Health care innovations from policy to practice: A case study of a rapid HIV testing trial in general practice

PhDThe UK National Guidelines on HIV Testing 2008 recommended that adults in areas where more than 2/1000 people were living with HIV be considered for an HIV test at the point of registration with general practice. The RHIVA2 trial of rapid HIV testing in primary care implemented and evaluated this recommendation across 20 general practices in a single UK borough using a pragmatic cluster randomised controlled trial (RCT) design. This trial, and the policy that underpinned it, reflected two more general developments: first, the move towards population screening to detect and treat disease in early and latent stages and second, the emergence of ‘pragmatic’ clinical trials that seek to account for complexity and measure interventions in their context of use. This interdisciplinary case study uses multiple methods and theoretical frames to explore what happened in the RHIVA2 trial at both an empirical and a theoretical level. Sub-studies reveal how the trial was justified, enacted and became meaningful as a policy, as a trial, and as an intervention in the lives of patients. My analyses show that two operating logics informed the justification and enactment of the trial and patterned patient and provider experiences. The first, the logic of normalisation for HIV aims to treat HIV infection as a medical condition ‘like any other’. This logic emphasises general practice as a site of increased value and position in HIV management and as a space where population screening can be undertaken. Second, the logic of the pragmatic trial aims to measure interventions in the ‘real world’ but is revealed to produce unintended effects, raising questions about the claims of such trials to generalisability and reproducibility. This thesis demonstrates how contrasting versions of the research event (‘multiplicity’) can be produced through different modes of inquiry, raising questions about the tension between situated and generalisable findings.National Institute of Health Research Doctoral training programm

Targeted Mutagenesis of FOX0 Transcripts Using the Model Organism \u3cem\u3eCiona intestinalis\u3c/em\u3e Utilizing the CRISPR/Cas9 System

The chordate, Ciona intestinalis, has become an excellent model organism for the study of cardiac development. C. intestinalis is a member of the phylum Tunicata, which is the sister phylum to vertebrates. Since both phyla share a common ancestor, an orthologous gene has been identified in C. intestinalis and vertebrates, the FOX0 transcript. Multiple reasons makes Ciona intestinalis an interesting model organism. For instance, ease of access to the animal, close relation to vertebrates, and mapping of the genetic code of Ciona intestinalis makes this an excellent model organism. The FOX0 family of transcripts plays an important role in cardiac, muscular, and neural development in humans. Humans have four copies of the transcript while Ciona intestinalis only has one. However, the function of FOX01 in Ciona intestinalis is unknown. This study aims to investigate the function of FOX0 transcripts in C. intestinalis by incorporating transgenic DNA into embryos using fertilization, dechorionation, electroporation and the CRISPR/Cas9 system

Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis.

BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. FINDINGS: Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. INTERPRETATION: Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. FUNDING: NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care

The Grizzly, January 31, 1986

Nursing Homes: A Solution for the Elderly? Investigation 1 • Fetterolf Nears Completion • Smokers and Non-Smokers Must Meet Half Way • Horrible Hunger Continues • A Look at a Better Ursinus • Can a Dream Become a Reality? • The Limelight Shines on Lynne Edwards • Profile: John French Adds a Musical Twist • Pain Brings Gain for the Swimmin\u27 Women • Gymnasts Vaulting Into a New Season • Track Season Starts at the Gun • Basketball Hall of Fame Cites Women\u27s Team as Second in All-Time Victories • Wellness Bear Spotted! • Applications Being Taken for St. Andrew\u27s Scholarship • Women\u27s Studies Program Seeks Campus Wide Interest • Profile: Mr. Rue Keeps Records Straight • Ursinus Professor Publishes Books on Pennsylvania Dutch • Ursinus Professor\u27s Philosophy Text Publishedhttps://digitalcommons.ursinus.edu/grizzlynews/1155/thumbnail.jp

The Grizzly, January 31, 1986

Nursing Homes: A Solution for the Elderly? Investigation 1 • Fetterolf Nears Completion • Smokers and Non-Smokers Must Meet Half Way • Horrible Hunger Continues • A Look at a Better Ursinus • Can a Dream Become a Reality? • The Limelight Shines on Lynne Edwards • Profile: John French Adds a Musical Twist • Pain Brings Gain for the Swimmin\u27 Women • Gymnasts Vaulting Into a New Season • Track Season Starts at the Gun • Basketball Hall of Fame Cites Women\u27s Team as Second in All-Time Victories • Wellness Bear Spotted! • Applications Being Taken for St. Andrew\u27s Scholarship • Women\u27s Studies Program Seeks Campus Wide Interest • Profile: Mr. Rue Keeps Records Straight • Ursinus Professor Publishes Books on Pennsylvania Dutch • Ursinus Professor\u27s Philosophy Text Publishedhttps://digitalcommons.ursinus.edu/grizzlynews/1155/thumbnail.jp

Accounting for complexity - Intervention design in the context of studying social accountability for reproductive health.

Background: Social accountability interventions aim to propel change by raising community voices and holding duty bearers accountable for delivering on rights and entitlements. Evidence on the role of such interventions for improving community health outcomes is steadily emerging, including for sexual and reproductive health and rights (SRHR). However, these interventions are complex social processes with numerous actors, multiple components, and a highly influential local context. Unsurprisingly, determining the mechanisms of change and what outcomes may be transferable to other similar settings can be a challenge. We report our methodological considerations to account for complexity in a social accountability intervention exploring contraceptive uptake and use in Ghana and Tanzania. Main Body: The Community and Provider driven Social Accountability Intervention (CaPSAI) study explores the relationship between a health facility-focused social accountability intervention and contraceptive service provision in two countries. This 24-month mixed-method quasi-experimental study, using an interrupted time series with a parallel control group, is being undertaken in 16 sites across Ghana and Tanzania in collaboration with local research and implementation partners. The primary outcomes include changes in contraceptive uptake and use. We also measure outcomes related to current social accountability theories of change and undertake a process evaluation. We present three design features: co-design, 'conceptual' fidelity, and how we aim to track the intervention as 'intended vs. implemented' to explore how the intervention could be responsive to the embedded routines, local contextual realities, and the processual nature of the social accountability intervention. Conclusions: Through a discussion of these design features and their rationale, we conclude by suggesting approaches to intervention design that may go some way in responding to recent challenges in accounting for social accountability interventions, bearing relevance for evaluating health system interventions

The Complex Genetic Architecture of the Metabolome

Discovering links between the genotype of an organism and its metabolite levels can increase our understanding of metabolism, its controls, and the indirect effects of metabolism on other quantitative traits. Recent technological advances in both DNA sequencing and metabolite profiling allow the use of broad-spectrum, untargeted metabolite profiling to generate phenotypic data for genome-wide association studies that investigate quantitative genetic control of metabolism within species. We conducted a genome-wide association study of natural variation in plant metabolism using the results of untargeted metabolite analyses performed on a collection of wild Arabidopsis thaliana accessions. Testing 327 metabolites against >200,000 single nucleotide polymorphisms identified numerous genotype–metabolite associations distributed non-randomly within the genome. These clusters of genotype–metabolite associations (hotspots) included regions of the A. thaliana genome previously identified as subject to recent strong positive selection (selective sweeps) and regions showing trans-linkage to these putative sweeps, suggesting that these selective forces have impacted genome-wide control of A. thaliana metabolism. Comparing the metabolic variation detected within this collection of wild accessions to a laboratory-derived population of recombinant inbred lines (derived from two of the accessions used in this study) showed that the higher level of genetic variation present within the wild accessions did not correspond to higher variance in metabolic phenotypes, suggesting that evolutionary constraints limit metabolic variation. While a major goal of genome-wide association studies is to develop catalogues of intraspecific variation, the results of multiple independent experiments performed for this study showed that the genotype–metabolite associations identified are sensitive to environmental fluctuations. Thus, studies of intraspecific variation conducted via genome-wide association will require analyses of genotype by environment interaction. Interestingly, the network structure of metabolite linkages was also sensitive to environmental differences, suggesting that key aspects of network architecture are malleable

Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion

Insulin secretion plays a critical role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion1,2; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5% to 5%) and rare (MAF<0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 non-diabetic Finnish males. We identified low-frequency coding variants associated with fasting proinsulin levels at the SGSM2 and MADD GWAS loci and three novel genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1, and PAM. We also demonstrate that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs nearby and megabases (Mb) away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine