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Showing papers by "University of Birmingham published in 2016"


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Matthew Abernathy1  +1008 moreInstitutions (96)
TL;DR: This is the first direct detection of gravitational waves and the first observation of a binary black hole merger, and these observations demonstrate the existence of binary stellar-mass black hole systems.
Abstract: On September 14, 2015 at 09:50:45 UTC the two detectors of the Laser Interferometer Gravitational-Wave Observatory simultaneously observed a transient gravitational-wave signal. The signal sweeps upwards in frequency from 35 to 250 Hz with a peak gravitational-wave strain of $1.0 \times 10^{-21}$. It matches the waveform predicted by general relativity for the inspiral and merger of a pair of black holes and the ringdown of the resulting single black hole. The signal was observed with a matched-filter signal-to-noise ratio of 24 and a false alarm rate estimated to be less than 1 event per 203 000 years, equivalent to a significance greater than 5.1 {\sigma}. The source lies at a luminosity distance of $410^{+160}_{-180}$ Mpc corresponding to a redshift $z = 0.09^{+0.03}_{-0.04}$. In the source frame, the initial black hole masses are $36^{+5}_{-4} M_\odot$ and $29^{+4}_{-4} M_\odot$, and the final black hole mass is $62^{+4}_{-4} M_\odot$, with $3.0^{+0.5}_{-0.5} M_\odot c^2$ radiated in gravitational waves. All uncertainties define 90% credible intervals.These observations demonstrate the existence of binary stellar-mass black hole systems. This is the first direct detection of gravitational waves and the first observation of a binary black hole merger.

9,596 citations


Journal ArticleDOI
12 Oct 2016-BMJ
TL;DR: Risk of Bias In Non-randomised Studies - of Interventions is developed, a new tool for evaluating risk of bias in estimates of the comparative effectiveness of interventions from studies that did not use randomisation to allocate units or clusters of individuals to comparison groups.
Abstract: Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.

8,028 citations


Journal ArticleDOI
01 Nov 2016-Europace
TL;DR: The Task Force for the management of atrial fibrillation of the European Society of Cardiology has been endorsed by the European Stroke Organisation (ESO).
Abstract: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke Organisation (ESO)

5,255 citations


Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations


Journal ArticleDOI
Theo Vos1, Christine Allen1, Megha Arora1, Ryan M Barber1  +696 moreInstitutions (260)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.

5,050 citations


Journal ArticleDOI
Haidong Wang1, Mohsen Naghavi1, Christine Allen1, Ryan M Barber1  +841 moreInstitutions (293)
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.

4,804 citations


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, M. R. Abernathy3  +970 moreInstitutions (114)
TL;DR: This second gravitational-wave observation provides improved constraints on stellar populations and on deviations from general relativity.
Abstract: We report the observation of a gravitational-wave signal produced by the coalescence of two stellar-mass black holes. The signal, GW151226, was observed by the twin detectors of the Laser Interferometer Gravitational-Wave Observatory (LIGO) on December 26, 2015 at 03:38:53 UTC. The signal was initially identified within 70 s by an online matched-filter search targeting binary coalescences. Subsequent off-line analyses recovered GW151226 with a network signal-to-noise ratio of 13 and a significance greater than 5 σ. The signal persisted in the LIGO frequency band for approximately 1 s, increasing in frequency and amplitude over about 55 cycles from 35 to 450 Hz, and reached a peak gravitational strain of 3.4+0.7−0.9×10−22. The inferred source-frame initial black hole masses are 14.2+8.3−3.7M⊙ and 7.5+2.3−2.3M⊙ and the final black hole mass is 20.8+6.1−1.7M⊙. We find that at least one of the component black holes has spin greater than 0.2. This source is located at a luminosity distance of 440+180−190 Mpc corresponding to a redshift 0.09+0.03−0.04. All uncertainties define a 90 % credible interval. This second gravitational-wave observation provides improved constraints on stellar populations and on deviations from general relativity.

3,448 citations


Journal ArticleDOI
01 Feb 2016-Gut
TL;DR: The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.
Abstract: Over the last 10–15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new ‘omic’ technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.

1,596 citations


Journal ArticleDOI
TL;DR: In this paper, the authors used three long-term satellite leaf area index (LAI) records and ten global ecosystem models to investigate four key drivers of LAI trends during 1982-2009.
Abstract: Global environmental change is rapidly altering the dynamics of terrestrial vegetation, with consequences for the functioning of the Earth system and provision of ecosystem services(1,2). Yet how global vegetation is responding to the changing environment is not well established. Here we use three long-term satellite leaf area index (LAI) records and ten global ecosystem models to investigate four key drivers of LAI trends during 1982-2009. We show a persistent and widespread increase of growing season integrated LAI (greening) over 25% to 50% of the global vegetated area, whereas less than 4% of the globe shows decreasing LAI (browning). Factorial simulations with multiple global ecosystem models suggest that CO2 fertilization effects explain 70% of the observed greening trend, followed by nitrogen deposition (9%), climate change (8%) and land cover change (LCC) (4%). CO2 fertilization effects explain most of the greening trends in the tropics, whereas climate change resulted in greening of the high latitudes and the Tibetan Plateau. LCC contributed most to the regional greening observed in southeast China and the eastern United States. The regional effects of unexplained factors suggest that the next generation of ecosystem models will need to explore the impacts of forest demography, differences in regional management intensities for cropland and pastures, and other emerging productivity constraints such as phosphorus availability.

1,534 citations


Journal ArticleDOI
Nicholas J Kassebaum1, Megha Arora1, Ryan M Barber1, Zulfiqar A Bhutta2  +679 moreInstitutions (268)
TL;DR: In this paper, the authors used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.

1,533 citations


Journal ArticleDOI
TL;DR: In this paper, the authors proposed a framework to combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, M. R. Abernathy1  +976 moreInstitutions (107)
TL;DR: It is found that the final remnant's mass and spin, as determined from the low-frequency and high-frequency phases of the signal, are mutually consistent with the binary black-hole solution in general relativity.
Abstract: The LIGO detection of GW150914 provides an unprecedented opportunity to study the two-body motion of a compact-object binary in the large-velocity, highly nonlinear regime, and to witness the final merger of the binary and the excitation of uniquely relativistic modes of the gravitational field. We carry out several investigations to determine whether GW150914 is consistent with a binary black-hole merger in general relativity. We find that the final remnant’s mass and spin, as determined from the low-frequency (inspiral) and high-frequency (postinspiral) phases of the signal, are mutually consistent with the binary black-hole solution in general relativity. Furthermore, the data following the peak of GW150914 are consistent with the least-damped quasinormal mode inferred from the mass and spin of the remnant black hole. By using waveform models that allow for parametrized general-relativity violations during the inspiral and merger phases, we perform quantitative tests on the gravitational-wave phase in the dynamical regime and we determine the first empirical bounds on several high-order post-Newtonian coefficients. We constrain the graviton Compton wavelength, assuming that gravitons are dispersed in vacuum in the same way as particles with mass, obtaining a 90%-confidence lower bound of 1013 km. In conclusion, within our statistical uncertainties, we find no evidence for violations of general relativity in the genuinely strong-field regime of gravity.


Journal ArticleDOI
TL;DR: This paper presents a comprehensive survey of the state-of-the-art work on EC for feature selection, which identifies the contributions of these different algorithms.
Abstract: Feature selection is an important task in data mining and machine learning to reduce the dimensionality of the data and increase the performance of an algorithm, such as a classification algorithm. However, feature selection is a challenging task due mainly to the large search space. A variety of methods have been applied to solve feature selection problems, where evolutionary computation (EC) techniques have recently gained much attention and shown some success. However, there are no comprehensive guidelines on the strengths and weaknesses of alternative approaches. This leads to a disjointed and fragmented field with ultimately lost opportunities for improving performance and successful applications. This paper presents a comprehensive survey of the state-of-the-art work on EC for feature selection, which identifies the contributions of these different algorithms. In addition, current issues and challenges are also discussed to identify promising areas for future research.

Journal ArticleDOI
Joshua Quick1, Nicholas J. Loman1, Sophie Duraffour2, Jared T. Simpson3, Jared T. Simpson4, Ettore Severi5, Ettore Severi6, Lauren A. Cowley, Joseph Akoi Bore2, Raymond Koundouno2, Gytis Dudas7, Amy Mikhail, Nobila Ouedraogo8, Babak Afrough, Amadou Bah9, Jonathan H.J. Baum2, Beate Becker-Ziaja2, Jan Peter Boettcher8, Mar Cabeza-Cabrerizo2, Álvaro Camino-Sánchez2, Lisa L. Carter10, Juliane Doerrbecker2, Theresa Enkirch11, Isabel García-Dorival12, Nicole Hetzelt8, Julia Hinzmann8, Tobias Holm2, Liana E. Kafetzopoulou6, Liana E. Kafetzopoulou13, Michel Koropogui, Abigael Kosgey14, Eeva Kuisma6, Christopher H. Logue6, Antonio Mazzarelli, Sarah Meisel2, Marc Mertens15, Janine Michel8, Didier Ngabo, Katja Nitzsche2, Elisa Pallasch2, Livia Victoria Patrono2, Jasmine Portmann, Johanna Repits16, Natasha Y. Rickett12, Andreas Sachse8, Katrin Singethan17, Inês Vitoriano, Rahel L. Yemanaberhan2, Elsa Gayle Zekeng12, Trina Racine18, Alexander Bello18, Amadou A. Sall19, Ousmane Faye19, Oumar Faye19, N’Faly Magassouba, Cecelia V. Williams20, Victoria Amburgey20, Linda Winona20, Emily Davis21, Jon Gerlach21, Frank Washington21, Vanessa Monteil, Marine Jourdain, Marion Bererd, Alimou Camara, Hermann Somlare, Abdoulaye Camara, Marianne Gerard, Guillaume Bado, Bernard Baillet, Déborah Delaune, Koumpingnin Yacouba Nebie22, Abdoulaye Diarra22, Yacouba Savane22, Raymond Pallawo22, Giovanna Jaramillo Gutierrez23, Natacha Milhano5, Natacha Milhano24, Isabelle Roger22, Christopher Williams, Facinet Yattara, Kuiama Lewandowski, James E. Taylor, Phillip A. Rachwal25, Daniel J. Turner, Georgios Pollakis12, Julian A. Hiscox12, David A. Matthews, Matthew K. O'Shea, Andrew Johnston, Duncan W. Wilson, Emma Hutley, Erasmus Smit6, Antonino Di Caro, Roman Wölfel26, Kilian Stoecker26, Erna Fleischmann26, Martin Gabriel2, Simon A. Weller25, Lamine Koivogui, Boubacar Diallo22, Sakoba Keita, Andrew Rambaut27, Andrew Rambaut7, Pierre Formenty22, Stephan Günther2, Miles W. Carroll 
11 Feb 2016-Nature
TL;DR: This paper presents sequence data and analysis of 142 EBOV samples collected during the period March to October 2015 and shows that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.
Abstract: A nanopore DNA sequencer is used for real-time genomic surveillance of the Ebola virus epidemic in the field in Guinea; the authors demonstrate that it is possible to pack a genomic surveillance laboratory in a suitcase and transport it to the field for on-site virus sequencing, generating results within 24 hours of sample collection. This paper reports the use of nanopore DNA sequencers (known as MinIONs) for real-time genomic surveillance of the Ebola virus epidemic, in the field in Guinea. The authors demonstrate that it is possible to pack a genomic surveillance laboratory in a suitcase and transport it to the field for on-site virus sequencing, generating results within 24 hours of sample collection. The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths1. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10−3 and 1.42 × 10−3 mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic2,3,4,5,6,7. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions8. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities9. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Matthew Abernathy3  +978 moreInstitutions (112)
TL;DR: The first observational run of the Advanced LIGO detectors, from September 12, 2015 to January 19, 2016, saw the first detections of gravitational waves from binary black hole mergers as discussed by the authors.
Abstract: The first observational run of the Advanced LIGO detectors, from September 12, 2015 to January 19, 2016, saw the first detections of gravitational waves from binary black hole mergers. In this paper we present full results from a search for binary black hole merger signals with total masses up to 100M⊙ and detailed implications from our observations of these systems. Our search, based on general-relativistic models of gravitational wave signals from binary black hole systems, unambiguously identified two signals, GW150914 and GW151226, with a significance of greater than 5σ over the observing period. It also identified a third possible signal, LVT151012, with substantially lower significance, which has a 87% probability of being of astrophysical origin. We provide detailed estimates of the parameters of the observed systems. Both GW150914 and GW151226 provide an unprecedented opportunity to study the two-body motion of a compact-object binary in the large velocity, highly nonlinear regime. We do not observe any deviations from general relativity, and place improved empirical bounds on several high-order post-Newtonian coefficients. From our observations we infer stellar-mass binary black hole merger rates lying in the range 9−240Gpc−3yr−1. These observations are beginning to inform astrophysical predictions of binary black hole formation rates, and indicate that future observing runs of the Advanced detector network will yield many more gravitational wave detections.

Journal ArticleDOI
TL;DR: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose thrombolysis in Myocardial Infarction plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding.
Abstract: BackgroundIn patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain. MethodsWe randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according...

Journal ArticleDOI
TL;DR: Evidence of the usefulness of DLS to study the homogeneity of proteins, nucleic acids, and complexes of protein–protein or protein–nucleic acid preparations, as well as to study protein–small molecule interactions is provided.
Abstract: Dynamic light scattering (DLS), also known as photon correlation spectroscopy (PCS), is a very powerful tool for studying the diffusion behaviour of macromolecules in solution. The diffusion coefficient, and hence the hydrodynamic radii calculated from it, depends on the size and shape of macromolecules. In this review, we provide evidence of the usefulness of DLS to study the homogeneity of proteins, nucleic acids, and complexes of protein–protein or protein–nucleic acid preparations, as well as to study protein–small molecule interactions. Further, we provide examples of DLS’s application both as a complementary method to analytical ultracentrifugation studies and as a screening tool to validate solution scattering models using determined hydrodynamic radii.

Journal ArticleDOI
TL;DR: In this article, the authors classify different types of sol-gel precursors and how these can influence a solgel process, from self-assembly and ordering in the initial solution, to phase separation during the gelation process and finally to crystallographic transformations at high temperature.
Abstract: From its initial use to describe hydrolysis and condensation processes, the term ‘sol–gel’ is now used for a diverse range of chemistries. In fact, it is perhaps better defined more broadly as covering the synthesis of solid materials such as metal oxides from solution-state precursors. These can include metal alkoxides that crosslink to form metal–oxane gels, but also metal ion–chelate complexes or organic polymer gels containing metal species. What is important across all of these examples is how the choice of precursor can have a significant impact on the structure and composition of the solid product. In this review, we will attempt to classify different types of sol–gel precursor and how these can influence a sol–gel process, from self-assembly and ordering in the initial solution, to phase separation during the gelation process and finally to crystallographic transformations at high temperature.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Matthew Abernathy1  +984 moreInstitutions (116)
TL;DR: The data around the time of the event were analyzed coherently across the LIGO network using a suite of accurate waveform models that describe gravitational waves from a compact binary system in general relativity.
Abstract: On September 14, 2015, the Laser Interferometer Gravitational-wave Observatory (LIGO) detected a gravitational-wave transient (GW150914); we characterise the properties of the source and its parameters. The data around the time of the event were analysed coherently across the LIGO network using a suite of accurate waveform models that describe gravitational waves from a compact binary system in general relativity. GW150914 was produced by a nearly equal mass binary black hole of $36^{+5}_{-4} M_\odot$ and $29^{+4}_{-4} M_\odot$ (for each parameter we report the median value and the range of the 90% credible interval). The dimensionless spin magnitude of the more massive black hole is bound to be $0.7$ (at 90% probability). The luminosity distance to the source is $410^{+160}_{-180}$ Mpc, corresponding to a redshift $0.09^{+0.03}_{-0.04}$ assuming standard cosmology. The source location is constrained to an annulus section of $590$ deg$^2$, primarily in the southern hemisphere. The binary merges into a black hole of $62^{+4}_{-4} M_\odot$ and spin $0.67^{+0.05}_{-0.07}$. This black hole is significantly more massive than any other known in the stellar-mass regime.

Journal ArticleDOI
TL;DR: The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.
Abstract: Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.

Journal ArticleDOI
TL;DR: Regular monitoring of vaccine attitudes – coupled with monitoring of local immunization rates – at the national and sub-national levels can identify populations with declining confidence and acceptance.

Journal ArticleDOI
TL;DR: Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo.
Abstract: Background Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. Methods In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Results Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P Conclusions Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).

Book ChapterDOI
Matej Kristan1, Ales Leonardis2, Jiří Matas3, Michael Felsberg4, Roman Pflugfelder5, Luka Cehovin1, Tomas Vojir3, Gustav Häger4, Alan Lukežič1, Gustavo Fernandez5, Abhinav Gupta6, Alfredo Petrosino7, Alireza Memarmoghadam8, Alvaro Garcia-Martin9, Andres Solis Montero10, Andrea Vedaldi11, Andreas Robinson4, Andy J. Ma12, Anton Varfolomieiev13, A. Aydin Alatan14, Aykut Erdem15, Bernard Ghanem16, Bin Liu, Bohyung Han17, Brais Martinez18, Chang-Ming Chang19, Changsheng Xu20, Chong Sun21, Daijin Kim17, Dapeng Chen22, Dawei Du20, Deepak Mishra23, Dit-Yan Yeung24, Erhan Gundogdu25, Erkut Erdem15, Fahad Shahbaz Khan4, Fatih Porikli26, Fatih Porikli27, Fei Zhao20, Filiz Bunyak28, Francesco Battistone7, Gao Zhu26, Giorgio Roffo29, Gorthi R. K. Sai Subrahmanyam23, Guilherme Sousa Bastos30, Guna Seetharaman31, Henry Medeiros32, Hongdong Li26, Honggang Qi20, Horst Bischof33, Horst Possegger33, Huchuan Lu21, Hyemin Lee17, Hyeonseob Nam34, Hyung Jin Chang35, Isabela Drummond30, Jack Valmadre11, Jae-chan Jeong36, Jaeil Cho36, Jae-Yeong Lee36, Jianke Zhu37, Jiayi Feng20, Jin Gao20, Jin-Young Choi, Jingjing Xiao2, Ji-Wan Kim36, Jiyeoup Jeong, João F. Henriques11, Jochen Lang10, Jongwon Choi, José M. Martínez9, Junliang Xing20, Junyu Gao20, Kannappan Palaniappan28, Karel Lebeda38, Ke Gao28, Krystian Mikolajczyk35, Lei Qin20, Lijun Wang21, Longyin Wen19, Luca Bertinetto11, Madan Kumar Rapuru23, Mahdieh Poostchi28, Mario Edoardo Maresca7, Martin Danelljan4, Matthias Mueller16, Mengdan Zhang20, Michael Arens, Michel Valstar18, Ming Tang20, Mooyeol Baek17, Muhammad Haris Khan18, Naiyan Wang24, Nana Fan39, Noor M. Al-Shakarji28, Ondrej Miksik11, Osman Akin15, Payman Moallem8, Pedro Senna30, Philip H. S. Torr11, Pong C. Yuen12, Qingming Huang39, Qingming Huang20, Rafael Martin-Nieto9, Rengarajan Pelapur28, Richard Bowden38, Robert Laganiere10, Rustam Stolkin2, Ryan Walsh32, Sebastian B. Krah, Shengkun Li19, Shengping Zhang39, Shizeng Yao28, Simon Hadfield38, Simone Melzi29, Siwei Lyu19, Siyi Li24, Stefan Becker, Stuart Golodetz11, Sumithra Kakanuru23, Sunglok Choi36, Tao Hu20, Thomas Mauthner33, Tianzhu Zhang20, Tony P. Pridmore18, Vincenzo Santopietro7, Weiming Hu20, Wenbo Li40, Wolfgang Hübner, Xiangyuan Lan12, Xiaomeng Wang18, Xin Li39, Yang Li37, Yiannis Demiris35, Yifan Wang21, Yuankai Qi39, Zejian Yuan22, Zexiong Cai12, Zhan Xu37, Zhenyu He39, Zhizhen Chi21 
08 Oct 2016
TL;DR: The Visual Object Tracking challenge VOT2016 goes beyond its predecessors by introducing a new semi-automatic ground truth bounding box annotation methodology and extending the evaluation system with the no-reset experiment.
Abstract: The Visual Object Tracking challenge VOT2016 aims at comparing short-term single-object visual trackers that do not apply pre-learned models of object appearance. Results of 70 trackers are presented, with a large number of trackers being published at major computer vision conferences and journals in the recent years. The number of tested state-of-the-art trackers makes the VOT 2016 the largest and most challenging benchmark on short-term tracking to date. For each participating tracker, a short description is provided in the Appendix. The VOT2016 goes beyond its predecessors by (i) introducing a new semi-automatic ground truth bounding box annotation methodology and (ii) extending the evaluation system with the no-reset experiment. The dataset, the evaluation kit as well as the results are publicly available at the challenge website (http://votchallenge.net).

