NIHRDataInsights/HRCSData huggingface dataset:
Title: Evaluation of the introduction of a novel device in the management of hypertension and shock in pregnancy in low-resource settings
Funder: Medical Research Council

Abstract: Hypothesis: Implementation of the CRADLE package, the Microlife CRADLE Vital Sign Alert (VSA) device, a novel semi-automated vital-sign device incorporating a traffic light early warning system, and simple education package, to healthcare providers (HCPs) at community and facility levels will reduce maternal mortality and morbidity in low-income country (LIC) populations. Aim: To reduce a composite of (all-cause) maternal mortality or major morbidity by 25%. Objective: To determine whether the CRADLE package prevents adverse maternal outcomes of the three leading causes of maternal death worldwide (obstetric haemorrhage, sepsis and pre-eclampsia) Study Design: A multicentre stepped wedge cluster randomised controlled trial of the CRADLE package to maternity care settings (comprising of secondary or tertiary health centre with multiple satellite primary care centres). Eight LIC trial areas (Zimbabwe, Zambia (x2 areas), Sierra Leone, Uganda (x2 areas), Haiti, Malawi, and Ethiopia) and one Indian area will take part in the RCT and, before the trial begins, randomly allocated the date from when they are given the intervention.7 Outcomes: Primary outcome: a composite of maternal mortality or major morbidity (one of maternal death, ICU admission, eclampsia, stroke, or hysterectomy with no double counting). Exploitation of research results: Following trial completion, we plan to publish our findings in high impact peer-reviewed research journals, with open-access publication, as well as disseminating our findings through high profile international and national global health and women's health conferences (e.g. FIGO).


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Impacts of Demand Side financing Instruments on the Continuum of Care for Maternal and Child Health in India and Bangladesh
Funder: Medical Research Council

Abstract: This research project aims to generate robust empirical evidence leading to the design of a new model financing mechanism that can effectively incentivise behaviours that improve health outcomes for women and children. Using India and Bangladesh as the research setting, we examine the interplay of factors related to demand for health services, socioeconomic attributes, quality of services being offered and the overarching health system characteristics that operates in a dynamic framework to determine how major demand-side financing (DSF) instruments are successful in influencing desired outcomes. We extend the research scope by aligning the objectives with recent global priorities in improving maternal and child health, which places emphasis on a wider continuum of Reproductive, Maternal, Neonatal and Child Health outcomes, as measured through key health service coverage indicators. The research approach involves extensive use of available household survey data and fresh data collected through primary surveys in three Indian states and two divisions in Bangladesh. Among them, the surveys will cover the three most important schemes regarding financial incentives in the two countries - the Janani Suraksha Yojana (Maternity Security Scheme) and Chiranjeevi (or the Long-Life Scheme) schemes in India and the Maternal Health Voucher Scheme (MHVS) in Bangladesh. Several innovative tools such as a comprehensive module to assess quality of care combining both clinical and users' perspectives, facility surveys, retrospective collection of event histories through surveying a cohort of women that automatically controls for variations in programme implementation over a staggered period enriches the empirical methods and strengthens the potential adaptability of the results.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: NeoEPOCH: Neonatal Electronic health record data for Point Of Care Health research and continuous incremental improvement in neonatal care
Funder: Medical Research Council

Abstract: Aims 1. Demonstrate feasibility, efficacy and efficiency of neonatal point-of-care trials (PoCT) using Electronic Health Record (EHR) data held by the National Neonatal Research Database (NNRD) 2. Develop a platform to leverage PoCT to improve neonatal care Objectives and methods Measure neonatal EHR data quality - Methods: internal/external validation Synthesise evidence for improving EHR data - Methods: systematic review, meta-analysis Develop parent-centred EHR data; test it alongside interventions identified from systematic review to see if it improves data quality - Methods: Focus group, cluster randomised trial Develop a core outcome set for neonatal PoCT - Method: Delphi consensus process Predict the influence of variable data quality on PoCT - Method: Statistical modelling Complete a pilot PoCT - Method: A multi-centre, superiority, randomised point of care trial (WHEAT) Map and prioritise neonatal treatment uncertainties - Method: Delphi consensus process Develop best practice for implementing PoCT results - Methods: qualitative interviews with leaders/stakeholders Scientific opportunities: NeoEPOCH will reduce waste in neonatal research by testing multiple uncertainties in large pragmatic trials, identifying research questions of importance and disseminating trial results. NeoEPOCH aims to increase research participation by making parent and public participation central and will develop into an open platform for POCT. By facilitating collaborative, efficient, national trials NeoEPOCH will increase the attraction of UK neonatal services to multinational and commercial research funders. Medical opportunities: NeoEPOCH meets to need to improve neonatal clinical care by rapidly reducing treatment uncertainties, thus making it truly evidence based. By building a research platform around parent involvement NeoEPOCH aims to improve participation in research and build public trust in electronic health record data.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Placental inflammation in high risk pregnancies: a novel therapeutic target to prevent stillbirth?
Funder: Medical Research Council

Abstract: Stillbirth is a devastating pregnancy outcome, affecting 1:220 pregnancies in UK. Although stillbirth is strongly associated with fetal growth restriction (FGR) and placental dysfunction, the underlying mechanisms are poorly understood and no diagnostic or treatment options are currently available to address placental dysfunction. Animal models have demonstrated that excessive inflammation at the maternal-fetal interface adversely affects placental function, resulting in FGR and fetal death. Combating inflammation in a rat model with targeted anti-inflammatory therapy protects the placenta, preventing adverse fetal outcomes. We recently identified a distinct placental pro-inflammatory cytokine profile in pregnancies at high risk of stillbirth, which was also evident in the maternal circulation. These women did not exhibit clinical signs of infection, but had elevated circulating levels of endogenous mediators of inflammation - the alarmins (uric acid, high-mobility group box 1 (HMGB1) and cell-free fetal DNA (cffDNA)) - suggesting these danger signals could trigger inflammation. Our preliminary data demonstrates alarmins induce placental dysfunction in vitro and in animal models, and have defined a central role for placental interleukin(IL)-1 as a downstream mediator. We propose that alarmins released following an early pregnancy insult, such as hypoxia, oxidative stress or subclinical infection, induce placental inflammation, thus exacerbating placental dysfunction and leading to FGR and stillbirth. We aim to improve understanding of the link between alarmin-induced inflammation, placental dysfunction and adverse fetal outcome and investigate whether inflammatory biomarkers can identify pregnancies at greatest risk of stillbirth. We will determine whether inflammation exacerbates existing placental dysfunction and test the therapeutic potential of anti-inflammatory therapy to protect against placental dysfunction and stillbirth using in vitro and in vivo models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Community pharmacist provision of contraception services for women receiving opiate substitution treatment
Funder: Medical Research Council

Abstract: Women with an opiate addiction often experience a reversible loss of fertility due to the combined effects of their drug use, poor diet and weight loss [1]. Once stabilised on opiate substitution treatment (OST, e.g. methadone) fertility returns, often without the woman's realisation, who may continue to have sex without contraception under the assumption that she is unable to conceive [1,3]. Unplanned pregnancies are common amongst women receiving opiate substitution treatment (WRO). Despite this, fewer than half of WRO receive advice or access to contraception [3, 4]. WRO attend their community pharmacy on a daily to weekly basis to receive their OST. Community pharmacists (CPs) may be well placed to provide brief, and on-going contraception advice and facilitate access to contraception for WRO. Taking a qualitative approach this early phase study aims to design and develop a multi-faceted CP led intervention to support WRO in accessing contraception advice and contraception. The objectives of the research are to 1) explore the factors that affect WRO contraception decisions, accessing and using contraception and advice, 2) determine whether a CP-led intervention to encourage contraceptive use would be acceptable to WRO and, if so, what the intervention would look like 3) develop a model of the processes, mechanisms of action and outcomes of this intervention; 4) evaluate how a contraception intervention could fit into CPs' current practice, what training or resources are needed, and what the potential barriers to delivering this service are. Data collection will involve observations of CPs' current practice and semi-structured interviews with WRO and CPs to address the research objectives. Data will be analysed using framework analysis [14,15] with the COM-B system (Capability, Opportunity, Motivation to Behaviour) [16] as the theoretical framework. The analysis will inform the development of a CP-led contraception intervention to reduce unplanned pregnancies.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Blood flow (dys)regulation and transfer function in the human placenta: an integrated in silico and ex vivo approach to fetal growth restriction
Funder: Medical Research Council

Abstract: Fetal growth restriction (FGR), the inability of a fetus to achieve complete genetic growth potential, is a serious pregnancy condition that carries a high risk of stillbirth or cardiovascular, metabolic and neurological disorders later in life. FGR is associated with inadequate placental function and altered villous structure, but their interrelation is poorly understood, particularly in the case of flow-limited oxygen transfer. Furthermore, existing clinical tools (such as ultrasound and MRI) cannot resolve fine details of placental circulation and thus fail to assist in the early detection of FGR. Here we aim to dissect the relative contributions of disrupted villous microstructure and dysregulated, via altered flow resistance, placental circulation to the net oxygen delivery in healthy and FGR placentas. We will undertake a systems approach to build an integrative computational framework informed and validated by multiple experimental streams. We will use in-vivo sonography of umbilical and uterine flow followed by a combination of 3D microscopy for materno- and micro-CT for feto-placental structural characterisation ex-vivo. The formidable complexity of the placenta does not permit direct computation at the organ-scale. We will address this challenge with upscaling technique based on our prior work. Image-based meshing and computational fluid dynamics at the micro-scale will help to estimate key physiological parameters that will then be fed into an upscaled simulation of net oxygen transfer, which will be gauged against ex-vivo placental perfusion with oxygen and inert solute antipyrine, and their modulation in the presence of vasoactive agonists. The study will be the first to offer a mechanistic placenta-specific model of circulation and oxygen delivery that bridges the gap between structural and functional placental health, and will form a base for further development of computer-aided diagnostics and identifying the best intervention targets in FGR.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Mouse models of forebrain defects caused by Pax6 haploinsufficiency
Funder: Medical Research Council

Abstract: The overall aim is to study forebrain defects resulting from Pax6+/- heterozygosity in mice. These defects have been identified in our pilot work. Aim 1. Callosal defects: Aim 1a. To identify the age of onset of abnormal callosal thinning in Pax6+/- mice by studying histological sections of the forebrain. Aim 1b. To discover the cellular cause of callosal thinning in Pax6+/- mice. This will involve testing the hypothesis that a lowering of the number of contralaterally projecting cortical neurons contributes to callosal thinning, using retrograde tracers combined with specific molecular markers of callosal neurons and indicators of cell death. We shall use electron microscopy to test whether reduced axonal diameter and/ or reduced myelination contribute to callosal thinning. Aim 1c. To test whether callosal defects are cell autonomous or cell non-autonomous by making chimeric mice comprising a mixture of Pax6+/+ and Pax6+/- cells and applying the approaches used in Aim 1b to them. Aim 1d. To test Pax6+/- mice for behavioural abnormalities that have been linked with callosal abnormalities. Aim 2. Diencephalic defects: Aim 2a. To examine what happens to the perinatal defects of Pax6+/- geniculate Zic4-lineage cells during the postnatal development of Zic4Cre;Pax6fl/+ conditional mutants, using immunohistochemistry to identify Zic4-lineage cells for quantification. Aim 2b. To study the cortex of Zic4Cre;Pax6fl/+ conditional mutants using immunohistochemistry and in vivo calcium imaging to measure the extent of the visual and other cortical areas. Aim 2c. To test the cause of the enlarged populations of Pax6+/- geniculate Zic4-lineage cells in Zic4Cre;Pax6fl/+ conditional mutants using markers of proliferating cells and immunohistochemical methods to measure cell cycle parameters. Aim 2d. To study the nature of defects of geniculate Zic4-lineage cells in constitutive Pax6+/- mutants, using the approaches in Aims 2a-c to identify the defects.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Women's reproductive health and its relation to diabetes and cardiovascular health.
Funder: Medical Research Council

Abstract: Single indicators of reproductive health in women (e.g. earlier age of menarche or menopause, hormonal use, cycle irregularity, pregnancy complications, parity and menopausal symptoms) are associated with greater risk of diabetes or cardiovascular disease (CVD). However, whether collectively they can improve risk stratification or facilitate better understanding of the aetiology of cardiometabolic diseases in women is unknown. I aim to: 1. Examine the separate and joint associations of multiple reproductive indicators with cardiometabolic outcomes. 2. Identify causal effects of reproductive indicators on cardiometabolic diseases. 3. Determine whether reproductive indicators can improve risk prediction for diabetes and CVD. I will address these by using data from established cohorts (Generation Scotland, UK Biobank) or population level datasets, which are complementary in terms of richness of phenotype and sample size. Using multiple analytical approaches and establishing consistency of my findings across these strategies, and replicating the findings across the cohorts will enhance the validity of the findings. Analytical approaches will include multiple regression, structural equation modelling, G-computation and Mendelian randomisation. The findings of the project will enable early identification of women at risk of diabetes and CVD, thus facilitating timely interventions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Early life DNA methylation patterns linking intra-uterine events to adverse cardiometabolic outcomes
Funder: Medical Research Council

Abstract: In the early stages of the fellowship, I will perform the largest to-date EWAS case/control study for GDM (N=600/600 in subjects originating from Tianjin, China. Subsequently, I will replicate/validate my findings in an independent set of GDM samples (N=200/800). Association testing will be carried out by fitting probe-wise linear models, with adjustments for biological and technical confounders (control probe principal components). The relevance of DNA methylation hits can be tested by robust pathway enrichment tests of genes associated with the differentially methylated CpG sites with functional ontologies using custom developed scripts that adjust for probe coverage bias (goseq). Overlaying relevant Roadmap Epigenome data by performing permutation tests utilizing random sampling of matched CpG sites. I expect this work to identify specific DNA methylation sites, with a detectable and predominant association with GDM. In the later stages of the fellowship, I will lead the experimental design for the methylation experiments by performing large-scale epigenome-wide association scans. This will include detecting associations of IUGR/SGA with methylation by using cases and controls recruited at delivery (N=600/600) and finding methylation marker associated with foetal growth in a longitudinal study (N~2,500) with multiple anthropometric measurements throughout pregnancy. The multi-ethnic design of this study will also allow me to establish transethnic effects. Lastly, I will be utilizing genetic variants as instrumental variables in two-step Mendelian Randomization to determine whether epigenetic markers are in causal pathways downstream to intra-uterine events.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Is kynurenine pathway manipulation a novel therapeutic strategy for ameliorating features of pre-eclampsia?
Funder: Medical Research Council

Abstract: In normal pregnancy, the kynurenine (KYN) pathway of tryptophan degradation is highly active in the placenta where it has a physiological role in preventing immune rejection of the fetus. This pathway is less active in pre-eclampsia (PE), a pregnancy-specific disease of maternal hypertension and proteinuria accompanied by inflammatory activation, endothelial dysfunction and increased vascular tone. The principal pathway enzyme (IDO1) causes T-cell suppression and is also a potent free radical scavenger that reduces oxidative stress. KYN administration to hypertensive mice causes systemic blood pressure reduction and my preliminary data demonstrate that KYN can relax human maternal blood vessels. This CRTF will test the hypothesis that KYN pathway manipulation can ameliorate maternal features of PE. Using human placental and maternal biopsies, this study will compare KYN pathway expression, activity and vascular effects in normal pregnancy and PE. These data will facilitate the design of strategies aimed at increasing KYN pathway activity in models of PE using commercially-available KYN pathway metabolites or activators/inhibitors of target enzymes. I will determine if manipulation of the KYN pathway can rescue the dysfunctional phenotypes of arteries and cultured endothelial cells in well-characterised in vitro models of PE. Strategies for manipulating the KYN pathway that successfully rescue the PE phenotype in vitro will be translated to a murine model of PE. Using the STOX1 model of PE, which recapitulates many features observed in the human disease, I will determine if KYN pathway manipulation can ameliorate maternal features of PE; the primary outcome will be maternal hypertension with secondary outcomes including; proteinuria and histological renal changes. It is anticipated that this research will lead to further investigations translating findings into human clinical trials, with the long-term objective of identifying a new treatment for PE.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MRC Centre for Reproductive Health at the University of Edinburgh
Funder: Medical Research Council

Abstract: The MRC-CRH will integrate its proven strengths in reproductive health and biology (training, multilevel basic/clinical research, clinical trials and implementation of new treatments/procedures) around four scientific themes linking basic and clinical researchers to enhance translational output: (1) Reproductive resilience, proliferation, differentiation and repair; (2) Reproductive system cancers: aetiology, pathogenesis and therapy; (3) Optimizing life-long health through pregnancy and perinatal interventions; (4) Immune-endocrine interactions in reproductive health. These will be reinforced by a dedicated interdisciplinary reproductive health/biology PhD training programme (3-4 years) for both clinical and non-clinical scientists. The programme will produce and sustain a generation of new academic/clinical reproductive health/biology experts increasing UK research capacity in this important field. Emphasis will be put on extending our current research infrastructure by implementing state-of-the-art technologies in micro-injection and oocyte handling and increasing our capabilities for in situ quantitative monitoring of biological processes using real-time intravital fluorescent and interference microscopy. This will be associated with recruitment of imaging specialist and database manager to maintain the systems, provide training and facilitate image processing, analysis and bioinformatics. We intend to enhance our general public training/education activities and online presence which will be facilitated by recruitment of a dedicated scientific communications manager.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH