NIHRDataInsights/HRCSData huggingface dataset:
Title: Civil society participation and sexual health policy in Brazil: A critical ethnography of policy-making processes in Pernambuco.
Funder: Wellcome Trust

Abstract: I will use ethnographic research methods and analytical methods from anthropology, policy analysis, organisational behaviour and critical theory to document and examine civil society participation in policy-making in the North Eastern state of Pernambuco, Brazil. I will take a comparative approach, looking at how policy is made (and un-made) within the Conselhos de Saude (councils for structured lay participation in policy-making in Brazils public health system, or SUS), as well as the alternati ve strategies that CSOs use to influence the policy agenda outside of the SUS structure. It will assess the effectiveness of these processes, while also exploring participants perceptions of citizenship and participatory democratic processes in the current socio-political environment. I will conduct this research over the build up to, and following, the National Health Conference in 2015, a hugely significant event in Brazilian health policy-making, held every four years. By gathering compreh ensive qualitative data on this topic my work will contribute to the discussion around how citizens and CSOs communicate their concerns about health and social issues to policy-makers, and the impacts this has on local, national and global health policy.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: How does poor maternal diet affect foetal neural stem cell activity leading to adult behavioural disease
Funder: Wessex Medical Research

Abstract: How does poor maternal diet affect foetal neural stem cell activity leading to adult behavioural disease


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;MENTAL HEALTH
Title: Community interventions for primary and secondary prevention of violence against women and girls: a cluster randomized controlled trial in urban India
Funder: Wellcome Trust

Abstract: In a cluster randomised controlled trial in Mumbai slums, we will test the effects of community mobilisation through groups and individual volunteers on the prevalence of violence against women and girls. One in three women in India have survived physical or sexual violence, making it a major public health burden. Reviews recommend community mobilization to address violence, but trial evidence is limited. Already implemented in other areas, our intervention has been developed over 16 years of programmatic experience and two years of formative research. Guided by a theory of change, we will compare 24 areas receiving support services, community group, and volunteer activities with 24 areas receiving support services only. These community mobilisation activities will be evaluated through a follow-up survey after three years. Primary outcomes will be prevalence of intimate partner violence, and prevalence of domestic violence, in the preceding year. Secondary outcomes will describe disclosure of violence to support services, community attitudes to violence, bystander intervention, gender equality, and prevalence of non-partner sexual violence. Backed by public engagement, advocacy, and open publication, our vision is of a replicable community-led intervention to address the public health burden of violence against women and girls.

Lay abstract: In slums in Mumbai, we will test the effects of community mobilization through groups and volunteers to prevent violence against women and girls. In India, 29% of women report physical violence in the last year, 7% sexual violence, and 30% multiple forms of violence, causing physical, mental, societal, and economic harms. Reviews suggest community mobilisation as a promising approach, but there have been few large enough trials of prevention programmes. Our community intervention has been developed over 16 years of programmatic experience and two years of preparatory research, and our understanding of its effects is encapsulated in a theory of change. We will compare 24 areas receiving support services, community group, and volunteer activities with 24 areas receiving support services only, primarily in terms of effects on occurrence of intimate partner violence and domestic violence in the last year. We will also examine disclosure of violence to support services, and community attitudes to violence, bystander intervention, gender equality, and occurrence of non-partner sexual violence. Backed by public engagement, advocacy, and open publication, our vision is of a replicable community-led intervention to address the public health burden of violence against women and girls.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;MENTAL HEALTH
Title: Over two years for neuropsychological testing in children aged 8-10 years in the Controlled Antenatal Thyroid Screening (CATS) Study II
Funder: Action Medical Research

