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Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

OBJECTIVE: To ascertain the role of low birth weight (LBW) in neonatal mortality in a periurban setting in Bangladesh. METHODS: LBW neonates were recruited prospectively and followed up at one month of age. The cohort of neonates were recruited after delivery in a hospital in Dhaka, Bangladesh, and 776 were successfully followed up either at home or, in the event of early death, in hospital. FINDINGS: The neonatal mortality rate (NMR) for these infants was 133 per 1000 live births (95% confidence interval: 110-159). The corresponding NMRs (and confidence intervals) for early and late neonates were 112 (91-136) and 21 (12-33) per thousand live births, respectively. The NMR for infants born after fewer than 32 weeks of gestation was 769 (563-910); and was 780 (640-885) for infants whose birth weights were under 1500g. Eighty-four per cent of neonatal deaths occurred in the first seven days; half within 48 hours. Preterm delivery was implicated in three-quarters of neonatal deaths, but was associated with only one-third of LBW neonates. CONCLUSION: Policy-relevant findings were: that LBW approximately doubles the NMR in a periurban setting in Bangladesh; that neonatal mortality tends to occur early; and that preterm delivery is the most important contributor to the NMR. The group of infants most likely to benefit from improvements in low-cost essential care for the newborn accounted for almost 61% of neonatal mortalities in the cohort.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Abstract Background Reducing maternal and child mortality requires focused attention on better access, utilisation and coverage of good quality health services and interventions aimed at improving maternal and newborn health among target populations, in particular, pregnant women. Intervention coverage in resource and data poor settings is rarely documented. This paper describes four different methods, and their underlying assumptions, to estimate coverage of a community mobilisation women’s group intervention for maternal and newborn health among a population of pregnant women in rural Bangladesh. Methods Primary and secondary data sources were used to estimate the intervention’s coverage among pregnant women. Four methods were used: (1) direct measurement of a proxy indicator using intervention survey data; (2) direct measurement among intervention participants and modelled extrapolation based on routine longitudinal surveillance of births; (3) direct measurement among participants and modelled extrapolation based on cross-sectional measurements and national data; and (4) direct measurement among participants and modelled extrapolation based on published national data. Results The estimated women’s group intervention’s coverage among pregnant women ranged from 30% to 34%, depending on method used. Differences likely reflect differing assumptions and methodological biases of the various methods. Conclusion In the absence of complete and timely population data, choice of coverage estimation method must be based on the strengths and limitations of available methods, capacity and resources for measurement and the ultimate end user needs. Each of the methods presented and discussed here is likely to provide a useful understanding of intervention coverage at a single point in time and Methods 1 and 2 may also provide more reliable estimates of coverage trends. Footnotes 1Unpublished data from three focus group discussions with women’s group members and facilitators participating in the Women’s Groups intervention.

Abstract Background The fifth Millennium Development Goal target for 90% of births in low and middle income countries to have a skilled birth attendant (SBA) by 2015 will not be met. In response to this, policy has focused on increasing SBA access. However, reducing maternal mortality also requires policies to prevent deaths among women giving birth unattended. We aimed to generate estimates of the absolute number of non-SBA births between 2011 and 2015 in South Asia and sub-Saharan Africa, given optimistic assumptions of future trends in SBA attendance. These estimates could be used by decision makers to inform the extent to which reductions in maternal mortality will depend on policies aimed specifically at those women giving birth unattended. Methods For each country within South Asia and sub-Saharan Africa we estimated recent trends in SBA attendance and used these as the basis for three increasingly optimistic projections for future changes in SBA attendance. For each country we obtained estimates for the current SBA attendance in rural and urban settings and forecasts for the number of births and changes in rural/urban population over 2011-2015. Based on these, we calculated estimates for the number of non-SBA births for 2011-2015 under a variety of scenarios. Results Conservative estimates are that there will be between 130 and 180 million non-SBA births in South Asia and sub-Saharan Africa from 2011 to 2015 (90% of these in rural areas). Currently, there are more non-SBA births per year in South Asia than sub-Saharan Africa, but our projections suggest that the regions will have approximately the same number of non-SBA births by 2015. We also present results for each of the six countries currently accounting for more than 50% of global maternal deaths. Conclusions Over the next five years, many millions of women within South Asia and sub-Saharan Africa will give birth without an SBA. Efforts to improve access to skilled attendance should be accompanied by interventions to improve the safety of non-attended deliveries.

