NIHRDataInsights/HRCSData huggingface dataset:
Title: A randomized trial comparing oral misoprostol alone with oral misoprostol followed by oxytocin in women induced for hypertension of pregnancy
Funder: Medical Research Council

Abstract: Every year approximately 30 000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is the optimal method for labour induction in low resource settings. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion (M/Ox). Some studies have shown that you can continue oral misoprostol into active labour (M/M protocol). In the Cochrane review on labour induction, those on the M/M protocol had 42% less CSs than those on the M/Ox protocol (15% vs 26%). This protocol may also be simpler, safer and more acceptable to women. However, these two protocol have never been directly compared. We propose a pragmatic, open-label, randomised trial to compare an M/M labour induction protocol with the standard M/Ox protocol. We will recruit 1000 women with hypertensive disease of pregnancy over 24 months in 3 Indian government hospitals. After informed consent, the treatment will be allocated using sequentially numbered, sealed envelopes. The M/M group will be induced using oral misoprostol tablets (25 mcg) every 2 hours for a maximum of 12 doses, with artificial rupture of membranes (ARM) once in active labour. In the M/Ox arm, the misoprostol will be replaced with an intravenous oxytocin infusion following ARM if a good contraction pattern hasn't established. The primary outcome will be caesarean section. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and the relative cost-effectiveness. The Mother-Generated Index will be used to assess satisfaction alongside individual in-depth interviews with staff and patients. A situational analysis will explore health providers' knowledge, attitudes and practices regarding the use of uterotonics in labour in two districts adjacent to Nagpur.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: SMARThealth Pregnancy: Development of a complex intervention using clinical decision support to detect & refer high-risk pregnant women in rural India
Funder: Medical Research Council

Abstract: Aims: To adopt a life-course approach to prevention of non-communicable diseases (NCDs) in women through early detection & referral of women at high risk of cardiovascular disease during and after pregnancy, through the development of a complex intervention using a mobile clinical decision support system in rural India. Objectives: To develop and assess the feasibility and acceptability of a mobile clinical decision support system (SMARThealth Pregnancy) for use by CHWs for improving the detection and follow-up of high-risk pregnancies in rural Andhra Pradesh, India. Methodology: This will be a mixed methods feasibility study with four stages: 1) Formative research: Exploring the local context using in-depth qualitative interviews & focus groups with key stakeholders to identify barriers & enablers within the health system to providing best practice antenatal and postnatal follow-up for high-risk pregnancies. 2) Development and validation of the SMARThealth Pregnancy Application: Algorithm development using best practice guidelines, and a two-step validation process. 3) Training, content and usability testing with end-users in a series of workshops. 4) Field trial to evaluate the acceptability and feasibility of SMARThealth Pregnancy use by CHWS and Primary care doctors, using a mixed methods approach to generate data to inform a clinical trial. Scientific & Medical Opportunities: a) Improved detection, referral and management of high-risk pregnancies in rural India, to improve perinatal & long-term women's health. b) Education and up-skilling of CHWs and their communities through increased awareness of NCDs. c) Informing the debate for task-shifting to lower-skilled cadres of health workers in areas where medically-trained professionals are scarce. d) To help inform the basis of a larger cluster-randomised controlled trial looking at clinical outcomes, process evaluation and cost-effectiveness.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Women and Children's Health
Funder: Department of Health and Social Care

Abstract: Aims Utilise novel, integrated approaches to design and develop maternal and childhood interventions to improve population health:  Identify individualised markers of disease susceptibility (genomic, biochemical and imaging profiles) to enable a personalised approach to therapeutics in pregnancy, infancy and childhood;  Pump-prime ‘first in man’ trials of novel therapies and repurposed interventions;  Extend into phase II/III trials. Objectives Short term:  Expand bioformatics competence within Cluster 3 (Data Analytics);  With BRC Research Platforms, utilise existing bioresources to refine existing prediction/diagnostic tools in e.g. gestational diabetes, cholestasis and prematurity;  Continue bioresource/data collection from ongoing trials and observational studies in pregnant women, fetuses, infants and children;  Building on final prediction and diagnostic tools, attract grant income for phase I/phase II trials (see details in research strategy section). Medium term:  Using BRC Research Platforms and MR Imaging facilities, complete fetal, maternal, infant and childhood deep phenotyping in pregnancy, infant and childhood studies;  Undertake phase I/II trials to evaluate prediction tools and new/repurposed intervention strategies to improve pregnancy (gestational diabetes, obstetric cholestasis), fetal (congenital heart disease), newborn (birth asphyxia) and childhood disorders (allergy); (see details in research strategy section);  Define interactions between early life exposures (complicated pregnancy, neonatal neurodevelopmental impairment) and maternal and child mental health, and develop intervention strategies;  Attract funding for phase III trials. Long term:  Expand therapeutic trials to individuals most at need within our high-risk South London population and throughout the UK via CRN.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Enabling Research Award: Optimal nutrition for prevention of hypertension in pregnancy using a personalised approach (OptiPREG)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: There is growing evidence of the potential preventative roles of folate and the related B vitamins in hypertensive disorders of pregnancy and related adverse outcomes. Of particular relevance is evidence linking the common 677C→T polymorphism in the folate gene MTHFR with hypertension in pregnancy. Furthermore, vitamin B2 (riboflavin, a cofactor for MTHFR) has been shown to drive the blood pressure phenotype and risk of hypertension associated with this folate polymorphism. In three randomised controlled trials (RCTs) published to date, we showed that blood pressure was highly responsive to intervention with riboflavin in patients who were pre-screened to select those with the MTHFR 677TT genotype. It is therefore highly likely (but remains to be proven) that riboflavin will be beneficial in modulating blood pressure in women the TT genotype during pregnancy. The aim of the NETS study will be to validate the use of riboflavin as a novel, non-drug, personalised approach to preventing hypertension in pregnancy in genetically at-risk women. The hypothesis will be that targeted supplementation with low-dose riboflavin will prevent the much greater blood pressure increase in pregnant women with the TT genotype compared to those without this genetic variant, CC genotype (as observed in our preliminary pregnancy studies). In collaboration with 3 hospitals in the Northern and Western Trusts, and 2 large centres in England, we will screen 1500 pregnant women from which 150 with the relevant TT genotype and 150 age-matched controls with the CC genotype will be investigated (observational phase); the RCT with riboflavin will be conducted from gestational week 16 to the end of pregnancy in the TT genotype group (intervention phase). The pilot study (ERA project) will generate the data required to support a larger application to NIHR for the proposed multi-centred trial. OptiPREG will advance State of The Art in this highly novel research area and address important gaps in the evidence-base.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The mechanistic and therapeutic role of circulating microRNA-142 in pregnancies complicated by maternal obesity with fetal cardiac dysfunction
Funder: Medical Research Council

Abstract: Maternal obesity is associated with cardiac dysfunction in the fetus and offspring. The mechanisms are unknown. In a pilot study, we determined that circulating microRNA-142 (miR-142) is upregulated in fetuses of women with obesity. Previous studies link circulating miR-142 with postnatal obesity and cardiomyopathy and show that miR-142 inhibition prevents systolic dysfunction in genetically manipulated mice. We hypothesise that obesity-induced fetal cardiac dysfunction is caused by elevated fetal circulating miR-142 and prevented by inhibiting miR-142, which is secreted by the placenta. We propose three aims: (1) Define the relationship between fetal circulating miR-142 abundance and late-gestation cardiac dysfunction in fetuses of pregnant women with obesity. Circulating miR-142 will be quantified, using RNA-Seq, in umbilical cord plasma samples collected from fetuses who underwent third-trimester echocardiography. (2) Establish the therapeutic efficacy of inhibiting miR-142, by using systemic antagomir administration to mitigate fetal cardiac dysfunction in a mouse model of maternal obesity. A locked nucleic acid antagomir inhibitor targeting miR-142 will be infused into pregnant mice with diet-induced obesity and fetal cardiac phenotype will be assessed by echocardiography. (3) Demonstrate that human trophoblast cells export miR-142 in a RAB27A (Ras-related protein 27A)-dependent manner and determine the effect of placenta-specific Rab27a knockdown on feto-placental development in mice. Lentiviral, small hairpin RNA vectors will be used to knockdown RAB27A/Rab27a in primary human trophoblast cells and mouse blastocysts. MiR-142 abundance will then be determined in trophoblast conditioned medium and placental and fetal cardiac phenotype will be assessed in mouse conceptuses, after embryo transfer. The results will pave the way for therapies that mitigate fetal cardiac dysfunction by blocking miR-142, potentially using therapeutics targeted to the placenta.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Elucidating the role of GCN2 in the pathogenesis of pulmonary vascular disease
Funder: Medical Research Council

Abstract: Pulmonary veno-occlusive disease (PVOD) is a severe form of pulmonary arterial hypertension (PAH), which carries an appalling prognosis. Most patients die within 2-3 years of diagnosis if not transplanted. Very little is known about PVOD, and patients are treated empirically with medications validated in PAH. Recently, mutations in eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4, also known as general control nonderepressible 2 or GCN2) were described in PVOD patients. GCN2 controls the response to amino acid deficiency by phosphorylating the translation initiation factor eIF2-alpha to trigger the Integrated Stress Response (ISR). GCN2 has not been implicated previously in cardio-pulmonary disease and represents a completely novel therapeutic target. I hypothesise that GCN2 deficiency promotes the development of PVOD via dysregulated BMP and inflammatory signalling. I shall test this hypothesis in three aims: a) Defining the effects of GCN2 deficiency on a cellular level. b) Determining the mechanism linking GCN2 and BMP signalling. c) Determining the consequences of deranged GCN2 signalling in mice and exploring the possibility of similar mechanisms in patients. I plan to use Drosophila and cell models to rapidly screen for points of interaction between GCN2 and BMPR2 pathways. I will then validate these pathways in mice and in patient-derived serum and tissue samples. I have established colonies of gcn2-/- and bmpr2R899X/+ mice and have crossed these mice to produce a doubly-deficient line. After phenotyping these mice from a structural, physiological, metabolic and inflammatory basis I intend to expose them to chronic activation of the ISR, both by itself and in conjunction with known PAH-causing stimuli such as hypoxia and chronic LPS. I will also phenotype and follow-up patients with GCN2 mutations from the UK-PAH cohort. Eventually I plan to modulate GCN2-dependent pathways to treat pulmonary vascular disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RESPIRATORY
Title: Stratified adaptive therapeutic studies in pulmonary arterial hypertension caused by mutations in BMPR2
Funder: Medical Research Council

Abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease with no current cure. Patients are classically diagnosed young, face life-long invasive and costly treatments including continuous intravenous infusions and eventually lung transplantation. In the UK, 5-year mortality is stuck at 57%. Current treatment approaches address the consequences, not the causes of disease. Transforming outcomes in PAH will require approaches that better stratify aetiology of this heterogeneous disease. The most pertinent aetiology of PAH ready for this approach is the genetic form of the disease, mutations in the bone morphogenetic protein type-2 receptor (BMPR2). Mutations in this single pathway cause 29% of all cases of idiopathic and familial PAH and have additionally been strongly implicated in other forms of PAH. There are currently no therapies developed that target the BMPR2 pathway. We propose to address this by undertaking randomised placebo-controlled trials (RCTs) in preclinically validated and repurposed therapies demonstrated in human and animal models to rescue BMPR2 function and reverse disease; hydroxychloroquine and phenylbutyrate. We will address this by means of a novel Bayesian stratified response-adaptive trial design which is aimed at providing a personalised approach to treatment. Utilising a multi-stage design, we will first define the optimum biomarkers of BMPR2 target engagement, and subsequently conduct a multiple-arm phase 2a RCT testing the hypothesis that BMPR2 dysfunction can be reversed and has potential for disease modification.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;RESPIRATORY
Title: Structure and function in desmosomal junctions.
Funder: Wellcome Trust

Abstract: Desmosomes are junctions found between cells in epithelia and cardiac muscle. They are essential for the maintenance of tissue integrity; loss of desmosomal adhesion can have devastating consequences for human health causing life-threatening diseases of the skin and heart. Desmosomes are not just static adhesive rivets; they are dynamic structures that regulate intercellular adhesion and thereby participate in fundamental processes such as cell proliferation, differentiation, morphogenesis and wound healing. Much remains to be determined of the biological role of desmosomes and their mechanisms of action. Here we focus on the molecular mechanisms cytoplasmic desmosomal proteins, their system of interactions remains unclear yet is at the heart of the function of desmosome junctions. The work will lead to a much clearer picture of desmosome biology, a vital and necessary step for understanding the process of cell adhesion in normal development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;SKIN
Title: Meta-analyses of randomized trials studying the effects of treatments on vascular disease risk
Funder: Medical Research Council

Abstract: For many drugs that influence the risk of major vascular events (myocardial infarction, stroke, vascular disease mortality), individual trials provide only limited information about the magnitude of their effects, and their safety, in different types of patients, and the time period over which such effects emerge. This programme is focused on several ongoing collaborations in which investigators have provided detailed individual patient data from their randomized trials studying the effects of a particular class of drug. The aim in each project is to provide publications with the most comprehensive information available worldwide about the clinical benefits and risks of drugs in relevant disease areas, thereby helping to influence treatment guidelines and clinical practice. Current work is focused on 4 main areas: (i) The Cholesterol Treatment Trialists’ (CTT) Collaboration aims to test claims of particular side-effects of statins arising from observational studies (for example, an increased risk of cataract, sleep disturbances, memory loss, or depression), concerns about which are inhibiting prescribing of statins in patients at high risk of cardiovascular disease, with potentially adverse effects on public health. We are currently working with the sponsors of 29 large trials that have previously provided data on vascular events, cancer and mortality in order to obtain supplementary datasets on adverse events, which will then be merged with existing data. We plan to conduct meta-analyses of the effects of statins on a wide range of adverse events once data collection is complete. (ii) In accordance with a published protocol, the Stroke Thrombolysis Trialists’ (STT) Collaboration has already reported analyses of the effects of alteplase on the proportions surviving without disability and the risks of haemorrhagic stroke in 10 trials conducted in acute ischaemic stroke. We now plan supplementary analyses of the existing database, new data collection to permit analyses of CT scan data, and the incorporation of additional data from completed or ongoing randomized trials. (iii) The Antithrombotic Trialists’ (ATT) Collaboration is planning updated individual patient data analyses of the effects of aspirin on vascular outcomes in low-risk populations with and without diabetes, which will incorporate the results of major ongoing trials, including the Unit’s own ASCEND trial among 15,000 people with diabetes but no known history of vascular disease. (iv) The Marfan Trialists’ Collaboration (MTC) is preparing to collect individual patient data from 10 randomized trials examining the effects of angiotensin-receptor blockers and of beta-blockers in order to reduce the rate of expansion of the aortic root, which ultimately can lead to fatal aortic rupture.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;STROKE
Title: Regulation of active/deactive transition of mitochondrial complex I in health and pathology
Funder: Medical Research Council

Abstract: In our previous work we characterised two interconvertible subpopulations of Complex I in vitro and in vivo: catalytically active (A) or de-active (D). Our recent findings indicate that we have uncovered a key mitochondrial mechanism directly involved into these processes. However the details of the dynamics of conversion between the two forms of the enzyme in situ are still not clear. We will study the regulation of the A/D transition of mitochondrial Complex I and characterise the effect of several endogenous effectors on ischaemia/reperfusion (I/R) damage. In the proposed project we will: RQ1. Characterise the interaction of nitrosothiols, peroxynitrite and ROS with both forms of Complex I from brain mitochondria RQ2. Investigate the effect of free fatty acids and their metabolites on the ability of the enzyme to undergo A to D and D to A conversion RQ3. Characterise the A/D transition of Complex I from mitochondria isolated from obese animals RQ4. Identify the role of anaerobic NADH:fumarate reductase activity catalysed by Complexes I and II together in modulating of A/D equilibrium in situ. This work will include a detailed analysis of the A/D transition in brain mitochondria, neuronal and cardiac cell lines and tissues ex vivo. We will assess the effect of several types of fatty acid metabolite. After identification, effectors with the most manifest action will be used to test the effect of metabolites on cell cultures of neurones in an I/R model. The analysis would also consist of monitoring enzymatic activities, A/D ratio and ROS production during fast reoxygenation of hypoxic cells. Together with other parameters such as respiration, degree of oxidative damage and cell viability it would give us a reliable picture of how A/D equilibrium is regulated and what is happening with mitochondrial bioenergetics during I/R. Furthermore this will enable us to correlate the state of Complex I with the physiological state of the tissue before and after I/R damage


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;STROKE
Title: Tracking hydrogel therapeutics using quantitative whole-body imaging
Funder: Medical Research Council

Abstract: Hydrogels such as alginate are cross-linked polymers with high water content, tuneable porosity, elasticity, and degradation rate. This suits their use in tissue engineering and drug delivery, with several formulations in widespread clinical use, and emerging therapies for various diseases in preclinical development and clinical trials. Due to its similarity to soft tissue, alginate hydrogel cannot be detected with conventional imaging (MRI, CT, ultrasound), posing a challenge for assessing its biodistribution once in the body. We propose a labelling and imaging method to address this challenge. Our tool will allow serial assessment of delivery, retention and function of alginate hydrogels in vivo so that the safety and efficacy of therapies can be assesed non-invasively. Alginate hydrogels are formed via Ca2+ ion crosslinking with negative carboxylates across separate alginate polymers. We have shown that certain radioisotopes,commonly used with the medical imaging modalities SPECT and PET, can also be used alongside Ca2+ to form the alginate. This allows hydrogel location to be quantitatively monitored within the body, informing on retention and degradation in the preclincal and clinical setting. We will characterise chemical and mechanical properties of hydrogels crosslinked with our novel method. We will then demonstrate the use of SPECT and PET imaging in tracking transplantated human mesenchymal stem cells in labelled a hydrogel scaffold for cardiac repair, and nose-to-brain drug delivery using a hydrogel vector containing a radiolabelled small molecule drug. The information provided by this labelling/imaging tool will accelerate the development of many emerging alginate-based therapeutics, providing non-invasive, quantitative information on their delivery and retention. Our labelling technique can be achieved by combining materials already in clinical use without the need for further chemical modification, making rapid translation highly feasible.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR;STROKE