Automated Analysis of MUTEX Algorithms with FASE

In this paper we study the liveness of several MUTEX solutions by representing them as processes in PAFAS s, a CCS-like process algebra with a specific operator for modelling non-blocking reading behaviours. Verification is carried out using the tool FASE, exploiting a correspondence between violations of the liveness property and a special kind of cycles (called catastrophic cycles) in some transition system. We also compare our approach with others in the literature. The aim of this paper is twofold: on the one hand, we want to demonstrate the applicability of FASE to some concrete, meaningful examples; on the other hand, we want to study the impact of introducing non-blocking behaviours in modelling concurrent systems.Comment: In Proceedings GandALF 2011, arXiv:1106.081

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

We thank Manuel Kulagin for technical help, Pierre Bonnaventure for portal vein blood sampling, Francisco Sepulveda for technical assistance in GS-MS acquisition, and Dorothee Hahne (Metabolomics Australia, University of Western Australia) for human samples SCFA isolation, acquisition, and analysis. We also thank Cristina Cartoni (Phenotyping Unit, EPFL) for Milliplex analysis, Jessica Dessimoz and her team from the Histology Core Facility (EPFL), Miguel Garcia and his team from the Flow Cytometry Core Facility (EPFL), and staff from the EPFL CPG animal house for excellent animal care. The computations were partially performed at the Vital-IT Center for high-performance computing of the SIB Swiss Institute of Bioinformatics (http://www.vital-it.ch). The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 310948. Funding for A.W.W. and a subset of the 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Second generation anticoagulant rodenticide residues in barn owls 2016

CEH contract report to the Campaign for Responsible Rodenticide Use (CRRU) UK

Epigenetic Contributions to Clinical Risk Prediction of Cardiovascular Disease

BACKGROUND: Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort.METHODS: Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (n cases≥1274; n controls≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed. RESULTS: Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI ( P&lt;0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; P=3.7×10 - 3; 0.3% increase in C-statistic). CONCLUSIONS: EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.</p

Second generation anticoagulant rodenticide residues in barn owls 2017

CEH contract report to the Campaign for Responsible Rodenticide Use (CRRU) UK. A wide range of avian and mammalian predators and scavengers in rural Britain is known to be exposed to Second Generation Anticoagulant Rodenticides (SGARs). The barn owl Tyto alba is a sentinel for species that are generalist predators of small mammals in rural areas in the UK and monitoring of liver SGAR residues in barn owls has been adopted as an element of the monitoring undertaken as part of anticoagulant rodenticide stewardship. Monitoring of liver SGAR residues in some 100 barn owls per year is conducted in support of stewardship and annually collected data are compared with those from 395 barn owls that died between 2006 and 2012 (hereafter termed baseline years), prior to the 2016 changes in anticoagulant rodenticide (AR) authorisations and onset of stewardship. The rationale for using data on SGAR residues in barn owls that died between 2006 and 2012 as a baseline was that all measurements had been made using the same analytical techniques, there had been little clear change in exposure over that time period, and the data were the most recent available. The aim of the current study was to measure SGAR exposure in barn owls in 2017. As in the baseline years, the compounds detected most frequently in barn owls that died in 2017 were bromadiolone, difenacoum and brodifacoum. Overall, 90% of the owls had detectable liver residues of one or more SGAR. The metrics to be used for stewardship monitoring are reported below in terms of differences between owls that died in 2017 and in baseline years. Numbers of barn owls containing detectable residues of flocoumafen and difethialone. There was no significant difference in the proportion of barn owls with detectable liver residues of either flocoumafen or difethialone between the baseline years and 2017. The ratio of birds with ”low” (100 ng/g wet wt.) concentrations for any single SGAR or for ∑SGARs. There was no significant difference between barn owls from baseline years and from 2017 for any individual compound or for summed SGARs (∑SGARs) Average concentrations of brodifacoum, difenacoum, bromadiolone and ∑SGARs in the cohort of owls with “low” residues (100 ng/g wet wt.). There was no significant difference between barn owls from baseline years and from 2017 in the concentrations of either “low” or “high” residues for bromadiolone, difenacoum and brodifacoum, or for all residues summed (∑SGARs). Although not statistically significant, the median and 75th percentile values of “low residues” of most compounds and ∑SGARs were lower in 2017 [and 2016] than in the baseline years Overall, the lack of statistically significant differences in SGAR accumulation by barn owls in 2017 compared within baseline years suggests that full implementation of stewardship since 2016 has yet to be reflected by a detectable general reduction in exposure of barn owls

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease:the ALL-HEART RCT and economic evaluation

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting: Four hundred and twenty-four UK primary care practices. Participants: Aged 60 years and over with ischaemic heart disease but no gout. Interventions: Participants were randomised (1: 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a ‘within trial’ cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval −0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout.</p

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease : the ALL-HEART RCT and economic evaluation

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.Peer reviewe

Incorporating environmental variability in a spatially-explicit individual-based model of European sea bass✰

The northern stock of European sea bass (Dicentrarchus labrax) is a large, high value, slow growing and late maturing fish that is an important target species for both commercial and recreational fisheries. Around the UK, scientific assessments have shown a rapid eight-year decline in spawning stock biomass since 2010 attributed to poor recruitment; this was likely driven by environmental factors and high fishing mortality. Management of the stock is informed by scientific assessments in which a population model is fitted to the available data and used to forecast the possible consequences of various catch options. However, the model currently used cannot represent the spatial distribution of the stock or any effects of environmental variability. One approach that may be used to represent the effects of spatial and temporal variation in environmental drivers is with Individual based models (IBMs). In IBMs populations are represented by their constituent individuals that interact with their environment and each other. The mechanistic nature of IBMs is often advantageous as a management tool for complex systems including fisheries. Here we add to an existing IBM to produce a spatio-temporally explicit IBM of the northern stock of sea bass in which individual fish respond to local food supply and sea surface temperature. All life stages (i.e., pelagic stages, juvenile and mature fish) are modelled and individual fish have their own realistic energy budgets driven by observed dynamic maps of phytoplankton density and sea surface temperature. The model is calibrated using Approximate Bayesian Computation (ABC). After calibration by ABC the model gives good fits to key population parameters including spawning stock biomass. The model provides a mechanistic link between observed local food supplies and sea surface temperatures and overall population dynamics. Plots of spatial biomass distribution show how the model uses the energy budget to predict spatial and temporal change in sea bass biomass distribution in response to environmental variability. Our results indicate that the IBM is a promising approach that could be used to support stock assessment with scope for testing a range of spatially and temporally explicit management scenarios in addition to testing stock responses to novel environmental change

3-Nitrooxypropanol substantially decreased enteric methane emissions of dairy cows fed true protein- or urea-containing diets

Methane is a potent but short-lived greenhouse gas targeted for short-term amelioration of climate change, with enteric methane emitted by ruminants being the most important anthropogenic source of methane. Ruminant production also releases nitrogen to the environment, resulting in groundwater pollution and emissions of greenhouse gas nitrous oxide. We hypothesized that inhibiting rumen methanogenesis in dairy cows with chemical inhibitor 3-nitrooxypropanol (3-NOP) would redirect metabolic hydrogen towards synthesis of microbial amino acids. Our objective was to investigate the effects of 3-NOP on methane emissions, rumen fermentation and nitrogen metabolism of dairy cows fed true protein or urea as nitrogen sources. Eight ruminally-cannulated cows were fed a plant protein or a urea-containing diet during a Control experimental period followed by a methanogenesis inhibition period with 3-NOP supplementation. All diets were unintentionally deficient in nitrogen, and diets supplemented with 3-NOP had higher fiber than diets fed in the Control period. Higher dietary fiber content in the 3-NOP period would be expected to cause higher methane emissions; however, methane emissions adjusted by dry matter and digested organic matter intake were 54% lower with 3-NOP supplementation. Also, despite of the more fibrous diet, 3-NOP shifted rumen fermentation from acetate to propionate. The post-feeding rumen ammonium peak was substantially lower in the 3-NOP period, although that did not translate into greater rumen microbial protein production nor lesser nitrogen excretion in urine. Presumably, because all diets resulted in low rumen ammonium, and intake of digestible organic matter was lower in the 3-NOP period compared to the Control period, the synthesis of microbial amino acids was limited by nitrogen and energy, precluding the evaluation of our hypothesis. Supplementation with 3-NOP was highly effective at decreasing methane emissions with a lower quality diet, both with true protein and urea as nitrogen sources