Variations in Rates of Discharges to Nursing Homes after Acute Hospitalization for Stroke and the Influence of Service Heterogeneity: An Anglia Stroke Clinical Network Evaluation Study.

Nursing home placement after stroke indicates a poor outcome but numbers placed vary between hospitals. The aim of this study is to determine whether between-hospital variations in new nursing home placements post-stroke are reliant solely on case-mix differences or whether service heterogeneity plays a role. A prospective, multi-center cohort study of acute stroke patients admitted to eight National Health Service acute hospitals within the Anglia Stroke and Heart Clinical Network between 2009 and 2011 was conducted. We modeled the association between hospitals (as a fixed-effect) and rates of new discharges to nursing homes using multiple logistic regression, adjusting for important patient risk factors. Descriptive and graphical data analyses were undertaken to explore the role of hospital characteristics. Of 1335 stroke admissions, 135 (10%) were discharged to a nursing home but rates varied considerably from 6% to 19% between hospitals. The hospital with the highest adjusted odds ratio of nursing home discharges (OR 4.26; 95% CI 1.69 to 10.73), was the only hospital that did not provide rehabilitation beds in the stroke unit. Increasing hospital size appeared to be related to an increased odds of nursing home placement, although attenuated by the number of hospital stroke admissions. Our results highlight the potential influence of hospital characteristics on this important outcome, independently of patient-level factors

Desert particulate matter from Afghanistan increases airway obstruction in human distal lungs exposed to type 2 cytokine IL-13

IntroductionDeployment related asthma-like symptoms including distal airway obstruction have been described in U.S. military personnel who served in Iraq and Afghanistan. The mechanisms responsible for the development of distal airway obstruction in deployers exposed to desert particulate matter (PM) is not well understood. We sought to determine if respiratory exposure to PM from Afghanistan (PMa) increases human distal airway hyperresponsiveness (AHR) with or without exposures to IL-13, a type 2 cytokine. We further tested whether mitochondrial dysfunction, such as ATP signaling and oxidative stress, may contribute to PMa- mediated AHR.MethodsPrecision-cut lung slices from donors without a history of lung disease, tobacco smoking, or vaping were pre-treated with IL-13 for 24 h. This was followed by exposure to PMa or PM from California (PMc, control for PMa) for up to 72 h. The role of hydrogen peroxide and ATP in AHR was assessed using the antioxidant enzyme catalase or an ATP receptor P2Y13 antagonist MRS2211. AHR in response to methacholine challenges as well as cytokine IL-8 production were measured.ResultsPMa alone, but not PMc alone, trended to increase AHR. Importantly, the combination of PMa and IL-13 significantly amplified AHR compared to control or PMc+IL-13. PMa alone and in combination with IL-13 increased IL-8 as compared to the control. PMa increased H2O2 and ATP. MRS211 and catalase reduced AHR in PCLS exposed to both PMa and IL-13.DiscussionOur data suggests that PMa in a type 2 inflammation-high lung increased AHR in part through oxidative stress and ATP signaling

Important factors in predicting mortality outcome from stroke: Findings from the Anglia Stroke Clinical Network Evaluation Study

Background: although variation in stroke service provision and outcomes have been previously investigated, it is less well known what service characteristics are associated with reduced short- and medium-term mortality. Methods: data from a prospective multicentre study (2009–12) in eight acute regional NHS trusts with a catchment population of about 2.6 million were used to examine the prognostic value of patient-related factors and service characteristics on stroke mortality outcome at 7, 30 and 365 days post stroke, and time to death within 1 year. Results: a total of 2,388 acute stroke patients (mean (standard deviation) 76.9 (12.7) years; 47.3% men, 87% ischaemic stroke) were included in the study. Among patients characteristics examined increasing age, haemorrhagic stroke, total anterior circulation stroke type, higher prestroke frailty, history of hypertension and ischaemic heart disease and admission hyperglycaemia predicted 1-year mortality. Additional inclusion of stroke service characteristics controlling for patient and service level characteristics showed varying prognostic impact of service characteristics on stroke mortality over the disease course during first year after stroke at different time points. The most consistent finding was the benefit of higher nursing levels; an increase in one trained nurses per 10 beds was associated with reductions in 30-day mortality of 11–28% (P < 0.0001) and in 1-year mortality of 8–12% (P < 0.001). Conclusions: there appears to be consistent and robust evidence of direct clinical benefit on mortality up to 1 year after acute stroke of higher numbers of trained nursing staff over and above that of other recognised mortality risk factors

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing β-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases

Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90+years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score=- 0.02; 95% CI=- 0.05 to 0.02; p value=0.3; n=18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits. © The Author(s) 2014

Evaluation of stroke services in Anglia Stroke Clinical Network to examine the variation in acute services and stroke outcomes.

BACKGROUND: Stroke is the third leading cause of death in developed countries and the leading cause of long-term disability worldwide. A series of national stroke audits in the UK highlighted the differences in stroke care between hospitals. The study aims to describe variation in outcomes following stroke and to identify the characteristics of services that are associated with better outcomes, after accounting for case mix differences and individual prognostic factors. METHODS/DESIGN: We will conduct a cohort study in eight acute NHS trusts within East of England, with at least one year of follow-up after stroke. The study population will be a systematically selected representative sample of patients admitted with stroke during the study period, recruited within each hospital. We will collect individual patient data on prognostic characteristics, health care received, outcomes and costs of care and we will also record relevant characteristics of each provider organisation. The determinants of one year outcome including patient reported outcome will be assessed statistically with proportional hazards regression models. Self (or proxy) completed EuroQol (EQ-5D) questionnaires will measure quality of life at baseline and follow-up for cost utility analyses. DISCUSSION: This study will provide observational data about health service factors associated with variations in patient outcomes and health care costs following hospital admission for acute stroke. This will form the basis for future RCTs by identifying promising health service interventions, assessing the feasibility of recruiting and following up trial patients, and provide evidence about frequency and variances in outcomes, and intra-cluster correlation of outcomes, for sample size calculations. The results will inform clinicians, public, service providers, commissioners and policy makers to drive further improvement in health services which will bring direct benefit to the patients.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Parallel adaptation of rabbit populations to myxoma virus.

In the 1950s the myxoma virus was released into European rabbit populations in Australia and Europe, decimating populations and resulting in the rapid evolution of resistance. We investigated the genetic basis of resistance by comparing the exomes of rabbits collected before and after the pandemic. We found a strong pattern of parallel evolution, with selection on standing genetic variation favoring the same alleles in Australia, France, and the United Kingdom. Many of these changes occurred in immunity-related genes, supporting a polygenic basis of resistance. We experimentally validated the role of several genes in viral replication and showed that selection acting on an interferon protein has increased the protein's antiviral effect.This work was supported by grants from the Programa Operacional Potencial Humano–Quadro de Referência Estratégica Nacional funds from the European Social Fund and Portuguese Ministério da Ciência, Tecnologia e Ensino Superior to M.C. (IF/00283/2014/CP1256/CT0012), to P.J.E. (IF/00376/2015) and to J.M.A. (SFRH/BD/72381/2010). AM was supported by the European Research Council (grant 647787-LocalAdaptation). FJ was supported by the European Research Council (grant 281668). LL was supported by the European Research Council grant (339941-ADAPT). McFadden Lab is supported by National Institute of Health (NIH) grant R01 AI080607. S.C.G. holds a Sir Henry Dale Fellowship, co-funded by the Wellcome Trust and the Royal Society (098406/Z/12/Z)

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes