Improvement in Prediction of Coronary Heart Disease Risk over Conventional Risk Factors Using SNPs Identified in Genome-Wide Association Studies

We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction.SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55-75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI).There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, P<0.001; C-index 0.671 to 0.740, P = 0.001), as well as MI or coronary intervention, (NRI of 44%, P<0.001; C-index 0.717 to 0.750, P = 0.256). ROC curves showed that addition of SNPs better improved discrimination when the sensitivity of conventional risk factors was low for prediction of MI or coronary intervention.There was significant improvement in risk prediction of CHD over 15 years when SNPs identified from GWAS were added to conventional risk factors. This effect may be particularly useful for identifying individuals with a low prognostic index who are in fact at increased risk of disease than indicated by conventional risk factors alone

Outcomes of interfacility critical care adult patient transport: a systematic review

INTRODUCTION: We aimed to determine the adverse events and important prognostic factors associated with interfacility transport of intubated and mechanically ventilated adult patients. METHODS: We performed a systematic review of MEDLINE, CENTRAL, EMBASE, CINAHL, HEALTHSTAR, and Web of Science (from inception until 10 January 2005) for all clinical studies describing the incidence and predictors of adverse events in intubated and mechanically ventilated adult patients undergoing interfacility transport. The bibliographies of selected articles were also examined. RESULTS: Five studies (245 patients) met the inclusion criteria. All were case-series and two were prospective in design. Due to the paucity of studies and significant heterogeneity in study population, outcome events, and results, we synthesized data in a qualitative manner. Pre-transport severity of illness was reported in only one study. The most common indication for transport was a need for investigations and/or specialist care (three studies, 220 patients). Transport modalities included air (fixed or rotor wing; 66% of patients) and ground (31%) ambulance, and commercial aircraft (3%). Transport teams included a physician in three studies (220 patients). Death during transfer was rare (n = 1). No other adverse events or significant therapeutic interventions during transport were reported. One study reported a 19% (28/145) incidence of respiratory alkalosis on arrival and another study documented a 30% overall intensive care unit mortality, while no adverse events or outcomes were reported after arrival in the three other studies. CONCLUSION: Insufficient data exist to draw firm conclusions regarding the mortality, morbidity, or risk factors associated with the interfacility transport of intubated and mechanically ventilated adult patients. Further study is required to define the risks and benefits of interfacility transfer in this patient population. Such information is important for the planning and allocation of resources related to transporting critically ill adults

Jetstream: A self-provisoned, scalable science and engineering cloud environment

The paper describes the motivation behind Jetstream, its functions, hardware configuration, software environment, user interface, design, use cases, relationships with other projects such as Wrangler and iPlant, and challenges in implementation.Funded by the National Science Foundation Award #ACI - 144560

Measuring the effects of listening for leisure on outcome after stroke (MELLO):A pilot randomized controlled trial of mindful music listening

Background: Cognitive deficits and low mood are common post-stroke. Music listening is suggested to have beneficial effects on cognition, while mindfulness may improve mood. Combining these approaches may enhance cognitive recovery and improve mood early post-stroke. Aims: To assess the feasibility and acceptability of a novel mindful music listening intervention. Methods: A parallel group randomized controlled feasibility trial with ischemic stroke patients, comparing three groups; mindful music listening, music listening and audiobook listening (control group), eight weeks intervention. Feasibility was measured using adherence to protocol and questionnaires. Cognition (including measures of verbal memory and attention) and mood (Hospital Anxiety and Depression Scale) were assessed at baseline, end of intervention and at six-months post-stroke. Results: Seventy-two participants were randomized to mindful music listening (n = 23), music listening (n = 24), or audiobook listening (n = 25). Feasibility and acceptability measures were encouraging: 94% fully consistent with protocol; 68.1% completing ≥6/8 treatment visits; 80–107% listening adherence; 83% retention to six-month endpoint. Treatment effect sizes for cognition at six month follow-up ranged from d = 0.00 ([−0.64,0.64], music alone), d = 0.31, ([0.36,0.97], mindful music) for list learning; to d = 0.58 ([0.06,1.11], music alone), d = 0.51 ([−0.07,1.09], mindful music) for immediate story recall; and d = 0.67 ([0.12,1.22], music alone), d = 0.77 ([0.16,1.38]mindful music) for attentional switching compared to audiobooks. No signal of change was seen for mood. A definitive study would require 306 participants to detect a clinically substantial difference in improvement (z-score difference = 0.66, p = 0.017, 80% power) in verbal memory (delayed story recall). Conclusions: Mindful music listening is feasible and acceptable post-stroke. Music listening interventions appear to be a promising approach to improving recovery from stroke

Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks

Moral relativism as a disconnect between behavioural and experienced warm glow

We examine the robustness of warm glow preferences to changes in the choice set. Behavioural warm glow is measured using the crowded-out charity dictator game of Crumpler and Grossman (2008). In the give treatment, subjects could donate any part of their endowment to charity where their donations completely crowd out the charity's own initial endowment. In the give/take treatment, the option to take any part of the charity's endowment was added to the subjects' choice set. Experienced warm glow is measured by a series of post-decision self-reports of positive affect. Within each treatment behavioural and experienced warm glow are positively correlated, such that the more subjects donated to charity the better they claimed to feel about themselves. However, when comparing across treatments the addition of the take option results in a fall in behavioural warm glow but a rise in experienced warm glow. We interpret these results as evidence for i) a utility function increasing in both money and morality and ii) a type of moral relativism whereby the morally good action is defined in relation to the available options. This means that utility is derived from both the chosen option and from foregone opportunities, the implication of which is that the transitivity axiom becomes practically unfalsifiable

European Bat Lyssavirus in Scottish Bats

Daubenton bats may roost infrequently in human dwellings, so risk for human contact is low

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Corrigendum to "Overview: oxidant and particle photochemical processes above a south-east Asian tropical rainforest (the OP3 project): introduction, rationale, location characteristics and tools" published in Atmos. Chem. Phys., 10, 169–199, 2010

Author(s): Hewitt, CN; Lee, JD; MacKenzie, AR; Barkley, MP; Carslaw, N; Carver, GD; Chappell, NA; Coe, H; Collier, C; Commane, R; Davies, F; Davison, B; DiCarlo, P; Di Marco, CF; Dorsey, JR; Edwards, PM; Evans, MJ; Fowler, D; Furneaux, KL; Gallagher, M; Guenther, A; Heard, DE; Helfter, C; Hopkins, J; Ingham, T; Irwin, M; Jones, C; Karunaharan, A; Langford, B; Lewis, AC; Lim, SF; MacDonald, SM; Mahajan, AS; Malpass, S; McFiggans, G; Mills, G; Misztal, P; Moller, S; Monks, PS; Nemitz, E; Nicolas-Perea, V; Oetjen, H; Oram, DE; Palmer, PI; Phillips, GJ; Pike, R; Plane, JMC; Pugh, T; Pyle, JA; Reeves, CE; Robinson, NH; Stewart, D; Stone, D; Whalley, LK; Yang,

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p &amp;lt; 0.001). Lesion volume (Spearman’s rho rs= 0.38, p &amp;lt; 0.001) and g-ratio (rs= 0.24 p &amp;lt; 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p &amp;lt; 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament