Showing papers by "Ludwig Maximilian University of Munich 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
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
1,898 citations
TL;DR: This work presents a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and shows that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
1,620 citations
University of Southern California1, Duke University2, Stockholm School of Economics3, University of Virginia4, Center for Open Science5, University of Amsterdam6, University of Pennsylvania7, University of North Carolina at Chapel Hill8, University of Regensburg9, California Institute of Technology10, Research Institute of Industrial Economics11, New York University12, Cardiff University13, Mathematica Policy Research14, Northwestern University15, Ohio State University16, University of Sussex17, Texas A&M University18, Royal Holloway, University of London19, University of Zurich20, University of Melbourne21, University of Wisconsin-Madison22, University of Michigan23, Stanford University24, Rutgers University25, Columbia University26, University of Washington27, University of Edinburgh28, National University of Singapore29, Utrecht University30, Arizona State University31, Princeton University32, University of California, Los Angeles33, Imperial College London34, University of Innsbruck35, Harvard University36, University of Chicago37, University of Pittsburgh38, University of Notre Dame39, University of California, Berkeley40, Johns Hopkins University41, University of Bristol42, University of New South Wales43, Dartmouth College44, Whitman College45, University of Puerto Rico46, University of Milan47, University of California, Irvine48, Paris Dauphine University49, University of British Columbia50, Ludwig Maximilian University of Munich51, Purdue University52, Washington University in St. Louis53, University of California, Davis54, Microsoft55
TL;DR: The default P-value threshold for statistical significance is proposed to be changed from 0.05 to 0.005 for claims of new discoveries in order to reduce uncertainty in the number of discoveries.
Abstract: We propose to change the default P-value threshold for statistical significance from 0.05 to 0.005 for claims of new discoveries.
1,586 citations
University of East Anglia1, University of Exeter2, Alfred Wegener Institute for Polar and Marine Research3, Max Planck Society4, Ludwig Maximilian University of Munich5, Commonwealth Scientific and Industrial Research Organisation6, Karlsruhe Institute of Technology7, Cooperative Institute for Marine and Atmospheric Studies8, Atlantic Oceanographic and Meteorological Laboratory9, École Normale Supérieure10, Centre national de la recherche scientifique11, University of Maryland, College Park12, University of Virginia13, Flanders Marine Institute14, Oak Ridge National Laboratory15, Woods Hole Research Center16, University of Illinois at Urbana–Champaign17, Geophysical Institute, University of Bergen18, Met Office19, University of California, San Diego20, Utrecht University21, Netherlands Environmental Assessment Agency22, University of Paris23, Oeschger Centre for Climate Change Research24, Tsinghua University25, National Center for Atmospheric Research26, Institute of Arctic and Alpine Research27, National Institute for Environmental Studies28, Hobart Corporation29, Cooperative Research Centre30, Japan Agency for Marine-Earth Science and Technology31, Wageningen University and Research Centre32, University of Groningen33, Bjerknes Centre for Climate Research34, Goddard Space Flight Center35, Leibniz Institute for Baltic Sea Research36, Princeton University37, Leibniz Institute of Marine Sciences38, National Oceanic and Atmospheric Administration39, Auburn University40, Food and Agriculture Organization41, VU University Amsterdam42
TL;DR: In this article, the authors describe data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties, including emissions from land use and land-use change data and bookkeeping models.
Abstract: . Accurate assessment of anthropogenic carbon dioxide
( CO2 ) emissions and their redistribution among the atmosphere,
ocean, and terrestrial biosphere – the “global carbon budget” – is
important to better understand the global carbon cycle, support the
development of climate policies, and project future climate change. Here we
describe data sets and methodology to quantify the five major components of
the global carbon budget and their uncertainties. Fossil CO2
emissions ( EFF ) are based on energy statistics and cement
production data, while emissions from land use and land-use change ( ELUC ),
mainly deforestation, are based on land use and land-use change data and
bookkeeping models. Atmospheric CO2 concentration is measured
directly and its growth rate ( GATM ) is computed from the annual
changes in concentration. The ocean CO2 sink ( SOCEAN )
and terrestrial CO2 sink ( SLAND ) are estimated with
global process models constrained by observations. The resulting carbon
budget imbalance ( BIM ), the difference between the estimated
total emissions and the estimated changes in the atmosphere, ocean, and
terrestrial biosphere, is a measure of imperfect data and understanding of
the contemporary carbon cycle. All uncertainties are reported as ±1σ . For the last decade available (2008–2017), EFF was
9.4±0.5 GtC yr −1 , ELUC 1.5±0.7 GtC yr −1 , GATM 4.7±0.02 GtC yr −1 ,
SOCEAN 2.4±0.5 GtC yr −1 , and SLAND 3.2±0.8 GtC yr −1 , with a budget imbalance BIM of
0.5 GtC yr −1 indicating overestimated emissions and/or underestimated
sinks. For the year 2017 alone, the growth in EFF was about 1.6 %
and emissions increased to 9.9±0.5 GtC yr −1 . Also for 2017,
ELUC was 1.4±0.7 GtC yr −1 , GATM was 4.6±0.2 GtC yr −1 , SOCEAN was 2.5±0.5 GtC yr −1 , and SLAND was 3.8±0.8 GtC yr −1 ,
with a BIM of 0.3 GtC. The global atmospheric
CO2 concentration reached 405.0±0.1 ppm averaged over 2017.
For 2018, preliminary data for the first 6–9 months indicate a renewed
growth in EFF of + 2.7 % (range of 1.8 % to 3.7 %) based
on national emission projections for China, the US, the EU, and India and
projections of gross domestic product corrected for recent changes in the
carbon intensity of the economy for the rest of the world. The analysis
presented here shows that the mean and trend in the five components of the
global carbon budget are consistently estimated over the period of 1959–2017,
but discrepancies of up to 1 GtC yr −1 persist for the representation
of semi-decadal variability in CO2 fluxes. A detailed comparison
among individual estimates and the introduction of a broad range of
observations show (1) no consensus in the mean and trend in land-use change
emissions, (2) a persistent low agreement among the different methods on
the magnitude of the land CO2 flux in the northern extra-tropics,
and (3) an apparent underestimation of the CO2 variability by ocean
models, originating outside the tropics. This living data update documents
changes in the methods and data sets used in this new global carbon budget
and the progress in understanding the global carbon cycle compared with
previous publications of this data set (Le Quere et al., 2018, 2016,
2015a, b, 2014, 2013). All results presented here can be downloaded from
https://doi.org/10.18160/GCP-2018 .
1,458 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan1, Brendan Bulik-Sullivan2 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
Cardiff University1, Charité2, Harvard University3, King's College London4, Broad Institute5, University of Adelaide6, Centre for Mental Health7, University of Queensland8, University of Münster9, University of Edinburgh10, QIMR Berghofer Medical Research Institute11, University of Vigo12, University of California, Los Angeles13, Icahn School of Medicine at Mount Sinai14, University of Oviedo15, Lundbeck16, Aarhus University17, Oslo University Hospital18, University of Oslo19, Statens Serum Institut20, University of Bergen21, Aarhus University Hospital22, University of Copenhagen23, University of Belgrade24, Tbilisi State Medical University25, deCODE genetics26, University of Verona27, Mental Health Services28, Eli Lilly and Company29, Martin Luther University of Halle-Wittenberg30, Ludwig Maximilian University of Munich31
TL;DR: A new genome-wide association study of schizophrenia is reported, and through meta-analysis with existing data and integrating genomic fine-mapping with brain expression and chromosome conformation data, 50 novel associated loci and 145 loci are identified.
Abstract: Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
1,259 citations
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
University of Milan1, Instituto Português de Oncologia Francisco Gentil2, Curie Institute3, Leiden University Medical Center4, Vienna General Hospital5, University College London6, Leiden University7, Institut Jules Bordet8, Netherlands Cancer Institute9, Turku University Hospital10, University of Oxford11, University of Mannheim12, Ludwig Maximilian University of Munich13, Helsinki University Central Hospital14, The Royal Marsden NHS Foundation Trust15, Institute of Cancer Research16, University Medical Center Groningen17, Radboud University Nijmegen18, Institut Gustave Roussy19, Tel Aviv Sourasky Medical Center20, University Hospital of Lausanne21, University of Bologna22, University of Turin23, Weston Park Hospital24, Aarhus University Hospital25, Katholieke Universiteit Leuven26, Erasmus University Rotterdam27, Oslo University Hospital28, University College Hospital29, Claude Bernard University Lyon 130
1,150 citations
University of Oxford1, University of Michigan2, Wellcome Trust Sanger Institute3, Amgen4, University of Cambridge5, University of Copenhagen6, University of Liverpool7, University of Freiburg8, Boston University9, University of Tartu10, Erasmus University Medical Center11, Leiden University Medical Center12, Pasteur Institute13, Icahn School of Medicine at Mount Sinai14, UCLA Medical Center15, Vanderbilt University Medical Center16, Wake Forest University17, National University of Singapore18, London North West Healthcare NHS Trust19, Imperial College London20, Charité21, Innsbruck Medical University22, Washington University in St. Louis23, Queen Mary University of London24, University of Southern Denmark25, National and Kapodistrian University of Athens26, Robertson Centre for Biostatistics27, University of Exeter28, Uppsala University29, University of Düsseldorf30, Steno Diabetes Center31, Aalborg University32, University of Eastern Finland33, Broad Institute34, Frederiksberg Hospital35, Lund University36, University of Bergen37, Technische Universität München38, University of North Carolina at Chapel Hill39, Ninewells Hospital40, University of Edinburgh41, University of Minnesota42, University of Glasgow43, Ludwig Maximilian University of Munich44, University of Iceland45, Aarhus University46, Science for Life Laboratory47, Stanford University48, University of Helsinki49, National Institutes of Health50, University of Dundee51, Harvard University52
TL;DR: Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
1,136 citations
TL;DR: This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors and gives practical guidance to the management of the cytokine release syndrome.
Abstract: During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.
Susanne Gröbner1, Barbara C. Worst, Joachim Weischenfeldt2, Joachim Weischenfeldt3 +182 more•Institutions (23)
TL;DR: The data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
Abstract: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
TL;DR: This work used live-cell superresolution and light-sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly and suggests that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.
Abstract: Models of gene control have emerged from genetic and biochemical studies, with limited consideration of the spatial organization and dynamics of key components in living cells. We used live-cell superresolution and light-sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly. Mediator and Pol II each form small transient and large stable clusters in living embryonic stem cells. Mediator and Pol II are colocalized in the stable clusters, which associate with chromatin, have properties of phase-separated condensates, and are sensitive to transcriptional inhibitors. We suggest that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.
TL;DR: The Global Preference Survey (GPS) as discussed by the authors ) is an experimentally validated survey dataset of time preference, risk preference, positive and negative reciprocity, altruism, and trust from 80,000 individuals in 76 countries.
Abstract: This paper studies the global variation in economic preferences. For this purpose, we present the Global Preference Survey (GPS), an experimentally validated survey dataset of time preference, risk preference, positive and negative reciprocity, altruism, and trust from 80,000 individuals in 76 countries. The data reveal substantial heterogeneity in preferences across countries, but even larger within-country heterogeneity. Across individuals, preferences vary with age, gender, and cognitive ability, yet these relationships appear partly country specific. At the country level, the data reveal correlations between preferences and bio-geographic and cultural variables such as agricultural suitability, language structure, and religion. Variation in preferences is also correlated with economic outcomes and behaviors. Within countries and subnational regions, preferences are linked to individual savings decisions, labor market choices, and prosocial behaviors. Across countries, preferences vary with aggregate outcomes ranging from per capita income, to entrepreneurial activities, to the frequency of armed conflicts.
TL;DR: Covalent organic frameworks (COFs) as mentioned in this paper are crystalline porous polymers formed by a bottom-up approach from molecular building units having a predesigned geometry that are connected through covalent bonds.
Abstract: Covalent organic frameworks (COFs) are crystalline porous polymers formed by a bottom-up approach from molecular building units having a predesigned geometry that are connected through covalent bonds. They offer positional control over their building blocks in two and three dimensions. This control enables the synthesis of rigid porous structures with a high regularity and the ability to fine-tune the chemical and physical properties of the network. This Feature Article provides a comprehensive overview over the structures realized to date in the fast growing field of covalent organic framework development. Different synthesis strategies to meet diverse demands, such as high crystallinity, straightforward processability, or the formation of thin films are discussed. Furthermore, insights into the growing fields of COF applications, including gas storage and separations, sensing, electrochemical energy storage, and optoelectronics are provided.
Harvard University1, University of Chile2, Rice University3, Heidelberg University4, Pontifical Catholic University of Chile5, University of Nevada, Las Vegas6, Ludwig Maximilian University of Munich7, Tsinghua University8, University of Grenoble9, Wesleyan University10, California State University, Northridge11
TL;DR: The Disk Substructures at High Angular Resolution Project (DSHARP) as mentioned in this paper was the first large-scale project to find and characterize substructures in the spatial distributions of solid particles for a sample of 20 nearby protoplanetary disks, using very high resolution (similar to 0'' 035 or 5 au, FWHM) observations of their 240 GHz (1.25 mm) continuum emission.
Abstract: We introduce the Disk Substructures at High Angular Resolution Project (DSHARP), one of the initial Large Programs conducted with the Atacama Large Millimeter/submillimeter Array (ALMA). The primary goal of DSHARP is to find and characterize substructures in the spatial distributions of solid particles for a sample of 20 nearby protoplanetary disks, using very high resolution (similar to 0.'' 035, or 5 au, FWHM) observations of their 240 GHz (1.25 mm) continuum emission. These data provide a first homogeneous look at the small-scale features in disks that are directly relevant to the planet formation process, quantifying their prevalence, morphologies, spatial scales, spacings, symmetry, and amplitudes, for targets with a variety of disk and stellar host properties. We find that these substructures are ubiquitous in this sample of large, bright disks. They are most frequently manifested as concentric, narrow emission rings and depleted gaps, although large-scale spiral patterns and small arc-shaped azimuthal asymmetries are also present in some cases. These substructures are found at a wide range of disk radii (from a few astronomical units to more than 100 au), are usually compact (less than or similar to 10 au), and show a wide range of amplitudes (brightness contrasts). Here we discuss the motivation for the project, describe the survey design and the sample properties, detail the observations and data calibration, highlight some basic results, and provide a general overview of the key conclusions that are presented in more detail in a series of accompanying articles. The DSHARP data-including visibilities, images, calibration scripts, and more-are released for community use at https://almascience.org/alma-data/lp/DSHARP.
TL;DR: The authors leverage strongly localised plasmonic heating of graphene carriers to detect a second photothermoelectric effect occurring across a homogeneous channel in the presence of an electronic temperature gradient.
Abstract: Graphene has emerged as a promising material for optoelectronics due to its potential for ultrafast and broad-band photodetection. The photoresponse of graphene junctions is characterized by two competing photocurrent generation mechanisms: a conventional photovoltaic effect and a more dominant hot-carrier-assisted photothermoelectric (PTE) effect. The PTE effect is understood to rely on variations in the Seebeck coefficient through the graphene doping profile. A second PTE effect can occur across a homogeneous graphene channel in the presence of an electronic temperature gradient. Here, we study the latter effect facilitated by strongly localised plasmonic heating of graphene carriers in the presence of nanostructured electrical contacts resulting in electronic temperatures of the order of 2000 K. At certain conditions, the plasmon-induced PTE photocurrent contribution can be isolated. In this regime, the device effectively operates as a sensitive electronic thermometer and as such represents an enabling technology for development of hot carrier based plasmonic devices.
California Institute of Technology1, Stockholm School of Economics2, University of Innsbruck3, National University of Singapore4, University of Pennsylvania5, University of Virginia6, Center for Open Science7, Harvard University8, Ludwig Maximilian University of Munich9, University of Amsterdam10, Harbin Institute of Technology11
TL;DR: It is found that peer beliefs of replicability are strongly related to replicable, suggesting that the research community could predict which results would replicate and that failures to replicate were not the result of chance alone.
Abstract: Being able to replicate scientific findings is crucial for scientific progress. We replicate 21 systematically selected experimental studies in the social sciences published in Nature and Science between 2010 and 2015. The replications follow analysis plans reviewed by the original authors and pre-registered prior to the replications. The replications are high powered, with sample sizes on average about five times higher than in the original studies. We find a significant effect in the same direction as the original study for 13 (62%) studies, and the effect size of the replications is on average about 50% of the original effect size. Replicability varies between 12 (57%) and 14 (67%) studies for complementary replicability indicators. Consistent with these results, the estimated true-positive rate is 67% in a Bayesian analysis. The relative effect size of true positives is estimated to be 71%, suggesting that both false positives and inflated effect sizes of true positives contribute to imperfect reproducibility. Furthermore, we find that peer beliefs of replicability are strongly related to replicability, suggesting that the research community could predict which results would replicate and that failures to replicate were not the result of chance alone.
Ludwig Maximilian University of Munich1, University of Bonn2, University Hospital of Lausanne3, Aarhus University Hospital4, University of Verona5, University of Padua6, University of Zurich7, University of Bern8, Boston Children's Hospital9, Wrocław Medical University10, Hannover Medical School11, Technische Universität München12
TL;DR: This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients, and is a consensus‐based guideline, taking available evidence from other guidelines, systematic reviews and published studies into account.
Abstract: This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus-based guideline, taking available evidence from other guidelines, systematic reviews and published studies into account. This second part of the guideline covers antimicrobial therapy, systemic treatment, allergen-specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions, whereas the first part covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti-inflammatory therapy, phototherapy and antipruritic therapy. Management of AE must consider the individual clinical variability of the disease. Systemic immunosuppressive treatment with cyclosporine, methotrexate, azathioprine and mycophenolic acid is established option for severe refractory cases, and widely available. Biologicals targeting the T helper 2 pathway such as dupilumab may be a safe and effective, disease-modifying alternative when available. Oral drugs such as JAK inhibitors and histamine 4 receptor antagonists are in development. Microbial colonization and superinfection may cause disease exacerbation and can require additional antimicrobial treatment. Allergen-specific immunotherapy with aeroallergens may be considered in selected cases. Psychosomatic counselling is recommended especially in stress-induced exacerbations. Therapeutic patient education ('Eczema school') is recommended for children and adult patients. General measures, basic emollient treatment, bathing, dietary intervention, topical anti-inflammatory therapy, phototherapy and antipruritic therapy have been addressed in the first part of the guideline.
King's College London1, Policlinico Umberto I2, Zhengzhou University3, University of Bergen4, University of Medicine and Pharmacy of Craiova5, University of Trieste6, University of Pavia7, Ludwig Maximilian University of Munich8, Imperial College London9, University of Verona10, Sapienza University of Rome11, Derriford Hospital12, University Hospital Regensburg13, University of Innsbruck14, Université Paris-Saclay15, University of Barcelona16, University of Copenhagen17, University of Bologna18, University of Virginia19, University of Vienna20, Eindhoven University of Technology21
TL;DR: The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.
Abstract: The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.
University Hospital Bonn1, University of Massachusetts Medical School2, University of Bonn3, Ludwig Maximilian University of Munich4, Broad Institute5, Radboud University Nijmegen6, University Medical Center Groningen7, Texas A&M University8, Harvard University9, Norwegian University of Science and Technology10, German Center for Neurodegenerative Diseases11
TL;DR: NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.
Paris Descartes University1, UCL Institute of Child Health2, Kuwait University3, Boston Children's Hospital4, Manchester Academic Health Science Centre5, Icahn School of Medicine at Mount Sinai6, University of Antioquia7, Ludwig Maximilian University of Munich8, Tokyo Medical and Dental University9, Seattle Children's Research Institute10, Paris Diderot University11, University of California, San Francisco12, Royal Children's Hospital13, University of Melbourne14, University of New South Wales15, Garvan Institute of Medical Research16, Children's Hospital of Philadelphia17
TL;DR: The classification described here will serve as a critical reference for immunologists and researchers worldwide and the categorization and listing of 354 inborn errors of immunity are detailed.
Abstract: Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
University of Texas MD Anderson Cancer Center1, Seoul National University Hospital2, Harvard University3, Ludwig Maximilian University of Munich4, University of California, Los Angeles5, University Health System6, National Cancer Research Institute7, University of Ulsan8, Kidwai Memorial Institute of Oncology9, University of Ottawa10, Samsung Medical Center11, American University of Beirut12, Novartis13, National Taiwan University14
TL;DR: In this paper, ribociclib plus endocrine therapy showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer.
Abstract: Summary Background In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. Methods This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18–59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. Findings Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2–not reached) in the ribociclib group compared with 13·0 months (11·0–16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44–0·69; p Interpretation Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. Funding Novartis.
TL;DR: In this paper, a deep neural network is used to represent all atmospheric subgrid processes in a climate model by learning from a multiscale model in which convection is treated explicitly.
Abstract: The representation of nonlinear subgrid processes, especially clouds, has been a major source of uncertainty in climate models for decades. Cloud-resolving models better represent many of these processes and can now be run globally but only for short-term simulations of at most a few years because of computational limitations. Here we demonstrate that deep learning can be used to capture many advantages of cloud-resolving modeling at a fraction of the computational cost. We train a deep neural network to represent all atmospheric subgrid processes in a climate model by learning from a multiscale model in which convection is treated explicitly. The trained neural network then replaces the traditional subgrid parameterizations in a global general circulation model in which it freely interacts with the resolved dynamics and the surface-flux scheme. The prognostic multiyear simulations are stable and closely reproduce not only the mean climate of the cloud-resolving simulation but also key aspects of variability, including precipitation extremes and the equatorial wave spectrum. Furthermore, the neural network approximately conserves energy despite not being explicitly instructed to. Finally, we show that the neural network parameterization generalizes to new surface forcing patterns but struggles to cope with temperatures far outside its training manifold. Our results show the feasibility of using deep learning for climate model parameterization. In a broader context, we anticipate that data-driven Earth system model development could play a key role in reducing climate prediction uncertainty in the coming decade.
Stanford University1, Rigshospitalet2, Ludwig Maximilian University of Munich3, Karolinska Institutet4, Örebro University5, Masaryk University6, Leipzig University7, United States Department of Veterans Affairs8, Emory University9, Tulane University10, Golden Jubilee National Hospital11, University of Bern12, University of Toronto13
TL;DR: In patients with stable coronary artery disease, an initial FFR‐guided PCI strategy was associated with a significantly lower rate of the primary composite end point of death, myocardial infarction, or urgent revascularization at 5 years than medical therapy alone.
Abstract: Background We hypothesized that fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) would be superior to medical therapy as initial treatment in patients with stable coronary artery disease. Methods Among 1220 patients with angiographically significant stenoses, those in whom at least one stenosis was hemodynamically significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus medical therapy or to medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy and were entered into a registry. The primary end point was a composite of death, myocardial infarction, or urgent revascularization. Results A total of 888 patients underwent randomization (447 patients in the PCI group and 441 in the medical-therapy group). At 5 years, the rate of the primary end point was lower in the PCI group than in the medical-therapy group (13.9% vs. 27.0%; hazard ratio, 0.46; 95% confidence interval [CI], 0.34 to 0.63; P<0.001). The dif...
TL;DR: The first public data release of the DES DR1 dataset is described in this paper, consisting of reduced single-epoch images, co-add images, and co-added source catalogs, and associated products and services.
