Novel imaging method to quantify stratum corneum in dermatopharmacokinetic studies:Proof-of-concept with acyclovir formulations

Purpose: Tape stripping the stratum corneum (SC) is used in topical bioequivalence studies. Formulations are compared using drug concentration profiles as a function of relative SC position; both of these parameters require quantification of SC amount removed per tape. Here, a novel imaging method to quantify SC on tape strips is described. Comparisons are made with established SC quantification methods, specifically weighing and UV pseudo-absorption. Methods: Six stratum corneum tape strips were measured 15 times by the three methods, which were compared for precision, signal:noise ratio, sample size and speed. Furthermore, 600 tape strips were assayed by each method, and correlations examined. Results: Weighing exhibited low precision, extremely low signal:noise ratio, and was slow. UV pseudo-absorption had high precision, acceptable signal:noise ratio and was quick. However, only a fraction of the total SC removed is analysed, and inhomogeneity can affect the results. The new imaging method was precise, with high signal:noise ratio, and measured the whole SC sample, unaffected by inhomogeneity. In addition, the approach was rapid and has the potential for fast automated scanning of multiple tapes and for further image analysis. Conclusion: The novel imaging method has many advantages over established methods for quantifying SC amount per tape.</p

‘At risk’ waist-to-height ratio cut-off points recently adopted by NICE and US Department of Defense will unfairly penalize shorter adults. What is the solution?

Objectives To a) demonstrate that adopting ‘at risk’ waist-to-height ratio (WHTR) cut-off points, recently approved by National Institute for Health and Care Excellence (NICE) and the United States Department of Defense (USDoD), will unfairly penalize shorter individuals and will be too lenient for taller individuals, b) to confirm that waist circumference (WC) of a sample of US service personnel, scales to approximately height0.5, supporting the notion that WC, to be independent of height (HT), should be normalized using WC.HT−0.5 (WHT•5R), and c) to identify the WHT•5R cut-off points that will reduce or eliminate this unwanted bias. Subjects/methods We employed a three independent cross-sectional sample design. All n = 58,742 participants underwent anthropometric assessment of body mass, stature and waist circumference. Results The allometric power-law model WC=a.HT^b for US service personnel identified the height exponent to be b= 0.418 (95 % CI 0.251–0.585), confirming that the simple body-shape index for WC to be independent of HT, should be WC.HT−0.5. Chi-square tests of independence and for linear trend confirmed that by adopting WHTR cut-off point, shorter individuals (both service personnel and non-service participants) will be over penalized (classified as being ‘at risk’). New WC independent-of-height ratio cut-off points were found to resolve this problem. Conclusions Adopting WHTR cut-off thresholds (either 0.5 or 0.55) will lead to shorter adults being unfairly classified as being ‘at risk’ in terms of their central adiposity and general health status. Adopting new WHT•5R cut-off point thresholds were found to greatly reduce or eliminate this bias

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

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

The induction of maternal behavior in non-parturient adoptive mares

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