NIHRDataInsights/HRCSData huggingface dataset:
Title: Adapting the health system in Ghana to reach the urban poor
Funder: Medical Research Council

Abstract: In rural Ghana the Community Health Planning and Services (CHPS) has been successfully implemented. Evaluations identify reductions in childhood mortality and fertility rates. Despite government policy to scale CHPS nationally, benefits do not extend to urban populations. Ghana is urbanising rapidly; inequities are unacceptably high. Few studies analyse potentially scale-able models in LMICs. We aim to 1) adapt Ghana's CHPS to reach and engage the urban poor to effectively improve their health. 2) To understand social structures, health seeking and insurance behaviour and needs of urban poor 3) develop system-wide approaches addressing community engagement, access to insurance, human resource skills and service delivery for effective CHPS delivery. In partnership with Ghana Health Service (GHS), we will select 3 urban areas of differing characteristics to implement a prototype urban CHPS model. In the 3 areas we will assess baseline service utilisation, conduct focus groups (6) and interviews (24) to understand social and health behaviours. We will conduct 20 interviews with CHPS staff and communities in the few existing urban CHPS pilots. Following workshops with government and communities, we will use participatory action research (PAR) with CHPS staff and communities to observe implementation of the redesigned CHPS model. Routine data will be analysed to assess utilisation and cost per utilisation compared to baseline and across the 3 areas. Further interviews (20) with marginalised households will be conducted. Interviews and focus groups will be audio-recorded and transcribed. Detailed notes will be taken during PAR. Data will be analysed thematically using Brunton's (2013) framework to understand engagement in the urban health system. Our team includes senior members of GHS including CHPS, ensuring future implementation and research. Development of policy, operational guidelines, training materials will further facilitate scale-up of the urban CHPS model.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Testing The Health And Therapeutic Potential Of In Vitro Derived Oocytes For The Restoration Of Female Fertility And The Treatment of Infertility
Funder: Medical Research Council

Abstract: Premature ovarian insufficiency (POI) or total sterility can occur in girls & young women as a result of genetic defects, surgery, abdominal trauma, or more commonly as a side effect of radiation or chemotherapy treatment for cancers or haematological disease. POI has adverse clinical & psychological effects on women's health. Ovarian cryopreservation can now be used to safeguard the fertility of girls & young women at high risk of sterility or POI. Primordial follicles, containing primordial oocytes, can be cryopreserved in ovarian cortex & stored long-term at -196C. When the patient wishes to start her family, the stored tissue is autografted back at an orthotopic or heterotopic site to restore fertility. However, for girls & women with blood-born leukaemias or cancers with a high risk of ovarian metastasis, ovarian autografting risks reseeding the cancer through the transplant. For these individuals fertility restoration can only be safely achieved in the laboratory by the complete in vitro growth & maturation (IVGM) of cryopreserved primordial oocytes into fertile metaphase II (MII) oocytes. Following in vitro fertilisation, a healthy embryo can be transferred to the patient to produce a pregnancy. The therapeutic potential of IVGM is huge but the technology is extremely challenging. Never-the-less significant advances in IVGM have recently been made by the applicants' laboratories. We now aim to: (i) complete IVGM optimization by testing the health, fertility & developmental competence of oocytes & embryos derived using slow vs. fast grow IVGM systems; (ii) conduct a pilot study to test the implantation & pregnancy potential of embryos derived from IVGM oocytes in (i) & (iii) conduct an embryo transfer trial to confirm the safety & hence therapeutic potential of IVGM oocytes for fertility restoration. These studies will be conducted in sheep as a proven, physiologically and clinically relevant model for fertility preservation & restoration in women.


Research activity codes: 5.4 SURGERY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Mechanisms regulating the timing of developmental events in the early mouse embryo
Funder: Medical Research Council

Abstract: A fundamental question in biology is what ensures that individuals of a particular species are all roughly the same size at birth. In spite of the importance of this question, there is relatively little known about it. Here we will tackle this unknown by studying the mechanisms that regulate embryo size during early post-implantation mouse development. For this we will compare normal embryos to double-sized embryos, that reduce in size at the time of gastrulation, and to half-sized embryos, that catch up in growth just after gastrulation. As part of this comparison we will do three things: First, we will establish the relative importance of changes in proliferation and cell death for the scaling of over- and under-sized embryos. Second, we will study the pathways that regulate early embryo size. This will be done by focussing on mTOR signalling, a nutrient and growth factor sensing pathway revealed by our preliminary data. As part of this analysis, we will study how mTOR is activated during embryo scaling, what inputs determine its activity and how these inputs ensure that embryo size is appropriate for the developmental stage at which the embryo is at. This candidate pathway approach will be complemented by an unbiassed search for novel pathways involved in embryo scaling, performed by comparing the single cell transcriptome of normal embryos to that of over- and under-sized embryos. Finally, we will study how the mechanism that regulate embryo size impact the patterning and morphogenesis of the embryo. For this, we will compare the timing of gastrulation of over-sized and under-sized embryos to that of normal embryos. Using these embryos we will also study how embryo size affects the signals that induce gastrulation. Together, we anticipate that the experiments described will provide invaluable information regarding how embryo size is regulated during early mammalian development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Validation of risk factors as causal for preterm birth and prematurity-mediated effects on early child development using a population cohort study
Funder: Medical Research Council

Abstract: Preterm birth is a major public health concern affecting 15 million neonates annually and associated with over 50% of all neonatal deaths. Preterm infants are inclined to developmental delays. Many risk factors including genetic factors are known, but are not validated as causal factors yet. My research aims to validate risk factors as causal for preterm birth and further investigate the role of preterm birth in the complex causal mechanism leading to early child development delay (ECDD). To this end, I am proposing a novel design and a randomisation-based statistical inferential framework that combines data mining and bootstrapping techniques. The proposed inferential framework tests multiple risk factors and requires adjustment for the Type I error. I will apply the "cross-screening" strategy consisting of splitting data in half at random, using each half to carry out the procedure and reporting the more favorable conclusions from the two partitioned data, correcting the inference using the Bonferroni inequality. Genetic data collected on the triad of father-mother-child will be analysed using an extension of the Genome-Wide Association Study method to accommodate data from relatives. Investigations of complex causal mechanism are often done using mediation analyses. Recent advances in causal inference have led to more elaborate mediation analysis methods with transparent assumptions and there exist approaches for assessing how severe violations to those assumptions should be to reverse the results. The performance of the proposed method will first be assessed via simulations. Alternative existing methods such as the bias-corrected matching estimator and augmented inverse-probability weighting will also be applied. Identifying causal factors including gene variants will improve our understanding of the mechanism underlying preterm birth and ECDD and help researchers develop preventive and curative interventions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Calcium supplementation to prevent pre-eclampsia in Low- and Middle-Income Countries: IPD meta-analysis, network meta-analysis and economic evaluation
Funder: Medical Research Council

Abstract: AIMS AND OBJECTIVES: To determine if the effects of calcium vary according to the maternal characteristics and the intervention type in preventing pre-eclampsia and other complications, to rank various calcium supplementation strategies by effect, to determine the barriers to its uptake and use, and its cost-effectiveness DESIGN: IPD meta-analysis of randomised trials, network meta-analysis, economic evaluation DURATION: 21 months POPULATION: Pregnant women (varied age, parity, pre-eclampsia risk, calcium status) INTERVENTION: Calcium supplementation (varied dose, timing, duration) CONTROL: Placebo or usual care OUTCOMES: Primary: Pre-eclampsia of any onset Secondary: Early-onset pre-eclampsia (<34 weeks), maternal and offspring complications, side effects from calcium, costs METHODS WP1: IPD random-effect meta-analyses to assess overall, and differential effects of calcium supplementation on pre-eclampsia; network meta-analysis to rank intervention effects WP2: Systematic reviews, Delphi surveys and focus groups on barriers to the uptake and implementation of the effective calcium supplementation regimens to mothers, healthcare professionals and policymakers, with Patient and Public Involvement (PPI) WP3: Economic evaluation from a healthcare perspective in terms of cost per disability-adjusted life years (DALYs) averted for mothers in LMIC WP4: Research capacity of partners strengthened through workshops to sustain the living IPD database SAMPLE SIZE: i-CIP (Calcium In pregnancy to prevent Pre-eclampsia) IPD collaborators have so far agreed to share data of 27,824 women (11 trials). Assuming heterogeneity of 1-8% in pre-eclampsia rates in the low-risk group in each trial, we have over 98% power to detect an interaction OR of 0.62 in our IPD meta-analysis for differential effect by maternal risk-status DISSEMINATION: WHO guidelines, conferences, publications, links with WHO regional hubs, Collaborating Centres and LMIC policymaker


Research activity codes: 6.1 PHARMACEUTICALS;8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Understanding phenotype and mechanisms of spontaneous preterm birth in sub-Saharan Africa (PRECISE-SPTB)
Funder: Medical Research Council

Abstract: Preterm birth is a major contributor to neonatal mortality and morbidity in sub-Saharan Africa. Recent estimates indicate births in Asian and sub-Saharan countries accounted for approximately 80% of preterm births globally, a significant proportion of which will be caused by spontaneous onset of labour and/or preterm premature rupture of membranes (classified together as spontaneous preterm birth, SPTB). Despite knowledge of the global impact of SPTB, a skewed emphasis of SPTB research in high income countries means less is known of SPTB amongst women from low income countries. The aetiology of SPTB is complex and heavily influenced by environment, infection nutrition and other co-exposures; it follows that region-specific research into epidemiology and other major contextual and biological drivers of SPTB is an essential pre-requisite to improved maternal and newborn healthcare where the burden is greatest. This project will utilize the PRECISE Network bio-repository and database (a UKRI Global Challenges Research Funded project) which is storing well curated samples from approximately 10,000 pregnant women recruited in rural and urban sites in Kenya, The Gambia and Mozambique. Using a combination of clinical phenotyping (n=5000 women) and a multi-omics approach (n=600 women), we will integrate clinical factors with cervicovaginal, plasma and placental biomarkers to characterise SPTB sub-groups. Mechanistic insights into the drivers for SPTB in sub Saharan populations has potential to identify novel biomarkers for predicting risk of SPTB as well as enabling enable comparisons with our understanding of preterm birth in other countries. This work will impact future strategies for clinical risk management, prevention and treatment that specifically addresses the needs of women in sub-Saharan Africa.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Development, Field-Testing and Piloting of a refractory postpartum haemorrhage management package: the PPH ReAct (PPH Refractory Action) study
Funder: Medical Research Council

Abstract: Every six minutes a mother dies from postpartum haemorrhage (PPH) in low-resource countries, in the prime of her life and often leaving behind a young family. When a mother dies in childbirth, her infant has less than a 20% chance of surviving past the first month. PPH is the commonest reason maternal deaths worldwide. Effective first-line treatment can stop bleeding in most women diagnosed with PPH. However, those who continue to bleed despite first-line treatment are the women who suffer major morbidity and mortality. We have developed a provisional management package for refractory PPH, called the 'PPH ReAct' package. We wish to refine this management package, develop an implementation strategy for this, field-test these and finally pilot the approach in 5 health facilities in Kenya. Our objectives are: Objective 1: Refine the 'ReAct' refractory PPH management package through evidence synthesis, stakeholder engagement, and expert technical consultations. Objective 2: Develop an implementation strategy for refractory PPH management, through mixed-methods research, and a consensus-building co-design workshop. Objective 3: Field-test the refractory PPH management package and the implementation strategy in two health facilities in Kenya, through qualitative and quantitative methods. Objective 4: Pilot the refractory PPH management package and implementation strategy from objective 3 in five health facilities in Kenya, to evaluate its effects on process outcomes, as well as explore the feasibility of conducting a large scale implementation trial.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The impact of microbial and inflammatory exposures on birth outcomes in rural Zimbabwe
Funder: Medical Research Council

Abstract: Children born small-for-gestational age (SGA) or preterm have elevated mortality. Together, SGA and preterm lead to low birthweight and increased risk of stunting, which impairs lifelong health and human capital. New interventions to reduce SGA and preterm are needed to reduce mortality and end stunting. We hypothesise that maternal dysbiosis and inflammation at multiple sites in pregnancy drive SGA and preterm birth. A combined antimicrobial and anti-inflammatory intervention in pregnancy may modulate microbial and inflammatory exposures and improve birth outcomes. We will capitalise on a placebo-controlled, randomised trial of cotrimoxazole among pregnant women in rural Zimbabwe to longitudinally characterise oral, intestinal and vaginal dysbiosis and inflammation; evaluate their associations with SGA and preterm birth; and study the effect of cotrimoxazole on these mechanistic pathways. We will undertake 3 specific aims: 1) Characterise microbial and inflammatory exposures during pregnancy and their association with adverse birth outcomes: We will compare microbiome characteristics and inflammation in oral samples, vaginal swabs and stool samples collected at baseline and late pregnancy from mothers of SGA, preterm and AGA/term infants, and evaluate associations between microbial and inflammatory exposures and adverse birth outcomes. 2) Determine the impact of cotrimoxazole on maternal microbiomes and inflammation: We will compare oral, gut and vaginal microbiomes, local and systemic inflammation between women randomised to cotrimoxazole or placebo (N=100/arm). 3) Determine whether maternal cotrimoxazole confers neonatal health benefits: We will compare linear growth, hospitalisation, microbiome and inflammation between infants of mothers randomised to cotrimoxazole or placebo at delivery and 4 weeks (N=100/arm). We will characterise inflammation and immune function in placenta and cord blood, and assess vertical pathogen transmission and AMR.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Using lactate testing to improve maternal sepsis identification: a multi-country test accuracy study and feasibility assessment
Funder: Medical Research Council

