Selective Inhibition of Retinal Angiogenesis by Targeting PI3 Kinase

Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Abstract: The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Modifying the health system to maximize voluntary medical male circumcision uptake: a qualitative study in Botswana

Background: In 2007, the World Health Organization and the Joint United Nations Programme on HIV/AIDS endorsed voluntary medical male circumcision (VMMC) as an add-on HIV-prevention strategy. Similar to many other sub-Saharan countries, VMMC uptake in Botswana has been low; as of February 2016, only 42.7% of the program target had been achieved. Previous work has examined how individual-level factors, such as knowledge and attitudes, influence the update of VMMC. This paper examines how factors related to the health system can be leveraged to maximize uptake of circumcision services, with a focus on demand creation, access to services, and service delivery. Methods: Twenty-seven focus group discussions with 238 participants were conducted in four communities in Botswana among men (stratified by circumcision status and age), women (stratified by age), and community leaders. A semi-structured guide was used by a trained same-gender interviewer to facilitate discussions, which were audio recorded, transcribed, translated to English, and analyzed using an inductive analytic approach. Results: Participants felt demand creation activities utilizing age- and gender-appropriate mobilizers and community leaders were more effective than mass media campaigns. Participants felt improved access to VMMC clinics would facilitate service uptake, as would designated men’s clinics with male-friendly providers for VMMC service delivery. Additionally, providing comprehensive pre-procedure counseling and education, outlining the benefits and disadvantages of the surgical procedure, and explaining the differences between the surgical and non-surgical procedures, were suggested by participants to increase understanding and uptake of VMMC. Conclusion: Cultural acceptability of circumcision services can be improved by engaging age- and gender-appropriate community mobilizers. Involving influential community leaders, providing a forum for men to discuss health issues, and bringing services closer to people can increase VMMC utilization. Service delivery can be improved by communicating the pros and cons of the procedure to the clients for informed decision-making

Transfusion-related acute lung injury: incidence and risk factors.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI