An Exploratory, Randomized, Crossover MRI Study of Microbicide Delivery with the SILCS Diaphragm Compared to a Vaginal Applicator

Background—Microbicide gels studied for HIV prevention often are delivered via a single-use vaginal applicator. Using a contraceptive diaphragm such as the SILCS diaphragm for gel delivery could have advantages, including lower cost and additional pregnancy prevention. Study Design—We performed an exploratory, nonblinded, randomized, crossover study among healthy, sexually active, nonpregnant women. Using BufferGel®, we evaluated three microbicide delivery methods for gel distribution and retention: SILCS single-sided gel delivery, SILCS double-sided gel delivery and a vaginal applicator (without SILCS). Magnetic resonance images were taken at baseline, after gel insertion, and immediately and 6 h after simulated intercourse. Three women completed all gel delivery methods described in this article. Results—Magnetic resonance imaging analysis indicated similar gel spread in the vagina among all three methods. SILCS single-sided gel application resulted in the most consistent longitudinal coverage; SILCS double-sided gel application was the most consistent in the transverse dimension. Conclusions—Gel coverage was similar with all three methods. These results suggest that the SILCS microbicide delivery system is comparable to vaginal applicators for delivery of gel products intravaginally

Prioritizing investments in innovations to protect women from the leading causes of maternal death

PATH, an international nonprofit organization, assessed nearly 40 technologies for their potential to reduce maternal mortality from postpartum hemorrhage and preeclampsia and eclampsia in low-resource settings. The evaluation used a new Excel-based prioritization tool covering 22 criteria developed by PATH, the Maternal and Neonatal Directed Assessment of Technology (MANDATE) model, and consultations with experts. It identified five innovations with especially high potential: technologies to improve use of oxytocin, a uterine balloon tamponade, simplified dosing of magnesium sulfate, an improved proteinuria test, and better blood pressure measurement devices. Investments are needed to realize the potential of these technologies to reduce mortality

The Association of the Metabolic Syndrome with PAI-1 and t-PA Levels

Background. We used a random sample (n = 2, 495) from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study population to examine the association of the metabolic syndrome (Met S) with plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) antigen levels. Results. The overall prevalence of the Met S was 18%, was dependent on age and gender, and was positively associated with higher antigen levels of both PAI-1 and t-PA. These significant effects were maintained after adjustment for age, gender, BMI, elevated C-reactive protein, smoking status, urinary albumin excretion, and insulin levels. We found no significant interactions between the Met S and other covariates on PAI-1 and t-PA levels. Conclusions. Our study demonstrates that those with the Met S have significantly higher levels of PAI-1 and t-PA antigen, factors known to increase the risk of cardiovascular disease

An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene Interactions on risk of myocardial infarction: The importance of model validation

BACKGROUND: To examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation. RESULTS: The overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance. CONCLUSIONS: The significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings

Microarray patch for HIV prevention and as a multipurpose prevention technology to prevent HIV and unplanned pregnancy: an assessment of potential acceptability, usability, and programmatic fit in Kenya

BackgroundMicroarray patches (MAPs), a novel drug delivery system, are being developed for HIV pre-exposure prophylaxis (PrEP) delivery and as a multipurpose prevention technology (MPT) to protect from both HIV and unintended pregnancy. Prevention technologies must meet the needs of target audiences, be acceptable, easy to use, and fit health system requirements.MethodologyWe explored perceptions about MAP technology and assessed usability, hypothetical acceptability, and potential programmatic fit of MAP prototypes using focus group discussions (FGD), usability exercises, and key informant interviews (KII) among key populations in Kiambu County, Kenya. Adolescent girls and young women (AGYW), female sex workers (FSW), and men who have sex with men (MSM) assessed the usability and acceptability of a MAP prototype. Male partners of AGYW/FSW assessed MAP acceptability as partners of likely users. We analyzed data using NVivo, applying an inductive approach. Health service providers and policymakers assessed programmatic fit. Usability exercise participants applied a no-drug, no-microneedle MAP prototype and assessed MAP features.ResultsWe implemented 10 FGD (4 AGYW; 2 FSW; 2 MSM; 2 male partners); 47 mock use exercises (19 AGYW; 9 FSW; 8 MSM; 11 HSP); and 6 policymaker KII. Participants reported high interest in MAPs due to discreet and easy use, long-term protection, and potential for self-administration. MAP size and duration of protection were key characteristics influencing acceptability. Most AGYW preferred the MPT MAP over an HIV PrEP-only MAP. FSW saw value in both MAP indications and voiced need for MPTs that protect from other infections. Preferred duration of protection was 1–3 months. Some participants would accept a larger MAP if it provided longer protection. Participants suggested revisions to the feedback indicator to improve confidence. Policymakers described the MPT MAP as “killing two birds with one stone,” in addressing AGYW needs for both HIV protection and contraception. An MPT MAP is aligned with Kenya's policy of integrating health care programs.ConclusionsMAPs for HIV PrEP and as an MPT both were acceptable across participant groups. Some groups valued an MPT MAP over an HIV PrEP MAP. Prototype refinements will improve usability and confidence

Cardiovascular Risk Associated with Interactions among Polymorphisms in Genes from the Renin-Angiotensin, Bradykinin, and Fibrinolytic Systems

Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study

Count every newborn; a measurement improvement roadmap for coverage data.

BACKGROUND: The Every Newborn Action Plan (ENAP), launched in 2014, aims to end preventable newborn deaths and stillbirths, with national targets of ≤12 neonatal deaths per 1000 live births and ≤12 stillbirths per 1000 total births by 2030. This requires ambitious improvement of the data on care at birth and of small and sick newborns, particularly to track coverage, quality and equity. METHODS: In a multistage process, a matrix of 70 indicators were assessed by the Every Newborn steering group. Indicators were graded based on their availability and importance to ENAP, resulting in 10 core and 10 additional indicators. A consultation process was undertaken to assess the status of each ENAP core indicator definition, data availability and measurement feasibility. Coverage indicators for the specific ENAP treatment interventions were assigned task teams and given priority as they were identified as requiring the most technical work. Consultations were held throughout. RESULTS: ENAP published 10 core indicators plus 10 additional indicators. Three core impact indicators (neonatal mortality rate, maternal mortality ratio, stillbirth rate) are well defined, with future efforts needed to focus on improving data quantity and quality. Three core indicators on coverage of care for all mothers and newborns (intrapartum/skilled birth attendance, early postnatal care, essential newborn care) have defined contact points, but gaps exist in measuring content and quality of the interventions. Four core (antenatal corticosteroids, neonatal resuscitation, treatment of serious neonatal infections, kangaroo mother care) and one additional coverage indicator for newborns at risk or with complications (chlorhexidine cord cleansing) lack indicator definitions or data, especially for denominators (population in need). To address these gaps, feasible coverage indicator definitions are presented for validity testing. Measurable process indicators to help monitor health service readiness are also presented. A major measurement gap exists to monitor care of small and sick babies, yet signal functions could be tracked similarly to emergency obstetric care. CONCLUSIONS: The ENAP Measurement Improvement Roadmap (2015-2020) outlines tools to be developed (e.g., improved birth and death registration, audit, and minimum perinatal dataset) and actions to test, validate and institutionalise proposed coverage indicators. The roadmap presents a unique opportunity to strengthen routine health information systems, crosslinking these data with civil registration and vital statistics and population-based surveys. Real measurement change requires intentional transfer of leadership to countries with the greatest disease burden and will be achieved by working with centres of excellence and existing networks

Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4

<p>Abstract</p> <p>Background</p> <p>Chemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α.</p> <p>Methods</p> <p>Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability.</p> <p>Results</p> <p>CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α <it>in vitro</it>. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness.</p> <p>Conclusions</p> <p>CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.</p