Expression of Human nPTB Is Limited by Extreme Suboptimal Codon Content

Background: The frequency of synonymous codon usage varies widely between organisms. Suboptimal codon content limits expression of viral, experimental or therapeutic heterologous proteins due to limiting cognate tRNAs. Codon content is therefore often adjusted to match codon bias of the host organism. Codon content also varies between genes within individual mammalian species. However, little attention has been paid to the consequences of codon content upon translation of host proteins. Methodology/Principal Findings: In comparing the splicing repressor activities of transfected human PTB and its two tissue-restricted paralogs–nPTB and ROD1–we found that the three proteins were expressed at widely varying levels. nPTB was expressed at 1–3 % the level of PTB despite similar levels of mRNA expression and 74 % amino acid identity. The low nPTB expression was due to the high proportion of codons with A or U at the third codon position, which are suboptimal in human mRNAs. Optimization of the nPTB codon content, akin to the ‘‘humanization’ ’ of foreign ORFs, allowed efficient translation in vivo and in vitro to levels comparable with PTB. We were then able to demonstrate that all three proteins act as splicing repressors. Conclusions/Significance: Our results provide a striking illustration of the importance of mRNA codon content in determining levels of protein expression, even within cells of the natural host species

Assessing trends in the content of maternal and child care following a health system strengthening initiative in rural Madagascar : a longitudinal cohort study

Author summary Why was this study done? One of the largest contributors to preventable deaths in low- and middle-income countries is poor quality of care delivered by the public health system. Yet, given the multiple dimensions of care quality, there are currently no standard measures to evaluate impacts in this domain. While health system strengthening (HSS) initiatives strive to simultaneously increase access to healthcare and improve care quality, few studies have evaluated the impact of HSS initiatives on both targets. Our study sought to determine whether an HSS intervention in a rural health district of Madagascar, one of the world's poorest countries, improved the quality of maternal and child care at the population level. What did the researchers do and find? We used data from a district-representative open longitudinal cohort that followed over 1,500 households between 2014 and 2016, in order to compare trends in the content of care as a proxy for care quality, inside and outside the intervention catchment, through difference-in-differences analyses. We also analysed data from a Service Availability and Readiness Assessment (SARA) conducted in health facilities supported by the HSS intervention. Our data set included self-reported information on health seeking behaviors and care content for common illnesses of children under five ( = 657 in 2014; 411 in 2016), and for maternal care before and during live births that occurred in the previous two years ( = 552 in 2014; 524 in 2016). nnWe found that compared to the non-intervention group, the intervention group experienced a larger improvement in most care content outputs for childhood illnesses (e.g., 24.4% more children with diarrhea were prescribed oral rehydration therapy after two years than in the non-intervention area) and for perinatal care, whereas trends in antenatal care content were more similar in both populations. Despite progress, there remained important gaps in the provision of essential health services for individuals in both the intervention and non-intervention groups. What do these findings mean? The study provides evidence that HSS initiatives can successfully increase access to healthcare in target populations while also improving the quality of certain primary care services provided. The approach used here can be adapted to other local HSS initiatives to stimulate more comprehensive impact evaluations. Evidence from this study can help guide investments in integrated primary care systems that are needed globally to improve maternal and child care. The interpretation of the study findings is limited by the absence of randomization in the allocation of the intervention's programs and by the reliance on self-reported answers. Background In order to reach the health-related Sustainable Development Goals (SDGs) by 2030, gains attained in access to primary healthcare must be matched by gains in the quality of services delivered. Despite the broad consensus around the need to address quality, studies on the impact of health system strengthening (HSS) have focused predominantly on measures of healthcare access. Here, we examine changes in the content of maternal and child care as a proxy for healthcare quality, to better evaluate the effectiveness of an HSS intervention in a rural district of Madagascar. The intervention aimed at improving system readiness at all levels of care (community health, primary health centers, district hospital) through facility renovations, staffing, equipment, and training, while removing logistical and financial barriers to medical care (e.g., ambulance network and user-fee exemptions). Methods and findings We carried out a district-representative open longitudinal cohort study, with surveys administered to 1,522 households in the Ifanadiana district of Madagascar at the start of the HSS intervention in 2014, and again to 1,514 households in 2016. We examined changes in healthcare seeking behavior and outputs for sick-child care among children <5 years old, as well as for antenatal care and perinatal care among women a

