Role of the Uteroplacental Renin-Angiotensin System in Placental Development and Function, and Its Implication in the Preeclampsia Pathogenesis.

Placental development and function implicate important morphological and physiological adaptations to thereby ensure efficient maternal-fetal exchanges, as well as pregnancy-specific hormone secretion and immune modulation. Incorrect placental development can lead to severe pregnancy disorders, such as preeclampsia (PE), which endangers both the mother and the infant. The implication of the systemic renin-angiotensin system (RAS) in the pregnancy-related physiological changes is now well established. However, despite the fact that the local uteroplacental RAS has been described for several decades, its role in placental development and function seems to have been underestimated. In this review, we provide an overview of the multiple roles of the uteroplacental RAS in several cellular processes of placental development, its implication in the regulation of placental function during pregnancy, and the consequences of its dysregulation in PE pathogenesis.

Women and babies are dying from inertia: a collaborative framework for obstetrical drug development is urgently needed.

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.

From current vaccine recommendations to everyday practices: An analysis in five sub-Saharan African countries.

BACKGROUND: Estimates of WHO and UNICEF vaccination coverage may provide little insight into the extent to which vaccinations are administered on time. Yet, lack of adherence to the recommended age to receive a specific vaccination may have detrimental health consequences. For example, delays in receiving vaccination will prolong the risk of lack of protection, often when disease risk is highest, such as during early infancy. We estimated the reported age at vaccination, and vaccine coverage at different ages in children from five sub-Saharan African countries. METHODS: We analyzed data from the latest Demographic and Health Programme databases available for Burkina Faso 2010 (n=15,044 observations), Ghana 2008 (n=2992), Kenya 2008-9 (n=6079), Senegal 2010-11 (n=12,326), and Tanzania 2010 (n=8023). We assessed, amongst vaccinees, the exact age when vaccine was administered for the three infant doses of pentavalent vaccine (DTP) and the first dose of measles-containing-vaccine (MCV), as well as the proportion of children immunized with these antigens by a certain age. Vitamin A supplementation (VAS) coverage was evaluated as a potential contact visit for vaccine introduction. RESULTS: For all DTP doses, the median intervals between recommended and actual ages of receiving vaccination ranged from 12, 17 and 23 days in Kenya, to 22, 33 and 45 days in Senegal. MCV was mostly given during the recommended age of 9 months. In each country, there was a large discrepancy in the median age at DTP vaccination between regions. VAS coverage in young children ranged from 30.3% in Kenya to 78.4% in Senegal, with large variations observed between areas within each study country. CONCLUSION: In the context of new vaccine introduction, age of children at vaccination should be monitored to interpret data on vaccine-preventable disease burden, vaccine effectiveness, and vaccine safety, and to adapt targeted interventions and messages.

Potential future impact of a partially effective HIV vaccine in a southern African setting.

BACKGROUND: It is important for public health and within the HIV vaccine development field to understand the potential population level impact of an HIV vaccine of partial efficacy--both in preventing infection and in reducing viral load in vaccinated individuals who become infected--in the context of a realistic future implementation scenario in resource limited settings. METHODS: An individual level model of HIV transmission, progression and the effect of antiretroviral therapy was used to predict the outcome to 2060 of introduction in 2025 of a partially effective vaccine with various combinations of efficacy characteristics, in the context of continued ART roll-out in southern Africa. RESULTS: In the context of our base case epidemic (in 2015 HIV prevalence 28% and incidence 1.7 per 100 person years), a vaccine with only 30% preventative efficacy could make a substantial difference in the rate with which HIV incidence declines; the impact on incidence in relative terms is projected to increase over time, with a projected 67% lower HIV incidence in 2060 compared with no vaccine introduction. The projected mean decline in the general adult population death rate 2040-2060 is 11%. A vaccine with no prevention efficacy but which reduces viral load by 1 log is predicted to result in a modest (14%) reduction in HIV incidence and an 8% reduction in death rate in the general adult population (mean 2040-2060). These effects were broadly similar in multivariable uncertainty analysis. INTERPRETATION: Introduction of a partially effective preventive HIV vaccine would make a substantial long-term impact on HIV epidemics in southern Africa, in addition to the effects of ART. Development of an HIV vaccine, even of relatively low apparent efficacy at the individual level, remains a critical global public health goal.

Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial.

OBJECTIVE: We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS: Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS: 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15 years at first sexual intercourse, higher number of sexual partners during the past 12 months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12 months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.

Diet and breast cancer: a review of the prospective observational studies.

The role of diet for the risk of breast cancer is of great interest as a potentially modifiable risk factor. The evidence from prospective observational studies was reviewed and summarized on selected dietary factors, gene-diet interactions, and breast cancer incidence. Dietary factors were considered that, based on their nutritional constituents, are of particular interest in the context of breast cancer: fat intake, biomarkers of fat intake, fruit and vegetable consumption, antioxidant vitamins (vitamins A, C, E, and beta-carotene), serum antioxidants, carbohydrate intake, glycemic index and glycemic load, dairy consumption (including vitamin D), consumption of soy products and isoflavones, green tea, heterocyclic amines, and adolescent diet. The PubMed database was searched for all prospective studies that relate these dietary items to the incidence of breast cancer or consider gene-diet interactions. Among the prospective epidemiologic studies conducted on diet and breast cancer incidence and gene-diet interactions and breast cancer incidence, to date there is no association that is consistent, strong, and statistically significant, with the exception of alcohol intake, overweight, and weight gain. The apparent lack of association between diet and breast cancer may reflect a true absence of association between diet and breast cancer incidence or may be due to measurement error exceeding the variation in the diet studied, lack of sufficient follow-up, and focus on an age range of low susceptibility. The risk of breast cancer can be reduced by avoidance of weight gain in adulthood and limiting the consumption of alcohol.