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Showing papers by "Cardiff University published in 2018"


Journal ArticleDOI
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4  +414 moreInstitutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

5,988 citations


Journal ArticleDOI
Gregory A. Roth1, Gregory A. Roth2, Degu Abate3, Kalkidan Hassen Abate4  +1025 moreInstitutions (333)
TL;DR: Non-communicable diseases comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2).

5,211 citations


Journal ArticleDOI
Nabila Aghanim1, Yashar Akrami2, Yashar Akrami3, Yashar Akrami4  +229 moreInstitutions (70)
TL;DR: In this paper, the cosmological parameter results from the final full-mission Planck measurements of the CMB anisotropies were presented, with good consistency with the standard spatially-flat 6-parameter CDM cosmology having a power-law spectrum of adiabatic scalar perturbations from polarization, temperature, and lensing separately and in combination.
Abstract: We present cosmological parameter results from the final full-mission Planck measurements of the CMB anisotropies. We find good consistency with the standard spatially-flat 6-parameter $\Lambda$CDM cosmology having a power-law spectrum of adiabatic scalar perturbations (denoted "base $\Lambda$CDM" in this paper), from polarization, temperature, and lensing, separately and in combination. A combined analysis gives dark matter density $\Omega_c h^2 = 0.120\pm 0.001$, baryon density $\Omega_b h^2 = 0.0224\pm 0.0001$, scalar spectral index $n_s = 0.965\pm 0.004$, and optical depth $\tau = 0.054\pm 0.007$ (in this abstract we quote $68\,\%$ confidence regions on measured parameters and $95\,\%$ on upper limits). The angular acoustic scale is measured to $0.03\,\%$ precision, with $100\theta_*=1.0411\pm 0.0003$. These results are only weakly dependent on the cosmological model and remain stable, with somewhat increased errors, in many commonly considered extensions. Assuming the base-$\Lambda$CDM cosmology, the inferred late-Universe parameters are: Hubble constant $H_0 = (67.4\pm 0.5)$km/s/Mpc; matter density parameter $\Omega_m = 0.315\pm 0.007$; and matter fluctuation amplitude $\sigma_8 = 0.811\pm 0.006$. We find no compelling evidence for extensions to the base-$\Lambda$CDM model. Combining with BAO we constrain the effective extra relativistic degrees of freedom to be $N_{\rm eff} = 2.99\pm 0.17$, and the neutrino mass is tightly constrained to $\sum m_ u< 0.12$eV. The CMB spectra continue to prefer higher lensing amplitudes than predicted in base -$\Lambda$CDM at over $2\,\sigma$, which pulls some parameters that affect the lensing amplitude away from the base-$\Lambda$CDM model; however, this is not supported by the lensing reconstruction or (in models that also change the background geometry) BAO data. (Abridged)

3,077 citations


Journal ArticleDOI
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1  +1050 moreInstitutions (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


Journal ArticleDOI
Naomi R. Wray1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +259 moreInstitutions (79)
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


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1235 moreInstitutions (132)
TL;DR: This analysis expands upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars.
Abstract: On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function pðρÞ of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R1 ¼ 10.8 þ2.0 −1.7 km for the heavier star and R2 ¼ 10.7 þ2.1 −1.5 km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M⊙ as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R1 ¼ 11.9 þ1.4 −1.4 km and R2 ¼ 11.9 þ1.4 −1.4 km at the 90% credible level. Finally, we obtain constraints on pðρÞ at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5 þ2.7 −1.7 × 1034 dyn cm−2 at the 90% level.

1,595 citations


Journal ArticleDOI
Daniel J. Benjamin1, James O. Berger2, Magnus Johannesson1, Magnus Johannesson3, Brian A. Nosek4, Brian A. Nosek5, Eric-Jan Wagenmakers6, Richard A. Berk7, Kenneth A. Bollen8, Björn Brembs9, Lawrence D. Brown7, Colin F. Camerer10, David Cesarini11, David Cesarini12, Christopher D. Chambers13, Merlise A. Clyde2, Thomas D. Cook14, Thomas D. Cook15, Paul De Boeck16, Zoltan Dienes17, Anna Dreber3, Kenny Easwaran18, Charles Efferson19, Ernst Fehr20, Fiona Fidler21, Andy P. Field17, Malcolm R. Forster22, Edward I. George7, Richard Gonzalez23, Steven N. Goodman24, Edwin J. Green25, Donald P. Green26, Anthony G. Greenwald27, Jarrod D. Hadfield28, Larry V. Hedges14, Leonhard Held20, Teck-Hua Ho29, Herbert Hoijtink30, Daniel J. Hruschka31, Kosuke Imai32, Guido W. Imbens24, John P. A. Ioannidis24, Minjeong Jeon33, James Holland Jones34, Michael Kirchler35, David Laibson36, John A. List37, Roderick J. A. Little23, Arthur Lupia23, Edouard Machery38, Scott E. Maxwell39, Michael A. McCarthy21, Don A. Moore40, Stephen L. Morgan41, Marcus R. Munafò42, Shinichi Nakagawa43, Brendan Nyhan44, Timothy H. Parker45, Luis R. Pericchi46, Marco Perugini47, Jeffrey N. Rouder48, Judith Rousseau49, Victoria Savalei50, Felix D. Schönbrodt51, Thomas Sellke52, Betsy Sinclair53, Dustin Tingley36, Trisha Van Zandt16, Simine Vazire54, Duncan J. Watts55, Christopher Winship36, Robert L. Wolpert2, Yu Xie32, Cristobal Young24, Jonathan Zinman44, Valen E. Johnson18, Valen E. Johnson1 
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, Northwestern University14, Mathematica Policy Research15, 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


Journal ArticleDOI
22 Jun 2018-Science
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


Journal ArticleDOI
Antonio F. Pardiñas1, Peter Holmans1, Andrew Pocklington1, Valentina Escott-Price1, Stephan Ripke2, Stephan Ripke3, Noa Carrera1, Sophie E. Legge1, Sophie Bishop1, D. F. Cameron1, Marian L. Hamshere1, Jun Han1, Leon Hubbard1, Amy Lynham1, Kiran Kumar Mantripragada1, Elliott Rees1, James H. MacCabe4, Steven A. McCarroll5, Bernhard T. Baune6, Gerome Breen4, Gerome Breen7, Enda M. Byrne8, Udo Dannlowski9, Thalia C. Eley4, Caroline Hayward10, Nicholas G. Martin11, Nicholas G. Martin8, Andrew M. McIntosh10, Robert Plomin4, David J. Porteous10, Naomi R. Wray8, Armando Caballero12, Daniel H. Geschwind13, Laura M. Huckins14, Douglas M. Ruderfer14, Enrique Santiago15, Pamela Sklar14, Eli A. Stahl14, Hyejung Won13, Esben Agerbo16, Esben Agerbo17, Thomas Damm Als17, Thomas Damm Als16, Ole A. Andreassen18, Ole A. Andreassen19, Marie Bækvad-Hansen20, Marie Bækvad-Hansen16, Preben Bo Mortensen17, Preben Bo Mortensen16, Carsten Bøcker Pedersen17, Carsten Bøcker Pedersen16, Anders D. Børglum16, Anders D. Børglum17, Jonas Bybjerg-Grauholm20, Jonas Bybjerg-Grauholm16, Srdjan Djurovic21, Srdjan Djurovic19, Naser Durmishi, Marianne Giørtz Pedersen17, Marianne Giørtz Pedersen16, Vera Golimbet, Jakob Grove, David M. Hougaard16, David M. Hougaard20, Manuel Mattheisen17, Manuel Mattheisen16, Espen Molden, Ole Mors22, Ole Mors16, Merete Nordentoft16, Merete Nordentoft23, Milica Pejovic-Milovancevic24, Engilbert Sigurdsson, Teimuraz Silagadze25, Christine Søholm Hansen16, Christine Søholm Hansen20, Kari Stefansson26, Hreinn Stefansson26, Stacy Steinberg26, Sarah Tosato27, Thomas Werge23, Thomas Werge16, Thomas Werge28, David A. Collier4, David A. Collier29, Dan Rujescu30, Dan Rujescu31, George Kirov1, Michael J. Owen1, Michael Conlon O'Donovan1, James T.R. Walters1 
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


Journal ArticleDOI
TL;DR: This part of this series introduces JASP (http://www.jasp-stats.org), an open-source, cross-platform, user-friendly graphical software package that allows users to carry out Bayesian hypothesis tests for standard statistical problems.
Abstract: Bayesian hypothesis testing presents an attractive alternative to p value hypothesis testing. Part I of this series outlined several advantages of Bayesian hypothesis testing, including the ability to quantify evidence and the ability to monitor and update this evidence as data come in, without the need to know the intention with which the data were collected. Despite these and other practical advantages, Bayesian hypothesis tests are still reported relatively rarely. An important impediment to the widespread adoption of Bayesian tests is arguably the lack of user-friendly software for the run-of-the-mill statistical problems that confront psychologists for the analysis of almost every experiment: the t-test, ANOVA, correlation, regression, and contingency tables. In Part II of this series we introduce JASP (http://www.jasp-stats.org), an open-source, cross-platform, user-friendly graphical software package that allows users to carry out Bayesian hypothesis tests for standard statistical problems. JASP is based in part on the Bayesian analyses implemented in Morey and Rouder’s BayesFactor package for R. Armed with JASP, the practical advantages of Bayesian hypothesis testing are only a mouse click away.

1,031 citations


Journal ArticleDOI
TL;DR: Ten prominent advantages of the Bayesian approach are outlined, and several objections to Bayesian hypothesis testing are countered.
Abstract: Bayesian parameter estimation and Bayesian hypothesis testing present attractive alternatives to classical inference using confidence intervals and p values. In part I of this series we outline ten prominent advantages of the Bayesian approach. Many of these advantages translate to concrete opportunities for pragmatic researchers. For instance, Bayesian hypothesis testing allows researchers to quantify evidence and monitor its progression as data come in, without needing to know the intention with which the data were collected. We end by countering several objections to Bayesian hypothesis testing. Part II of this series discusses JASP, a free and open source software program that makes it easy to conduct Bayesian estimation and testing for a range of popular statistical scenarios (Wagenmakers et al. this issue).

Journal ArticleDOI
TL;DR: In this article, the authors highlight previous influential studies and ongoing research to use this chemical as a viable energy vector for power applications, emphasizing the challenges that each of the reviewed technologies faces before implementation and commercial deployment is achieved at a larger scale.

Journal ArticleDOI
TL;DR: The very reason such tasks produce robust and easily replicable experimental effects – low between-participant variability – makes their use as correlational tools problematic, and it is demonstrated that taking reliability estimates into account has the potential to qualitatively change theoretical conclusions.
Abstract: Individual differences in cognitive paradigms are increasingly employed to relate cognition to brain structure, chemistry, and function. However, such efforts are often unfruitful, even with the most well established tasks. Here we offer an explanation for failures in the application of robust cognitive paradigms to the study of individual differences. Experimental effects become well established – and thus those tasks become popular – when between-subject variability is low. However, low between-subject variability causes low reliability for individual differences, destroying replicable correlations with other factors and potentially undermining published conclusions drawn from correlational relationships. Though these statistical issues have a long history in psychology, they are widely overlooked in cognitive psychology and neuroscience today. In three studies, we assessed test-retest reliability of seven classic tasks: Eriksen Flanker, Stroop, stop-signal, go/no-go, Posner cueing, Navon, and Spatial-Numerical Association of Response Code (SNARC). Reliabilities ranged from 0 to .82, being surprisingly low for most tasks given their common use. As we predicted, this emerged from low variance between individuals rather than high measurement variance. In other words, the very reason such tasks produce robust and easily replicable experimental effects – low between-participant variability – makes their use as correlational tools problematic. We demonstrate that taking such reliability estimates into account has the potential to qualitatively change theoretical conclusions. The implications of our findings are that well-established approaches in experimental psychology and neuropsychology may not directly translate to the study of individual differences in brain structure, chemistry, and function, and alternative metrics may be required.

