Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The development of a reliability methodology for manufacturing process-related systems

SIGLEAvailable from British Library Document Supply Centre- DSC:DX76800 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Mineral prospectivity of the King Leopold Orogen and Lennard Shelf: analysis of potential field data in the west Kimberley region

The mineral potential of the west Kimberley region was investigated following interpretation of regional gravity and magnetic data. Emphasis was placed on identifying geological structures that may have importance for the mineral potential of the region. Subsurface structure was constrained through combined gravity and magnetic modelling along three transects. Crustal-scale faults were interpreted and investigated to determine their depth extent, because they may act as fluid conduits that localize mineralization. Crustal-scale features bound regions of different geological and geophysical character and may also control the formation of the oldest geological units. The Artesian Fault, identified during this study, is interpreted to extend from the Paperbark Supersuite into the Kimberley Basin. \ud \ud The potential field interpretations and section models were linked to tectonic events and mineralization episodes in order to map the distribution of economically important regions using a knowledge-driven mineral systems approach to mineral prospectivity mapping. The mineral systems considered were 1) magmatic nickel sulfide, 2) carbonate-hosted base metals, 3) orogenic and epithermal gold, 4) sediment-hosted stratiform base metals, 5) intrusion-related base metals (including tin–tungsten, iron oxide– copper–gold and copper–gold porphyry deposits). Prospectivity modelling shows that a geologically complex belt in the south of the Kimberley Basin, at the boundary with the King Leopold Orogen, is prospective for magmatic-related and hydrothermal mineral systems. In addition, a structural high on the Lennard Shelf is prospective for carbonate-hosted base metals, and parts of the King Leopold Orogen are prospective for sediment-hosted stratiform base metals. These results show that knowledge-driven modelling of mineral systems can be effective in identifying prospectivity in regional studies of underexplored areas