Abstract: Maternal sepsis is a major cause of maternal mortality and morbidity requiring increased programmatic focus. Recent estimates suggest that it contributes to half of all maternal deaths world-wide, so without progress in this area the Sustainable Development Goal for maternal mortality will not be achieved. A "care bundle" approach in the adult population, in high income settings, is effective at reducing sepsis mortality. A care bundle has been optimised and feasibility tested specifically for maternal sepsis in low resource settings. This bundle "FAST-M", developed with broad consensus, includes only elements that are reliably available to healthcare providers in these settings: fluids, antibiotics, source identification and control, transfer (if required) and vital signs monitoring. However triggering the bundle in the correct women remains a major challenge. We propose to investigate if lactate measurement, available as a point-of-care test, has incremental benefit over conventional maternal vital sign assessment in the diagnosis of sepsis and identification of women at risk of severe morbidity and mortality in low resource settings. We will determine the diagnostic and prognostic accuracy of venous lactate measurement in the maternity population, in low resource settings, which is unknown. We will also investigate how to optimally implement this approach in low resource hospital settings, using a mixed methods evaluation. We will determine if the increased complexity of the addition of lactate measurement to the FAST-M approach impacts on compliance. Detailed qualitative and quantitative analysis will be undertaken to provide rich and detailed understanding of the process of implementation. This study will be multi-country to increase the generalisability of our results under both objectives. The chosen study sites are in Malawi, Pakistan and Uganda.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving maternal-neonatal outcomes through implementing Quality Midwifery Services in India: a case study of facilitators and barriers
Funder: Medical Research Council

Abstract: The Indian Government's key strategy to improve the quality of maternal and newborn care and to reduce preventable mortality and morbidity is to implement high quality midwifery services. This preliminary study will investigate the lessons that can be learned from the first sites to implement professional midwifery to inform future scale-up across India. The study uses ecological systems theory and quality care frameworks to analyse barriers and facilitators to the integration of the new cadre of Nurse Practitioners in Midwifery into the health system, and to highlight gaps in the quality of care. The study design combines community-based participatory research using human-centred design with case study methods to address three objectives: 1). to assess women's perceptions of current maternity services and the acceptability of midwives as key providers; 2) to identify barriers and facilitators to integrating professional midwives into current maternity services; and 3) to identify important outcomes measures that could be used in future research and to explore if review of maternal and newborn deaths is feasible to highlight gaps in care quality. The two case studies in Gujarat and Telangana comprise interviews and focus groups with a total 40 women and community influencers; in-depth interviews with 40 health providers including midwives, nurses and doctors; and exploratory case reviews of maternal and newborn deaths. We will conduct a systematic review to identify potential outcome measure for future research. Aspects of the study, including an integrated knowledge transfer plan will be co-designed by a stakeholder working group that includes women, healthcare providers and policymakers to ensure outputs are relevant. The key outputs of the study is policy options to strengthen implementation of midwifery across India and a plans for future research to test feasibility of conducting a cost-effectiveness study of professional midwifery in India.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: INSTINCT Study: Intranasal Stem Cells for Improving Neurodevelopmental Outcomes in Neonatal Encephalopathy
Funder: Medical Research Council

Abstract: Neonatal Encephalopathy (NE) is an important cause of death and disability, affecting 1-3/1000 births in the UK and 10-25/1000 births in sub Saharan Africa. Even with therapeutic hypothermia (HT), over 50% of treated babies have adverse outcomes. HT protocols have been optimised, adjunct therapies are urgently needed. Cell therapy offers a paradigm shift in NE therapy. Our primary aim is to assess neuroprotective effects of intranasal (IN) human umbilical cord stem cells (huMSC; clinical grade, manufactured at UCL). The proposal is based on pilot data in a male piglet model of hypoxia ischemia (HI). Compared to HT, IN 30 million huMSC at 24 & 48h after HI, with HT, improved: (i) recovery of aEEG over 72h; (ii) brain energy metabolism on magnetic resonance spectroscopy (MRS); (iii) white matter injury (TUNEL positive cells). There was no effect of intravenous huMSC. For clinical translation we must assess gender and temperature effects. The beneficial anti-inflammatory and repair effects of huMSC are mediated mainly through paracrine effects, by secretion of extracellular vesicles (EVs) in response to the brain ischemic milieu. Promising data exists for IN EVs in stroke models; EVs are attractive as they overcome some limitations of huMSC. Our second aim is to assess the safety and efficacy of IN EVs in the piglet model (similar anti-inflammatory effect of 30 million huMSC). The study will have 3 milestones: - M1: Preparation of huMSC and EV - M2A: Piglet Study 1. 2 doses IN huMSC at 12 & 36h with & without HT (4 groups, 16 piglets/group, (8 male, 8 female), total n=64). Of these n=3/group, PKH-labelled huMSC for TUNEL co-localization M2B: Dose finding - in vitro EV anti-inflammatory equivalence to 30 million huMSC - M3A: Piglet Study 2. 2 doses IN EV at 12 & 36h with & without HT (4 groups, 16 piglets/group (reduced to 10 if no gender effect), 75% of the controls used from M2, total n=40) M3B: MHRA Scientific Advice Meeting


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH