Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

A consensus guide to capturing the ability to inhibit actions and impulsive behaviors in the stop-signal task.

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa

Clinical and physical signs for identification of impending and current water-loss dehydration in older people

This is the protocol for a review and there is no abstract. The objectives are as follows:.To determine the diagnostic accuracy of state, minimally invasive clinical and physical signs (or sets of signs) to be used as screening tests for detecting impending or current water-loss dehydration, or both, in older people by systematically reviewing studies that have measured a reference standard and at least one index test in people aged 65 years and over..To assess the effect of different cut offs of index test results assessed using continuous data on sensitivity and specificity in diagnosis of impending or current water-loss dehydration..To identify clinical and physical signs that may be used in screening for impending or current water-loss dehydration in older people..To identify clinical and physical signs that are not useful in screening for impending or current water-loss dehydration in older people..To directly compare promising index tests (sensitivity ? 0.60 and specificity ? 0.75) where two or more are measured in a single study (direct comparison)..To carry out an exploratory analysis to assess the value of combining the best three index tests where the three tests each have some predictive ability of their own, and individual studies include participants who had all three tests.We will explore sources of heterogeneity of diagnostic accuracy of individual clinical and physical signs that show some evidence of discrimination by the reference standard used, cut off value for tests providing continuous data, type of participants (community-dwelling older people, those in residential care, and those in hospital), sex, and baseline prevalence of dehydration.5. To carry out an exploratory analysis to assess the value of combining the best three index tests where the three tests each have some predictive ability of their own, and individual studies include participants who had all three tests.We will explore sources of heterogeneity of diagnostic accuracy of individual clinical and physical signs that show some evidence ofdiscrimination by the reference standard used, cut off value for tests providing continuous data, type of participants (communitydwellingolder people, those in residential care, and those in hospital), sex, and baseline prevalence of dehydration

Seaweed biopolymers as additives for unfired clay bricks

Unfired clay bricks are an environmentally friendly alternative to conventional masonry materials such as fired bricks and concrete blocks but their use is currently limited by their relatively poor mechanical and durability properties. While products like cement and lime are commonly added to earthen materials in an effort to improve their physical performance, these additives can also have a negative influence on the overall environmental impact. The purpose of this research is to investigate the use of alginate, a natural and renewable biopolymer obtained from brown seaweeds, as an admixture for unfired clay blocks. A total of 5 different alginates have been investigated and combined with 3 soil compositions to create prototype specimens which have then been characterised and compared in relation to flexural and compressive strength, microstructure, abrasive strength and hygroscopic behaviour. The results demonstrate that improvements in mechanical strength are dependent on the type of alginate used and the composition of the soil. The greatest increase in compressive strength is achieved using an alginate sourced from the Laminaria Hyperborea seaweed and offers a value more than double that of the equivalent control specimen. Increases in the alginate dosage do not necessarily lead to an increase in strength suggesting that there is an optimum concentration at which strength improvement is most effective