Employing Demand-Based Volumetric Forecasting to Identify Potential for and Roles of Devices in Scale-Up of Medical Male Circumcision in Zambia and Zimbabwe

Introduction: Devices for male circumcision (MC) are becoming available in 14 priority countries where MC is being implemented for HIV prevention. Understanding potential impact on demand for services is one important programmatic consideration because countries determine whether to scale up devices within MC programs. Methods: A population-based survey measuring willingness to undergo MC, assuming availability of surgical MC and 3 devices, was conducted among 1250 uncircumcised men, ages 10–49 years in Zambia and 1000 uncircumcised men, ages 13–49 years in Zimbabwe. Simulated Test Market methodology was used to estimate incremental MC demand and the extent to which devices might be preferred over surgery, assuming availability of: surgical MC in both countries; the devices PrePex, ShangRing, and Unicirc in Zambia; and PrePex in Zimbabwe. Results: Modeled estimates indicate PrePex has the potential to provide an overall increase in MC demand ranging from an estimated 13%–50%, depending on country and WHO prequalification ages, replacing 11%–41% of surgical procedures. In Zambia, ShangRing could provide 8% overall increase, replacing 45% of surgical procedures, and Unicirc could provide 30% overall increase, replacing 85% of surgical procedures. Conclusions: In both countries, devices have potential to increase overall demand for MC, assuming wide scale awareness and availability of circumcision by the devices. With consideration for age and country, PrePex may provide the greatest potential increase in demand, followed by Unicirc (measured in Zambia only) and ShangRing (also Zambia only). These results inform one program dimension for decision making on potential device introduction strategies; however, they must be considered within the broader programmatic context

Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer

Background Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. Methodology/Principal Findings Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. Conclusions/Significance Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies

DNA methylation-based measures of biological age:meta-analysis predicting time to death

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p ≤ 8.2 x 10-9), independent of chronological age, even after adjusting for additional risk factors (p < 5.4 x 10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p≤ 7.5 x 10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality

Attitudes and decision-making about early-infant versus early-adolescent male circumcision: Demand-side insights for sustainable HIV prevention strategies in Zambia and Zimbabwe

As countries approach their scale-up targets for the voluntary medical male circumcision program for HIV prevention, they are strategizing and planning for the sustainability phase to follow. Global guidance recommends circumcising adolescent (below 14 years) and/or early infant boys (aged 0–60 days), and countries need to consider several factors before prioritizing a cohort for their sustainability phase. We provide community and healthcare provider-side insights on attitudes and decision-making process as a key input for this strategic decision in Zambia and Zimbabwe. We studied expectant parents, parents of infant boys (aged 0–60 days), family members and neo-natal and ante-natal healthcare providers in Zambia and Zimbabwe. Our integrated methodology consisted of in-depth qualitative and quantitative one-on-one interviews, and a simulated-decision-making game, to uncover attitudes towards, and the decision-making process for, early adolescent or early infant medical circumcision (EAMC or EIMC). In both countries, parents viewed early infancy and early adolescence as equally ideal ages for circumcision (38% EIMC vs. 37% EAMC in Zambia; 24% vs. 27% in Zimbabwe). If offered for free, about half of Zambian parents and almost 2 in 5 Zimbabwean parents indicated they would likely circumcise their infant boy; however, half of parents in each country perceived that the community would not accept EIMC. Nurses believed their facilities currently could not absorb EIMC services and that they would have limited ability to influence fathers, who were seen as having the primary decision-making authority. Our analysis suggests that EAMC is more accepted by the community than EIMC and is the path of least resistance for the sustainability phase of VMMC. However, parents or community members do not reject EIMC. Should countries choose to prioritize this cohort for their sustainability phase, a number of barriers around information, decision-making by parents, and supply side will need to be addressed

Categorizing and assessing comprehensive drivers of provider behavior for optimizing quality of health care.

Inadequate quality of care in healthcare facilities is one of the primary causes of patient mortality in low- and middle-income countries, and understanding the behavior of healthcare providers is key to addressing it. Much of the existing research concentrates on improving resource-focused issues, such as staffing or training, but these interventions do not fully close the gaps in quality of care. By contrast, there is a lack of knowledge regarding the full contextual and internal drivers-such as social norms, beliefs, and emotions-that influence the clinical behaviors of healthcare providers. We aimed to provide two conceptual frameworks to identify such drivers, and investigate them in a facility setting where inadequate quality of care is pronounced. Using immersion interviews and a novel decision-making game incorporating concepts from behavioral science, we systematically and qualitatively identified an extensive set of contextual and internal behavioral drivers in staff nurses working in reproductive, maternal, newborn, and child health (RMNCH) in government public health facilities in Uttar Pradesh, India. We found that the nurses operate in an environment of stress, blame, and lack of control, which appears to influence their perception of their role as often significantly different from the RMNCH program's perspective. That context influences their perceptions of risk for themselves and for their patients, as well as self-efficacy beliefs, which could lead to avoidance of responsibility, or incorrect care. A limitation of the study is its use of only qualitative methods, which provide depth, rather than prevalence estimates of findings. This exploratory study identified previously under-researched contextual and internal drivers influencing the care-related behavior of staff nurses in public facilities in Uttar Pradesh. We recommend four types of interventions to close the gap between actual and target behaviors: structural improvements, systemic changes, community-level shifts, and interventions within healthcare facilities

A case study for a psychographic-behavioral segmentation approach for targeted demand generation in voluntary medical male circumcision

Public health programs are starting to recognize the need to move beyond a one-size-fits-all approach in demand generation, and instead tailor interventions to the heterogeneity underlying human decision making. Currently, however, there is a lack of methods to enable such targeting. We describe a novel hybrid behavioral-psychographic segmentation approach to segment stakeholders on potential barriers to a target behavior. We then apply the method in a case study of demand generation for voluntary medical male circumcision (VMMC) among 15–29 year-old males in Zambia and Zimbabwe. Canonical correlations and hierarchical clustering techniques were applied on representative samples of men in each country who were differentiated by their underlying reasons for their propensity to get circumcised. We characterized six distinct segments of men in Zimbabwe, and seven segments in Zambia, according to their needs, perceptions, attitudes and behaviors towards VMMC, thus highlighting distinct reasons for a failure to engage in the desired behavior

Sources of information about circumcising baby boys, ages 0 to 2 months after birth.

<p>Sources of information about circumcising baby boys, ages 0 to 2 months after birth.</p

Influences of parents in decision-making to circumcise baby boy.

<p>Influences of parents in decision-making to circumcise baby boy.</p

Main perceived benefits and concerns of circumcising infant boys.

<p>Main perceived benefits and concerns of circumcising infant boys.</p