Collaborative review of pilot projects to inform policy: A methodological remedy for pilotitis?

BACKGROUND In rural health and other health service development contexts, there is frustration with a reliance on pilot projects as a means of informing policy and service innovation. There is also an emerging recognition that existing research methods do not draw lessons from the failed sustainability that characterises many of these pilots and demonstration projects. DISCUSSION: This article describes critical aspects of the methodology of a successful collaborative, multi-method, systematic synthesis of exemplary primary health care pilot projects in rural and remote Australia, which synthesised principles from a number of pilot projects to inform policy makers and planners. Hallmarks of the method were: the nature of the source materials for the research, the subsequent research engagement with the actual pilot projects, the extent of collaboration throughout the study with end-users from policy and planning arenas, and the attention to procedural quality. SUMMARY: The methodology, while time consuming, has resulted in applied, policy-relevant findings, and evidence of consideration by policy-makers

Atypical Haemolytic Uraemic Syndrome Associated with a Hybrid Complement Gene

BACKGROUND: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1–5; aliases CFHR1–5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. METHODS AND FINDINGS: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1–21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS. CONCLUSIONS: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene

Gender Roles and Medical Progress

Maternal mortality was the second-leading cause of death for women in childbearing years up until the mid-1930s in the United States. For each death, twenty times as many mothers were estimated to suffer pregnancy-related conditions, often leading to severe and prolonged disablement. Poor maternal health made it particularly hard for mothers to engage in market work. Between 1930 and 1960, there was a remarkable reduction in maternal mortality and morbidity, thanks to medical advances. We argue that these medical advances, by enabling women to reconcile work and motherhood, were essential for the joint rise in married women's labor force participation and fertility over this period. We also show that the diffusion of infant formula played an important auxiliary role

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Background:Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods:We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results: In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions:These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial

BackgroundBreast cancer diagnosis may be a teachable moment for lifestyle behaviour change and to prevent adjuvant therapy associated weight gain. We assessed the acceptability and effectiveness of two weight control programmes initiated soon after breast cancer diagnosis to reduce weight amongst overweight or obese women and prevent gains in normal-weight women.MethodsOverweight or obese (n?=?243) and normal weight (n?=?166) women were randomised to a three-month unsupervised home (home), a supervised community weight control programme (community) or to standard written advice (control). Primary end points were change in weight and body fat at 12 months. Secondary end points included change in insulin, cardiovascular risk markers, quality of life and cost-effectiveness of the programmes.ResultsForty-three percent of eligible women were recruited. Both programmes reduced weight and body fat: home vs. control mean (95% CI); weight ?2.3 (?3.5, ?1.0) kg, body fat ?1.6 (?2.6, ?0.7) kg, community vs. control; weight ?2.4 (?3.6, ?1.1) kg, body fat ?1.4 (?2.4, ?0.5) kg (all p?&#x3c;?0.001). The community group increased physical activity, reduced insulin, cardiovascular disease risk markers, increased QOL and was cost-effective.ConclusionsThe programmes were equally effective for weight control, but the community programme had additional benefits.Clinical trial registrationISRCTN6857614

Here or There? How Configuration of Transnational Teams Impacts Social Capital

Part 10: Human-Work Interaction DesignInternational audienceThe many challenges of distributed communication and the many challenges of intercultural collaboration have been researched and discussed at length in the literature. What is lacking is a combined approach that looks at both issues of distance and diversity in collaboration. We conducted research in a large, multinational technology company to better understand team configurational factors in transnational work. In this case study, we found that the development of social capital is impacted by whether a person is in their home context or transplanted and their expectations based on that context. This has implications for the development of intellectual capital in the team. We highlight factors in the creation of social capital as well as some mechanisms that may mitigate cultural difference. In addition to bringing into focus the challenges that arise in various configurations, this study contributes to the transnational literature by highlighting the importance of local context in diverse collaborations

Here or There?: How Configuration of Transnational Teams Impacts Social Capital

Abstract. The many challenges of distributed communication and the many challenges of intercultural collaboration have been researched and discussed at length in the literature. What is lacking is a combined approach that looks at both issues of distance and diversity in collaboration. We conducted research in a large, multinational technology company to better understand team configurational factors in transnational work. In this case study, we found that the development of social capital is impacted by whether a person is in their home context or transplanted and their expectations based on that context. This has implications for the development of intellectual capital in the team. We highlight factors in the creation of social capital as well as some mechanisms that may mitigate cultural difference. In addition to bringing into focus the challenges that arise in various configurations, this study contributes to the transnational literature by highlighting the importance of local context in diverse collaborations