Showing papers by "University College London published in 2013"
Max Planck Society1, Yale University2, Space Telescope Science Institute3, Harvard University4, University of Colorado Boulder5, Columbia University6, University of Toronto7, Argonne National Laboratory8, Ohio State University9, European Southern Observatory10, Aix-Marseille University11, ETH Zurich12, California Institute of Technology13, New York University14, Louisiana State University15, Australian National University16, Cornell University17, University College London18, Goddard Space Flight Center19, Leibniz Institute for Astrophysics Potsdam20
TL;DR: Astropy as discussed by the authors is a Python package for astronomy-related functionality, including support for domain-specific file formats such as flexible image transport system (FITS) files, Virtual Observatory (VO) tables, common ASCII table formats, unit and physical quantity conversions, physical constants specific to astronomy, celestial coordinate and time transformations, world coordinate system (WCS) support, generalized containers for representing gridded as well as tabular data, and a framework for cosmological transformations and conversions.
Abstract: We present the first public version (v02) of the open-source and community-developed Python package, Astropy This package provides core astronomy-related functionality to the community, including support for domain-specific file formats such as flexible image transport system (FITS) files, Virtual Observatory (VO) tables, and common ASCII table formats, unit and physical quantity conversions, physical constants specific to astronomy, celestial coordinate and time transformations, world coordinate system (WCS) support, generalized containers for representing gridded as well as tabular data, and a framework for cosmological transformations and conversions Significant functionality is under activedevelopment, such as a model fitting framework, VO client and server tools, and aperture and point spread function (PSF) photometry tools The core development team is actively making additions and enhancements to the current code base, and we encourage anyone interested to participate in the development of future Astropy versions
9,720 citations
TL;DR: It is estimated that undernutrition in the aggregate--including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding--is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011.
5,574 citations
TL;DR: “BCT taxonomy v1,” an extensive taxonomy of 93 consensually agreed, distinct BCTs, offers a step change as a method for specifying interventions, but the authors anticipate further development and evaluation based on international, interdisciplinary consensus.
Abstract: CONSORT guidelines call for precise reporting of behavior change interventions: we need rigorous methods of characterizing active content of interventions with precision and specificity. The objective of this study is to develop an extensive, consensually agreed hierarchically structured taxonomy of techniques [behavior change techniques (BCTs)] used in behavior change interventions. In a Delphi-type exercise, 14 experts rated labels and definitions of 124 BCTs from six published classification systems. Another 18 experts grouped BCTs according to similarity of active ingredients in an open-sort task. Inter-rater agreement amongst six researchers coding 85 intervention descriptions by BCTs was assessed. This resulted in 93 BCTs clustered into 16 groups. Of the 26 BCTs occurring at least five times, 23 had adjusted kappas of 0.60 or above. “BCT taxonomy v1,” an extensive taxonomy of 93 consensually agreed, distinct BCTs, offers a step change as a method for specifying interventions, but we anticipate further development and evaluation based on international, interdisciplinary consensus.
4,568 citations
Jean-Charles Lambert1, Jean-Charles Lambert2, Jean-Charles Lambert3, Carla A. Ibrahim-Verbaas4 +212 more•Institutions (75)
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
3,726 citations
University of Edinburgh1, University of Calgary2, Medical University of Graz3, The George Institute for Global Health4, University of Cambridge5, VU University Amsterdam6, University of British Columbia7, Sunnybrook Health Sciences Centre8, German Center for Neurodegenerative Diseases9, Paris Diderot University10, University of California, Davis11, Radboud University Nijmegen Medical Centre12, Ludwig Maximilian University of Munich13, University College London14, Harvard University15, University of Western Ontario16, The Chinese University of Hong Kong17, Maastricht University18, University of Florence19, Otto-von-Guericke University Magdeburg20, Newcastle University21, National University of Singapore22, Leiden University Medical Center23, University of Saint Mary24
TL;DR: This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
Abstract: Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
3,691 citations
Radboud University Nijmegen Medical Centre1, University of Michigan2, Radboud University Nijmegen3, University of Toronto4, McGill University5, University of Basel6, University of Florence7, Auckland City Hospital8, University of Pittsburgh9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, University of Colorado Denver26, National Health Service27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, Rutgers University31, Thomas Jefferson University32, Amgen33, University of Toledo34, Boston University35, Medical University of South Carolina36, University of Pennsylvania37, Northwestern University38
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
2,743 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
National Institutes of Health1, University College London2, Mayo Clinic3, University of Toronto4, Brigham Young University5, Cardiff University6, Lille University of Science and Technology7, Washington University in St. Louis8, University of Nottingham9, King's College London10, University of Cambridge11
TL;DR: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.
Abstract: BACKGROUND:
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
METHODS:
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
RESULTS:
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
CONCLUSIONS:
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
2,333 citations
TL;DR: The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.
Abstract: In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.
2,265 citations
TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
2,058 citations
Copenhagen University Hospital1, French Institute of Health and Medical Research2, University College London3, Columbia University4, University of Gothenburg5, University of Western Ontario6, University of the Witwatersrand7, University of Amsterdam8, University of São Paulo9, University of Western Australia10, Ludwig Maximilian University of Munich11, University of Palermo12, University of Milan13, University Medical Center14, University of Groningen15, University of California, Los Angeles16, University of London17, Radboud University Nijmegen18, University of Helsinki19, University of Copenhagen20
TL;DR: There is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition, familial hypercholesterolaemia.
Abstract: Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).
Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.
Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
Max Planck Society1, Yale University2, Space Telescope Science Institute3, Harvard University4, University of Colorado Boulder5, Columbia University6, University of Toronto7, Argonne National Laboratory8, Ohio State University9, European Southern Observatory10, Aix-Marseille University11, ETH Zurich12, California Institute of Technology13, New York University14, Louisiana State University15, Australian National University16, Cornell University17, University College London18, Goddard Space Flight Center19, Leibniz Institute for Astrophysics Potsdam20
TL;DR: Astropy as mentioned in this paper provides core astronomy-related functionality to the community, including support for domain-specific file formats such as Flexible Image Transport System (FITS) files, Virtual Observatory (VO) tables, and common ASCII table formats, unit and physical quantity conversions, physical constants specific to astronomy, celestial coordinate and time transformations, world coordinate system (WCS) support, generalized containers for representing gridded as well as tabular data, and a framework for cosmological transformations and conversions.
Abstract: We present the first public version (v0.2) of the open-source and community-developed Python package, Astropy. This package provides core astronomy-related functionality to the community, including support for domain-specific file formats such as Flexible Image Transport System (FITS) files, Virtual Observatory (VO) tables, and common ASCII table formats, unit and physical quantity conversions, physical constants specific to astronomy, celestial coordinate and time transformations, world coordinate system (WCS) support, generalized containers for representing gridded as well as tabular data, and a framework for cosmological transformations and conversions. Significant functionality is under active development, such as a model fitting framework, VO client and server tools, and aperture and point spread function (PSF) photometry tools. The core development team is actively making additions and enhancements to the current code base, and we encourage anyone interested to participate in the development of future Astropy versions.
TL;DR: Insight is gained into the common pathways of tumour evolution that could support the development of future therapeutic strategies and shape the evolution of the cancer genome through a plethora of mechanisms.
Abstract: Recent studies have revealed extensive genetic diversity both between and within tumours. This heterogeneity affects key cancer pathways, driving phenotypic variation, and poses a significant challenge to personalized cancer medicine. A major cause of genetic heterogeneity in cancer is genomic instability. This instability leads to an increased mutation rate and can shape the evolution of the cancer genome through a plethora of mechanisms. By understanding these mechanisms we can gain insight into the common pathways of tumour evolution that could support the development of future therapeutic strategies.
Radboud University Nijmegen1, University of Michigan2, University of Toronto3, McGill University4, University of Basel5, University of Florence6, Auckland City Hospital7, University of Pittsburgh8, Complutense University of Madrid9, Charité10, University of California, Los Angeles11, University College London12, University of Zurich13, University of Paris14, Marche Polytechnic University15, University of Texas Health Science Center at Houston16, Newcastle University17, University of Pécs18, Georgetown University19, Istanbul University20, Medical University of Białystok21, University of Giessen22, Seconda Università degli Studi di Napoli23, University College Dublin24, Stanford University25, Amgen26, University of Colorado Denver27, Medical College of Wisconsin28, University of Alabama at Birmingham29, University of Manchester30, National Health Service31, Rutgers University32, Thomas Jefferson University33, University of Toledo34, Boston University35, University of Pennsylvania36, Medical University of South Carolina37, Northwestern University38, University of Western Ontario39
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud9s phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
TL;DR: It is demonstrated, through a combination of state-of-the-art materials simulation techniques and X-ray photoemission experiments, that a type-II, staggered, band alignment of ~ 0.4 eV exists between anatase and rutile with anatase possessing the higher electron affinity, or work function.
Abstract: The most widely used oxide for photocatalytic applications owing to its low cost and high activity is TiO2. The discovery of the photolysis of water on the surface of TiO2 in 19721 launched four decades of intensive research into the underlying chemical and physical processes involved2, 3, 4, 5. Despite much collected evidence, a thoroughly convincing explanation of why mixed-phase samples of anatase and rutile outperform the individual polymorphs has remained elusive6. One long-standing controversy is the energetic alignment of the band edges of the rutile and anatase polymorphs of TiO2 (ref. 7). We demonstrate, through a combination of state-of-the-art materials simulation techniques and X-ray photoemission experiments, that a type-II, staggered, band alignment of ~ 0.4 eV exists between anatase and rutile with anatase possessing the higher electron affinity, or work function. Our results help to explain the robust separation of photoexcited charge carriers between the two phases and highlight a route to improved photocatalysts.
TL;DR: A test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens is described.
Abstract: As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.
TL;DR: A number of new therapeutic strategies currently under investigation for preventing myocardial reperfusion injury have the potential to improve clinical outcomes in patients with acute MI treated with PPCI.
Abstract: Acute myocardial infarction (MI) is a major cause of death and disability worldwide. In patients with MI, the treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PPCI). However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. A number of new therapeutic strategies currently under investigation for preventing myocardial reperfusion injury have the potential to improve clinical outcomes in patients with acute MI treated with PPCI.
TL;DR: This work shows a novel mechanism that can fundamentally alter dendrite formation in lithium-ion batteries as well as other metal batteries and transform the surface uniformity of coatings deposited in many general electrodeposition processes.
Abstract: Rechargeable lithium metal batteries are considered the “Holy Grail” of energy storage systems. Unfortunately, uncontrollable dendritic lithium growth inherent in these batteries (upon repeated charge/discharge cycling) has prevented their practical application over the past 40 years. We show a novel mechanism that can fundamentally alter dendrite formation. At low concentrations, selected cations (such as cesium or rubidium ions) exhibit an effective reduction potential below the standard reduction potential of lithium ions. During lithium deposition, these additive cations form a positively charged electrostatic shield around the initial growth tip of the protuberances without reduction and deposition of the additives. This forces further deposition of lithium to adjacent regions of the anode and eliminates dendrite formation in lithium metal batteries. This strategy may also prevent dendrite growth in lithium-ion batteries as well as other metal batteries and transform the surface uniformity of coating...
University Medical Center Groningen1, University of Tartu2, University of Exeter3, Greifswald University Hospital4, National Institute for Health and Welfare5, University of Washington6, Churchill Hospital7, Technische Universität München8, University of Queensland9, University Medical Center Utrecht10, Erasmus University Rotterdam11, Leiden University Medical Center12, National Institutes of Health13, University College London14, University of Auckland15, QIMR Berghofer Medical Research Institute16, Wellcome Trust Centre for Human Genetics17, University of Düsseldorf18, Ludwig Maximilian University of Munich19, University of Groningen20, Group Health Cooperative21, Wellcome Trust Sanger Institute22, University of Helsinki23
TL;DR: Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
Abstract: Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
Memorial Sloan Kettering Cancer Center1, Baylor University Medical Center2, Northwestern University3, University of Manchester4, Peking University5, Mount Vernon Hospital6, Ludwig Maximilian University of Munich7, University of Sydney8, University of Miami9, University College London10, University of Glasgow11, Kindai University12, Karolinska Institutet13, Peking Union Medical College14, GlaxoSmithKline15, Harvard University16
TL;DR: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazoSmithKline Pharmaceuticals.
Abstract: Background Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. Methods We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. Results Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any caus...
TL;DR: It was found that mortality was higher among more socially isolated and more lonely participants, and the effect of loneliness was not independent of demographic characteristics or health problems and did not contribute to the risk associated with social isolation.
Abstract: Both social isolation and loneliness are associated with increased mortality, but it is uncertain whether their effects are independent or whether loneliness represents the emotional pathway through which social isolation impairs health. We therefore assessed the extent to which the association between social isolation and mortality is mediated by loneliness. We assessed social isolation in terms of contact with family and friends and participation in civic organizations in 6,500 men and women aged 52 and older who took part in the English Longitudinal Study of Ageing in 2004–2005. A standard questionnaire measure of loneliness was administered also. We monitored all-cause mortality up to March 2012 (mean follow-up 7.25 y) and analyzed results using Cox proportional hazards regression. We found that mortality was higher among more socially isolated and more lonely participants. However, after adjusting statistically for demographic factors and baseline health, social isolation remained significantly associated with mortality (hazard ratio 1.26, 95% confidence interval, 1.08–1.48 for the top quintile of isolation), but loneliness did not (hazard ratio 0.92, 95% confidence interval, 0.78–1.09). The association of social isolation with mortality was unchanged when loneliness was included in the model. Both social isolation and loneliness were associated with increased mortality. However, the effect of loneliness was not independent of demographic characteristics or health problems and did not contribute to the risk associated with social isolation. Although both isolation and loneliness impair quality of life and well-being, efforts to reduce isolation are likely to be more relevant to mortality.
TL;DR: It is concluded that memory training programs appear to produce short-term, specific training effects that do not generalize, and cast doubt on both the clinical relevance of working memory training Programs and their utility as methods of enhancing cognitive functioning in typically developing children and healthy adults.
Abstract: It has been suggested that working memory training programs are effective both as treatments for attention-deficit/hyperactivity disorder (ADHD) and other cognitive disorders in children and as a tool to improve cognitive ability and scholastic attainment in typically developing children and adults. However, effects across studies appear to be variable, and a systematic meta-analytic review was undertaken. To be included in the review, studies had to be randomized controlled trials or quasi-experiments without randomization, have a treatment, and have either a treated group or an untreated control group. Twenty-three studies with 30 group comparisons met the criteria for inclusion. The studies included involved clinical samples and samples of typically developing children and adults. Meta-analyses indicated that the programs produced reliable short-term improvements in working memory skills. For verbal working memory, these near-transfer effects were not sustained at follow-up, whereas for visuospatial working memory, limited evidence suggested that such effects might be maintained. More importantly, there was no convincing evidence of the generalization of working memory training to other skills (nonverbal and verbal ability, inhibitory processes in attention, word decoding, and arithmetic). The authors conclude that memory training programs appear to produce short-term, specific training effects that do not generalize. Possible limitations of the review (including age differences in the samples and the variety of different clinical conditions included) are noted. However, current findings cast doubt on both the clinical relevance of working memory training programs and their utility as methods of enhancing cognitive functioning in typically developing children and healthy adults.
University College London1, University of Texas at Austin2, Goethe University Frankfurt3, Goddard Space Flight Center4, Utrecht University5, University of Rennes6, James Cook University7, University of California, Irvine8, University of Oxford9, United States Geological Survey10, United States Department of Agriculture11, Sun Yat-sen University12, British Geological Survey13, Rutgers University14, Colorado School of Mines15, San Francisco State University16, Simon Fraser University17, University of East Anglia18, Cranfield University19
TL;DR: In this paper, the authors critically review recent research assessing the impacts of climate on ground water through natural and human-induced processes as well as through groundwater-driven feedbacks on the climate system, and highlight the possible opportunities and challenges of using and sustaining groundwater resources in climate adaptation strategies.
Abstract: As the world's largest distributed store of fresh water, ground water plays a central part in sustaining ecosystems and enabling human adaptation to climate variability and change. The strategic importance of ground water for global water and food security will probably intensify under climate change as more frequent and intense climate extremes (droughts and floods) increase variability in precipitation, soil moisture and surface water. Here we critically review recent research assessing the impacts of climate on ground water through natural and human-induced processes as well as through groundwater-driven feedbacks on the climate system. Furthermore, we examine the possible opportunities and challenges of using and sustaining groundwater resources in climate adaptation strategies, and highlight the lack of groundwater observations, which, at present, limits our understanding of the dynamic relationship between ground water and climate.
TL;DR: It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a Diffusion-Partition-Solubility theory.
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01 Jan 2013TL;DR: The case for putting fairness at the heart of all policy making is reviewed, highlighting the need for action on the social determinants of health in order to address health inequalities and the social gradient in health outcomes.
Abstract: The final report of the World Health Organization Commission on the Social Determinants of Health (CSDH), published in 2008, affirmed that social injustice was killing on a grand scale, with a toxic combination of 'poor social policies and programmes, unfair economic arrangements, and bad politics' being responsible for producing and reinforcing health inequalities. It provided a comprehensive evidence-based discussion of pervasive inequalities of health in many countries, demonstrating the presence of a social gradient in health outcomes associated with the unfair distribution of the social determinants of health. The social determinants of health include the conditions in which people are born, grow, live, work and age, and the fundamental drivers of these conditions: the distribution of power; money; and resources. Following publication of the CSDH report and recommendations for action, the UK Government commissioned a Strategic Review of Health Inequalities in England. This article provides an overview and reflection on the findings from the CSDH and the Strategic Review of Health Inequalities in England, reviewing the case for putting fairness at the heart of all policy making. In the process, it highlights the need for action on the social determinants of health in order to address health inequalities and the social gradient in health outcomes.
Broad Institute1, Harvard University2, Karolinska Institutet3, University of North Carolina at Chapel Hill4, Oslo University Hospital5, Icahn School of Medicine at Mount Sinai6, University of Queensland7, deCODE genetics8, Lundbeck9, Aarhus University10, Aarhus University Hospital11, Trinity College, Dublin12, Cardiff University13, Radboud University Nijmegen14, VU University Amsterdam15, Russian Academy16, Statens Serum Institut17, Virginia Commonwealth University18, King's College London19, Queen's University Belfast20, University of Belgrade21, Erasmus University Rotterdam22, Ludwig Maximilian University of Munich23, Martin Luther University of Halle-Wittenberg24, University of Iceland25, Tbilisi State Medical University26, National Institutes of Health27, University of Verona28, University College London29
TL;DR: The authors conducted a multi-stage genome-wide association study (GWAS) for schizophrenia and found that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia.
Abstract: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
TL;DR: A comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown was performed and skeletal muscle loss was determined through serial ultrasound measurement.
Abstract: Importance Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. Objective To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Design, Setting, and Participants Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. Main Outcomes and Measures Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. Results There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% [95% CI, −20.9% to −4.8%]; P P P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) ( P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04). Conclusions and Relevance Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.
TL;DR: The PSIPRED Protein Analysis Workbench unites all of the previously available analysis methods into a single web-based framework and provides a greatly streamlined user interface with a number of new features to allow users to better explore their results.
Abstract: Here, we present the new UCL Bioinformatics Group’s PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/.
TL;DR: Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities, and major gaps in knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition.
Abstract: Summary Background Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities. Methods We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR. Findings 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]). Interpretation Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition. Funding None.
TL;DR: A novel model-based intra-array normalization strategy for 450 k data, called BMIQ (Beta MIxture Quantile dilation), to adjust the beta-values of type2 design probes into a statistical distribution characteristic of type1 probes is proposed.
Abstract: Motivation: The Illumina Infinium 450 k DNA Methylation Beadchip is a prime candidate technology for Epigenome-Wide Association Studies (EWAS). However, a difficulty associated with these beadarrays is that probes come in two different designs, characterized by widely different DNA methylation distributions and dynamic range, which may bias downstream analyses. A key statistical issue is therefore how best to adjust for the two different probe designs.
Results: Here we propose a novel model-based intra-array normalization strategy for 450 k data, called BMIQ (Beta MIxture Quantile dilation), to adjust the beta-values of type2 design probes into a statistical distribution characteristic of type1 probes. The strategy involves application of a three-state beta-mixture model to assign probes to methylation states, subsequent transformation of probabilities into quantiles and finally a methylation-dependent dilation transformation to preserve the monotonicity and continuity of the data. We validate our method on cell-line data, fresh frozen and paraffin-embedded tumour tissue samples and demonstrate that BMIQ compares favourably with two competing methods. Specifically, we show that BMIQ improves the robustness of the normalization procedure, reduces the technical variation and bias of type2 probe values and successfully eliminates the type1 enrichment bias caused by the lower dynamic range of type2 probes. BMIQ will be useful as a preprocessing step for any study using the Illumina Infinium 450 k platform.
Availability: BMIQ is freely available from http://code.google.com/p/bmiq/.
Contact: a.teschendorff@ucl.ac.uk
Supplementary information:Supplementary data are available at Bioinformatics online