Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies

Utility of temporal artery biopsy samples for genome-wide analysis of giant cell arteritis

Giant Cell Arteritis (GCA) is the most common vasculitis affecting the elderly. Archived formalin-fixed paraffin-embedded (FFPE) temporal artery biopsy (TAB) specimens potentially represent a valuable resource for large-scale genetic analysis of this disease. FFPE TAB samples were obtained from 12 patients with GCA. Extracted TAB DNA was assessed by real time PCR before restoration using the Illumina HD FFPE Restore Kit. Paired FFPE-blood samples were genotyped on the Illumina OmniExpress FFPE microarray. The FFPE samples that passed stringent quality control measures had a mean genotyping success of >97%. When compared with their matching peripheral blood DNA, the mean discordant heterozygote and homozygote single nucleotide polymorphisms calls were 0.0028 and 0.0003, respectively, which is within the accepted tolerance of reproducibility. This work demonstrates that it is possible to successfully obtain high-quality microarray-based genotypes FFPE TAB samples and that this data is similar to that obtained from peripheral blood

A systematic review of current understandings of employability

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Education and Work on 7th November 2015, available online: http://www.tandfonline.com/10.1080/13639080.2015.1102210.A theoretical framework is essential for the effective evaluation of employability. However, there are a wide range of definitions of employability coexisting in current literature. A review into existing ways in which employability has been conceptualised is needed to inform a better understanding of the nature of contributions made by various employability development opportunities, and appropriate assessment of these contributions. A systematic review is presented, assessing the similarities and differences between the components of employability conceptualisations, focusing on employability at an individual level. Relevant publications were identified through a sensitive search strategy of eight electronic bibliographic databases from 1960 to 2014. Data were extracted from 16 eligible manuscripts. Capital, career management and contextual dimensions were identified as unifying themes in these components. Findings indicate that success in developing employability needs to be contextualised within a conceptualisation of employability as a multifaceted construct

Investigation into the genetic architecture of Giant Cell Arteritis through a genome-wide association study

Elisabeth De Smit, Catherine Hill, Tony Merriman, Katie Cremin, Paul Leo, Penny McKelvie, David Evans, Matt A Brown, Alex W Hewit

How much demand for New HIV prevention technologies can we really expect? Results from a discrete choice experiment in South Africa.

BACKGROUND: For the first time in the history of HIV, new bio-medical interventions have been shown to be effective in preventing HIV transmission. For these new HIV prevention technologies (NPTs) to have an impact on the epidemic, they must be widely used. This study uses a discrete choice experiment (DCE) to: understand the relative strength of women's preferences for product characteristics, understand the implications for substitution away from male condoms, and inform realistic modelling of their potential impact and cost-effectiveness. METHODS: A DCE was conducted among 1017 women in urban South Africa. Women were presented with choices between potential women's NPTs (microbicides, diaphragm, female condom) and 'what I did last time' (use or not use a condom) with different HIV and pregnancy prevention effectiveness' and prices. Choice probabilities are estimated using the nested logit model and used to predict uptake. RESULTS: In this high HIV prevalence setting, HIV prevention effectiveness is the main driver of uptake followed by pregnancy prevention effectiveness. For example a microbicide with poor effectiveness would have niche appeal at just 11% predicted uptake, while a highly effective microbicide (95% effective against HIV and pregnancy) would have far wider appeal (56% predicted uptake). Though women who reported not using condoms were more likely to choose the NPTs, at current very high rates of male condom use in South Africa (60%), about half of microbicide uptake is projected to be among those currently not using condoms. CONCLUSIONS: Women are very interested in NPTs, especially if highly effective in preventing HIV and pregnancy. Women in greatest need were also most likely to switch to the new products. Where products are not yet available for distribution, proxy data, such as that generated by DCEs, can bring realism to overly optimistic uptake scenarios found in many current impact models

Did national HIV prevention programs contribute to HIV decline in eastern Zimbabwe?: evidence from a prospective community survey

Objective: To add to the evidence on the impact of national HIV prevention programs in reducing HIV risk in sub-Saharan African countries. Methods: Statistical analysis of prospective data on exposure to HIV prevention programs, relatives with AIDS and unemployment, and sexual behavior change and HIV incidence, in a population cohort of 4047 adults, collected over a period (1998 - 2003) when HIV prevalence and risk-behavior declined in eastern Zimbabwe. Results: Exposure to HIV prevention programs and relatives with AIDS-but not unemployment-increased from 1998 to 2003. Men and women exposed to media campaigns and HIV/AIDS meetings had greater knowledge and self-efficacy, attributes that were concomitantly protective against HIV infection. Women attending community HIV/AIDS meetings before recruitment were more likely than other women to adopt lower-risk behavior (96.4% vs. 90.8%; adjusted odds ratio, 3.09; 95% confidence interval [CI], 1.27-7.49) and had lower HIV incidence (0.9% vs. 1.8%; adjusted incidence rate ratio, 0.63; 95% CI, 0.32-1.24) during the intersurvey period. Prior exposure to relatives with AIDS was not associated with differences in behavior change. More newly unemployed men as compared with employed men adopted lower-risk behavior (84.2% vs. 76.0%; adjusted odds ratio, 2.13; 95% CI, 0.98-4.59). Conclusions: Community-based HIV/AIDS meetings reduced risk-behavior amongst women who attended them, contributing to HIV decline in eastern Zimbabwe

The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost-effectiveness modelling studies.

BACKGROUND: Cost-effectiveness studies inform resource allocation, strategy, and policy development. However, due to their complexity, dependence on assumptions made, and inherent uncertainty, synthesising, and generalising the results can be difficult. We assess cost-effectiveness models evaluating expected health gains and costs of HIV pre-exposure prophylaxis (PrEP) interventions. METHODS AND FINDINGS: We conducted a systematic review comparing epidemiological and economic assumptions of cost-effectiveness studies using various modelling approaches. The following databases were searched (until January 2013): PubMed/Medline, ISI Web of Knowledge, Centre for Reviews and Dissemination databases, EconLIT, and region-specific databases. We included modelling studies reporting both cost and expected impact of a PrEP roll-out. We explored five issues: prioritisation strategies, adherence, behaviour change, toxicity, and resistance. Of 961 studies retrieved, 13 were included. Studies modelled populations (heterosexual couples, men who have sex with men, people who inject drugs) in generalised and concentrated epidemics from Southern Africa (including South Africa), Ukraine, USA, and Peru. PrEP was found to have the potential to be a cost-effective addition to HIV prevention programmes in specific settings. The extent of the impact of PrEP depended upon assumptions made concerning cost, epidemic context, programme coverage, prioritisation strategies, and individual-level adherence. Delivery of PrEP to key populations at highest risk of HIV exposure appears the most cost-effective strategy. Limitations of this review include the partial geographical coverage, our inability to perform a meta-analysis, and the paucity of information available exploring trade-offs between early treatment and PrEP. CONCLUSIONS: Our review identifies the main considerations to address in assessing cost-effectiveness analyses of a PrEP intervention--cost, epidemic context, individual adherence level, PrEP programme coverage, and prioritisation strategy. Cost-effectiveness studies indicating where resources can be applied for greatest impact are essential to guide resource allocation decisions; however, the results of such analyses must be considered within the context of the underlying assumptions made. Please see later in the article for the Editors' Summary

Energiebericht 1990

SIGLEAvailable from FIZ Karlsruhe / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman