Showing papers by "Newcastle University published in 2014"
Icahn School of Medicine at Mount Sinai1, Carnegie Mellon University2, Harvard University3, University of Toronto4, Wellcome Trust Sanger Institute5, University of Pittsburgh6, Nagoya University7, University of Freiburg8, King's College London9, Vanderbilt University10, University of Santiago de Compostela11, King Abdulaziz University12, University of Utah13, Duke University14, Memorial University of Newfoundland15, Trinity College, Dublin16, University of Pennsylvania17, University of Illinois at Chicago18, Boston Children's Hospital19, Columbia University20, German Cancer Research Center21, University College London22, Kaiser Permanente23, Broad Institute24, Cardiff University25, Complutense University of Madrid26, Newcastle University27, Baylor College of Medicine28, University of California, San Francisco29, RWTH Aachen University30, National Health Service31, McMaster University32, Saarland University33, Karolinska Institutet34, National Institutes of Health35, University of Helsinki36, Emory University37
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
2,228 citations
TL;DR: In this article, the authors address Ronkko and Evermann's criticisms of the Partial Least Squares (PLS) approach to structural equation modeling and conclude that PLS should continue to be used as an important statistical tool for management and organizational research, as well as other social science disciplines.
Abstract: This article addresses Ronkko and Evermann’s criticisms of the partial least squares (PLS) approach to structural equation modeling. We contend that the alleged shortcomings of PLS are not due to problems with the technique, but instead to three problems with Ronkko and Evermann’s study: (a) the adherence to the common factor model, (b) a very limited simulation designs, and (c) overstretched generalizations of their findings. Whereas Ronkko and Evermann claim to be dispelling myths about PLS, they have in reality created new myths that we, in turn, debunk. By examining their claims, our article contributes to reestablishing a constructive discussion of the PLS method and its properties. We show that PLS does offer advantages for exploratory research and that it is a viable estimator for composite factor models. This can pose an interesting alternative if the common factor model does not hold. Therefore, we can conclude that PLS should continue to be used as an important statistical tool for management and organizational research, as well as other social science disciplines.
1,906 citations
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
University of Surrey1, University of New Mexico2, Colorado School of Mines3, Pennsylvania State University4, Georgia Institute of Technology5, Imperial College London6, University of Connecticut7, MESA+ Institute for Nanotechnology8, Newcastle University9, University of Science and Technology of China10, Wuhan University11
TL;DR: In this paper, an up-to-date perspective on the use of anion-exchange membranes in fuel cells, electrolysers, redox flow batteries, reverse electrodialysis cells, and bioelectrochemical systems (e.g. microbial fuel cells).
Abstract: This article provides an up-to-date perspective on the use of anion-exchange membranes in fuel cells, electrolysers, redox flow batteries, reverse electrodialysis cells, and bioelectrochemical systems (e.g. microbial fuel cells). The aim is to highlight key concepts, misconceptions, the current state-of-the-art, technological and scientific limitations, and the future challenges (research priorities) related to the use of anion-exchange membranes in these energy technologies. All the references that the authors deemed relevant, and were available on the web by the manuscript submission date (30th April 2014), are included.
1,526 citations
TL;DR: The Theory of Planned Behaviour (TPB; Ajzen...
Abstract: It doesn't matter how beautiful your theory is, it doesn't matter how smart you are. If it doesn't agree with experiment, it's wrong. (Richard P. Feynman)The Theory of Planned Behaviour (TPB; Ajzen...
1,077 citations
Columbia University1, University of Pennsylvania2, Rush University Medical Center3, University of Kentucky4, Uppsala University5, Newcastle University6, Northwestern University7, Washington University in St. Louis8, Mayo Clinic9, Emory University10, University of São Paulo11, University of California12, Icahn School of Medicine at Mount Sinai13, Harvard University14, Medical University of Vienna15, University of Pittsburgh16, University of Washington17, University of British Columbia18, University of California, San Diego19, Boston University20, University of California, San Francisco21, University of Iowa22, University of Ulm23, University of Texas Southwestern Medical Center24, New York University25, Oregon Health & Science University26, Kanazawa University27
TL;DR: A new term is recommended, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.
Abstract: We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
1,016 citations
TL;DR: The Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia is developed as a joint venture of three societies representing specialists with a natural interest in hyponatonemia to obtain a common and holistic view.
Abstract: Hyponatraemia, defined as a serum sodium concentration !135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.
879 citations
TL;DR: In this paper, a review examines the evidence for sub-daily extreme rainfall intensification due to anthropogenic climate change and describes the current physical understanding of the association between sub-day extreme rainfall intensity and atmospheric temperature.
Abstract: Evidence that extreme rainfall intensity is increasing at the global scale has strengthened considerably in recent years Research now indicates that the greatest increases are likely to occur in short-duration storms lasting less than a day, potentially leading to an increase in the magnitude and frequency of flash floods This review examines the evidence for subdaily extreme rainfall intensification due to anthropogenic climate change and describes our current physical understanding of the association between subdaily extreme rainfall intensity and atmospheric temperature We also examine the nature, quality, and quantity of information needed to allow society to adapt successfully to predicted future changes, and discuss the roles of observational and modeling studies in helping us to better understand the physical processes that can influence subdaily extreme rainfall characteristics We conclude by describing the types of research required to produce a more thorough understanding of the relationships between local-scale thermodynamic effects, large-scale atmospheric circulation, and subdaily extreme rainfall intensity
862 citations
Icahn School of Medicine at Mount Sinai1, Pierre-and-Marie-Curie University2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Toronto5, Trinity College, Dublin6, University of Pittsburgh7, Utrecht University8, McMaster University9, University College Dublin10, Our Lady's Children's Hospital11, University of Oxford12, Instituto Nacional de Saúde Dr. Ricardo Jorge13, University of Lisbon14, University of California, Los Angeles15, University of Miami16, Goethe University Frankfurt17, University of Pennsylvania18, Vanderbilt University19, Temple University20, University of Bologna21, Cancer Care Ontario22, University of Southern California23, University of Alberta24, University of Birmingham25, Université de Montréal26, Rush University Medical Center27, University of Coimbra28, Kaiser Permanente29, Cornell University30, Newcastle University31, University of Illinois at Chicago32, University of Minnesota33, University of Gothenburg34, Memorial University of Newfoundland35, Duke University36, University of Paris37, Centre for Mental Health38, King's College London39, University of Washington40, Nationwide Children's Hospital41, Indiana University42, Tufts University43, German Cancer Research Center44, University of Utah45, Stanford University46
TL;DR: For example, the authors analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability.
Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
833 citations
Charité1, Lawrence Berkeley National Laboratory2, Cambridge University Hospitals NHS Foundation Trust3, Wellcome Trust Sanger Institute4, Paul Sabatier University5, University of Manchester6, Newcastle University7, University of Toronto8, Leeds Teaching Hospitals NHS Trust9, Katholieke Universiteit Leuven10, University of Kiel11, University College London12, Drexel University13, University of Cambridge14, Geisinger Medical Center15, St George’s University Hospitals NHS Foundation Trust16, University of Bristol17, Columbia University18, University of Oxford19, Radboud University Nijmegen20, University of Oregon21, Aberystwyth University22, Max Planck Society23
TL;DR: The updated HPO database is described, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO, allowing integration of existing datasets and interoperability with multiple biomedical resources.
Abstract: The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
801 citations
TL;DR: This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
TL;DR: It is uncertain whether interventions to improve adoption of SDM are effective given the low quality of the evidence, but any intervention that actively targets patients, healthcare professionals, or both, is better than none.
Abstract: Background
Shared decision making (SDM) is a process by which a healthcare choice is made jointly by the practitioner and the patient and is said to be the crux of patient-centred care. Policy makers perceive SDM as desirable because of its potential to a) reduce overuse of options not clearly associated with benefits for all (e.g., prostate cancer screening); b) enhance the use of options clearly associated with benefits for the vast majority (e.g., cardiovascular risk factor management); c) reduce unwarranted healthcare practice variations; d) foster the sustainability of the healthcare system; and e) promote the right of patients to be involved in decisions concerning their health. Despite this potential, SDM has not yet been widely adopted in clinical practice.
Objectives
To determine the effectiveness of interventions to improve healthcare professionals’ adoption of SDM.
Search methods
We searched the following electronic databases up to 18 March 2009: Cochrane Library (1970-), MEDLINE (1966-), EMBASE (1976-), CINAHL (1982-) and PsycINFO (1965-). We found additional studies by reviewing a) the bibliographies of studies and reviews found in the electronic databases; b) the clinicaltrials.gov registry; and c) proceedings of the International Shared Decision Making Conference and the conferences of the Society for Medical Decision Making. We included all languages of publication.
Selection criteria
We included randomised controlled trials (RCTs) or well-designed quasi-experimental studies (controlled clinical trials, controlled before and after studies, and interrupted time series analyses) that evaluated any type of intervention that aimed to improve healthcare professionals' adoption of shared decision making. We defined adoption as the extent to which healthcare professionals intended to or actually engaged in SDM in clinical practice or/and used interventions known to facilitate SDM. We deemed studies eligible if the primary outcomes were evaluated with an objective measure of the adoption of SDM by healthcare professionals (e.g., a third-observer instrument).
Data collection and analysis
At least two reviewers independently screened each abstract for inclusion and abstracted data independently using a modified version of the EPOC data collection checklist. We resolved disagreements by discussion. Statistical analysis considered categorical and continuous primary outcomes. We computed the standard effect size for each outcome separately with a 95% confidence interval. We evaluated global effects by calculating the median effect size and the range of effect sizes across studies.
Main results
The reviewers identified 6764 potentially relevant documents, of which we excluded 6582 by reviewing titles and abstracts. Of the remainder, we retrieved 182 full publications for more detailed screening. From these, we excluded 176 publications based on our inclusion criteria. This left in five studies, all RCTs. All five were conducted in ambulatory care: three in primary clinical care and two in specialised care. Four of the studies targeted physicians only and one targeted nurses only. In only two of the five RCTs was a statistically significant effect size associated with the intervention to have healthcare professionals adopt SDM. The first of these two studies compared a single intervention (a patient-mediated intervention: the Statin Choice decision aid) to another single intervention (also patient-mediated: a standard Mayo patient education pamphlet). In this study, the Statin Choice decision aid group performed better than the standard Mayo patient education pamphlet group (standard effect size = 1.06; 95% CI = 0.62 to 1.50). The other study compared a multifaceted intervention (distribution of educational material, educational meeting and audit and feedback) to usual care (control group) (standard effect size = 2.11; 95% CI = 1.30 to 2.90). This study was the only one to report an assessment of barriers prior to the elaboration of its multifaceted intervention.
Authors' conclusions
The results of this Cochrane review do not allow us to draw firm conclusions about the most effective types of intervention for increasing healthcare professionals' adoption of SDM. Healthcare professional training may be important, as may the implementation of patient-mediated interventions such as decision aids. Given the paucity of evidence, however, those motivated by the ethical impetus to increase SDM in clinical practice will need to weigh the costs and potential benefits of interventions. Subsequent research should involve well-designed studies with adequate power and procedures to minimise bias so that they may improve estimates of the effects of interventions on healthcare professionals' adoption of SDM. From a measurement perspective, consensus on how to assess professionals' adoption of SDM is desirable to facilitate cross-study comparisons.
TL;DR: In this article, the authors focus on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death.
TL;DR: There is evidence of moderate quality showing that caries is lower when free-sugars intake is < 10% E, and with the < 5% E cut-off, a significant relationship was observed, but the evidence was judged to be of very low quality.
Abstract: A systematic review of studies in humans was conducted to update evidence on the association between the amount of sugars intake and dental caries and on the effect of restricting sugars intake to < 10% and < 5% energy (E) on caries to inform the updating of World Health Organization guidelines on sugars consumption. Data sources included MEDLINE, EMBASE, Cochrane Database, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences, China National Knowledge Infrastructure, Wanfang, and South African Department of Health. Eligible studies reported the absolute amount of sugars and dental caries, measured as prevalence, incidence, or severity. The review was conducted and reported in accordance with the PRISMA statement, and the evidence was assessed according to GRADE Working Group guidelines. From 5,990 papers identified, 55 studies were eligible – 3 intervention, 8 cohort, 20 population, and 24 cross-sectional. Data variability limited meta-analysis. Of the studies, 42 out of 50 of those in children and 5 out of 5 in adults reported at least one positive association between sugars and caries. There is evidence of moderate quality showing that caries is lower when free-sugars intake is < 10% E. With the < 5% E cut-off, a significant relationship was observed, but the evidence was judged to be of very low quality. The findings are relevant to minimizing caries risk throughout the life course.
National Institutes of Health1, University of Turku2, Duke University3, Newcastle University4, Mayo Clinic5, University of Virginia6, University of Pennsylvania7, Texas Scottish Rite Hospital for Children8, Baylor University Medical Center9, Medical College of Wisconsin10, University of Washington11, MetroHealth12, University of North Carolina at Chapel Hill13, Hacettepe University14
TL;DR: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis, and were prevented by coinjection with nonmutated (but not with mutated) human C ECR1.
Abstract: BACKGROUND We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia — phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.)
TL;DR: This is the first study to provide normative data for grip strength across the life course and these centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.
Abstract: Introduction: Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol. Methods: We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing). Results: Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses
TL;DR: A framework of ecosystem services is suggested for systematizing the evidence on the provision of bio-physical benefits as well as social and psychological benefits that enable coping with or reducing the adverse effects of climate change.
TL;DR: Accelerometer outputs from AG and GA seem comparable when attached to the same body location in adults, whereas inconsistent differences are apparent between the two brands and placements in children, hence limiting the comparability between brands in this age group.
Abstract: PurposeThe study aims were to compare raw triaxial accelerometer output from ActiGraph GT3X+ (AG) and GENEActiv (GA) placed on the hip and the wrist and to develop regression equations for estimating energy expenditure.MethodsThirty children (7–11 yr) and 30 adults (18–65 yr) completed eight
Heidelberg University1, University of Edinburgh2, University of Copenhagen3, university of lille4, University of Debrecen5, Sheba Medical Center6, Utrecht University7, Newcastle University8, Turku University Hospital9, Saarland University10, University of Paris11, Helsinki University Central Hospital12, Sapienza University of Rome13, University Hospital Heidelberg14
TL;DR: Moderate- to high-quality evidence is found to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9–12, and avoidance of corticosteroids.
Abstract: Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach Results We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9‐12, and avoidance of corticosteroids Conclusion These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome
TL;DR: This article used a high-resolution model, typically used for weather forecasting, to simulate hourly rainfall in the UK in the year 2100 and found that short-duration rainfall intensified in summer, increasing the risk of flash flooding.
Abstract: Changes in precipitation extremes are occurring under climate change, but how they will manifest on sub-daily timescales is uncertain. This study used a high-resolution model, typically used for weather forecasting, to simulate hourly rainfall in the UK in the year 2100. The results confirmed previous findings of winter rainfall intensification and found that short-duration rainfall intensified in summer, increasing the risk of flash flooding.
TL;DR: Behavioural interventions that deal with both diet and physical activity show small but significant benefits on weight loss maintenance.
Abstract: Objective To systematically review and describe currently available approaches to supporting maintenance of weight loss in obese adults and to assess the evidence for the effectiveness of these interventions.
Design Systematic review with meta-analysis.
Data sources Medline, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials.
Study selection Studies were identified through to January 2014. Randomised trials of interventions to maintain weight loss provided to initially obese adults (aged ≥18) after weight loss of ≥5% body weight with long term (≥12 months) follow-up of weight change (main outcome) were included.
Study appraisal and synthesis Potential studies were screened independently and in duplicate; study characteristics and outcomes were extracted. Meta-analyses were conducted to estimate the effects of interventions on weight loss maintenance with the inverse variance method and a random effects model. Results are presented as mean differences in weight change, with 95% confidence intervals.
Results 45 trials involving 7788 individuals were included. Behavioural interventions focusing on both food intake and physical activity resulted in an average difference of −1.56 kg (95% confidence interval −2.27 to −0.86 kg; 25 comparisons, 2949 participants) in weight regain compared with controls at 12 months. Orlistat combined with behavioural interventions resulted in a −1.80 kg (−2.54 to −1.06; eight comparisons, 1738 participants) difference compared with placebo at 12 months. All orlistat studies reported higher frequencies of adverse gastrointestinal events in the experimental compared with placebo control groups. A dose-response relation for orlistat treatment was found, with 120 mg doses three times a day leading to greater weight loss maintenance (−2.34 kg, −3.03 to −1.65) compared with 60 mg and 30 mg three times a day (−0.70 kg, 95% confidence interval −1.92 to 0.52), P=0.02.
Conclusions Behavioural interventions that deal with both diet and physical activity show small but significant benefits on weight loss maintenance.
TL;DR: It is shown that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice, and frequency of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts.
Abstract: Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
TL;DR: Recent progress in the field is summarized, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally induced persistence.
TL;DR: The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease as mentioned in this paper, which suggest additive or synergistic effects of both pathologies on cognitive decline.
Abstract: Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia. Further studies are warranted to elucidate the many hitherto unanswered questions regarding the overlap between CVD and AD as well as the impact of both CVD and AD pathologies on the development and progression of dementia.
University of New South Wales1, Newcastle University2, University of Cambridge3, University of Gothenburg4, Nizam's Institute of Medical Sciences5, University of Toronto6, Harvard University7, Duke University8, National University of Singapore9, University of Southern California10, University of Pittsburgh11, University of California, San Diego12, Lille University of Science and Technology13, University of Iowa14, VU University Medical Center15, Dalhousie University16
TL;DR: The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies and can be harmonized with the DSM-5 criteria.
Abstract: Author(s): Sachdev, Perminder; Kalaria, Raj; O'Brien, John; Skoog, Ingmar; Alladi, Suvarna; Black, Sandra E; Blacker, Deborah; Blazer, Dan G; Chen, Christopher; Chui, Helena; Ganguli, Mary; Jellinger, Kurt; Jeste, Dilip V; Pasquier, Florence; Paulsen, Jane; Prins, Niels; Rockwood, Kenneth; Roman, Gustavo; Scheltens, Philip; Internationlal Society for Vascular Behavioral and Cognitive Disorders | Abstract: BackgroundSeveral sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.MethodsParticipants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.ResultsCognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.ConclusionsThe proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.
TL;DR: In this paper, an overview of systematic reviews and meta-analyses of the effectiveness of brief alcohol intervention in primary healthcare published between 2002 and 2012 is presented. But the authors highlight the large volume of primarily positive evidence supporting brief intervention effects as well as some unanswered questions with regards to the effect of brief intervention across different cultural settings and in specific population groups, and in respect of the optimum content of brief interventions.
Abstract: Aims: The aim of the study was to assess the cumulative evidence on the effectiveness of brief alcohol interventions in primary healthcare in order to highlight key knowledge gaps for further research. Methods: An overview of systematic reviews and meta-analyses of the effectiveness of brief alcohol intervention in primary healthcare published between 2002 and 2012. Findings: Twenty-four systematic reviews met the eligibility criteria (covering a total of 56 randomized controlled trials reported across 80 papers). Across the included studies, it was consistently reported that brief intervention was effective for addressing hazardous and harmful drinking in primary healthcare, particularly in middle-aged, male drinkers. Evidence gaps included: brief intervention effective- ness in key groups (women, older and younger drinkers, minority ethnic groups, dependent/co-morbid drinkers and those living in tran- sitional and developing countries); and the optimum brief intervention length and frequency to maintain longer-term effectiveness. Conclusion: This overview highlights the large volume of primarily positive evidence supporting brief alcohol intervention effects as well as some unanswered questions with regards to the effectiveness of brief alcohol intervention across different cultural settings and in specific population groups, and in respect of the optimum content of brief interventions that might benefit from further research.
TL;DR: Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women, and the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastroZole in post menopausal women at high risk of Breast cancer.
TL;DR: Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics, and its licence status might need to be reviewed.
Abstract: Summary Background Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. Methods We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin. Findings We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77–1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73–0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82–0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31–0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75–0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83–1·18; p=0·9). Doses of 3 mg/m 2 were associated with fewer early deaths than doses of 6 mg/m 2 , with equal efficacy. Interpretation Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed. Funding None.
TL;DR: The Kinect can accurately measure timing and gross spatial characteristics of clinically relevant movements but not with the same spatial accuracy for smaller movements, such as hand clasping.
TL;DR: This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
Abstract: The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.