NIHRDataInsights/HRCSData huggingface dataset:
Title: 3D Human Axial Development In Vitro: using novel human in vitro somitogenesis models to study birth defects with patient-relevant iPS cell lines
Funder: Medical Research Council

Abstract: Familial or sporadic cases of congenital scoliosis and segmentation defects of the vertebrae (SDV) including spondylocostal dysostosis (SCD) are frequent in human populations. It is thought that the origin of these defects lies in the process of somitogenesis, a core developmental event that lays out the segmented body plan of vertebrate embryos. Our current understanding of this process is based on model organisms such as fish, chicken or mouse. In contrast, our understanding of human somitogenesis is limited to descriptive anatomical studies. This restriction dramatically hampers not only our understanding of normal human development but also of diseases. Recently, using human Pluripotent Stem Cells (PSCs), it has been possible to recapitulate a number of features of somitogenesis, including the oscillatory activity of segmentation clock genes and induction of paraxial mesoderm. Despite these advances, we still lack a human 3D model of axially organised somitogenesis that would allow elucidation of the causes of the segmentation defects observed in many patients. Here we bring together two groups with complementary expertise and interests. The Alev group (Kyoto) has extensive experience of somitogenesis from the perspective of human disease and has recently described in vitro models based on patient-derived human induced PSCs. However, their systems lack the axial organisation that is a key feature of human somitogenesis. On the other hand, Martinez Arias and Moris (Cambridge) have developed a new human 'gastruloid' model whereby aggregates of human PSCs mimic the dynamic and axial organization of early human development. By bringing the two systems (disease-relevant hiPSC lines and human gastruloids) together, the proposed collaboration has the potential to create a powerful new approach to explore the mechanistic cause of several congenital spinal and muscle disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Menstrual health interventions, schooling and mental health symptoms among Ugandan students (MENISCUS): a school-based cluster-randomised trial
Funder: Medical Research Council

Abstract: There is little rigorous research on the effectiveness of menstrual health (MH) interventions to improve education and health outcomes. This evidence-gap precludes effective policy guidelines. Uganda is an ideal location for MH research leading to policy impact, given the Government's proven political will to improve menstrual health. We propose a cluster-randomised trial, with 48 secondary schools randomised 1:1 to receive either i) Government MH guidelines (control arm) or ii) guidelines plus the MENISCUS package (intervention arm). MENISCUS is an innovative multi-component intervention, addressing both the psychosocial (knowledge, attitudes, anxiety, stigma and distress) and physical barriers (pain management, access to appropriate materials to manage menstruation, improvement of WASH facilities) to good MH. The objective is to evaluate the effectiveness and cost-effectiveness of MENISCUS on educational attainment of material taught during the intervention year, and on mental health symptoms. Secondary outcomes include (in girls and boys) menstrual knowledge and attitudes, and (in girls) menstrual practices, self-efficacy in managing menstruation, school and class absenteeism, and prevalence of urogenital infections. To enhance buy-in and sustainability of the intervention, an MH Leadership group will be formed, including community gatekeepers and key influencers in the school community. The intervention will focus on delivering the intervention to students in Standard 2 (~10000 participants).The results will provide the costs of setting up and running the intervention package, describe the distribution of costs across the intervention elements, the unit cost per student reached and the cost of delivering all activities in intervention schools. Primary and selected (policy-relevant) secondary outcome measures will be used for the cost-effectiveness analysis of the intervention relative to the optimised usual care (represented by the control schools).


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MICA: MRC EVERREST: A Pre-clinical Efficacy Study for FGR
Funder: Medical Research Council

Abstract: Fetal growth restriction (FGR) is a potentially life-threatening pregnancy complication affecting about 8% of all pregnancies; it contributes to 50% of stillbirths globally. Pregnancies diagnosed with FGR, about 1 in 500 occur <28 weeks of gestation, classified as severe early onset. FGR can be due to fetal structural abnormalities, aneuploidy, maternal medical disorders and congenital infection. Most commonly however impaired uteroplacental function restricts delivery of nutrients and oxygen to the fetus, termed placental insufficiency. The underlying pathology is inadequate trophoblast invasion of the myometrial spiral arteries in early gestation causing reduced uterine artery (UtA) perfusion when compared to normal pregnancy. Animal studies confirm that fetal growth correlates with UtA blood flow. In FGR the UtAs remains in a state of high resistance causing generalised endothelial cell injury. There is reduced bioavailability of Vascular Endothelial Growth Factor (VEGF), which is essential for vasculogenesis and angiogenesis during development. There is currently no FGR therapy, and no intervention that can improve UtA perfusion and increase fetal growth. Our solution, maternal UtA gene therapy, is a promising therapeutic strategy for FGR using adenoviral vectors (Ad) encoding VEGF. Over a decade our pre-clinical research shows that UtA VEGF gene transfer improves fetal growth and neonatal outcome. Mechanistically it increases UtA blood flow, enhances vascular relaxation short term and reduces vascular contractility long term. Transduced UtAs are remodelled with increased endothelial cell proliferation in the perivascular adventitia. Safety and reproductive toxicology assessments show no vector spread to the fetus and no adverse risk to the mother or fetus. Using the proposed clinical trial Drug Product, an Ad. encoding the VEGF-D gene manufactured to GMP, we will study the safety and efficacy of this intervention in a well validated guinea pig model of FGR.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Resilience in the face of crises: Evaluating the implementation of a digital healthcare tool for newborns in Zimbabwe.
Funder: Medical Research Council

Abstract: Crises, such as the COVID-19 pandemic, will lead to excess mortality and morbidity in newborns in low-income settings, damaging recent improvements in care and survival. Few robust data exist to explore these impacts in Zimbabwe. Interventions to improve newborn care in these settings, where challenges are frequent and varied, must be resilient to be useful and require contextual process evaluation specifically during times of crises. I propose to undertake a mixed methods evaluation of an existing digital newborn quality of care intervention (the NeoTree) to support healthcare workers (HCWs) in clinical management of newborns during times of extrinsic challenge. The NeoTree has been embedded in daily clinical practice in Zimbabwe's largest neonatal unit. It provides data capture, education, clinical support and linkage to local data dashboards. Implementation is ongoing in a second Zimbabwean hospital. During the period of the NeoTree implementation Zimbabwe has suffered from several crises with substantial impact on health service delivery including economic upheaval, significant HCW industrial action and the COVID-19 pandemic. I will use quantitative neonatal data (from the NeoTree) to track and compare trends in case fatality rates, admission and discharge diagnosis during times of extrinsic challenges. An assessment of how the quality of data changes over time both with missingness and accuracy will also be reviewed. These data will be combined with both structured observation and qualitative interviews with HCWs to explore experience of health service delivery and use of the tool, specifically during times of crises. The triangulation of quantitative, data quality, qualitative and ethnographic data will provide actionable insights into implementation for local health systems and national health policy leads; "crisis implementation science".


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Born in Scotland in the 2020s - Pilot study
Funder: Medical Research Council

Abstract: We aim to conduct a pilot study to demonstrate the feasibility of establishing the proposed "Born in Scotland in the 2020s" population cohort of 100,000 pregnant women and their children in Scotland, including extensive data linkage from mothers, fathers and children linked to a bioresource. We plan an efficient study design by capitalising on routine data and biological sample collection. The cohort will be a sustainable resource to address fundamental and contemporaneous questions in our understanding of the drivers of long-term maternal and child health, including pregnancy and its complications. ROUTINE CLINICAL AND HEALTH SERVICE will be used to record details of: a) socio-demographic, medical and obstetric history b) details of the current pregnancy including laboratory results, fetal ultrasound scans, pregnancy complications c) birth outcomes d) healthcare usage BIOSAMPLES will be stored and banked for future use, utilising the well-established Scottish National Health Services Research Scotland (NRS) Biorepositories which enable storage of surplus samples which would otherwise be discarded after clinical use. LONG-TERM FOLLOW UP will be through prospective and retrospective record linkage of mothers, fathers and children using the Scottish Community Health Index (CHI) unique personal identifier to relevant health and healthcare databases, for example primary and secondary care and educational attainment. We bring together a multidisciplinary team with expertise in epidemiology, birth cohorts, life-course health, obstetric medicine, neonatology, biobanking, data science, clinical trials, public health and patient, public involvement. Together our research addresses the mechanisms, causes, consequences, optimal management of pregnancy, its complications and the long term health for mothers and their children giving us the skills and knowledge to develop a flexible, dynamic and sustainable resource, "Born in Scotland in the 2020s".


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: xC-Safe: Optimising maternal and perinatal outcomes through safe and appropriate caesarean sections in low- and middle-income countries (LMIC)
Funder: Medical Research Council

Abstract: THE PROBLEM Maternal and perinatal mortality following caesarean section (CS) is disproportionately high in low- and middle-income countries (LMICs) than in high-income countries (HIC). Unnecessary CSs and unsafe practices arising from limited intra-operative expertise and gaps in knowledge and skills to achieve safe vaginal births, particularly assisted vaginal delivery (AVD), contribute to adverse maternal and perinatal outcomes. EVIDENCE GAPS Studies have reported the effects of individual interventions to prevent specific intra-operative CS complications - but none have evaluated the interventions as a comprehensive package to avoid both maternal and perinatal complications following CS in LMICs. While there is a robust system to report 'in whom' CSs are performed, there is no equivalent system to report 'why' they are performed, with poor and varied reporting of CS indications. While the use of vacuum and forceps can avoid difficult and complex CSs, they are rarely used in LMICs - effective interventions are needed to increase AVD use along with physiological births. Unless all the above challenges are addressed in LMICs, we cannot achieve reductions in maternal and perinatal deaths following CS. AIM To achieve safe and appropriate CS, and where possible avoid CS, through comprehensive, effective, acceptable, implementable, scalable and sustainable intervention(s) in LMIC settings. OUR PLAN A Programme (C-Safe) with interlinked work packages co-developed with women and local teams on CS appropriateness (C-Why), CS safety (C-Op), and safe vaginal births including AVD (C-Non), underpinned by robust implementation strategy (training Programme, C-Safe Champions, team-based work, audit and feedback), to improve pregnancy outcomes. We will undertake systematic reviews, Delphi surveys, stepped-wedge cluster randomised trial (8 sites in India and Tanzania; 30,000 births) with mixed-method evaluation and meaningful stakeholder engagement.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Transition Support Award CSF Chris Gale
Funder: Medical Research Council

Abstract: Aims of Transitional Support Award 1. Implement the BUDS app to allow parents near real-time access to their baby's data and quantify impact on routinely recorded EHR data quality I. Continue app development - Methods: Co-design, linkage with EHR data, implementation in London neonatal units II. Evaluate impact on EHR data quality - Methods: Pre/post evaluation of parent satisfaction and EHR data completeness/accuracy III. Evaluate feasibility acceptability of BUDS app - Methods: Structured questionnaires and qualitative interviews 2. Extract and analyse data to underpin a range of neonatal EHR-embedded trials I. Calculate underpinning data e.g. intra-cluster coefficients/missing data proportions for core trial data items - Methods: Analyses of EHR data in the National Neonatal Research Database (NNRD) II. Model impact of degrees of missing/inaccurate data on individually/cluster randomised neonatal trials - Methods: Simulate multiple individually/cluster randomised neonatal trials using NNRD data; trial effect sizes/outcomes based on published trials - Outcomes: rates of missing/inaccurate data required to alter modelled trial findings 3. Validate the extraction of core neonatal outcomes in the NNRD I. Identify core neonatal outcomes (prioritised earlier in the fellowship) in the NNRD; formalise extraction; validate against published and existing trial data - Methods: Analyses NNRD data; systematic review of reported rates in similar high resource settings and large neonatal trials 4. Realise learning from research placement in Boston Veteran's Affairs and Children's Hospitals I. Disseminate qualitative data from research placement II. Consensus meetings to identify acceptable integration of "Learning Healthcare System" approach into NHS neonatal care


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Challenging the dogma of homogeneity in gestational diabetes
Funder: Medical Research Council

Abstract: The prevalence of GDM has increased globally, but mechanistic understanding of this common pregnancy complication has remained unchanged for decades. Reliance on the inaccurate oral glucose tolerance test (OGTT), and a lack of rigorous scientific investigation has led to empirical treatment strategies, often with sub-optimal outcomes. This proposal was prompted by reports that GDM may have at least two different aetiologies, paving the way for accurate mechanistic definition, targeted prevention/treatment strategies and better pregnancy outcome. This will be the first rigorous biological investigation of two proposed and predominant subtypes: 1) GDM resulting primarily from insulin resistance and 2) GDM resulting primarily from inadequacy of pancreatic beta-cell function. 750 women will be recruited; 400 of White European descent and 350 of South Asian descent. All will have two OGTTs (12-16 weeks, 24-28 weeks). Known biomarkers of insulin sensitivity and beta-cell function will be profiled in fasting and post-challenge blood samples to inform subtype allocation. Since the origins of beta cell dysfunction in GDM remain enigmatic, implicated pregnancy/placental hormones (eg kisspeptin) will be measured. Disease subtypes will be elucidated through integration of routine maternal and clinical data with targeted hormonal profiles captured during the two OGTTs, and the gestational glucose profile obtained using continuous glucose monitoring. Differences and similarities will be explored between women of White European and South Asian descent. To facilitate translation to clinical practice, including improved diagnosis and targeted treatment/prevention we shall work towards tests to discriminate between 1) GDM subtypes in the second trimester, 2) subtypes in early pregnancy before development of GDM, and 3) propose targeted treatment regimes. This study will lay the foundation for personalised, physiologically targeted therapy for GDM, leading to improved outcomes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Multimorbidity and Pregnancy: Determinants, Clusters, Consequences and Trajectories (MuM-PreDiCT)
Funder: Medical Research Council

Abstract: Our vision is to characterise and understand the determinants and consequences of pre-existing multimorbidity (MM) in pregnant women; and to predict and prevent MM and its adverse consequences in women and their offspring. We will use electronic health records and birth cohort data from across the four UK nations and European registries of congenital anomaly. We have already harmonised most of the definitions of variables and linkage algorithms to ensure comparable methods across the datasets. We have described the epidemiology of pre-existing MM in pregnant women. We will characterise MM clusters and trajectories. We will investigate if MM clusters and trajectories differ by parity, age, ethnicity, social-deprivation and lifestyle factors. Identifying the determinants of MM clusters and trajectories will enable development of preventive interventions and strategies to reduce inequalities. To improve maternity services, we will interview pregnant women with MM, their carers and health professionals to understand current service provision and their limitations. We will then hold workshops to co-design care pathways for pregnant women with MM. We will then study how maternal MM affects the outcomes of pregnancy, mothers and offspring. Initially we will use established consensus methods to develop a core outcome set for research of pregnant women with MM. Then we will determine the rates of these outcomes based on maternal MM status and then based on prescription combinations received. Findings will help women make informed decisions about their pregnancy, inform maternity care planning and improve safe prescribing during pregnancy. Our previous work has demonstrated that pregnancy complications are associated with development of future morbidities after pregnancy. Using this information and other covariates we will develop and validate prediction models to inform prevention and early detection of multiple long-term conditions postpartum.


Research activity codes: 6.1 PHARMACEUTICALS;2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MICA: Investigating kisspeptin receptor signalling to improve the treatment of reproductive disease
Funder: Medical Research Council

Abstract: Kisspeptin is a key driver of the reproductive axis by regulating hypothalamic GnRH release. We conducted the first-in-human administration studies of kisspeptin in 2004, and the first clinical trials of kisspeptin as part of assisted reproduction treatment in 2014. However, excessive high dose kisspeptin administration can result in tachyphylaxis, which would impede the use of chronic stimulation protocols to treat conditions of deficient kisspeptin, as part of the pathophysiology of several common hypogonadal disorders such as hypothalamic amenorrhoea (HA). Understanding signalling at the G-protein coupled kisspeptin receptor (KISS1R) to elucidate the mechanism of tachyphylaxis in order to facilitate chronic stimulation protocols, thus represents a major unmet clinical need. We have recently reported that a potent KISS1R agonist, MVT-602, has a markedly prolonged action in healthy and anovulatory women, which is enhanced by oestradiol. These unique properties of MVT-602 are not explained by pharmacokinetics or differences in canonical KISS1R-Gq/11 signalling. Therefore, this project aims to decipher the signal mechanisms induced by KISS1R agonists including novel oral analogues currently in development by our Industry partner, Crinetics. We will also employ unique KISS1R nanobodies that exhibit positive allosteric modulation and investigate distinct spatial-temporal signalling signatures for sustained activation. Critically, how these signal activity profiles, including the actions of oestradiol, modulate GnRH secretion will be assessed in both a human hypothalamic neuronal system derived from pluripotent stem cells and pre-clinical in vivo studies, including therapeutic assessment within a hypogonadal animal model of HA. Overall, we will be able to identify therapeutically desired activity signatures of novel KISS1R modulators to expedite translation of chronic kisspeptin-based treatments in reproductive disorders.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Metabolic determinants of early placental development: Acetyl-coA metabolism and histone acetylation during trophoblast differentiation
Funder: Medical Research Council

Abstract: Placenta-related pregnancy complications, including preeclampsia, are associated with abnormal placental development in the first-trimester of pregnancy, but there is little mechanistic understanding of how this occurs. The placenta's functional capacity is dependent on the coordination of placental trophoblast proliferation and differentiation into specialised lineages, occurring largely in the first-trimester. Trophoblast differentiation is dysregulated in preeclampsia, a disorder commonly associated with metabolic dysfunction. Acetyl-coA lies at the intersection of multiple pathways of energy metabolism and it is also the acetyl-donor for histone acetylation. Moreover, histone acetylation is highly sensitive to physiological changes in cellular acetyl-coA concentrations. This proposal will test the hypothesis that acetyl-coA metabolism regulates histone acetylation and trophoblast differentiation, and that these processes are dysregulated in preeclampsia. The overarching goal is to define the mechanistic links between acetyl-coA metabolism and histone acetylation in regulating trophoblast fate and placental development. The findings from this research address the broader question of how metabolism influences placental development in normal pregnancies, and how this process is dysregulated in preeclampsia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH