922017 research outputs found
Sort by
Pathway-specific Polygenic Risk Scores (PRS) identify OSA-related pathways differentially moderating genetic susceptibility to CAD
No full textBackground—Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia (IH), may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (e.g. inflammatory) and protective (e.g. increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. Methods—We selected a cross-sectional sample of 471,877 participants from the UK Biobank, among whom we ascertained 4,974 to have OSA, 25,988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores (PS-PRS) for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (GWAS), annotated tospecific genes and pathways using functional genomics databases. Based on evidence of involvement with IH and CAD, we tested PS-PRS for the HIF-1, VEGF, NFkB and TNF signaling pathways. Results—In a multivariable-adjusted logistic generalized additive model, elevated PS-PRSs for the KEGG VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, p = 6E-04). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA.Conclusions—We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner, consistent with the previously studied phenomena whereby features of OSA may have both positive and negative effects on CAD. These results provide evidence that gene-by-environment interaction influences CAD riskin certain pathways among people with OSA, an effect that is not well-captured by the genome-wise wide PRS. These results can be followed up to study how OSA interacts with genetic risk at the molecular level, and potentially to personalize OSA treatment and reduce CAD risk according to individual pathway-specific genetic risk profiles
Are we leaving money on the table in infertility RCTs? Trialists should statistically adjust for prespecified, prognostic covariates to increase power.
No full textInfertility RCTs are often too small to detect realistic treatment effects. Large observational studies have been proposed as a solution. However, this strategy threatens to weaken the evidence base further, because non-random assignment to treatments makes it impossible to distinguish effects of treatment from confounding factors. Alternative solutions are required. Power in an RCT can be increased by adjusting for prespecified, prognostic covariates when performing statistical analysis, and if stratified randomization or minimization has been used, it is essential to adjust in order to get the correct answer. We present data showing that this simple, free, and frequently necessary strategy for increasing power is seldom employed, even in trials appearing in leading journals. We use this to motivate a pedagogical discussion and provide a worked example. While covariate adjustment can’t solve the problem of underpowered trials outright, there is an imperative to use sound methodology to maximize the information each trial yields
Ventricular arrhythmias and sudden death in non-ischemic dilated cardiomyopathy: matter of sex or scar?
No full textAimsTo evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in non-ischemic dilated cardiomyopathy, including analysis of potential confounders.MethodsRetrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance (CMR) at two tertiary hospitals. The primary combined endpoint encompassed sustained VA, appropriate ICD therapies, resuscitated cardiac arrest and SD. ResultsWe included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar LVEF but the prevalence of late gadolinium enhancement (LGE) at CMR was significantly higher among males (48% vs 30%, p<0.001). Males had higher cumulative incidence of the primary endpoint (8% vs 4%, p=0.02) and male sex was a significant predictor of the primary endpoint at univariate analysis (HR 1.93, p=0.02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the HR of male sex adjusted for LGE was 1.29 (p=0.37). LGE+ females had significantly higher cumulative incidence of the primary endpoint than LGE- males (13% vs 1.8%, p<0.001).ConclusionsIn patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk-stratification algorithms for VA or SD in DCM.<br/
Women, gender, and the professionalisation of French cultural diplomacy in Britain, 1900–40
No full textSummary of Model Checking C++ Programs
No full textThis is an extended abstract of the article “Model Checking C++ Programs” by Felipe R. Monteiro, Mikhail R. Gadelha, and Lucas C. Cordeiro. We describe and evaluate anovel verification approach based on bounded model checking (BMC) and satisfiability modulo theories (SMT) to verify C++ programs. Our verification approach analyzes bounded C++ programs by encoding into SMT various sophisticated features that the C++ programming language offers, such as templates, inheritance, polymorphism, exception handling, and the StandardTemplate Libraries. We implemented our verification approach on top of ESBMC. We compare ESBMC to LLBMC and DIVINE, which are state-of-the-art verifiers to check C++ programs directly from the LLVM bitcode. Experimental results show thatESBMC can handle a wide range of C++ programs, presenting a higher number of correct verification results. Additionally, ESBMC has been applied to a commercial C++ application in the telecommunication domain and successfully detected arithmeticoverflow errors, which could lead to security vulnerabilities.Index Terms—C++, memory safety, model checking, SMT, software verification<br/
Advancing Australian Public Health Initiatives Targeting Dementia Risk Reduction
No full textPublic health initiatives aim to improve health outcomes for populations by preventing disease and the health consequences of environmental hazards and natural or human-made disasters. Whilst public health initiatives have been successfully used to modify behaviours for chronic diseases yet many initiatives targeting reduced dementia risk in older adults suffer from conceptual and statistical flaws that greatly limit their usefulness. The limited success in modifying lifestyle dementia risk factors has led us to fall short in building a successful roadmap to dementia risk reduction. Here we argue for adopting a population-level, holistic approach to dementia risk reduction strategies across the lifespan. This approach is supplemented by 10 strategies that focus on improving social policies, harnessing existing policy, legislature and incentive schemes, and identifying feasible approaches to increase recreational and transport-related physical activity to creating best practice healthcare that supports healthy brain ageing for all.Key words: Health policy, health services, public health, gerontology, dementi
Nickel encapsulated in silicalite-1 zeolite catalysts for steam reforming of glycerol (SRG) towards renewable hydrogen production
No full textValorisation of crude glycerol via steam reforming, i.e., SRG, is a promising method to produce sustainable hydrogen. However, catalyst deactivation under harsh SRG conditions is still a main challenge which hinders the further development of practical SRG. In this work, the encapsulated Ni catalyst in siliceous silicalite-1 zeolite (Ni@Si-1) were developed to show the improved performance and enhanced anti-deactivation potentials in catalytic SRG as compared with the conventional impregnated Ni catalysts (i.e., Ni/Si-1). Importantly, the post-synthetic treatment of Ni@Si-1 using TPAOH solution formed the encapsulated Ni catalyst with the mesoporous hollow structure (i.e., Ni@HolSi-1), which demonstrate even better performance in SRG with glycerol conversion of >95%, H2 yield of ~70%, H2/CO2 molar ratio of > 2.33 and CO/CO2 molar ratio of <1 at 750 °C. Specifically, highly dispersed ultrasmall encapsulated Ni particles were retained within the hollow crystals of siliceous silicalite-1, as confirmed by XPS and HRTEM characterisation. The activation energy for glycerol conversion over Ni@HolSi-1 (i.e., Ea = ~ 19 kJ mol−1) was much lower than that of Ni/Si-1 and Ni@Si-1. 100-h longevity tests over the three catalysts were investigated at 750 °C, and the Ni@HolSi-1 catalyst exhibited an excellent stability and activity, as well as insignificant coke deposition, which could be due to the enhancement of highly dispersed yet accessible Ni NPs within the hollow Si-1 crystals. The findings of the work show the promise of the encapsulation strategy and mesoporous zeolites for developing the future reforming catalysts. <br/
Risk Assessment of Cascading Failures in Power Systems with Increasing Wind Penetration
No full textThe ever-growing penetration of renewable based gen-eration is leading to significant increases in the risk of cascading failures in low-inertia, and interconnection-rich, power systems. This paper proposes a framework for quantifying the risk of cas-cading failures in renewable-rich power systems with fast fre-quency response (FFR) services. This is achieved by developing a novel time-based dynamic model of cascading failures to capture the transient behaviours of the system response and quantify the risk of blackout. This dynamic cascading failure model is comple-mented by unit commitment for representative dispatch and in-cludes the provision of FFR. The proposed framework is illus-trated using a modified version of the Illinois 200-bus synthetic system. As key outputs, the results emphasize the importance of accurate modelling of ancillary services associated with fre-quency regulation in cascading failure analysis, and indicate that increased wind penetration can lead to a higher probability of power outages. Adopting FFR services can help to mitigate the cascading risk but may introduce rotor angle instability issues
SPLITTING HAIRS WITH TRANSCENDENTAL ENTIRE FUNCTIONS
No full textIn recent years, there has been significant progress in the understanding of the dynamics of transcendental entire functions with bounded postsingular set. In particular, for certain classes of such functions, a complete description of their topological dynamics in terms of a simpler model has been given inspired by methods from polynomial dynamics. In this paper, and for the first time, we give analogous results in cases when the postsingular set is unbounded. More specifically, we show that if f is of finite order, has bounded criticality on its Julia set J(f), and its singular set consists of finitely many critical values that escape to infinity and satisfy a certain separation condition, then J(f) is a collection of dynamic rays or hairs, that split at critical points, together with their corresponding landing points. In fact, our result holds for a much larger class of functions with bounded singular set. Moreover, this result is a consequence of a significantly more general one: we provide a topological model for the action of f on its Julia set