Abstract: Background In hypothyroidism the thyroid gland produces insufficient hormones, slowing metabolism and producing symptoms such as tiredness and weight gain. The diagnosis is confirmed by blood tests and treated by thyroid hormone replacement. If patients become pregnant, treatment is adjusted to ensure optimum hormone levels in mother and baby. However, in suboptimal thyroid function (SOT), thyroid blood tests are mildly abnormal but the patient experiences no symptoms If this occurs during pregnancy, the baby may experience adverse effects with an impact on future development and memory skills. Currently, routine thyroid function screening is not performed during pregnancy, but evidence suggests that children born to mothers with SOT have a lower IQ than children of mothers with normal thyroid function during pregnancy. Also, UK women of child-bearing age have low iodine levels (iodine is a component of thyroid hormone) and research suggests that children in the UK are performing less well educationally than their peers in similar countries. The research project The aim of the project is to establish whether routine testing of thyroid function in pregnant women and correction of thyroid hormone deficiency have beneficial effects on future child development. The researchers will study a group of women from the Controlled Antenatal Thyroid Screening (CATS) study I, whose thyroid function was tested when they were pregnant. About 700 (of 16,500) women were identified with SOT and half of them were treated with thyroid hormone replacement. The IQ and development of their children were tested at three years of age. The team intend to use a wider range of tests in the children (now aged eight to ten years) to assess their IQ and other behaviour issues such as attention deficit hyperactivity disorder (ADHD). The results of the study will improve understanding of the effects of thyroid function during pregnancy on future child development and indicate whether or not there is a need for routine thyroid testing in pregnancy in the UK and worldwide.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Can metformin be used to treat pregnant diabetic mothers to reduce future risk to obesity and metabolic syndrome in their offspring?
Funder: Diabetes UK

Abstract: Pregnancies that are complicated by maternal obesity and diabetes are associated with poor fetal outcome, including postnatal metabolic disturbances and increased risk of obesity, diabetes and the metabolic syndrome in adulthood. We have recently shown in a mouse model that exposure of the developing fetus to increased maternal fat intake during early development can lead to future development of obesity, glucose intolerance and the phenotypic characteristic of metabolic syndrome in humans. We will test using this mouse model the following questions: (I) does treatment of pregnant obese mothers with metformin improve their glycaemic control? (II) do the offspring from mothers treated with metformin have decreased risk to obesity and metabolic syndrome in adulthood, when exposed to an obesogenic diet? Although the use of metformin during pregnancy might seem to be a radical treatment, folic acid treatment in the pre-conception period and during pregnancy has become an accepted treatment to decrease risk of neural tube defects in the offspring. Therefore, since metformin is safe during pregnancy, evidence is now needed to test the effect of metformin consumption during pregnancy on the health of the next generation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Maternal over-nutrition and offspring health: role of translational programming of insulin action
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The developmental origins of health and disease hypothesis links the intrauterine environment to long term health of offspring. There is evidence from human and animal studies that metabolic health of offspring is adversely affected by maternal obesity and diabetes during pregnancy. Using a mouse model of maternal diet-induced obesity we found that exposure to an obesogenic environment in utero led to the development of insulin resistance in young adult life. This was associated with altered expression of insulin signalling proteins in muscle, liver and adipose tissue. Notably, there was a marked decrease in IRS-1 protein in adipose tissue without any change in IRS-1 mRNA. Using primary cultured pre-adipocytes we showed that this reflects decreased synthesis of IRS-1 protein and that it is paralleled by an increased level of miRNA-126 that targets IRS-1 mRNA. We therefore hypothesise that maternal diet-induced obesity programmes adipose tissue insulin action in offspring through cell autonomous, post-transcriptional mechanisms that influence levels of IRS-1 and other proteins. The overall aim of this project is to elucidate the molecular mechanisms underlying this programming. We will take a global approach to identify miRNAs in adipose tissue that are programmed by maternal over-nutrition and identify targets of these miRNAs using a combination of bioinformatics, RNA-Seq and Ago2 immunoprecipitation. We will then define the role of selected miRNAs, including miR-126, in programming adipose tissue insulin sensitivity and function, by using miR mimics and antagonists. Finally, we will establish whether normalisation of maternal insulin in obese dams can prevent programming of adipocytes. These studies will advance understanding of developmental programming arising from maternal over-nutrition and how such programming might be ameliorated. Most importantly, our experiments in animal models will inform debate on how to manage the corresponding human condition.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: The use of the hormone kisspeptin to improve safety and efficacy of IVF treatment
Funder: Department of Health (England)

Abstract: In vitro fertilisation (IVF) treatment is widely and successfully used to treat infertility, but can result in the life threatening condition called ovarian hyperstimulation syndrome (OHSS). Mild forms of OHSS occur in approximately 1 in 3 of all IVF cycles, whilst approximately 1 in 10 IVF cycles result in moderate or severe OHSS. The cause is the use of a drug in IVF treatment which too powerfully stimulates the release of reproductive hormones. Kisspeptin is a hormone found naturally in men and women which stimulates reproductive hormone secretion similarly to the stimulation which occurs in women with a normal menstrual cycle. I will use kisspeptin in patients requiring IVF treatment to determine if it improves pregnancy rates and reduces the risk of OHSS.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: New technologies to improve glucose control and infant outcomes in pregnant women with type 1 diabetes
Funder: Department of Health (England)

Abstract: Our team has pioneered technological advances in diabetes, with computerised closed-loop algorithms (mathematical instructions) linking insulin delivery with continuous glucose monitoring. This means that closed-loop responds to changes in glucose levels, more like a functioning pancreas. This fellowship will allow me to continue the development of closed-loop systems, aiming to improve blood glucose control during pregnancy. My goal is to progress closed-loop from an experimental laboratory technology into a real-life treatment option for pregnant women. Specifically I will: Refine and evaluate home closed-loop in pregnancy; Determine the role of existing CGM technology in the clinical management of diabetes pregnancy.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.3 MEDICAL DEVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Improving pregnancy outcome in obese women – the UK Pregnancies: Better Eating and Activity Trial (UPBEAT)
Funder: Chief Scientist Office (Scotland)

Abstract: Obesity affects ~20% of women of reproductive age, and is a major determinant of adverse maternal and perinatal outcomes, including gestational diabetes, pre-eclampsia and prematurity. Furthermore, offspring born to obese mothers have increased adiposity and type 2 diabetes in later life. Maternal insulin resistance and glycaemic load strongly contribute to these associations. Notably alteration of diet and activity levels can lessen progression to diabetes in non-pregnant individuals and pilot studies support this likelihood in pregnancy. This proposal will examine for the first time in a multicentre randomised controlled trial whether a complex lifestyle intervention will reduce maternal insulin resistance and the incidence of large for gestational age infants. The current proposal is a critical component of a NIHR sponsored study and inclusion will ensure applicability to the Scottish population and local health service provision.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Glibenclamide and metfoRmin versus stAndard Care in gEstational diabeteS (GRACES) – a feasibility open label randomised trial
Funder: Chief Scientist Office (Scotland)

Abstract: The aim of this open label feasibility study is to determine recruitment rates, to a randomised controlled trial of glibenclamide compared with insulin (in addition to maximum tolerated metformin) for the treatment of gestational diabetes mellitus (GDM). Additionally, we will compare glycaemic control, acceptability and clinical outcomes in the two groups. Gestational diabetes mellitus is increasingly prevalent in pregnancy. Glucose lowering strategies are recommended to improve pregnancy outcome. Both metformin and glibenclamide are useful in maintaining normoglycaemia in women with GDM, with data from two large randomized trials suggesting each drug is as safe as insulin. Metformin is used most commonly as first line drug treatment for GDM in Scotland, with supplemental insulin for those who remain hyperglycaemic despite maximum tolerated metformin. We hypothesise that addition of glibenclamide to metformin (combination therapy) will reduce the number of pregnant women with GDM who require insulin, without compromising glycaemic control or adversely affecting other clinical outcomes. This feasibility trial will inform the design of a future substantive multicentre trial to test this hypothesis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: The central role for androgens in development of polycystic ovary syndrome
Funder: Medical Research Council

Abstract: Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women and is estimated to affect more than 5% of women of reproductive age. It is the commonest cause of anovulatory infertility, menstrual disturbance and of hirsutism. The most consistent biochemical abnormality is hypersecretion of androgens, predominantly of ovarian origin. In addition to its implications for reproductive function, PCOS is associated with metabolic abnormalities (in particular insulin resistance) and women with PCOS are at increased risk of developing type 2 diabetes and cardiovascular disease in later life. Despite a plethora of studies in the last decade, the aetiology of PCOS remains uncertain. We have proposed that PCOS has its origins in early life (and quite possibly in prenatal life) and that the polycystic ovary is genetically predisposed to hypersecrete androgens, certainly at puberty but also in the early postnatal period. We hypothesise that increased exposure to androgens during development leads to the abnormalities of endocrine and metabolic function that are characteristic of PCOS. The purpose of the proposed programme of work is to use both animal models and studies of women with PCOS (both clinical and laboratory-based) (a) to study the effects of androgens on the reproductive system and their mechanism of action (b) to determine the source of androgen production in the normal and polycystic ovary and (c) to investigate the metabolic effects of androgen in animal models of PCOS and in human ovary and adipose tissue. Metabolic studies in prenatally androgenised mice will include studying the role of anti-androgens, given at puberty in reducing the impact of metabolic sequelae in adult life. The studies will enhance the further understanding of the pathogenesis of PCOS, will provide insight into its relationship with metabolic abnormalities and diabetes, and will offer the prospect of finding a a??windowa?? of therapeutic intervention to attenuate or prevent the adverse reproductive and metabolic effects of the syndrome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: P450 oxidoreductase: Novel regulator of steroid synthesis and metabolism in health and disease
Funder: Medical Research Council

Abstract: The proposed research will investigate the role of two novel metabolic pathways in human health and disease. We recently discovered that mutations in P450 oxidoreductase (POR) and PAPS synthase 2 (PAPSS2) disrupt dehydroepiandrosterone (DHEA) synthesis and metabolism, respectively, resulting in androgen excess, a major feature of the polycystic ovary syndrome (PCOS). POR has a pivotal role as electron donor to all microsomal cytochrome P450 (CYP) enzymes including key enzymes of steroidogenesis and hepatic drug metabolism. In this proposal we will define the differential impact of variant POR on steroidogenesis and hepatic drug detoxification. POR deficiency is unique in that affected children of both sexes can present with disordered sex development. Undervirilisation in boys is readily explained by impaired DHEA synthesis, which however is incongruous with virilisation in affected girls. We have proposed that this apparent contradiction is explained by an alternative androgen pathway in early human life, with recent evidence supporting this hypothesis. We will examine the role of the alternative androgen pathway in human sex development, analysing its expression and activity during pregnancy and the early neonatal period in normal and disordered sex development. DHEA is the major precursor of androgen synthesis via the classic pathway unless inactivated to DHEAS by DHEA sulfotransferase, which requires the universal sulfate donor PAPS for catalytic activity. We have identified inactivating mutations in PAPSS2 encoding human PAPS synthase 2 in a girl presenting with premature pubarche followed by development of PCOS. We have established PAPSS2 deficiency as a novel monogenic cause of androgen excess, revealing DHEA sulfation as a gatekeeper to human androgen synthesis. We will identify and characterise further cases of PAPSS2 deficiency in premature pubarche and PCOS. Furthermore, we will examine whether common variation in PAPSS2 contributes to PCOS susceptibility by performing dense tagSNP genotyping in large PCOS and control cohorts. Finally, we will analyse the differential effects of the two PAPS synthase isoforms to clarify why ubiquitously expressed PAPSS1 cannot compensate for the loss of PAPSS2 activity. Taken together, this programme of research will investigate the physiological and clinical significance of two crucial metabolic pathways, the provision of electrons by POR to microsomal CYP enzymes and the provision of PAPS to sulfotransferases. The clinical significance of an improved understanding of these systems cannot be underestimated and includes a major modulatory role of POR and PAPS in hepatic phase 1 and phase 2 detoxification, current key targets of pharmacogenomics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Investigating the developmental programming of obesogenic adipogenesis
Funder: Medical Research Council

Abstract: Recent studies have shown that adipogenesis may be enhanced in offspring of obese mothers yet these studies only reported in vitro findings. Thus, key questions remained unanswered, such as whether maternal obesity resulted in offspring adipose tissue hyperplasia in-vivo and whether it affected developmental or obesogenic adipogenesis. This is particularly important as these two adipogenic processes have recently been shown to require distinct subpopulations of adipocyte progenitors and utilize different signalling pathways. Our unpublished preliminary findings have revealed that maternal obesity increases obesogenic adipogenesis in offspring but plays no role in developmental adipogenesis. Furthermore, this increased hyperplastic response in offspring adipose tissue following maternal obesity is attenuated by maternal metformin treatment during pregnancy and lactation. We discovered that mRNA expression of the adipocyte progenitor marker CD34 is upregulated in the adipose tissue of offspring from obese mothers, suggesting an increased presence of adipocyte progenitors in offspring adipose tissue in response to maternal obesity. The purpose of this proposal is to uncover the precise molecular mechanisms behind the developmental programming of obesogenic adipogenesis and establish how metformin impacts upon it. We hypothesize that the fat mass and obesity-associated (FTO) gene is a key mediator in this process given that we have recently shown it to regulate adipocyte progenitor proliferation (Merkestein et al. Nature Communications, 2015). Furthermore, in our prelimary studies, FTO mRNA expression was elevated in fibroblastic cells isolated from embryos of obese mothers. We will test this hypothesis using a range of molecular biology techniques and mouse models of maternal obesity. This proposal not only serves to establish the precise molecular mechanisms underlying a new phenomenon but also aims to generate clinically relevant outputs for obesity treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE