The zebrafish eye—a paradigm for investigating human ocular genetics

Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.Eye advance online publication, 9 September 2016; doi:10.1038/eye.2016.198

Routine care of peripheral intravenous catheters versus clinically indicated replacement: randomised controlled trial

Objective To compare routine replacement of intravenous peripheral catheters with replacement only when clinically indicated

Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model

Choroideremia (CHM) is an X-linked chorioretinal dystrophy that is caused by mutations within a single gene, CHM Currently no effective treatment exists for these patients. Since over 30% of patients harbour nonsense mutations in CHM, nonsense suppression therapy using translational readthrough inducing drugs may provide functional rescue of REP1, thus attenuating progressive sight loss. Here, we employed two CHM model systems to systematically test the efficacy and safety of ataluren (PTC124) and its novel analog PTC-414: (1) the chm(ru848) zebrafish, the only nonsense mutation animal model of CHM harbouring a TAA nonsense mutation, and (2) a primary human fibroblast cell line from a CHM patient harbouring a TAG nonsense mutation. PTC124 or PTC-414 treatment of chm(ru848) embryos led to a ∼2.0-fold increase in survival, prevented the onset of retinal degeneration with reduced oxidative stress and apoptosis, increased rep1 protein by 23.1% (PTC124) and 17.2% (PTC-414) and restored biochemical function as confirmed through in vitro prenylation assays (98 ± 2% [PTC124] and 68 ± 5% [PTC-414]). In CHM(Y42X/y) fibroblasts, there was a recovery of prenylation activity following treatment with either PTC124 (42 ± 5%) or PTC-414 (36 ± 11%), although an increase in REP1 protein was not detected in these cells, in contrast to the zebrafish model. This comprehensive study on the use of PTC124 and PTC-414 as successful nonsense suppression agents for the treatment of CHM highlights the translational potential of these drugs for inherited retinal disease

Medical Students and Pandemic Influenza

To assess knowledge of pandemic influenza, we administered a questionnaire to all medical students at the University of Alberta; 354 (69%) of 510 students responded. Data from questionnaires such as this could help determine the role of medical students during a public health emergency

Bird Migration Routes and Risk for Pathogen Dispersion into Western Mediterranean Wetlands

Migratory movements of wild birds likely spread zoonotic infectious agents, such as avian influenza and West Nile viruses

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Achieving universal health coverage for people with stroke in South Africa: protocol for a scoping review

Introduction: Stroke is the second most common cause of death after HIV/AIDS and a significant health burden in South Africa. The extent to which universal health coverage (UHC) is achieved for people with stroke in South Africa is unknown. Therefore, a scoping review to explore the opportunities and challenges within the South African health system to facilitate the achievement of UHC for people with stroke is warranted. Methods and analysis: The scoping review will follow the approach recommended by Levac, Colquhoun and O’Brien, which includes five steps: (1) identifying the research question, (2) identifying relevant studies, (3) selecting the studies, (4) charting the data, and (5) collating, summarising and reporting the results. Health Systems Dynamics Framework and WHO Framework on integrated people-centred health services will be used to map, synthesise and analyse data thematically. Ethics and dissemination: Ethical approval is not required for this scoping review, as it will only include published and publicly available data. The findings of this review will be published in an open-access, peer-reviewed journal and we will develop an accessible summary of the results for website posting and stakeholder meetings

What mechanisms drive uptake of family planning when integrated with childhood immunisation in Ethiopia? A realist evaluation.

BACKGROUND: Maternal and child health are key priorities among the Sustainable Development Goals, which include a particular focus on reducing morbidity and mortality among women of reproductive age, newborns, and children under the age of five. Two components of maternal and child health are family planning (FP) and immunisation. Providing these services through an integrated delivery system could increase the uptake of vaccines and modern contraceptive methods (MCMs) particularly during the post-partum period. METHODS: A realist evaluation was conducted in two woredas in Ethiopia to determine the key mechanisms and their triggers that drive successful implementation and service uptake of an intervention of integrated delivery of immunisations and FP. The methodological approach included the development of an initial programme theory and the selection of relevant, published implementation related theoretical frameworks to aid organisation and cumulation of findings. Data from 23 semi-structured interviews were then analysed to determine key empirical mechanisms and drivers and to test the initial programme theory. These mechanisms were mapped against published theoretical frameworks and a revised programme theory comprised of context-mechanism-outcome configurations was developed. A critique of theoretical frameworks for abstracting empirical mechanisms was also conducted. RESULTS: Key contextual factors identified were: the use of trained Health Extension Workers (HEWs) to deliver FP services; a strong belief in values that challenged FP among religious leaders and community members; and a lack of support for FP from male partners based on religious values. Within these contexts, empirical mechanisms of acceptability, access, and adoption of innovations that drove decision making and intervention outcomes among health workers, religious leaders, and community members were identified to describe intervention implementation. CONCLUSIONS: Linking context and intervention components to the mechanisms they triggered helped explain the intervention outcomes, and more broadly how and for whom the intervention worked. Linking empirical mechanisms to constructs of implementation related theoretical frameworks provided a level of abstraction through which findings could be cumulated across time, space, and conditions by theorising middle-range mechanisms

Fixed-combination, low-dose, triple-pill antihypertensive medication versus usual care in patients with mild-to-moderate hypertension in Sri Lanka: a within-trial and modelled economic evaluation of the TRIUMPH trial.

BACKGROUND: Elevated blood pressure incurs a major health and economic burden, particularly in low-income and middle-income countries. The Triple Pill versus Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) trial showed a greater reduction in blood pressure in patients using fixed-combination, low-dose, triple-pill antihypertensive therapy (consisting of amlodipine, telmisartan, and chlorthalidone) than in those receiving usual care in Sri Lanka. We aimed to assess the cost-effectiveness of the triple-pill strategy. METHODS: We did a within-trial (6-month) and modelled (10-year) economic evaluation of the TRIUMPH trial, using the health system perspective. Health-care costs, reported in 2017 US dollars, were determined from trial records and published literature. A discrete-time simulation model was developed, extrapolating trial findings of reduced systolic blood pressure to 10-year health-care costs, cardiovascular disease events, and mortality. The primary outcomes were the proportion of people reaching blood pressure targets (at 6 months from baseline) and disability-adjusted life-years (DALYs) averted (at 10 years from baseline). Incremental cost-effectiveness ratios were calculated to estimate the cost per additional participant achieving target blood pressure at 6 months and cost per DALY averted over 10 years. FINDINGS: The triple-pill strategy, compared with usual care, cost an additional US$9·63 (95$347·75 (285·55 to 412·54) per person in the modelled analysis. Incremental cost-effectiveness ratios were estimated at $7·93 (95$2842·79 (-28·67 to 5714·24) per DALY averted over a 10-year period. INTERPRETATION: Compared with usual care, the triple-pill strategy is cost-effective for patients with mild-to-moderate hypertension. Scaled up investment in the triple pill for hypertension management in Sri Lanka should be supported to address the high population burden of cardiovascular disease. FUNDING: Australian National Health and Medical Research Council