Showing papers by "University of Leicester published in 2013"
Woolcock Institute of Medical Research1, University of Otago2, University of Cape Town3, Boston University4, University of California, San Francisco5, University of Wisconsin-Madison6, Creighton University7, University of Arizona8, University of Newcastle9, Erasmus University Rotterdam10, University of Groningen11, University of Edinburgh12, McMaster University13, Imperial College London14, University of Leicester15, University of Amsterdam16, University of Nevada, Reno17, University of Washington18, University of Aberdeen19, University of Pittsburgh20
TL;DR: This update is a supplement to the previous 2002 IIP classification document and outlines advances in the past decade and potential areas for future investigation.
Abstract: Background: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical “gold standard” of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs.Purpose: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs.Methods: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011.Results: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis–interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific inte...
2,931 citations
Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
2,585 citations
Kyle S. Dawson1, David J. Schlegel2, Christopher P. Ahn1, Scott F. Anderson3 +181 more•Institutions (51)
TL;DR: The Baryon Oscillation Spectroscopic Survey (BOSS) as discussed by the authors was designed to measure the scale of baryon acoustic oscillations (BAO) in the clustering of matter over a larger volume than the combined efforts of all previous spectroscopic surveys of large-scale structure.
Abstract: The Baryon Oscillation Spectroscopic Survey (BOSS) is designed to measure the scale of baryon acoustic oscillations (BAO) in the clustering of matter over a larger volume than the combined efforts of all previous spectroscopic surveys of large-scale structure. BOSS uses 1.5 million luminous galaxies as faint as i = 19.9 over 10,000 deg2 to measure BAO to redshifts z < 0.7. Observations of neutral hydrogen in the Lyα forest in more than 150,000 quasar spectra (g < 22) will constrain BAO over the redshift range 2.15 < z < 3.5. Early results from BOSS include the first detection of the large-scale three-dimensional clustering of the Lyα forest and a strong detection from the Data Release 9 data set of the BAO in the clustering of massive galaxies at an effective redshift z = 0.57. We project that BOSS will yield measurements of the angular diameter distance dA to an accuracy of 1.0% at redshifts z = 0.3 and z = 0.57 and measurements of H(z) to 1.8% and 1.7% at the same redshifts. Forecasts for Lyα forest constraints predict a measurement of an overall dilation factor that scales the highly degenerate DA (z) and H –1(z) parameters to an accuracy of 1.9% at z ~ 2.5 when the survey is complete. Here, we provide an overview of the selection of spectroscopic targets, planning of observations, and analysis of data and data quality of BOSS.
1,938 citations
TL;DR: In this paper, the authors argue that adopting saturation as a generic quality marker is inappropriate, considering issues of transparency and epistemology, and highlight the pertinent issues and encoura...
Abstract: Measuring quality in qualitative research is a contentious issue with diverse opinions and various frameworks available within the evidence base. One important and somewhat neglected argument within this field relates to the increasingly ubiquitous discourse of data saturation. While originally developed within grounded theory, theoretical saturation, and later termed data/thematic saturation for other qualitative methods, the meaning has evolved and become transformed. Problematically this temporal drift has been treated as unproblematic and saturation as a marker for sampling adequacy is becoming increasingly accepted and expected. In this article we challenge the unquestioned acceptance of the concept of saturation and consider its plausibility and transferability across all qualitative approaches. By considering issues of transparency and epistemology we argue that adopting saturation as a generic quality marker is inappropriate. The aim of this article is to highlight the pertinent issues and encoura...
1,927 citations
Panos Deloukas1, Stavroula Kanoni1, Christina Willenborg2, Martin Farrall3 +201 more•Institutions (64)
TL;DR: An association analysis in CAD cases and controls identifies 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants strongly associated with CAD at a 5% false discovery rate (FDR).
Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
1,518 citations
TL;DR: It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.
Abstract: Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
1,468 citations
TL;DR: This work presents, on the simplest possible case, what it considers as the very basic features of the (brand new) virtual element method, which is the ultimate evolution of the mimetic finite differences approach.
Abstract: We present, on the simplest possible case, what we consider as the very basic features of the (brand new) virtual element method. As the readers will easily recognize, the virtual element method could easily be regarded as the ultimate evolution of the mimetic finite differences approach. However, in their last step they became so close to the traditional finite elements that we decided to use a different perspective and a different name. Now the virtual element spaces are just like the usual finite element spaces with the addition of suitable non-polynomial functions. This is far from being a new idea. See for instance the very early approach of E. Wachspress [A Rational Finite Element Basic (Academic Press, 1975)] or the more recent overview of T.-P. Fries and T. Belytschko [The extended/generalized finite element method: An overview of the method and its applications, Int. J. Numer. Methods Engrg.84 (2010) 253–304]. The novelty here is to take the spaces and the degrees of freedom in such a way that th...
1,125 citations
TL;DR: In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability, and an ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive loweringof blood pressure.
Abstract: Background Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. Methods We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician’s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. Results Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The ordinal analysis showed significantly lower modi fied Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P = 0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. Conclusions In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indi cated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.)
1,105 citations
TL;DR: In this paper, the authors make a case for examining energy transition as a geographical process, involving the reconfiguration of current patterns and scales of economic and social activity, and provide a conceptual language with which to describe and assess the geographical implications of a transition towards low carbon energy.
945 citations
TL;DR: Use of the generalized linear model framework allows us to present a unified account of how models can be compared using the deviance information criterion and how goodness of fit can be assessed using the residual deviance.
Abstract: We set out a generalized linear model framework for the synthesis of data from randomized controlled trials. A common model is described, taking the form of a linear regression for both fixed and random effects synthesis, which can be implemented with normal, binomial, Poisson, and multinomial data. The familiar logistic model for meta-analysis with binomial data is a generalized linear model with a logit link function, which is appropriate for probability outcomes. The same linear regression framework can be applied to continuous outcomes, rate models, competing risks, or ordered category outcomes by using other link functions, such as identity, log, complementary log-log, and probit link functions. The common core model for the linear predictor can be applied to pairwise meta-analysis, indirect comparisons, synthesis of multiarm trials, and mixed treatment comparisons, also known as network meta-analysis, without distinction. We take a Bayesian approach to estimation and provide WinBUGS program code for a Bayesian analysis using Markov chain Monte Carlo simulation. An advantage of this approach is that it is straightforward to extend to shared parameter models where different randomized controlled trials report outcomes in different formats but from a common underlying model. Use of the generalized linear model framework allows us to present a unified account of how models can be compared using the deviance information criterion and how goodness of fit can be assessed using the residual deviance. The approach is illustrated through a range of worked examples for commonly encountered evidence formats.
912 citations
TL;DR: In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org, which has the potential for widespread implementation in a clinical setting.
Abstract: Aims Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF).
Methods and results The MAGGIC meta-analysis includes individual data on 39 372 patients with HF, both reduced and preserved left-ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin-receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively.
Conclusion In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website [www.heartfailurerisk.org][1]. The score has the potential for widespread implementation in a clinical setting.
[1]: http://www.heartfailurerisk.org
TL;DR: In this paper, an up-to-date along-strike synthesis of the Tianshan orogenic collage and a new tectonic model to explain its accretionary evolution is provided.
TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
TL;DR: Key changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants.
Abstract: Introduction: Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient. When these recommendations are implemented patient outcomes may be improved. Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document represents an updated version of the guideline published by the group in 2007 and updated in 2010. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature. Results: Key changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline also includes recommendations and a discussion of thromboprophylactic strategies for all patients following traumatic injury. The most significant addition is a new section that discusses the need for every institution to develop, implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. The remaining recommendations have been re-evaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies. Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensure that established protocols are consistently implemented will ensure a uniform and high standard of care across Europe and beyond.
Tulane University1, University of Pittsburgh2, Aarhus University3, University of Alberta4, University of Leicester5, Princeton University6, Oregon Health & Science University7, Korea Institute of Science and Technology8, Nazarbayev University9, Troy University10, Universidade Federal do Rio Grande do Sul11, University of Toronto12, University of Southern Mississippi13, University of Zurich14, DePauw University15
TL;DR: A detailed catalog of zebrafish behaviors that covers both larval and adult models is developed, representing a beginning of creating a more comprehensive ethogram ofZebrafish behavior, which will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebra fish neurobehavioral paradigms in their research.
Abstract: Zebrafish (Danio rerio) are rapidly gaining popularity in translational neuroscience and behavioral research. Physiological similarity to mammals, ease of genetic manipulations, sensitivity to pharmacological and genetic factors, robust behavior, low cost, and potential for high-throughput screening contribute to the growing utility of zebrafish models in this field. Understanding zebrafish behavioral phenotypes provides important insights into neural pathways, physiological biomarkers, and genetic underpinnings of normal and pathological brain function. Novel zebrafish paradigms continue to appear with an encouraging pace, thus necessitating a consistent terminology and improved understanding of the behavioral repertoire. What can zebrafish 'do', and how does their altered brain function translate into behavioral actions? To help address these questions, we have developed a detailed catalog of zebrafish behaviors (Zebrafish Behavior Catalog, ZBC) that covers both larval and adult models. Representing a beginning of creating a more comprehensive ethogram of zebrafish behavior, this effort will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebrafish neurobehavioral paradigms in their research. In addition, this glossary creates a framework for developing a zebrafish neurobehavioral ontology, ultimately to become part of a unified animal neurobehavioral ontology, which collectively will contribute to better integration of biological data within and across species.
TL;DR: In this article, optical and near-infrared observations were used to confirm that compact-object mergers are the progenitors of short-duration γ-ray bursts and the sites of significant production of r-process elements.
Abstract: Short-duration γ-ray bursts are intense flashes of cosmic γ-rays, lasting less than about two seconds, whose origin is unclear1, 2. The favoured hypothesis is that they are produced by a relativistic jet created by the merger of two compact stellar objects (specifically two neutron stars or a neutron star and a black hole). This is supported by indirect evidence such as the properties of their host galaxies3, but unambiguous confirmation of the model is still lacking. Mergers of this kind are also expected to create significant quantities of neutron-rich radioactive species4, 5, whose decay should result in a faint transient, known as a ‘kilonova’, in the days following the burst6, 7, 8. Indeed, it is speculated that this mechanism may be the predominant source of stable r-process elements in the Universe5, 9. Recent calculations suggest that much of the kilonova energy should appear in the near-infrared spectral range, because of the high optical opacity created by these heavy r-process elements10, 11, 12, 13. Here we report optical and near-infrared observations that provide strong evidence for such an event accompanying the short-duration γ-ray burst GRB 130603B. If this, the simplest interpretation of the data, is correct, then it confirms that compact-object mergers are the progenitors of short-duration γ-ray bursts and the sites of significant production of r-process elements. It also suggests that kilonovae offer an alternative, unbeamed electromagnetic signature of the most promising sources for direct detection of gravitational waves.
University of Leicester1, King's College London2, Leiden University3, Imperial College London4, VU University Amsterdam5, University of Tartu6, University of Helsinki7, QIMR Berghofer Medical Research Institute8, University of Groningen9, Karolinska Institutet10, University College London11, University of Cambridge12, Erasmus University Rotterdam13, University of Leeds14, University of Georgia15, University of Oulu16, University of Oxford17, University of Washington18, National Institutes of Health19, National Institute for Health and Welfare20, Wellcome Trust Centre for Human Genetics21, National Institute for Health Research22, Georgia Regents University23, Prevention Institute24, Ludwig Maximilian University of Munich25, University of North Carolina at Chapel Hill26, University of Texas MD Anderson Cancer Center27, University of Milan28, University of Pennsylvania29, Harvard University30, Broad Institute31, Glenfield Hospital32
TL;DR: In this paper, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL) (P < 5 × 10−8).
Abstract: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
TL;DR: The Cherenkov Telescope Array (CTA) as discussed by the authors is a very high-energy (VHE) gamma ray observatory with an international collaboration with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America.
TL;DR: In this paper, a simple function, dependent on the product of the atomic hydrogen column density, N(HI), and dust extinction, E(B-V), was derived to estimate the variation of the molecular hydrogen column densities over the sky.
Abstract: Prediction of the soft X-ray absorption along lines of sight through our Galaxy is crucial for understanding the spectra of extragalactic sources, but requires a good estimate of the foreground column density of photoelectric absorbing species. Assuming uniform elemental abundances this reduces to having a good estimate of the total hydrogen column density, N(Htot)=N(HI)+2N(H2). The atomic component, N(HI), is reliably provided using the mapped 21 cm radio emission but estimating the molecular hydrogen column density, N(H2), expected for any particular direction, is difficult. The X-ray afterglows of GRBs are ideal sources to probe X-ray absorption in our Galaxy because they are extragalactic, numerous, bright, have simple spectra and occur randomly across the entire sky. We describe an empirical method, utilizing 493 afterglows detected by the Swift XRT, to determine N(Htot) through the Milky Way which provides an improved estimate of the X-ray absorption in our Galaxy and thereby leads to more reliable measurements of the intrinsic X-ray absorption and, potentially, other spectral parameters, for extragalactic X-ray sources. We derive a simple function, dependent on the product of the atomic hydrogen column density, N(HI), and dust extinction, E(B-V), which describes the variation of the molecular hydrogen column density, N(H2), of our Galaxy, over the sky. Using the resulting N(Htot) we show that the dust-to-hydrogen ratio is correlated with the carbon monoxide emission and use this ratio to estimate the fraction of material which forms interstellar dust grains. Our resulting recipe represents a significant revision in Galactic absorption compared to previous standard methods, particularly at low Galactic latitudes.
TL;DR: A comprehensive, integrated checklist of determinants of practice (the TICD checklist) is described that aims to be comprehensive and to build on the strengths of each of the 12 included checklists.
Abstract: Background: Determinants of practice are factors that might prevent or enable improvements. Several checklists, frameworks, taxonomies, and classifications of determinants of healthcare professional practice have been published. In this paper, we describe the development of a comprehensive, integrated checklist of determinants of practice (the TICD checklist). Methods: We performed a systematic review of frameworks of determinants of practice followed by a consensus process. We searched electronic databases and screened the reference lists of key background documents. Two authors independently assessed titles and abstracts, and potentially relevant full text articles. We compiled a list of attributes that a checklist should have: comprehensiveness, relevance, applicability, simplicity, logic, clarity, usability, suitability, and usefulness. We assessed included articles using these criteria and collected information about the theory, model, or logic underlying how the factors (determinants) were selected, described, and grouped, the strengths and weaknesses of the checklist, and the determinants and the domains in each checklist. We drafted a preliminary checklist based on an aggregated list of determinants from the included checklists, and finalized the checklist by a consensus process among implementation researchers. Results: We screened 5,778 titles and abstracts and retrieved 87 potentially relevant papers in full text. Several of these papers had references to papers that we also retrieved in full text. We also checked potentially relevant papers we had on file that were not retrieved by the searches. We included 12 checklists. None of these were completely comprehensive when compared to the aggregated list of determinants and domains. We developed a checklist with 57 potential determinants of practice grouped in seven domains: guideline factors, individual health professional factors, patient factors, professional interactions, incentives and resources, capacity for organisational change, and social, political, and legal factors. We also developed five worksheets to facilitate the use of the checklist. Conclusions: Based on a systematic review and a consensus process we developed a checklist that aims to be comprehensive and to build on the strengths of each of the 12 included checklists. The checklist is accompanied with five worksheets to facilitate its use in implementation research and quality improvement projects.
TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
TL;DR: This review focuses on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and describes p53-mediated regulation of several physiological pathways that could mediate its role in both senescences and aging.
Abstract: p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.
TL;DR: It is suggested that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls and efforts should be made to improve recognition and treatment of anxiety.
Abstract: Summary Background Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls. Methods We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls. Findings Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7–16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0–12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96–1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8–23·6) in 48 964 cancer survivors and 13·9% (9·8–18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08–1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86–1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44–1·14; p=0·16) differed significantly between cancer patients and their spouses. Interpretation Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses. Funding None.
TL;DR: The role of prognostic factors in current clinical practice, randomised trials, and developing new interventions are discussed, and why and how prognostic factor research should be improved are explained.
Abstract: Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.
TL;DR: A genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry finds a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Institute for Health Metrics and Evaluation1, University of Manchester2, Public Health England3, St George's, University of London4, Clinical Trial Service Unit5, King's College London6, University of London7, Anglia Ruskin University8, Moorfields Eye Hospital9, University of Cambridge10, University of Liverpool11, University of Leicester12, Imperial College London13, Ulster University14, University of Bristol15, Swansea University16, Queen Mary University of London17, University of Oxford18, Harvard University19, University of Tokyo20, University of Nottingham21, Royal Cornwall Hospital22, University of Queensland23
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) as mentioned in this paper examined the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010.
TL;DR: In this article, a survey of 12CO emission in 40 luminous sub-millimetre galaxies (SMGs), with 850-μm fluxes of S850μm = 4-20 mJy, was conducted with the Plateau de Bure Interferometer.
Abstract: We present the results from a survey of 12CO emission in 40 luminous sub-millimetre galaxies (SMGs), with 850-μm fluxes of S850 μm = 4–20 mJy, conducted with the Plateau de Bure Interferometer. We detect 12CO emission in 32 SMGs at z ∼ 1.2–4.1, including 16 SMGs not previously published. Using multiple 12CO line (Jup = 2–7) observations, we derive a median spectral line energy distribution for luminous SMGs. We report the discovery of a fundamental relationship between 12CO FWHM and 12CO line luminosity in high-redshift starbursts, which we interpret as a natural consequence of the baryon-dominated dynamics within the regions probed by our observations. We use far-infrared luminosities to assess the star formation efficiency in our SMGs, finding that the slope of the L′CO-LFIR relation is close to linear. We derive molecular gas masses, finding a mean gas mass of (5.3 ± 1.0) × 1010 M⊙. Combining these with dynamical masses, we determine the redshift evolution of the gas content of SMGs, finding that they do not appear to be significantly more gas rich than less vigorously star-forming galaxies at high redshifts. Finally, we collate X-ray observations, and study the interdependence of gas and dynamical properties of SMGs with their AGN activity and supermassive black hole masses (MBH), finding that SMGs lie significantly below the local MBH-σ relation.
TL;DR: New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell–matrix junctions.
Abstract: Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling.
TL;DR: Oral treatment with a specific inhibitor of the kinase PERK, a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain.
Abstract: During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.
TL;DR: In this paper, it is predicted that the remnant of neutron star-neutron star mergers may not collapse immediately to a black hole (or even collapse at all), forming instead an unstable millisecond pulsar (magnetar) which powers a plateau phase in the X-ray light curve.
Abstract: A significant fraction of the long gamma-ray bursts (LGRBs) in the Swift sample have a plateau phase showing evidence of ongoing energy injection. We suggest that many short gamma-ray bursts (SGRBs) detected by the Swift satellite also show evidence of energy injection. Explaining this observation within the typical SGRB progenitor model is challenging as late time accretion, often used to explain plateaus in LGRBs, is likely to be absent from the SGRB population. Alternatively, it is predicted that the remnant of neutron star–neutron star mergers may not collapse immediately to a black hole (or even collapse at all), forming instead an unstable millisecond pulsar (magnetar) which powers a plateau phase in the X-ray light curve.
By fitting the magnetar model to all of the Swift SGRBs observed until 2012 May, we find that about half can be clearly fitted with a magnetar plateau phase while the rest are consistent with forming a magnetar but the data are insufficient to prove a plateau phase. More data, both at early times and a larger sample, are required to confirm this. This model can be tested by detecting the gravitational wave emission from events using the next generation gravitational wave observatories.