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B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Matthew Abernathy1  +961 moreInstitutions (100)
TL;DR: The discovery of the GW150914 with the Advanced LIGO detectors provides the first observational evidence for the existence of binary black-hole systems that inspiral and merge within the age of the Universe as mentioned in this paper.
Abstract: The discovery of the gravitational-wave source GW150914 with the Advanced LIGO detectors provides the first observational evidence for the existence of binary black-hole systems that inspiral and merge within the age of the Universe. Such black-hole mergers have been predicted in two main types of formation models, involving isolated binaries in galactic fields or dynamical interactions in young and old dense stellar environments. The measured masses robustly demonstrate that relatively "heavy" black holes (≳25M⊙) can form in nature. This discovery implies relatively weak massive-star winds and thus the formation of GW150914 in an environment with metallicity lower than ∼1/2 of the solar value. The rate of binary black-hole mergers inferred from the observation of GW150914 is consistent with the higher end of rate predictions (≳1Gpc−3yr−1) from both types of formation models. The low measured redshift (z∼0.1) of GW150914 and the low inferred metallicity of the stellar progenitor imply either binary black-hole formation in a low-mass galaxy in the local Universe and a prompt merger, or formation at high redshift with a time delay between formation and merger of several Gyr. This discovery motivates further studies of binary-black-hole formation astrophysics. It also has implications for future detections and studies by Advanced LIGO and Advanced Virgo, and gravitational-wave detectors in space.

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16 Jun 2016
TL;DR: The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucose-sparing regimes.
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

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TL;DR: Routine implementation of the eFI could enable delivery of evidence-based interventions to improve outcomes for this vulnerable group of older people with mild, moderate and severe frailty, with robust predictive validity for outcomes of mortality, hospitalisation and nursing home admission.
Abstract: Background: frailty is an especially problematic expression of population ageing. International guidelines recommend routine identification of frailty to provide evidence-based treatment, but currently available tools require additional resource. Objectives: to develop and validate an electronic frailty index (eFI) using routinely available primary care electronic health record data. Study design and setting: retrospective cohort study. Development and internal validation cohorts were established using a randomly split sample of the ResearchOne primary care database. External validation cohort established using THIN database. Participants: patients aged 65–95, registered with a ResearchOne or THIN practice on 14 October 2008. Predictors: we constructed the eFI using the cumulative deficit frailty model as our theoretical framework. The eFI score is calculated by the presence or absence of individual deficits as a proportion of the total possible. Categories of fit, mild, moderate and severe frailty were defined using population quartiles. Outcomes: outcomes were 1-, 3- and 5-year mortality, hospitalisation and nursing home admission. Statistical analysis: hazard ratios (HRs) were estimated using bivariate and multivariate Cox regression analyses. Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was assessed using pseudo-R2 estimates. Results: we include data from a total of 931,541 patients. The eFI incorporates 36 deficits constructed using 2,171 CTV3 codes. One-year adjusted HR for mortality was 1.92 (95% CI 1.81–2.04) for mild frailty, 3.10 (95% CI 2.91–3.31) for moderate frailty and 4.52 (95% CI 4.16–4.91) for severe frailty. Corresponding estimates for hospitalisation were 1.93 (95% CI 1.86–2.01), 3.04 (95% CI 2.90–3.19) and 4.73 (95% CI 4.43–5.06) and for nursing home admission were 1.89 (95% CI 1.63–2.15), 3.19 (95% CI 2.73–3.73) and 4.76 (95% CI 3.92–5.77), with good to moderate discrimination but low calibration estimates. Conclusions: the eFI uses routine data to identify older people with mild, moderate and severe frailty, with robust predictive validity for outcomes of mortality, hospitalisation and nursing home admission. Routine implementation of the eFI could enable delivery of evidence-based interventions to improve outcomes for this vulnerable group.

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TL;DR: Cardiorespiratory training and, to a lesser extent, mixed training reduce disability during or after usual stroke care; this could be mediated by improved mobility and balance.
Abstract: Stroke patients have impaired physical fitness and this may exacerbate their disability. It is not known whether improving physical fitness after stroke reduces disability. Objectives The primary aims were to establish whether physical fitness training reduces death, dependence and disability after stroke. The secondary aims included an investigation of the effects of fitness training on secondary outcome measures (including, physical fitness, mobility, physical function, health and quality of life, mood and the incidence of adverse events). Randomised controlled trials were included when an intervention represented a clear attempt to improve either muscle strength and/or cardiorespiratory fitness, and whose control groups comprised either usual care or a non-exercise intervention. A total of 12 trials were included in the review. No trials reported death and dependence data. Two small trials reporting disability showed no evidence of benefit. The remaining available secondary outcome data suggest that cardiorespiratory training improves walking ability (mobility). Observed benefits appear to be associated with specific or 'task-related' training.

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TL;DR: An update on the current knowledge of the oral microbiome in health and disease is given and implications for modern-day oral healthcare are discussed.
Abstract: For millions of years, our resident microbes have coevolved and coexisted with us in a mostly harmonious symbiotic relationship. We are not distinct entities from our microbiome, but together we form a 'superorganism' or holobiont, with the microbiome playing a significant role in our physiology and health. The mouth houses the second most diverse microbial community in the body, harbouring over 700 species of bacteria that colonise the hard surfaces of teeth and the soft tissues of the oral mucosa. Through recent advances in technology, we have started to unravel the complexities of the oral microbiome and gained new insights into its role during both health and disease. Perturbations of the oral microbiome through modern-day lifestyles can have detrimental consequences for our general and oral health. In dysbiosis, the finely-tuned equilibrium of the oral ecosystem is disrupted, allowing disease-promoting bacteria to manifest and cause conditions such as caries, gingivitis and periodontitis. For practitioners and patients alike, promoting a balanced microbiome is therefore important to effectively maintain or restore oral health. This article aims to give an update on our current knowledge of the oral microbiome in health and disease and to discuss implications for modern-day oral healthcare.

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TL;DR: For women who are already obese, renewed efforts should be made towards improved management during pregnancy, especially of blood glucose, and increased attention to post-partum weight management.