Journal ArticleDOI
TL;DR: Treatment duration for aspergillosis is strongly recommended based on clinical improvement, degree of immunosuppression and response on imaging, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, M. R. Abernathy3  +1135 moreInstitutions (139)
TL;DR: In this article, the authors present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves.
Abstract: We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5– 20 deg2 requires at least three detectors of sensitivity within a factor of ∼2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.

Journal ArticleDOI
TL;DR: This document aims to represent a significant step forward in the collaboration between the scientific societies and the industry since technical specifications of the software packages designed to post-process echocardiographic datasets have been agreed and shared before their actual development.
Abstract: The EACVI/ASE/Industry Task Force to standardize deformation imaging prepared this consensus document to standardize definitions and techniques for using two-dimensional (2D) speckle tracking echocardiography (STE) to assess left atrial, right ventricular, and right atrial myocardial deformation. This document is intended for both the technical engineering community and the clinical community at large to provide guidance on selecting the functional parameters to measure and how to measure them using 2D STE.This document aims to represent a significant step forward in the collaboration between the scientific societies and the industry since technical specifications of the software packages designed to post-process echocardiographic datasets have been agreed and shared before their actual development. Hopefully, this will lead to more clinically oriented software packages which will be better tailored to clinical needs and will allow industry to save time and resources in their development.

Journal ArticleDOI
TL;DR: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer, and the benefit would be greatest in patients with a low metastatic burden.

Journal ArticleDOI
TL;DR: This collection of GaN technology developments is not itself a road map but a valuable collection of global state-of-the-art GaN research that will inform the next phase of the technology as market driven requirements evolve.
Abstract: Gallium nitride (GaN) is a compound semiconductor that has tremendous potential to facilitate economic growth in a semiconductor industry that is silicon-based and currently faced with diminishing returns of performance versus cost of investment. At a material level, its high electric field strength and electron mobility have already shown tremendous potential for high frequency communications and photonic applications. Advances in growth on commercially viable large area substrates are now at the point where power conversion applications of GaN are at the cusp of commercialisation. The future for building on the work described here in ways driven by specific challenges emerging from entirely new markets and applications is very exciting. This collection of GaN technology developments is therefore not itself a road map but a valuable collection of global state-of-the-art GaN research that will inform the next phase of the technology as market driven requirements evolve. First generation production devices are igniting large new markets and applications that can only be achieved using the advantages of higher speed, low specific resistivity and low saturation switching transistors. Major investments are being made by industrial companies in a wide variety of markets exploring the use of the technology in new circuit topologies, packaging solutions and system architectures that are required to achieve and optimise the system advantages offered by GaN transistors. It is this momentum that will drive priorities for the next stages of device research gathered here.


Journal ArticleDOI
Angela M. Wood1, Stephen Kaptoge1, Adam S. Butterworth1, Peter Willeit1, Samantha Warnakula1, Thomas Bolton1, Ellie Paige2, Dirk S. Paul1, Michael J. Sweeting1, Stephen Burgess1, Steven Bell1, William J. Astle1, David Stevens1, Albert Koulman1, Randi Selmer3, W. M. Monique Verschuren4, Shinichi Sato, Inger Njølstad5, Mark Woodward6, Mark Woodward7, Mark Woodward8, Veikko Salomaa9, Børge G. Nordestgaard10, Børge G. Nordestgaard11, Bu B. Yeap12, Bu B. Yeap13, Bu B. Yeap14, Astrid E. Fletcher15, Olle Melander16, Lewis H. Kuller17, B. Balkau18, Michael Marmot19, Wolfgang Koenig20, Wolfgang Koenig21, Edoardo Casiglia22, Cyrus Cooper23, Volker Arndt24, Oscar H. Franco25, Patrik Wennberg26, John Gallacher27, Agustín Gómez de la Cámara, Henry Völzke28, Christina C. Dahm29, Caroline Dale19, Manuela M. Bergmann, Carlos J. Crespo30, Yvonne T. van der Schouw4, Rudolf Kaaks24, Leon A. Simons31, Pagona Lagiou32, Pagona Lagiou33, Josje D. Schoufour25, Jolanda M. A. Boer, Timothy J. Key7, Beatriz L. Rodriguez34, Conchi Moreno-Iribas, Karina W. Davidson35, James O. Taylor, Carlotta Sacerdote, Robert B. Wallace36, J. Ramón Quirós, Rosario Tumino, Dan G. Blazer37, Allan Linneberg11, Makoto Daimon38, Salvatore Panico, Barbara V. Howard39, Guri Skeie5, Timo E. Strandberg40, Timo E. Strandberg41, Elisabete Weiderpass, Paul J. Nietert42, Bruce M. Psaty43, Bruce M. Psaty44, Daan Kromhout45, Elena Salamanca-Fernández46, Stefan Kiechl, Harlan M. Krumholz47, Sara Grioni, Domenico Palli48, José María Huerta, Jackie F. Price49, Johan Sundström50, Larraitz Arriola51, Hisatomi Arima52, Hisatomi Arima53, Ruth C. Travis7, Demosthenes B. Panagiotakos54, Anna Karakatsani32, Antonia Trichopoulou32, Tilman Kühn24, Diederick E. Grobbee4, Elizabeth Barrett-Connor55, Natasja M. van Schoor56, Heiner Boeing, Kim Overvad29, Kim Overvad57, Jussi Kauhanen58, Nicholas J. Wareham1, Claudia Langenberg1, Nita G. Forouhi1, Maria Wennberg26, Jean-Pierre Després59, Mary Cushman60, Jackie A. Cooper19, Carlos J. Rodriguez61, Carlos J. Rodriguez62, Masaru Sakurai63, Jonathan E. Shaw64, Matthew Knuiman12, Trudy Voortman25, Christa Meisinger, Anne Tjønneland, Hermann Brenner65, Hermann Brenner24, Luigi Palmieri66, Jean Dallongeville67, Eric J. Brunner19, Gerd Assmann, Maurizio Trevisan68, Richard F. Gillum69, Ian Ford70, Naveed Sattar70, Mariana Lazo8, Simon G. Thompson1, Pietro Ferrari71, David A. Leon15, George Davey Smith72, Richard Peto7, Rod Jackson73, Emily Banks2, Emanuele Di Angelantonio1, John Danesh1 
University of Cambridge1, Australian National University2, Norwegian Institute of Public Health3, Utrecht University4, University of Tromsø5, The George Institute for Global Health6, University of Oxford7, Johns Hopkins University8, National Institutes of Health9, Copenhagen University Hospital10, University of Copenhagen11, University of Western Australia12, Harry Perkins Institute of Medical Research13, Fiona Stanley Hospital14, University of London15, Lund University16, University of Pittsburgh17, French Institute of Health and Medical Research18, University College London19, University of Ulm20, Technische Universität München21, University of Padua22, University of Southampton23, German Cancer Research Center24, Erasmus University Medical Center25, Umeå University26, Cardiff University27, Greifswald University Hospital28, Aarhus University29, Portland State University30, University of New South Wales31, National and Kapodistrian University of Athens32, Harvard University33, University of Hawaii34, Columbia University35, University of Iowa36, Duke University37, Yamagata University38, Tuskegee University39, University of Helsinki40, University of Oulu41, Medical University of South Carolina42, University of Washington43, Kaiser Permanente44, University of Groningen45, University of Granada46, Yale University47, Prevention Institute48, University of Edinburgh49, Uppsala University50, Basque Government51, Kyushu University52, Royal Prince Alfred Hospital53, Harokopio University54, University of California, San Diego55, VU University Medical Center56, Aalborg University57, University of Eastern Finland58, Laval University59, University of Vermont60, Wake Forest Baptist Medical Center61, Wake Forest University62, Kanazawa Medical University63, Baker IDI Heart and Diabetes Institute64, Heidelberg University65, Istituto Superiore di Sanità66, Pasteur Institute67, City College of New York68, Howard University69, University of Glasgow70, International Agency for Research on Cancer71, University of Bristol72, University of Auckland73
TL;DR: Current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week, and data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

Journal ArticleDOI
TL;DR: The Hospital Frailty Risk Score provides hospitals and health systems with a low-cost, systematic way to screen for frailty and identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful.

Journal ArticleDOI
Chenghua Zhang1, Jianzhong Wu1, Yue Zhou1, Meng Cheng1, Chao Long1 
TL;DR: Test results in a LV grid-connected Microgrid show that P2P energy trading is able to improve the local balance of energy generation and consumption and the increased diversity of generation and load profiles of peers is ability to further facilitate the balance.

Journal ArticleDOI
TL;DR: The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype, and concludes that patients with advanced TNBC benefit from characterization of BRC a/2 mutations, but not BRC1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy.
Abstract: Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.

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TL;DR: A timescale for early land plant evolution that integrates over topological uncertainty by exploring the impact of competing hypotheses on bryophyte−tracheophyte relationships, among other variables, on divergence time estimation is established.
Abstract: Establishing the timescale of early land plant evolution is essential for testing hypotheses on the coevolution of land plants and Earth's System. The sparseness of early land plant megafossils and stratigraphic controls on their distribution make the fossil record an unreliable guide, leaving only the molecular clock. However, the application of molecular clock methodology is challenged by the current impasse in attempts to resolve the evolutionary relationships among the living bryophytes and tracheophytes. Here, we establish a timescale for early land plant evolution that integrates over topological uncertainty by exploring the impact of competing hypotheses on bryophyte-tracheophyte relationships, among other variables, on divergence time estimation. We codify 37 fossil calibrations for Viridiplantae following best practice. We apply these calibrations in a Bayesian relaxed molecular clock analysis of a phylogenomic dataset encompassing the diversity of Embryophyta and their relatives within Viridiplantae. Topology and dataset sizes have little impact on age estimates, with greater differences among alternative clock models and calibration strategies. For all analyses, a Cambrian origin of Embryophyta is recovered with highest probability. The estimated ages for crown tracheophytes range from Late Ordovician to late Silurian. This timescale implies an early establishment of terrestrial ecosystems by land plants that is in close accord with recent estimates for the origin of terrestrial animal lineages. Biogeochemical models that are constrained by the fossil record of early land plants, or attempt to explain their impact, must consider the implications of a much earlier, middle Cambrian-Early Ordovician, origin.

Journal ArticleDOI
Douglas M. Ruderfer1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +628 moreInstitutions (156)
14 Jun 2018-Cell
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.

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TL;DR: The key roles of the IL-6 cytokine family in regulating innate and adaptive immunity, as well as other physiological responses are considered, which highlight the potential of targeting IL- 6 family members to treat inflammatory diseases and cancer.
Abstract: The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

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TL;DR: In the developed world, the prevalence of undiagnosed thyroid disease is likely falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation, however, continued vigilance against iodine deficiency remains essential in developed countries, particularly in Europe.
Abstract: Thyroid hormones are essential for growth, neuronal development, reproduction and regulation of energy metabolism. Hypothyroidism and hyperthyroidism are common conditions with potentially devastating health consequences that affect all populations worldwide. Iodine nutrition is a key determinant of thyroid disease risk; however, other factors, such as ageing, smoking status, genetic susceptibility, ethnicity, endocrine disruptors and the advent of novel therapeutics, including immune checkpoint inhibitors, also influence thyroid disease epidemiology. In the developed world, the prevalence of undiagnosed thyroid disease is likely falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation. However, continued vigilance against iodine deficiency remains essential in developed countries, particularly in Europe. In this report, we review the global incidence and prevalence of hyperthyroidism and hypothyroidism, highlighting geographical differences and the effect of environmental factors, such as iodine supplementation, on these data. We also highlight the pressing need for detailed epidemiological surveys of thyroid dysfunction and iodine status in developing countries.

Journal ArticleDOI
14 Dec 2018-Science
TL;DR: The generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood, reveal insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
Abstract: To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Journal ArticleDOI
Derrek P. Hibar1, Lars T. Westlye2, Lars T. Westlye3, Nhat Trung Doan3, Nhat Trung Doan2, Neda Jahanshad1, Joshua W. Cheung1, Christopher R.K. Ching1, Amelia Versace4, Amy C. Bilderbeck5, Anne Uhlmann6, Benson Mwangi7, Bernd Kramer8, Bronwyn Overs9, Cecilie B. Hartberg3, Christoph Abé10, Danai Dima11, Danai Dima12, Dominik Grotegerd13, Emma Sprooten14, Erlend Bøen, Esther Jiménez15, Fleur M. Howells6, G. Delvecchio, Henk Temmingh6, J Starke6, Jorge R. C. Almeida16, Jose Manuel Goikolea15, Josselin Houenou17, L M Beard18, Lisa Rauer8, Lucija Abramovic19, M Bonnin15, M F Ponteduro12, Maria Keil20, Maria M. Rive21, Nailin Yao22, Nailin Yao23, Nefize Yalin12, Pablo Najt24, P. G. P. Rosa25, Ronny Redlich13, Sarah Trost20, Saskia P. Hagenaars26, Scott C. Fears27, Scott C. Fears28, Silvia Alonso-Lana, T.G.M. van Erp29, Thomas Nickson26, Tiffany M. Chaim-Avancini25, Timothy B. Meier30, Timothy B. Meier31, Torbjørn Elvsåshagen3, Torbjørn Elvsåshagen2, Unn K. Haukvik3, Won Hee Lee14, Aart H. Schene32, Adrian J. Lloyd33, Allan H. Young12, Allison C. Nugent34, Anders M. Dale35, Andrea Pfennig36, Andrew M. McIntosh26, Beny Lafer25, Bernhard T. Baune37, C J Ekman10, Carlos A. Zarate34, Carrie E. Bearden27, Carrie E. Bearden38, Chantal Henry39, Chantal Henry17, Christian Simhandl, Colm McDonald24, C Bourne5, C Bourne40, Dan J. Stein6, Daniel H. Wolf18, Dara M. Cannon24, David C. Glahn23, David C. Glahn22, Dick J. Veltman41, Edith Pomarol-Clotet, Eduard Vieta15, Erick J. Canales-Rodríguez, Fabiano G. Nery42, Fabiano G. Nery25, Fábio L.S. Duran25, Geraldo F. Busatto25, Gloria Roberts43, Godfrey D. Pearlson22, Godfrey D. Pearlson23, Guy M. Goodwin5, Harald Kugel13, Heather C. Whalley26, Henricus G. Ruhé5, Jair C. Soares7, Janice M. Fullerton9, Janice M. Fullerton43, Janusz K. Rybakowski44, Jonathan Savitz31, Khallil T. Chaim25, M. Fatjó-Vilas, Márcio Gerhardt Soeiro-de-Souza25, Marco P. Boks19, Marcus V. Zanetti25, Maria Concepcion Garcia Otaduy25, Maristela S. Schaufelberger25, Martin Alda45, Martin Ingvar46, Martin Ingvar10, Mary L. Phillips4, Matthew J. Kempton12, Michael Bauer36, Mikael Landén10, Mikael Landén47, Natalia Lawrence48, N.E.M. van Haren19, Neil Horn6, Nelson B. Freimer38, Oliver Gruber8, Peter R. Schofield43, Peter R. Schofield9, Philip B. Mitchell43, René S. Kahn19, Rhoshel K. Lenroot9, Rhoshel K. Lenroot43, Rodrigo Machado-Vieira25, Rodrigo Machado-Vieira34, Roel A. Ophoff38, Roel A. Ophoff19, Salvador Sarró, Sophia Frangou14, Theodore D. Satterthwaite18, Tomas Hajek45, Tomas Hajek34, Udo Dannlowski13, Ulrik Fredrik Malt2, Ulrik Fredrik Malt3, Volker Arolt13, Wagner F. Gattaz25, Wayne C. Drevets49, Xavier Caseras50, Ingrid Agartz3, Paul M. Thompson1, Ole A. Andreassen3, Ole A. Andreassen2 
University of Southern California1, Oslo University Hospital2, University of Oslo3, University of Pittsburgh4, Oxford Health NHS Foundation Trust5, University of Cape Town6, University of Texas Health Science Center at Houston7, Heidelberg University8, Neuroscience Research Australia9, Karolinska Institutet10, City University London11, King's College London12, University of Münster13, Icahn School of Medicine at Mount Sinai14, University of Barcelona15, Brown University16, French Institute of Health and Medical Research17, University of Pennsylvania18, Utrecht University19, University of Göttingen20, University of Amsterdam21, Yale University22, Hartford Hospital23, National University of Ireland, Galway24, University of São Paulo25, University of Edinburgh26, University of California, Los Angeles27, West Los Angeles College28, University of California, Irvine29, Medical College of Wisconsin30, McGovern Institute for Brain Research31, Radboud University Nijmegen32, Northumberland, Tyne and Wear NHS Foundation Trust33, National Institutes of Health34, University of California, San Diego35, Dresden University of Technology36, University of Adelaide37, Semel Institute for Neuroscience and Human Behavior38, Pasteur Institute39, University of Birmingham40, VU University Medical Center41, University of Cincinnati Academic Health Center42, University of New South Wales43, Poznan University of Medical Sciences44, Dalhousie University45, Karolinska University Hospital46, University of Gothenburg47, University of Exeter48, Janssen Pharmaceutica49, Cardiff University50
TL;DR: The largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of bipolar disorder patients is performed, revealing previously undetected associations and providing an extensive analysis of potential confounding variables in neuroimaging studies of BD.
Abstract: Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

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TL;DR: Results from an analysis of all data taken by the bicep2/Keck CMB polarization experiments up to and including the 2015 observing season are presented, showing the strongest constraints to date on primordial gravitational waves.
Abstract: We present results from an analysis of all data taken by the bicep2/Keck CMB polarization experiments up to and including the 2015 observing season. This includes the first Keck Array observations at 220 GHz and additional observations at 95 and 150 GHz. The Q and U maps reach depths of 5.2, 2.9, and 26 μKCMB arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈400 square degrees. The 220 GHz maps achieve a signal to noise on polarized dust emission approximately equal to that of Planck at 353 GHz. We take auto and cross spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz. We evaluate the joint likelihood of the spectra versus a multicomponent model of lensed-ΛCDM+r+dust+synchrotron+noise. The foreground model has seven parameters, and we impose priors on some of these using external information from Planck and WMAP derived from larger regions of sky. The model is shown to be an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r0.05<0.07 at 95% confidence, which tightens to r0.05<0.06 in conjunction with Planck temperature measurements and other data. The lensing signal is detected at 8.8σ significance. Running a maximum likelihood search on simulations we obtain unbiased results and find that σ(r)=0.020. These are the strongest constraints to date on primordial gravitational waves.