Cohort Profile: Ifanadiana Health Outcomes and Prosperity longitudinal Evaluation (IHOPE)

International audienc

Factors associated with risk of developmental delay in preschool children in a setting with high rates of malnutrition : a cross-sectional analysis of data from the IHOPE study, Madagascar

Background 50% of Malagasy children have moderate to severe stunting. In 2016, a new 10 year National Nutrition Action Plan (PNAN III) was initiated to help address stunting and developmental delay. We report factors associated with risk of developmental delay in 3 and 4 year olds in the rural district of Ifanadiana in southeastern Madagascar in 2016. Methods The data are from a cross-sectional analysis of the 2016 wave of IHOPE panel data (a population-representative cohort study begun in 2014). We interviewed women ages 15-49 using the MICS Early Child Development Indicator (ECDI) module, which includes questions for physical, socio-emotional, learning and literacy/numeracy domains. We analyzed ECDI data using standardized z scores for relative relationships for 2 outcomes: at-risk-for-delay vs. an international standard, and lower-development-than-peers if ECDI z scores were > 1 standard deviation below study mean. Covariates included demographics, adult involvement, household environment, and selected child health factors. Variables significant at alpha of 0.1 were included a multivariable model; final models used backward stepwise regression, clustered at the sampling level. Results Of 432 children ages 3 and 4 years, 173 (40%) were at risk for delay compared to international norms and 68 children (16.0%) had lower-development than peers. This was driven mostly by the literacy/numeracy domain, with only 7% of children considered developmentally on track in that domain. 50.5% of children had moderate to severe stunting. 76 (17.6%) had > = 4 stimulation activities in past 3 days. Greater paternal engagement (OR 1.5 (1.09, 2.07)) was associated with increased delay vs. international norms. Adolescent motherhood (OR. 4.09 (1.40, 11.87)) decreased children's development vs. peers. Engagement from a non-parental adult reduced odds of delay for both outcomes (OR (95%CI = 0.76 (0.63, 0.91) & 0.27 (0.15, 0 48) respectively). Stunting was not associated with delay risk (1.36 (0.85, 2.15) or low development (0.92 (0.48, 1.78)) when controlling for other factors. Conclusions In this setting of high child malnutrition, stunting is not independently associated with developmental risk. A low proportion of children receive developmentally supportive stimulation from adults, but non-parent adults provide more stimulation in general than either mother or father. Stimulation from non-parent adults is associated with lower odds of delay

Early changes in intervention coverage and mortality rates following the implementation of an integrated health system intervention in Madagascar

Introduction The Sustainable Development Goals framed an unprecedented commitment to achieve global convergence in child and maternal mortality rates through 2030. To meet those targets, essential health services must be scaled via integration with strengthened health systems. This is especially urgent in Madagascar, the country with the lowest level of financing for health in the world. Here, we present an interim evaluation of the first 2 years of a district-level health system strengthening (HSS) initiative in rural Madagascar, using estimates of intervention coverage and mortality rates from a district-wide longitudinal cohort. Methods We carried out a district representative household survey at baseline of the HSS intervention in over 1500 households in Ifanadiana district. The first follow-up was after the first 2 years of the initiative. For each survey, we estimated maternal, newborn and child health (MNCH) coverage, healthcare inequalities and child mortality rates both in the initial intervention catchment area and in the rest of the district. We evaluated changes between the two areas through difference-in-differences analyses. We estimated annual changes in health centre per capita utilisation from 2013 to 2016. Results The intervention was associated with 19.1% and 36.4% decreases in under-five and neonatal mortality, respectively, although these were not statistically significant. The composite coverage index (a summary measure of MNCH coverage) increased by 30.1%, with a notable 63% increase in deliveries in health facilities. Improvements in coverage were substantially larger in the HSS catchment area and led to an overall reduction in healthcare inequalities. Health centre utilisation rates in the catchment tripled for most types of care during the study period. Conclusion At the earliest stages of an HSS intervention, the rapid improvements observed for Ifanadiana add to preliminary evidence supporting the untapped and poorly understood potential of integrated HSS interventions on population health

Early changes in intervention coverage and mortality rates following the implementation of an integrated health system intervention in Madagascar

Introduction: The Sustainable Development Goals framed an unprecedented commitment to achieve global convergence in child and maternal mortality rates through 2030. To meet those targets, essential health services must be scaled via integration with strengthened health systems. This is especially urgent in Madagascar, the country with the lowest level of financing for health in the world. Here, we present an interim evaluation of the first 2 years of a district-level health system strengthening (HSS) initiative in rural Madagascar, using estimates of intervention coverage and mortality rates from a district-wide longitudinal cohort. Methods: We carried out a district representative household survey at baseline of the HSS intervention in over 1500 households in Ifanadiana district. The first follow-up was after the first 2 years of the initiative. For each survey, we estimated maternal, newborn and child health (MNCH) coverage, healthcare inequalities and child mortality rates both in the initial intervention catchment area and in the rest of the district. We evaluated changes between the two areas through difference-in-differences analyses. We estimated annual changes in health centre per capita utilisation from 2013 to 2016. Results: The intervention was associated with 19.1% and 36.4% decreases in under-five and neonatal mortality, respectively, although these were not statistically significant. The composite coverage index (a summary measure of MNCH coverage) increased by 30.1%, with a notable 63% increase in deliveries in health facilities. Improvements in coverage were substantially larger in the HSS catchment area and led to an overall reduction in healthcare inequalities. Health centre utilisation rates in the catchment tripled for most types of care during the study period. Conclusion: At the earliest stages of an HSS intervention, the rapid improvements observed for Ifanadiana add to preliminary evidence supporting the untapped and poorly understood potential of integrated HSS interventions on population health

Advancing a Science for Sustaining Health: Establishing a Model Health District in Madagascar

AbstractObjectiveWe demonstrate a replicable model health district for Madagascar. The governments of many low-income countries have adopted health policies that follow international standards, and yet there are four hundred million people without basic access to primary care. Closing this global health delivery gap is typically framed as an issue of scale-up, accomplished primarily through integrating international donor funds with broad-based health system strengthening (HSS) efforts. However, there is no established process by which healthcare systems measure improvements at the point of service and how those, in turn, impact population health. There is no gold standard, equivalent to randomized trials of individual-level interventions, for health systems research. Here, we present a framework for a model district in Madagascar where national policies are implemented along with additional health system interventions to allow for bottom-up adaptation.SettingThe intervention takes place in a government district in Madagascar, which includes 1 district hospital, 20 primary care health centers, and a network of community health workers.InterventionThe program simultaneously strengthens the WHO’s six building blocks of HSS at all levels of the health system within a government district and pioneers a data platform that includes 1) strengthening the district’s health management information systems; 2) monitoring and evaluation dashboards; and 3) a longitudinal cohort demographic and health study of over 1,500 households, with a true baseline in intervention and comparison groups.ConclusionThe integrated intervention and data platform allows for the evaluation of system output indicators as well as population-level impact indicators, such as mortality rates. It thus supports field-based implementation and policy research to fill the know-do gap, while providing the foundation for a new science of sustaining health.Data Sharing StatementData can be made available upon request by [email protected].</jats:sec