Abstract: We describe the first public data release of the Dark Energy Survey, DES DR1, consisting of reduced single-epoch images, co-added images, co-added source catalogs, and associated products and services assembled over the first 3 yr of DES science operations. DES DR1 is based on optical/near-infrared imaging from 345 distinct nights (2013 August to 2016 February) by the Dark Energy Camera mounted on the 4 m Blanco telescope at the Cerro Tololo InterAmerican Observatory in Chile. We release data from the DES wide-area survey covering similar to 5000 deg(2) of the southern Galactic cap in five broad photometric bands, grizY. DES DR1 has a median delivered point-spread function of g = 1.12, r = 0.96, i = 0.88, z = 0.84, and Y = 0.'' 90 FWHM, a photometric precision of <1% in all bands, and an astrometric precision of 151 mas. The median co-added catalog depth for a 1.'' 95 diameter aperture at signal-to-noise ratio (S/N) = 10 is g = 24.33, r = 24.08, i = 23.44, z = 22.69, and Y = 21.44 mag. DES DR1 includes nearly 400 million distinct astronomical objects detected in similar to 10,000 co-add tiles of size 0.534 deg(2) produced from similar to 39,000 individual exposures. Benchmark galaxy and stellar samples contain similar to 310 million and similar to 80 million objects, respectively, following a basic object quality selection. These data are accessible through a range of interfaces, including query web clients, image cutout servers, jupyter notebooks, and an interactive co-add image visualization tool. DES DR1 constitutes the largest photometric data set to date at the achieved depth and photometric precision.
TL;DR: This Review consolidates the key information on the currently available animal models of obesity and diabetes and highlights the advantages, limitations and important caveats of each of these models.
Abstract: More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.
Max Planck Society1, University of Chile2, University of Grenoble3, Leiden University4, European Southern Observatory5, University of Oxford6, Paris Diderot University7, INAF8, École normale supérieure de Lyon9, Aix-Marseille University10, University of Tübingen11, University of Bern12, Hungarian Academy of Sciences13, ETH Zurich14, Diego Portales University15, Ludwig Maximilian University of Munich16, Kavli Institute for Theoretical Physics17, California Institute of Technology18, Rice University19, Stockholm University20, University of Cambridge21, Centre national de la recherche scientifique22, Valparaiso University23, University of Arizona24, Monash University, Clayton campus25, University of Geneva26, University of Hawaii at Manoa27, University of Atacama28, Heidelberg University29, University of Michigan30
TL;DR: In this article, the authors detect a point source within the gap of the transition disk at about 195 mas (~22 au) projected separation and detect a signal from an inner disk component.
Abstract: Context. Young circumstellar disks are the birthplaces of planets. Their study is of prime interest to understand the physical and chemical conditions under which planet formation takes place. Only very few detections of planet candidates within these disks exist, and most of them are currently suspected to be disk features.Aims. In this context, the transition disk around the young star PDS 70 is of particular interest, due to its large gap identified in previous observations, indicative of ongoing planet formation. We aim to search for the presence of an embedded young planet and search for disk structures that may be the result of disk–planet interactions and other evolutionary processes.Methods. We analyse new and archival near-infrared images of the transition disk PDS 70 obtained with the VLT/SPHERE, VLT/NaCo, and Gemini/NICI instruments in polarimetric differential imaging and angular differential imaging modes.Results. We detect a point source within the gap of the disk at about 195 mas (~22 au) projected separation. The detection is confirmed at five different epochs, in three filter bands and using different instruments. The astrometry results in an object of bound nature, with high significance. The comparison of the measured magnitudes and colours to evolutionary tracks suggests that the detection is a companion of planetary mass. The luminosity of the detected object is consistent with that of an L-type dwarf, but its IR colours are redder, possibly indicating the presence of warm surrounding material. Further, we confirm the detection of a large gap of ~54 au in size within the disk in our scattered light images, and detect a signal from an inner disk component. We find that its spatial extent is very likely smaller than ~17 au in radius, and its position angle is consistent with that of the outer disk. The images of the outer disk show evidence of a complex azimuthal brightness distribution which is different at different wavelengths and may in part be explained by Rayleigh scattering from very small grains.Conclusions. The detection of a young protoplanet within the gap of the transition disk around PDS 70 opens the door to a so far observationally unexplored parameter space of planetary formation and evolution. Future observations of this system at different wavelengths and continuing astrometry will allow us to test theoretical predictions regarding planet–disk interactions, planetary atmospheres, and evolutionary models.
Richard A. Klein1, Michelangelo Vianello2, Fred Hasselman3, Byron G. Adams4 +187 more•Institutions (118)
TL;DR: This paper conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings, and found that very little heterogeneity was attributable to the order in which the tasks were performed or whether the task were administered in lab versus online.
Abstract: We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.