MultiBUGS: A Parallel Implementation of the BUGS Modeling Framework for Faster Bayesian Inference

MultiBUGS is a new version of the general-purpose Bayesian modeling software BUGS that implements a generic algorithm for parallelizing Markov chain Monte Carlo (MCMC) algorithms to speed up posterior inference of Bayesian models. The algorithm parallelizes evaluation of the product-form likelihoods formed when a parameter has many children in the directed acyclic graph (DAG) representation; and parallelizes sampling of conditionally-independent sets of parameters. A heuristic algorithm is used to decide which approach to use for each parameter and to apportion computation across computational cores. This enables MultiBUGS to automatically parallelize the broad range of statistical models that can be fitted using BUGS-language software, making the dramatic speed-ups of modern multi-core computing accessible to applied statisticians, without requiring any experience of parallel programming. We demonstrate the use of MultiBUGS on simulated data designed to mimic a hierarchical e-health linked-data study of methadone prescriptions including 425,112 observations and 20,426 random effects. Posterior inference for the e-health model takes several hours in existing software, but MultiBUGS can perform inference in only 28 minutes using 48 computational cores

Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice

Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 (Atf4) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway

Medical applicant general practice experience and career aspirations: a questionnaire study

Background: Increasing access to general practice work experience placements for school students is a strategy for improving general practice recruitment, despite limited evidence and concerns surrounding equity of access to general practice experiences. Aims: To examine the association between undertaking general practice experience and the perceptions of general practice as an appealing future career among prospective medical applicants. To identify socioeconomic factors associated with obtaining general practice experience. Design & setting: Cross-sectional questionnaire study in the UK. Method: Participants were UK residents aged ≥16 years and seriously considering applying to study medicine in 2019/2020. They were invited to take part via the University Clinical Aptitude Test (UCAT). Questionnaire data were analysed using a linear regression of general practice appeal on general practice experience, adjusting for career motivations and demographics, and a logistic regression of general practice experience on measures of social capital and demographics. Results: Of 6391 responders, 4031 were in their last year of school. General practice experience predicted general practice appeal after adjusting for career motivation and demographics (b = 0.37, standard error [SE] = 0.06, P<0.00001). General practice experience was more common among students at private (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.31 to 2.08, P<0.0001) or grammar schools (OR = 1.33, 95% CI = 1.02 to 1.72, P = 0.03) and in the highest socioeconomic group (OR = 1.62, 95% CI = 1.28 to 2.05, P<0.0001), and less likely among students of ‘other’ ethnicity (OR = 0.37, 95% CI = 0.20 to 0.67, P = 0.0011). Conclusion: Having general practice experience prior to medical school was associated with finding general practice appealing, which supports its utility in recruitment. Applicants from more deprived backgrounds were less likely to have had a general practice experience, possibly through lack of accessible opportunities

Saharan dust and association between particulate matter and case-specific mortality: a case-crossover analysis in Madrid (Spain)

<p>Abstract</p> <p>Background</p> <p>Saharan dust intrusions are a common phenomenon in the Madrid atmosphere, leading induce exceedances of the 50 μg/m³- EU 24 h standard for PM₁₀.</p> <p>Methods</p> <p>We investigated the effects of exposure to PM₁₀between January 2003 and December 2005 in Madrid (Spain) on daily case-specific mortality; changes of effects between Saharan and non-Saharan dust days were assessed using a time-stratified case-crossover design.</p> <p>Results</p> <p>Saharan dust affected 20% of days in the city of Madrid. Mean concentration of PM₁₀was higher during dust days (47.7 μg/m³) than non-dust days (31.4 μg/m³). The rise of mortality per 10 μg/m³PM₁₀concentration were always largely for Saharan dust-days. When stratifying by season risks of PM₁₀, at lag 1, during Saharan dust days were stronger for respiratory causes during cold season (IR% = 3.34% (95% CI: 0.36, 6.41) versus 2.87% (95% CI: 1.30, 4.47)) while for circulatory causes effects were stronger during warm season (IR% = 4.19% (95% CI: 1.34, 7.13) versus 2.65% (95% CI: 0.12, 5.23)). No effects were found for cerebrovascular causes.</p> <p>Conclusions</p> <p>We found evidence of strongest effects of particulate matter during Saharan dust days, providing a suggestion of effect modification, even though interaction terms were not statistically significant. Further investigation is needed to understand the mechanism by which Saharan dust increases mortality.</p

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS