karolinska Institutet3, Kermanshah University of Medical Sciences4, University of Queensland5, Centre for Mental Health6, Tehran University of Medical Sciences7, South African Medical Research Council8, University of KwaZulu-Natal9, University of Colorado Boulder10, University of California, Irvine11, Fred Hutchinson Cancer Research Center12, Montefiore Medical Center13, Northeastern University14, University of Alabama at Birmingham15, Brown University16, San Diego State University17, University of Melbourne18, Albert Einstein College of Medicine19, Cambridge Health Alliance20, Johns Hopkins University21, University of Pittsburgh22, University of Cape Town23, Marshall University24, Case Western Reserve University25, University of London26, University of Illinois at Urbana–Champaign27, National Drug and Alcohol Research Centre28, Harvard University29, University of California, San Diego30, Yale University31, Georgetown University32, Veterans Health Administration33, Jackson State University34, University of Massachusetts Boston35, State University of New York System36, Simmons College37, University of California, Los Angeles38, Charles R. Drew University of Medicine and Science39, University of Oxford40, Norwegian Institute of Public Health41, Pacific Institute42, Curtin University43, Heidelberg University44, Jimma University45, Northwestern University46, Washington University in St. Louis47, Howard University48, University of New Mexico49, University at Buffalo50, University of Washington51, University of South Florida52, Tufts University53, University of Rochester Medical Center54, Kosin University55, Central South University56, Michigan State University57, Ball State University58, Nova Southeastern University59, Dalhousie University60, Mayo Clinic61, University of British Columbia62, Ohio State University63, Baylor University64, Wrocław Medical University65, Jagiellonian University Medical College66, Dartmouth College67, University of Western Ontario68, Oregon Health & Science University69, Virginia Commonwealth University70, Columbia University71, University of Canberra72, Aga Khan University73
TL;DR: There are wide differences in the burden of disease at the state level and specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention.
Abstract: Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.
University of California, Irvine1, California Institute of Technology2, Carnegie Institution for Science3, Joint Institute for Nuclear Research4, National Renewable Energy Laboratory5, Carnegie Mellon University6, Stanford University7, Colorado State University8, Massachusetts Institute of Technology9, Rocky Mountain Institute10, Imperial College London11, Joint BioEnergy Institute12, College of the Holy Cross13, University of Colorado Boulder14, Colorado School of Mines15, New York University16, Arizona State University17, University of California, Davis18, University of California, Berkeley19, Santa Fe Institute20
TL;DR: In this paper, the authors examine barriers and opportunities associated with these difficult-to-decarbonize services and processes, including possible technological solutions and research and development priorities, and examine the use of existing technologies to meet future demands for these services without net addition of CO2 to the atmosphere.
Abstract: Some energy services and industrial processes-such as long-distance freight transport, air travel, highly reliable electricity, and steel and cement manufacturing-are particularly difficult to provide without adding carbon dioxide (CO2) to the atmosphere. Rapidly growing demand for these services, combined with long lead times for technology development and long lifetimes of energy infrastructure, make decarbonization of these services both essential and urgent. We examine barriers and opportunities associated with these difficult-to-decarbonize services and processes, including possible technological solutions and research and development priorities. A range of existing technologies could meet future demands for these services and processes without net addition of CO2 to the atmosphere, but their use may depend on a combination of cost reductions via research and innovation, as well as coordinated deployment and integration of operations across currently discrete energy industries.
Harvard University1, University of Colorado Boulder2, Aix-Marseille University3, Curie Institute4, Texas Oncology5, University of Michigan6, Swansea University7, European Institute of Oncology8, Cross Cancer Institute9, Princess Margaret Cancer Centre10, Hospital General Universitario Gregorio Marañón11, Bristol-Myers Squibb12, The Royal Marsden NHS Foundation Trust13, Memorial Sloan Kettering Cancer Center14, Cornell University15
TL;DR: The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018.
Abstract: Summary Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44–0·67; p Interpretation The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. Funding Bristol-Myers Squibb.
University of Texas MD Anderson Cancer Center1, University of South Florida2, University of California, San Francisco3, Harvard University4, University of North Carolina at Chapel Hill5, University of Colorado Boulder6, University of Michigan7, Memorial Sloan Kettering Cancer Center8, Georgetown University9, Roswell Park Cancer Institute10, Emory University11, Stanford University12, University of Pittsburgh13, Cleveland Clinic14, New York University15, Bristol-Myers Squibb16, City of Hope National Medical Center17
TL;DR: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases.
Abstract: Background Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab ...
VU University Amsterdam1, Erasmus University Rotterdam2, Karolinska Institutet3, Charité4, Virginia Commonwealth University5, South London and Maudsley NHS Foundation Trust6, QIMR Berghofer Medical Research Institute7, King's College London8, University of Southern Denmark9, University of California, Riverside10, University of Southern California11, University of Minnesota12, University of Queensland13, University College London14, Johns Hopkins University15, University of California, Los Angeles16, University of Crete17, Veterans Health Administration18, Harvard University19, Icahn School of Medicine at Mount Sinai20, Yale University21, Haukeland University Hospital22, Trinity College, Dublin23, University of Edinburgh24, Hofstra University25, North Shore-LIJ Health System26, National Institutes of Health27, University of Bergen28, Oslo University Hospital29, National University of Ireland, Galway30, University of Helsinki31, University of Oslo32, Martin Luther University of Halle-Wittenberg33, Duke University34, Mental Health Research Institute35, National and Kapodistrian University of Athens36, University of Colorado Boulder37, Imperial College London38, University of Manchester39, Wellcome Trust40, Manchester Academic Health Science Centre41, Stanford University42, University of Oregon43, University of Toronto44, University of Michigan45, Erasmus University Medical Center46, Broad Institute47, University of North Carolina at Chapel Hill48
TL;DR: A large-scale genetic association study of intelligence identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure, a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
University of Leeds1, California Institute of Technology2, University of California, Irvine3, University of Washington4, Durham University5, University of Grenoble6, Goddard Space Flight Center7, University of Bristol8, University of Colorado Boulder9, Geological Survey of Denmark and Greenland10, University at Buffalo11, National Space Institute12, University of South Florida13, University of Texas at Austin14, University College London15, Dresden University of Technology16, Georgia Institute of Technology17, University of Lincoln18, University of Arizona19, Alfred Wegener Institute for Polar and Marine Research20, Technische Universität München21, Danish Meteorological Institute22, Memorial University of Newfoundland23, National Institute of Geophysics and Volcanology24, Bergen University College25, Remote Sensing Center26, University of Magallanes27, Newcastle University28, University of Toronto29, University of Bonn30, Delft University of Technology31, Seoul National University32, University of Urbino33, University of Stuttgart34
TL;DR: This work combines satellite observations of its changing volume, flow and gravitational attraction with modelling of its surface mass balance to show that the Antarctic Ice Sheet lost 2,720 ± 1,390 billion tonnes of ice between 1992 and 2017, which corresponds to an increase in mean sea level of 7.6‚¬3.9 millimetres.
Abstract: The Antarctic Ice Sheet is an important indicator of climate change and driver of sea-level rise. Here we combine satellite observations of its changing volume, flow and gravitational attraction with modelling of its surface mass balance to show that it lost 2,720 ± 1,390 billion tonnes of ice between 1992 and 2017, which corresponds to an increase in mean sea level of 7.6 ± 3.9 millimetres (errors are one standard deviation). Over this period, ocean-driven melting has caused rates of ice loss from West Antarctica to increase from 53 ± 29 billion to 159 ± 26 billion tonnes per year; ice-shelf collapse has increased the rate of ice loss from the Antarctic Peninsula from 7 ± 13 billion to 33 ± 16 billion tonnes per year. We find large variations in and among model estimates of surface mass balance and glacial isostatic adjustment for East Antarctica, with its average rate of mass gain over the period 1992–2017 (5 ± 46 billion tonnes per year) being the least certain.
TL;DR: The authors' models show that for the three most important grain crops—wheat, rice, and maize—yield lost to insects will increase by 10 to 25% per degree Celsius of warming, hitting hardest in the temperate zone.
Abstract: Insect pests substantially reduce yields of three staple grains—rice, maize, and wheat—but models assessing the agricultural impacts of global warming rarely consider crop losses to insects. We use established relationships between temperature and the population growth and metabolic rates of insects to estimate how and where climate warming will augment losses of rice, maize, and wheat to insects. Global yield losses of these grains are projected to increase by 10 to 25% per degree of global mean surface warming. Crop losses will be most acute in areas where warming increases both population growth and metabolic rates of insects. These conditions are centered primarily in temperate regions, where most grain is produced.
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.
Broad Institute1, Harvard University2, VU University Amsterdam3, University of Minnesota4, Hospital for Special Surgery5, University of Southern California6, University of Colorado Boulder7, Karolinska Institutet8, Uppsala University9, Stockholm School of Economics10, University of Queensland11, National Bureau of Economic Research12, New York University13, Research Institute of Industrial Economics14
TL;DR: Applying MTAG to summary statistics for depressive symptoms, neuroticism and subjective well-being increased discovery of associated loci as compared to single-trait analyses, yielding more informative bioinformatics analyses and increasing the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.
Abstract: We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (N eff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.
TL;DR: Any application of an optical-frequency source could benefit from the high-precision optical synthesis presented here, and leveraging high-volume semiconductor processing built around advanced materials could allow such low-cost, low-power and compact integrated-photonics devices to be widely used.
Abstract: Optical-frequency synthesizers, which generate frequency-stable light from a single microwave-frequency reference, are revolutionizing ultrafast science and metrology, but their size, power requirement and cost need to be reduced if they are to be more widely used. Integrated-photonics microchips can be used in high-coherence applications, such as data transmission1, highly optimized physical sensors2 and harnessing quantum states3, to lower cost and increase efficiency and portability. Here we describe a method for synthesizing the absolute frequency of a lightwave signal, using integrated photonics to create a phase-coherent microwave-to-optical link. We use a heterogeneously integrated III–V/silicon tunable laser, which is guided by nonlinear frequency combs fabricated on separate silicon chips and pumped by off-chip lasers. The laser frequency output of our optical-frequency synthesizer can be programmed by a microwave clock across 4 terahertz near 1,550 nanometres (the telecommunications C-band) with 1 hertz resolution. Our measurements verify that the output of the synthesizer is exceptionally stable across this region (synthesis error of 7.7 × 10−15 or below). Any application of an optical-frequency source could benefit from the high-precision optical synthesis presented here. Leveraging high-volume semiconductor processing built around advanced materials could allow such low-cost, low-power and compact integrated-photonics devices to be widely used. An optical-frequency synthesizer based on stabilized frequency combs has been developed utilizing chip-scale devices as key components, in a move towards using integrated photonics technology for ultrafast science and metrology.
Earth System Research Laboratory1, Cooperative Institute for Research in Environmental Sciences2, Colorado State University3, University of California, Davis4, University of Colorado Boulder5, National Center for Atmospheric Research6, Université de Montréal7, Yale University8, Virginia Tech9, University of California, Berkeley10
TL;DR: It is shown that human exposure to carbonaceous aerosols of fossil origin is transitioning away from transportation-related sources and toward VCPs, and the focus of efforts to mitigate ozone formation and toxic chemical burdens need to be adjusted.
Abstract: A gap in emission inventories of urban volatile organic compound (VOC) sources, which contribute to regional ozone and aerosol burdens, has increased as transportation emissions in the United States and Europe have declined rapidly. A detailed mass balance demonstrates that the use of volatile chemical products (VCPs)—including pesticides, coatings, printing inks, adhesives, cleaning agents, and personal care products—now constitutes half of fossil fuel VOC emissions in industrialized cities. The high fraction of VCP emissions is consistent with observed urban outdoor and indoor air measurements. We show that human exposure to carbonaceous aerosols of fossil origin is transitioning away from transportation-related sources and toward VCPs. Existing U.S. regulations on VCPs emphasize mitigating ozone and air toxics, but they currently exempt many chemicals that lead to secondary organic aerosols.
TL;DR: A way of integrating photonics with silicon nanoelectronics is described, using polycrystalline silicon on glass islands alongside transistors on bulk silicon complementary metal–oxide–semiconductor chips to address the demand for high-bandwidth optical interconnects in data centres and high-performance computing.
Abstract: Electronic and photonic technologies have transformed our lives-from computing and mobile devices, to information technology and the internet. Our future demands in these fields require innovation in each technology separately, but also depend on our ability to harness their complementary physics through integrated solutions1,2. This goal is hindered by the fact that most silicon nanotechnologies-which enable our processors, computer memory, communications chips and image sensors-rely on bulk silicon substrates, a cost-effective solution with an abundant supply chain, but with substantial limitations for the integration of photonic functions. Here we introduce photonics into bulk silicon complementary metal-oxide-semiconductor (CMOS) chips using a layer of polycrystalline silicon deposited on silicon oxide (glass) islands fabricated alongside transistors. We use this single deposited layer to realize optical waveguides and resonators, high-speed optical modulators and sensitive avalanche photodetectors. We integrated this photonic platform with a 65-nanometre-transistor bulk CMOS process technology inside a 300-millimetre-diameter-wafer microelectronics foundry. We then implemented integrated high-speed optical transceivers in this platform that operate at ten gigabits per second, composed of millions of transistors, and arrayed on a single optical bus for wavelength division multiplexing, to address the demand for high-bandwidth optical interconnects in data centres and high-performance computing3,4. By decoupling the formation of photonic devices from that of transistors, this integration approach can achieve many of the goals of multi-chip solutions 5 , but with the performance, complexity and scalability of 'systems on a chip'1,6-8. As transistors smaller than ten nanometres across become commercially available 9 , and as new nanotechnologies emerge10,11, this approach could provide a way to integrate photonics with state-of-the-art nanoelectronics.
TL;DR: A class of soft actuators is described, termed hydraulically amplified self-healing electrostatic (HASEL) actuators, which harness a mechanism that couples electrostatic and hydraulic forces to achieve a variety of actuation modes and demonstrate their robust, muscle-like performance as well as their ability to repeatedly self- heal after dielectric breakdown.
Abstract: Existing soft actuators have persistent challenges that restrain the potential of soft robotics, highlighting a need for soft transducers that are powerful, high-speed, efficient, and robust. We describe a class of soft actuators, termed hydraulically amplified self-healing electrostatic (HASEL) actuators, which harness a mechanism that couples electrostatic and hydraulic forces to achieve a variety of actuation modes. We introduce prototypical designs of HASEL actuators and demonstrate their robust, muscle-like performance as well as their ability to repeatedly self-heal after dielectric breakdown—all using widely available materials and common fabrication techniques. A soft gripper handling delicate objects and a self-sensing artificial muscle powering a robotic arm illustrate the wide potential of HASEL actuators for next-generation soft robotic devices.
Pusan National University1, University of Hawaii at Manoa2, Yonsei University3, Pohang University of Science and Technology4, Commonwealth Scientific and Industrial Research Organisation5, Hobart Corporation6, Ocean University of China7, University of Colorado Boulder8, Earth System Research Laboratory9, Georgia Institute of Technology10, University of Paris11, Pacific Marine Environmental Laboratory12, University Corporation for Atmospheric Research13, University of Washington14, Geophysical Fluid Dynamics Laboratory15, Leibniz Institute of Marine Sciences16, National Taiwan University17, Utah State University18, Monash University, Clayton campus19, University of Mary Washington20, University of Reading21, Centre national de la recherche scientifique22, Chonnam National University23, Met Office24, Ulsan National Institute of Science and Technology25, Asia-Pacific Economic Cooperation26, Bureau of Meteorology27, China Meteorological Administration28, University of New South Wales29, University of Exeter30, Chinese Academy of Sciences31, Hanyang University32, Gwangju Institute of Science and Technology33
TL;DR: A synopsis of the current understanding of the spatio-temporal complexity of this important climate mode and its influence on the Earth system is provided and a unifying framework that identifies the key factors for this complexity is proposed.
Abstract: El Nino events are characterized by surface warming of the tropical Pacific Ocean and weakening of equatorial trade winds that occur every few years Such conditions are accompanied by changes in atmospheric and oceanic circulation, affecting global climate, marine and terrestrial ecosystems, fisheries and human activities The alternation of warm El Nino and cold La Nina conditions, referred to as the El Nino–Southern Oscillation (ENSO), represents the strongest year-to-year fluctuation of the global climate system Here we provide a synopsis of our current understanding of the spatio-temporal complexity of this important climate mode and its influence on the Earth system
Environmental Defense Fund1, University of Texas at Austin2, Pennsylvania State University3, Stanford University4, Harvard University5, National Institute of Standards and Technology6, University of Michigan7, Washington State University8, Colorado State University9, Princeton University10, University of Colorado Boulder11, Earth System Research Laboratory12, Carnegie Mellon University13, Purdue University14, University of Cincinnati15
TL;DR: The magnitude of this leakage was reassessed and it was found that in 2015, supply chain emissions were ∼60% higher than the U.S. Environmental Protection Agency inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions.
Abstract: Methane emissions from the U.S. oil and natural gas supply chain were estimated by using ground-based, facility-scale measurements and validated with aircraft observations in areas accounting for ~30% of U.S. gas production. When scaled up nationally, our facility-based estimate of 2015 supply chain emissions is 13 ± 2 teragrams per year, equivalent to 2.3% of gross U.S. gas production. This value is ~60% higher than the U.S. Environmental Protection Agency inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions. Methane emissions of this magnitude, per unit of natural gas consumed, produce radiative forcing over a 20-year time horizon comparable to the CO2 from natural gas combustion. Substantial emission reductions are feasible through rapid detection of the root causes of high emissions and deployment of less failure-prone systems.
University College London1, International Institute for Applied Systems Analysis2, University of Reading3, University of London4, University of Sydney5, World Bank6, Cooperative Institute for Research in Environmental Sciences7, Umeå University8, Tsinghua University9, University of Geneva10, University of New England (United States)11, University of Birmingham12, Paris-Sorbonne University13, University of Washington14, Heidelberg University15, International Livestock Research Institute16, University of York17, Cayetano Heredia University18, University of Sussex19, Nelson Marlborough Institute of Technology20, University of North Texas21, Centre for Environment, Fisheries and Aquaculture Science22, University of Colorado Boulder23, University of Essex24, Iran University of Medical Sciences25, University of Exeter26, Imperial College London27, Atlantic Oceanographic and Meteorological Laboratory28
TL;DR: The Lancet Countdown tracks 41 indicators across five domains: climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; finance and economics; and public and political engagement.