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Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4–21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85–0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65–0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase III randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab [210 mg/month; 0.09 g/cm2 higher bone mineral density (BMD)], the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab), and with a higher risk of myocardial infarction (MI) and/or coronary revascularization and major adverse cardiovascular events (MACE). The same variants were also associated with increased risk of type 2 diabetes mellitus (T2D) and higher systolic blood pressure (SBP) and central adiposity. Taken together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

Background The development of research capacity among undergraduates is an important intervention in countering the documented decrease in medical and health sciences researchers. The literature on undergraduate research generally emanates from smaller scale studies that have been conducted in high income countries, with a focus on medical students. This cross-sectional study was conducted in a Sub-Saharan country, included a population of medical and allied health professions (AHP) students, and aimed to improve our understanding of the factors influencing undergraduate student research. Methods A questionnaire was distributed to all students enrolled in an undergraduate programme at the Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa (including Medicine and four AHP programmes). Data was collected on a number of demographic characteristics and on 3 major outcome-themes: “voluntary research involvement”, “self-perceived research competence” and “future research participation”. Associations between characteristics and outcome themes were explored. Results In total, 1815 students participated in the study (response rate 80.2%). Of all the demographic variables, discipline (AHP programmes vs. Medicine), male gender and prior undergraduate experience in a science degree were significantly associated with voluntary research involvement. Significantly higher levels of self-perceived research competence and greater interest in future research participation, were seen among participants from AHP programmes; males; and those with previous or current voluntary research involvement. Ethnicity and geographic background were not significantly associated with any of our outcomes. Conclusions Our results offer important new evidence in support of the imperative to diversify the research work-force, in Sub-Saharan Africa and globally. Enhanced efforts aimed at achieving better academic representation in terms of gender, ethnicity, geographical and socio-economic backgrounds are strengthened by the findings of this study. Potential student researchers represent an important group amenable to further intervention. Further research may be required to explore the factors that determine the progression from interest to future participation in research. Electronic supplementary material The online version of this article (10.1186/s12909-017-1025-x) contains supplementary material, which is available to authorized users.

Medical research capacity development is a national priority to improve healthcare in South Africa (SA). The 2011 National Health Research Summit set a target of training 1 000 doctoral candidates in health sciences over the next 10 years. We advocate revitalised research training opportunities for junior clinicians to help achieve this target and to contribute to the creation of a thriving medical research network across SA.