Abstract Background Program coverage is likely to be an important determinant of the effectiveness of community interventions to reduce neonatal mortality. Rigorous examination and documentation of methods to scale-up interventions and measure coverage are scarce, however. To address this knowledge gap, this paper describes the process and measurement of scaling-up coverage of a community mobilisation intervention for maternal, child and neonatal health in rural Bangladesh and critiques this real-life experience in relation to available literature on scaling-up. Methods Scale-up activities took place in nine unions in rural Bangladesh. Recruitment and training of those who deliver the intervention, communication and engagement with the community and other stakeholders and active dissemination of intervention activities are described. Process evaluation and population survey data are presented and used to measure coverage and the success of scale-up. Results The intervention was scaled-up from 162 women's groups to 810, representing a five-fold increase in population coverage. The proportion of women of reproductive age and pregnant women who were engaged in the intervention increased from 9% and 3%, respectively, to 23% and 29%. Conclusions Examination and documentation of how scaling-up was successfully initiated, led, managed and monitored in rural Bangladesh provide a deeper knowledge base and valuable lessons. Strong operational capabilities and institutional knowledge of the implementing organisation were critical to the success of scale-up. It was possible to increase community engagement with the intervention without financial incentives and without an increase in managerial staff. Monitoring and feedback systems that allow for periodic programme corrections and continued innovation are central to successful scale-up and require programmatic and operational flexibility.

Abstract Background Progress on neonatal survival has been slow in most countries. While there is evidence on what works to reduce newborn mortality, there is limited knowledge on how to deliver interventions effectively when health systems are weak. Cluster randomized trials have shown strong reductions in neonatal mortality using community mobilisation with women's groups in rural Nepal and India. A similar trial in Bangladesh showed no impact. A main hypothesis is that this negative finding is due to the much lower coverage of women's groups in the intervention population in Bangladesh compared to India and Nepal. For evidence-based policy making it is important to examine if women's group coverage is a main determinant of their impact. The study aims to test the effect on newborn and maternal health outcomes of a participatory women's group intervention with a high population coverage of women's groups. Methods A cluster randomised trial of a participatory women's group intervention will be conducted in 3 districts of rural Bangladesh. As we aim to study a women's group intervention with high population coverage, the same 9 intervention and 9 control unions will be used as in the 2005-2007 trial. These had been randomly allocated using the districts as strata. To increase coverage, 648 new groups were formed in addition to the 162 existing groups that were part of the previous trial. An open cohort of women who are permanent residents in the union in which their delivery or death was identified, is enrolled. Women and their newborns are included after birth, or, if a woman dies during pregnancy, after her death. Excluded are women who are temporary residents in the union in which their birth or death was identified. The primary outcome is neonatal mortality in the last 24 months of the study. A low cost surveillance system will be used to record all birth outcomes and deaths to women of reproductive age in the study population. Data on home care practices and health care use are collected through interviews. Trial registration ISRCTN: ISRCTN01805825

Abstract Background Verbal autopsy (VA) is a widely used method for analyzing cause of death in absence of vital registration systems. We adapted the InterVA method to extrapolate causes of death for stillbirths and neonatal deaths from verbal autopsy questionnaires, using data from Malawi, Zimbabwe, and Nepal. Methods We obtained 734 stillbirth and neonatal VAs from recent community studies in rural areas: 169 from Malawi, 385 from Nepal, and 180 from Zimbabwe. Initial refinement of the InterVA model was based on 100 physician-reviewed VAs from Malawi. InterVA indicators and matrix probabilities for cause of death were reviewed for clinical and epidemiological coherence by a pediatrician-researcher and an epidemiologist involved in the development of InterVA. The modified InterVA model was evaluated by comparing population-level cause-specific mortality fractions and individual agreement from two methods of interpretation (physician review and InterVA) for a further 69 VAs from Malawi, 385 from Nepal, and 180 from Zimbabwe. Results Case-by-case agreement between InterVA and reviewing physician diagnoses for 69 cases from Malawi, 180 cases from Zimbabwe, and 385 cases from Nepal were 83% (kappa 0.76 (0.75 - 0.80)), 71% (kappa 0.41(0.32-0.51)), and 74% (kappa 0.63 (0.60-0.63)), respectively. The proportion of stillbirths identified as fresh or macerated by the different methods of VA interpretation was similar in all three settings. Comparing across countries, the modified InterVA method found that proportions of preterm births and deaths due to infection were higher in Zimbabwe (44%) than in Malawi (28%) or Nepal (20%). Conclusion The modified InterVA method provides plausible results for stillbirths and newborn deaths, broadly comparable to physician review but with the advantage of internal consistency. The method allows standardized cross-country comparisons and eliminates the inconsistencies of physician review in such comparisons.

Abstract Background Around a quarter of the world's neonatal and maternal deaths occur in India. Morbidity and mortality are highest in rural areas and among the poorest wealth quintiles. Few interventions to improve maternal and newborn health outcomes with government-mandated community health workers have been rigorously evaluated at scale in this setting. The study aims to assess the impact of a community mobilisation intervention with women's groups facilitated by ASHAs to improve maternal and newborn health outcomes among rural tribal communities of Jharkhand and Orissa. Methods/design The study is a cluster-randomised controlled trial and will be implemented in five districts, three in Jharkhand and two in Orissa. The unit of randomisation is a rural cluster of approximately 5000 population. We identified villages within rural, tribal areas of five districts, approached them for participation in the study and enrolled them into 30 clusters, with approximately 10 ASHAs per cluster. Within each district, 6 clusters were randomly allocated to receive the community intervention or to the control group, resulting in 15 intervention and 15 control clusters. Randomisation was carried out in the presence of local stakeholders who selected the cluster numbers and allocated them to intervention or control using a pre-generated random number sequence. The intervention is a participatory learning and action cycle where ASHAs support community women's groups through a four-phase process in which they identify and prioritise local maternal and newborn health problems, implement strategies to address these and evaluate the result. The cycle is designed to fit with the ASHAs' mandate to mobilise communities for health and to complement their other tasks, including increasing institutional delivery rates and providing home visits to mothers and newborns. The trial's primary endpoint is neonatal mortality during 24 months of intervention. Additional endpoints include home care practices and health care-seeking in the antenatal, delivery and postnatal period. The impact of the intervention will be measured through a prospective surveillance system implemented by the project team, through which mothers will be interviewed around six weeks after delivery. Cost data and qualitative data are collected for cost-effectiveness and process evaluations. Study registration ISRCTN: ISRCTN31567106

Abstract Background Neonatal mortality remains high in rural Nepal. Previous work suggests that local women's groups can effect significant improvement through community mobilisation. The possibility of identification and management of newborn infections by community-based workers has also arisen. Methods/Design The objective of this trial is to evaluate the effects on newborn health of two community-based interventions involving Female Community Health Volunteers. MIRA Dhanusha community groups: a participatory intervention with women's groups. MIRA Dhanusha sepsis management: training of community volunteers in the recognition and management of neonatal sepsis. The study design is a cluster randomized controlled trial involving 60 village development committee clusters allocated 1:1 to two interventions in a factorial design. MIRA Dhanusha community groups: Female Community Health Volunteers (FCHVs) are supported in convening monthly women's groups. Nine groups per cluster (270 in total) work through two action research cycles in which they (i) identify local issues around maternity, newborn health and nutrition, (ii) prioritise key problems, (iii) develop strategies to address them, (iv) implement the strategies, and (v) evaluate their success. Cycle 1 focuses on maternal and newborn health and cycle 2 on nutrition in pregnancy and infancy and associated postpartum care practices. MIRA Dhanusha sepsis management: FCHVs are trained to care for vulnerable newborn infants. They (i) identify local births, (ii) identify low birth weight infants, (iii) identify possible newborn infection, (iv) manage the process of treatment with oral antibiotics and referral to a health facility to receive parenteral gentamicin, and (v) follow up infants and support families. Primary outcome: neonatal mortality rates. Secondary outcomes: MIRA Dhanusha community group: stillbirth, infant and under-two mortality rates, care practices and health care seeking behaviour, maternal diet, breastfeeding and complementary feeding practices, maternal and under-2 anthropometric status. MIRA Dhanusha sepsis management: identification and treatment of neonatal sepsis by community health volunteers, infection-specific neonatal mortality. Trial Registration no ISRCTN: ISRCTN87820538

Abstract Background There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective. Aims Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine: (i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles (ii) The temperature profile of encephalopathic infants with standard care (iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome (iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age Methods/Design Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months. Discussion We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future. Trial registration Current controlled trials ISRCTN92213707

Abstract Background Public health interventions are increasingly evaluated using cluster-randomised trials in which groups rather than individuals are allocated randomly to treatment and control arms. Outcomes for individuals within the same cluster are often more correlated than outcomes for individuals in different clusters. This needs to be taken into account in sample size estimations for planned trials, but most estimates of intracluster correlation for perinatal health outcomes come from hospital-based studies and may therefore not reflect outcomes in the community. In this study we report estimates for perinatal health outcomes from community-based trials to help researchers plan future evaluations. Methods We estimated the intracluster correlation and the coefficient of variation for a range of outcomes using data from five community-based cluster randomised controlled trials in three low-income countries: India, Bangladesh and Malawi. We also performed a simulation exercise to investigate the impact of cluster size and number of clusters on the reliability of estimates of the coefficient of variation for rare outcomes. Results Estimates of intracluster correlation for mortality outcomes were lower than those for process outcomes, with narrower confidence intervals throughout for trials with larger numbers of clusters. Estimates of intracluster correlation for maternal mortality were particularly variable with large confidence intervals. Stratified randomisation had the effect of reducing estimates of intracluster correlation. The simulation exercise showed that estimates of intracluster correlation are much less reliable for rare outcomes such as maternal mortality. The size of the cluster had a greater impact than the number of clusters on the reliability of estimates for rare outcomes. Conclusions The breadth of intracluster correlation estimates reported here in terms of outcomes and contexts will help researchers plan future community-based public health interventions around maternal and newborn health. Our study confirms previous work finding that estimates of intracluster correlation are associated with the prevalence of the outcome of interest, the nature of the outcome of interest (mortality or behavioural) and the size and number of clusters. Estimates of intracluster correlation for maternal mortality need to be treated with caution and a range of estimates should be used in planning future trials.

Abstract Background Birth attendance by trained health workers is low in rural Nepal. Local participation in improving health services and increased interaction between health systems and communities may stimulate demand for health services. Significant increases in birth attendance by trained health workers may be affected through community mobilisation by local women's groups and health management committee strengthening. We will test the effect of community mobilisation through women's groups, and health management committee strengthening, on institutional deliveries and home deliveries attended by trained health workers in Makwanpur District. Design Cluster randomised controlled trial involving 43 village development committee clusters. 21 clusters will receive the intervention and 22 clusters will serve as control areas. In intervention areas, Female Community Health Volunteers are supported in convening monthly women's groups. The groups work through an action research cycle in which they consider barriers to institutional delivery, plan and implement strategies to address these barriers with their communities, and evaluate their progress. Health management committees participate in three-day workshops that use appreciative inquiry methods to explore and plan ways to improve maternal and newborn health services. Follow-up meetings are conducted every three months to review progress. Primary outcomes are institutional deliveries and home deliveries conducted by trained health workers. Secondary outcome measures include uptake of antenatal and postnatal care, neonatal mortality and stillbirth rates, and maternal morbidity. Trial registration number ISRCTN99834806

Abstract Background Few large and rigorous evaluations of participatory interventions systematically describe their context and implementation, or attempt to explain the mechanisms behind their impact. This study reports process evaluation data from the Ekjut cluster-randomised controlled trial of a participatory learning and action cycle with women's groups to improve maternal and newborn health outcomes in Jharkhand and Orissa, eastern India (2005-2008). The study demonstrated a 45% reduction in neonatal mortality in the last two years of the intervention, largely driven by improvements in safe practices for home deliveries. Methods A participatory learning and action cycle with 244 women's groups was implemented in 18 intervention clusters covering an estimated population of 114 141. We describe the context, content, and implementation of this intervention, identify potential mechanisms behind its impact, and report challenges experienced in the field. Methods included a review of intervention documents, qualitative structured discussions with group members and non-group members, meeting observations, as well as descriptive statistical analysis of data on meeting attendance, activities, and characteristics of group attendees. Results Six broad, interrelated factors influenced the intervention's impact: (1) acceptability; (2) a participatory approach to the development of knowledge, skills and 'critical consciousness'; (3) community involvement beyond the groups; (4) a focus on marginalized communities; (5) the active recruitment of newly pregnant women into groups; (6) high population coverage. We hypothesize that these factors were responsible for the increase in safe delivery and care practices that led to the reduction in neonatal mortality demonstrated in the Ekjut trial. Conclusions Participatory interventions with community groups can influence maternal and child health outcomes if key intervention characteristics are preserved and tailored to local contexts. Scaling-up such interventions requires (1) a detailed understanding of the way in which context affects the acceptability and delivery of the intervention; (2) planned but flexible replication of key content and implementation features; (3) strong support for participatory methods from implementing agencies.

Abstract Background The UN Millennium Development Goals call for substantial reductions in maternal and child mortality, to be achieved through reductions in morbidity and mortality during pregnancy, delivery, postpartum and early childhood. The MaiMwana Project aims to test community-based interventions that tackle maternal and child health problems through increasing awareness and local action. Methods/Design This study uses a two-by-two factorial cluster-randomised controlled trial design to test the impact of two interventions. The impact of a community mobilisation intervention run through women's groups, on home care, health care-seeking behaviours and maternal and infant mortality, will be tested. The impact of a volunteer-led infant feeding and care support intervention, on rates of exclusive breastfeeding, uptake of HIV-prevention services and infant mortality, will also be tested. The women's group intervention will employ local female facilitators to guide women's groups through a four-phase cycle of problem identification and prioritisation, strategy identification, implementation and evaluation. Meetings will be held monthly at village level. The infant feeding intervention will select local volunteers to provide advice and support for breastfeeding, birth preparedness, newborn care and immunisation. They will visit pregnant and new mothers in their homes five times during and after pregnancy. The unit of intervention allocation will be clusters of rural villages of 2500-4000 population. 48 clusters have been defined and randomly allocated to either women's groups only, infant feeding support only, both interventions, or no intervention. Study villages are surrounded by 'buffer areas' of non-study villages to reduce contamination between intervention and control areas. Outcome indicators will be measured through a demographic surveillance system. Primary outcomes will be maternal, infant, neonatal and perinatal mortality for the women's group intervention, and exclusive breastfeeding rates and infant mortality for the infant feeding intervention. Structured interviews will be conducted with mothers one-month and six-months after birth to collect detailed quantitative data on care practices and health-care-seeking. Further qualitative, quantitative and economic data will be collected for process and economic evaluations. Trial registration ISRCTN06477126

Abstract Background Aggregate urban health statistics mask inequalities. We described maternity care in vulnerable slum communities in Mumbai, and examined differences in care and outcomes between more and less deprived groups. Methods We collected information through a birth surveillance system covering a population of over 280 000 in 48 vulnerable slum localities. Resident women identified births in their own localities and mothers and families were interviewed at 6 weeks after delivery. We analysed data on 5687 births over one year to September 2006. Socioeconomic status was classified using quartiles of standardized asset scores. Results Women in higher socioeconomic quartile groups were less likely to have married and conceived in their teens (Odds ratio 0.74, 95% confidence interval 0.69–0.79, and 0.82, 0.78–0.87, respectively). There was a socioeconomic gradient away from public sector maternity care with increasing socioeconomic status (0.75, 0.70–0.79 for antenatal care and 0.66, 0.61–0.71 for institutional delivery). Women in the least poor group were five times less likely to deliver at home (0.17, 0.10–0.27) as women in the poorest group and about four times less likely to deliver in the public sector (0.27, 0.21–0.35). Rising socioeconomic status was associated with a lower prevalence of low birth weight (0.91, 0.85–0.97). Stillbirth rates did not vary, but neonatal mortality rates fell non-significantly as socioeconomic status increased (0.88, 0.71–1.08). Conclusion Analyses of this type have usually been applied across the population spectrum from richest to poorest, and we were struck by the regularly stepped picture of inequalities within the urban poor, a group that might inadvertently be considered relatively homogeneous. The poorest slum residents are more dependent upon public sector health care, but the regular progression towards the private sector raises questions about its quality and regulation. It also underlines the need for healthcare provision strategies to take account of both sectors.

Abstract Background Nepal's Safe Delivery Incentive Programme (SDIP) was introduced nationwide in 2005 with the intention of increasing utilisation of professional care at childbirth. It provided cash to women giving birth in a health facility and an incentive to the health provider for each delivery attended, either at home or in the facility. We explored early implementation of the programme at the district-level to understand the factors that have contributed to its low uptake. Methods We conducted in ten study districts a series of key informant interviews and focus group discussions with staff from health facilities and the district health office and other stakeholders involved in implementation. Manual content analysis was used to categorise data under emerging themes. Results Problems at the central level imposed severe constraints on the ability of district-level actors to implement the programme. These included bureaucratic delays in the disbursement of funds, difficulties in communicating the policy, both to implementers and the wider public and the complexity of the programme's design. However, some district implementers were able to cope with these problems, providing reasons for why uptake of the programme varied considerably between districts. Actions appeared to be influenced by the pressure to meet local needs, as well individual perceptions and acceptance of the programme. The experience also sheds light on some of the adverse effects of the programme on the wider health system. Conclusion The success of conditional cash transfer programmes in Latin America has led to a wave of enthusiasm for their adoption in other parts of the world. However, context matters and proponents of similar programmes in south Asia should give due attention to the challenges to implementation when capacity is weak and health services inadequate.

Abstract Background The United Nations Millennium Development Goals look to substantial improvements in child and maternal survival. Morbidity and mortality during pregnancy, delivery and the postnatal period are prime obstacles to achieving these goals. Given the increasing importance of urban health to global prospects, Mumbai's City Initiative for Newborn Health aims to improve maternal and neonatal health in vulnerable urban slum communities, through a combination of health service quality improvement and community participation. The protocol describes a trial of community intervention aimed at improving prevention, care seeking and outcomes. Objective To test an intervention that supports local women as facilitators in mobilising communities for better health care. Community women's groups will build an understanding of their potential to improve maternal and infant health, and develop and implement strategies to do so. Design Cluster-randomized controlled trial. Methods The intervention will employ local community-based female facilitators to convene groups and help them to explore maternal and neonatal health issues. Groups will meet fortnightly through a seven-phase process of sharing experiences, discussion of the issues raised, discovery of potential community strengths, building of a vision for action, design and implementation of community strategies, and evaluation. The unit of allocation will be an urban slum cluster of 1000–1500 households. 48 clusters have been randomly selected after stratification by ward. 24 clusters have been randomly allocated to receive the community intervention. 24 clusters will act as control groups, but will benefit from health service quality improvement. Indicators of effect will be measured through a surveillance system implemented by the project. Key distal outcome indicators will be neonatal mortality and maternal and neonatal morbidity. Key proximate outcome indicators will be home care practices, uptake of antenatal, delivery and postnatal care, and care for maternal and neonatal illness. Data will be collected through a vital registration system for births and deaths in the 48 study clusters. Structured interviews with families will be conducted at about 6 weeks after index deliveries. We will also collect both quantitative and qualitative data to support a process evaluation. Trial registration Current controlled trials ISRCTN96256793

Abstract Background In places with poor vital registration, measurement of maternal mortality and monitoring the impact of interventions on maternal mortality is difficult and seldom undertaken. Mortality ratios are often estimated and policy decisions made without robust evidence. This paper presents a prospective key informant system to measure maternal mortality and the initial findings from the system. Methods In a population of 228 186, key informants identified all births and deaths to women of reproductive age, prospectively, over a period of 110 weeks. After birth verification, interviewers visited households six to eight weeks after delivery to collect information on the ante-partum, intra-partum and post-partum periods, as well as birth outcomes. For all deaths to women of reproductive age they ascertained whether they could be classified as maternal, pregnancy related or late maternal and if so, verbal autopsies were conducted. Results 13 602 births were identified, with a crude birth rate of 28.2 per 1000 population (C.I. 27.7–28.6) and a maternal mortality ratio of 722 per 100 000 live births (C.I. 591–882) recorded. Maternal deaths comprised 29% of all deaths to women aged 15–49. Approximately a quarter of maternal deaths occurred ante-partum, a half intra-partum and a quarter post-partum. Haemorrhage was the commonest cause of all maternal deaths (25%), but causation varied between the ante-partum, intra-partum and post-partum periods. The cost of operating the surveillance system was US$386 a month, or US$0.02 per capita per year. Conclusion This low cost key informant surveillance system produced high, but plausible birth and death rates in this remote population in India. This method could be used to monitor trends in maternal mortality and to test the impact of interventions in large populations with poor vital registration and thus assist policy makers in making evidence-based decisions.

Abstract Background Neonatal mortality rates are high in rural Nepal where more than 90% of deliveries are in the home. Evidence suggests that death rates can be reduced by interventions at community level. We describe an intervention which aimed to harness the power of community planning and decision making to improve maternal and newborn care in rural Nepal. Methods The development of 111 women's groups in a population of 86 704 in Makwanpur district, Nepal is described. The groups, facilitated by local women, were the intervention component of a randomized controlled trial to reduce perinatal and neonatal mortality rates. Through participant observation and analysis of reports, we describe the implementation of this intervention: the community entry process, the facilitation of monthly meetings through a participatory action cycle of problem identification, community planning, and implementation and evaluation of strategies to tackle the identified problems. Results In response to the needs of the group, participatory health education was added to the intervention and the women's groups developed varied strategies to tackle problems of maternal and newborn care: establishing mother and child health funds, producing clean home delivery kits and operating stretcher schemes. Close linkages with community leaders and community health workers improved strategy implementation. There were also indications of positive effects on group members and health services, and most groups remained active after 30 months. Conclusion A large scale and potentially sustainable participatory intervention with women's groups, which focused on pregnancy, childbirth and the newborn period, resulted in innovative strategies identified by local communities to tackle perinatal care problems.

PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Abstract Background Maternal, perinatal and neonatal mortality rates remain high in rural areas of developing countries. Most deliveries take place at home and care-seeking behaviour is often delayed. We report on a combined quantitative and qualitative study of care seeking obstacles and practices relating to perinatal illness in rural Makwanpur district, Nepal, with particular emphasis on consultation strategies. Methods The analysis included a survey of 8798 women who reported a birth in the previous two years [of whom 3557 reported illness in their pregnancy], on 30 case studies of perinatal morbidity and mortality, and on 43 focus group discussions with mothers, other family members and health workers. Results Early pregnancy was often concealed, preparation for birth was minimal and trained attendance at birth was uncommon. Family members were favoured attendants, particularly mothers-in-law. The most common recalled maternal complications were prolonged labour, postpartum haemorrhage and retained placenta. Neonatal death, though less definable, was often associated with cessation of suckling and shortness of breath. Many home-based care practices for maternal and neonatal illness were described. Self-medication was common. There were delays in recognising and acting on danger signs, and in seeking care beyond the household, in which the cultural requirement for maternal seclusion, and the perceived expense of care, played a part. Of the 760 women who sought care at a government facility, 70% took more than 12 hours from the decision to seek help to actual consultation. Consultation was primarily with traditional healers, who were key actors in the ascription of causation. Use of the government primary health care system was limited: the most common source of allopathic care was the district hospital. Conclusions Major obstacles to seeking care were: a limited capacity to recognise danger signs; the need to watch and wait; and an overwhelming preference to treat illness within the community. Safer motherhood and newborn care programmes in rural communities, must address both community and health facility care to have an impact on morbidity and mortality. The roles of community actors such as mothers-in-law, husbands, local healers and pharmacies, and increased access to properly trained birth attendants need to be addressed if delays in reaching health facilities are to be shortened.

Mini publics have become cornerstones of the European Union's Future of Europe (FoE) initiative. However, weaknesses in their designs bring their political influence into question. Often-unsystematic in design, they fail to strengthen participants' understandings of the issues under evaluation and induce silo-thinking and the formation of pseudo-preferences. These come at a cost to informed and deliberatively deduced recommendations which speak to underlying functional/operational technicalities which fundamentally determine the form and delivery of policy interests. Guided by the adage that form follows function, this paper argues that mini publics pertaining to the FoE must primarily encourage participants to think about the ways policies are made in the EU before they formulate policy recommendations. To do this, they must consider the EU's overall form (or prospective forms). Utilising data from focus group analysis, the paper demonstrates that scenario (vignette) models are conducive to strengthening participants' understandings of both existing and alternative EU forms, and their functional consequences for EU policies, thus enabling them to formulate concrete and potentially deliverable policy recommendations. Subsequently, the paper encourages organisers of relevant mini-publics to employ the European Commission's 'Five Scenarios for the FoE' as entry-points to strengthen the deliberative quality and democratic outputs of such exercises. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes. Methods: Two distinct cohorts of patients treated with radical prostatectomy were identified, based on the development of biochemical recurrence (BCR), one subgroup with high International Society of Urological Pathologists (ISUP) grade group, recurrent disease and a second with low grade, non-recurrent disease. A prostate immunohistochemical (IHC) antibody cocktail was used to differentiate tumor and peritumoral benign tissue. Specific CD8+, CD4+, FoxP3+, CD20+ and CD68+ cell subsets were identified using IHC staining of consecutive slides. PD-L1 and CD8/PD-L1 dual staining were also performed. Cell subset densities were quantified within tumor and peritumoral regions. We used descriptive statistics to report cell subset densities and T-tests to compare groups by age, grade and the development of BCR. Univariable and multivariable logistic regression were used to analyse risk factors for BCR and the development of metastatic disease. Results: A total of 175 patients were included, with a median age of 63 years and median pre-operative PSA of 8.2ng/ml. BCR occurred in 115 patients (66%) and 56 (32%) developed metastatic disease. CD68+ cells were the most abundant (median 648.8/mm2 intratumoral, 247.6/mm2 peritumoral), while PD-L1+ and PD-L1/CD8+ cell density was low overall (PD-L1+ median 162.4/mm2 intratumoral, 141.7/mm2 peritumoral; PD-L1/CD8+ (median 5.52/mm2 intratumoral, 3.41/mm2 peritumoral). Overall, grade group and T-stage were independently associated with BCR and metastatic disease. Higher density of peritumoral PD-L1+ cells was an independent risk factor for BCR (OR 5.33, 95%CI 1.31–21.61, p = 0.019).Although higher densities of CD8+ and CD4+ cells were observed in higher grade group 3–5 tumors, these were not associated with the development of BCR or metastasis. Conclusions: In our cohort of prostate cancer patients who underwent radical prostatectomy, higher grade group and T-stage were independent predictors of BCR and metastasis. Despite higher grade group being associated with higher CD8+ cell density, PD-L1+ and PD-L1/CD8+ cell densities were low overall, suggesting lower T cell receptor recognition of tumor antigens. Further understanding of this phenomenon would influence development of future immunotherapeutic strategies in prostate cancer. [ABSTRACT FROM AUTHOR]

Metastasis‐directed therapy (MDT) for oligometastatic prostate cancer (PCa), including stereotactic body radiotherapy (SBRT), has shown promise but is still considered investigational. This is the 5‐year analysis of the TRANSFORM trial, the largest prospective cohort of men with oligometastatic PCa treated with SBRT‐based MDT. The primary endpoint was 5‐year treatment escalation‐free survival (TE‐FS), defined as freedom from any new cancer therapy other than further SBRT. In total, 199 men received SBRT; 76.4% were hormone‐naïve at baseline. The rate of 5‐year TE‐FS was 21.7% (95% confidence interval [CI]: 15.7%–28.7%) overall and 25.4% (95% CI: 18.1%–33.9%) in the hormone‐naïve subgroup. The subgroups with International Society of Urological Pathology Grade Groups 4–5 disease (hazard ratio [HR] = 1.48, 95% CI: 1.05–2.01, p =.026), a higher baseline prostate‐specific antigen (PSA) (HR = 1.06, 95% CI: 1.03–1.09, p <.001) and those who received prior androgen deprivation therapy (ADT) (HR = 2.13, 95% CI: 1.40–3.26, p <.001), were at greater risk of treatment escalation. Outcomes for participants with four or five initial lesions were comparable to those with one to three lesions. At last follow‐up, 18.9% (95% CI: 13.2%–25.7%) of participants were free from treatment escalation (median follow‐up of 67.9 months) and two participants had an undetectable PSA level. No treatment‐related grade three or higher adverse events were reported. The findings of this study demonstrate that SBRT‐based MDT is an effective option for delaying systemic treatment escalation in the context of oligometastatic PCa. Future randomised trials comparing SBRT‐based MDT to standard‐of‐care ADT‐based approaches are required to evaluate the impact of delaying ADT on survival. [ABSTRACT FROM AUTHOR]