Bayesian clinical trial designs : Another option for trauma trials?

The UK-REBOA Trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/199/09). PP was supported by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1-R/N/P/B1).Peer reviewedPublisher PD

Population Studies of the Heritable Influences on the Mind and Brain

Decades of prior genetic research using twin modelling designs has shown that differences in human behavior are strongly influenced by differences in our DNA. Through advances in DNA genotyping it has become feasible to study the genetic factors that contribute to human variation by large-scale genome-wide association studies (GWAS). In this thesis, our aim was to study the genetic variants, genes and genetic pathways that explain variation in a broad diversity of behavioral outcomes making use of big data analyses in large population cohorts. By integrating GWAS results and GWAS-derived polygenic risk scores with gene-expression data, functional gene-sets and MRI imaging of the brain, this thesis provides a step forward in understanding the association between genetic variation and health-related phenotypes, including intelligence, neuroticism and depression, and insomnia, and the pathways and cell-types in the brain through which these genetic factors act

Genetic associations with childhood brain growth, defined in two longitudinal cohorts

Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10-9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study

A major QTL corresponding to the Rk locus for resistance to root-knot nematodes in cowpea (Vigna unguiculata L. Walp.).

Key messageGenome resolution of a major QTL associated with the Rk locus in cowpea for resistance to root-knot nematodes has significance for plant breeding programs and R gene characterization. Cowpea (Vigna unguiculata L. Walp.) is a susceptible host of root-knot nematodes (Meloidogyne spp.) (RKN), major plant-parasitic pests in global agriculture. To date, breeding for host resistance in cowpea has relied on phenotypic selection which requires time-consuming and expensive controlled infection assays. To facilitate marker-based selection, we aimed to identify and map quantitative trait loci (QTL) conferring the resistance trait. One recombinant inbred line (RIL) and two F2:3 populations, each derived from a cross between a susceptible and a resistant parent, were genotyped with genome-wide single nucleotide polymorphism (SNP) markers. The populations were screened in the field for root-galling symptoms and/or under growth-chamber conditions for nematode reproduction levels using M. incognita and M. javanica biotypes. One major QTL was mapped consistently on linkage group VuLG11 of each population. By genotyping additional cowpea lines and near-isogenic lines derived from conventional backcrossing, we confirmed that the detected QTL co-localized with the genome region associated with the Rk locus for RKN resistance that has been used in conventional breeding for many decades. This chromosomal location defined with flanking markers will be a valuable target in marker-assisted breeding and for positional cloning of genes controlling RKN resistance

A Novel Root-Knot Nematode Resistance QTL on Chromosome Vu01 in Cowpea.

The root-knot nematode (RKN) species Meloidogyne incognita and M. javanica cause substantial root system damage and suppress yield of susceptible cowpea cultivars. The narrow-based genetic resistance conferred by the Rk gene, present in some commercial cultivars, is not effective against Rk-virulent populations found in several cowpea production areas. The dynamics of virulence within RKN populations require a broadening of the genetic base of resistance in elite cowpea cultivars. As part of this goal, F1 and F2 populations from the cross CB46-Null (susceptible) x FN-2-9-04 (resistant) were phenotyped for M. javanica induced root-galling (RG) and egg-mass production (EM) in controlled growth chamber and greenhouse infection assays. In addition, F[Formula: see text] families of the same cross were phenotyped for RG on field sites infested with Rk-avirulent M. incognita and M. javanica The response of F1 to RG and EM indicated that resistance to RKN in FN-2-9-04 is partially dominant, as supported by the degree of dominance in the F2 and F[Formula: see text] populations. Two QTL associated with both RG and EM resistance were detected on chromosomes Vu01 and Vu04. The QTL on Vu01 was most effective against aggressive M. javanica, whereas both QTL were effective against avirulent M. incognita Allelism tests with CB46 x FN-2-9-04 progeny indicated that these parents share the same RKN resistance locus on Vu04, but the strong, broad-based resistance in FN-2-9-04 is conferred by the additive effect of the novel resistance QTL on Vu01. This novel resistance in FN-2-9-04 is an important resource for broadening RKN resistance in elite cowpea cultivars

SIENNA D6.1: Generalised methodology for ethical assessment of emerging technologies

This report provides a unique, comprehensive and carefully tested methodology for the ethical analysis of emerging technologies, a methodology that is motivated by our earlier studies in the SIENNA project. Our methodology contains seven key steps, the first four of which are directed at defining subject of analysis, aim and scope, and engaging in conceptual analysis and description, and the final three of which specify the actual ethical analysis, with both descriptive and normative components. We provide a detailed account of each of these seven steps and illustrate the application of our methodology to different emerging technologies. Our methodology makes use of methods of foresight analysis and social and environmental impact assessment (SIA), and of stakeholder engagement, and methods for these processes are described in additional sections of the report. We conclude the report by situating our approach within the broader landscape of approaches for technology assessment and impact assessment

Coronary evaginations and peri-scaffold aneurysms following implantation of bioresorbable scaffolds: incidence, outcome, and optical coherence tomography analysis of possible mechanisms

Background Peri-stent coronary evaginations may disturb flow and have been proposed as possible risk factor for late stent thrombosis. We describe incidence, predictors, and possible mechanisms of coronary evaginations 12 months after implantation of bioresorbable vascular scaffolds (BVS).Methods and results One hundred and two BVS implanted in 90 patients (age 63 ± 13 years, 71 males, 14 diabetics) were analysed with angiography and optical coherence tomography (OCT) 12 months after implantation. Evaginations were identified as any hollow in the luminal vessel contour between well-apposed struts and were classified as major when extending ≥3 mm with a depth ≥10% of the BVS diameter. Fifty-five (54%) of the BVS (50(56%) of the patients) had at least one evagination (6.1 ± 6.2 evaginations per BVS), with a mean volume of 1.9 ± 1.9 mm³. Major evaginations were only found in one patient, and in-BVS aneurysms in three patients (4BVS). The presence of evaginations was strongly associated with that of malapposition (P = 0.003) and strut fractures (P = 0.01). No association could be shown between the presence and volume of the evaginations and any clinical variable or the presence of uncovered struts (P > 0.5). Peri-strut low- intensity areas (PSLIA) were present in 29 (53%) of the BVS with evaginations and 12 (26%) of those without (P = 0.0049); their presence was independently associated with the presence, the number (P P = 0.004) and with that of strut fracture. Conclusions Optical coherence tomography-detected evaginations are relatively common after BVS implantation, but, as for modern drug-eluting metallic stents, major evaginations are very rare. Optical coherence tomography evidence of immature neointima and strut fractures were associated with more severe development of evaginations