NIHRDataInsights/HRCSData huggingface dataset:
Title: 2017 Doctoral Fellowship: The use of early pregnancy HbA1c in predicting excessive foetal growth in women at risk of glucose intolerance
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: The association of hyperglycaemia in pregnancy (gestational diabetes mellitus; GDM) with adverse maternal and foetal outcomes is clearly recognised. Traditionally the diagnosis is made at 28 weeks gestation at which stage children of affected women already have a two-fold rate of excessive weight gain (abdominal circumference > 90th percentile). This is attributed to foetal exposure to undiagnosed high blood glucose earlier in pregnancy. Indeed almost 25% of women with GDM develop the condition before 20 weeks gestation. Interventional studies in women diagnosed in the late second trimester have shown benefits in reducing foetal macrosomia. It is unknown whether screening in the first trimester would predict foetal macrosomia and allow more timely and effective intervention. To examine this question, we propose a prospective cohort study of 3,500 women at increased risk of GDM to determine if an elevated HbA1c (41-48mmool/l) in early pregnancy (<14 weeks) can identify babies at risk of excessive weight gain in later pregnancy, as determined by ultrasound measurement of abdominal circumference at 28 weeks gestation. The study will be largely integrated into routine clinical practice enabling a large number of women to participate. Study participants will all undergo formal screening (75g oral glucose tolerance test) for GDM at 28 weeks gestation. Secondary outcomes, namely the ability of early pregnancy HbA1c to predict later maternal GDM, and foetal and maternal complications of pregnancy will also be evaluated. The results of this study, if positive, are likely to impact upon patient care almost immediately following study completion. In addition, given the stability of the Northern Ireland population, the relatively unique data set will facilitate future work on predictive markers for cardiovascular disease, and prospective studies on the cardiovascular consequences of GDM on both mother and baby.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and intergenerational programming of diabesity
Funder: Medical Research Council

Abstract: There is an escalating global epidemic of type 2 diabetes, with developing countries experiencing the most rapid increase. Current strategies for preventing the disease rely mainly on altering adult lifestyles. Recent research suggests that factors acting during early development, including fetal growth restriction, and exposure to gestational diabetes (GDM) in the mother, increase diabetes and obesity risk in later life. Our research in India has shown that maternal vitamin B12 deficiency and hyper-homocysteinaemia, in combination with normal/high folate status, is associated with an increased risk of GDM in the mother, growth restriction in her fetus, and adiposity and insulin resistance in her children. These effects could act through epigenetic mechanisms and occur in paternal as well as maternal B12 deficiency. Improving the B12 status of women and men preparing for pregnancy could be a scalable and affordable intervention to prevent diabetes in future generations. Our proposed programme includes an RCT of B12 supplementation in rural Indian adolescents who will marry and conceive within the next 4 years, aiming to improve newborn B12 status and body composition and reduce diabetes risk in their children. We will also carry out 2 observational studies in the UK, to replicate the earlier Indian findings and study their wider relevance. We will measure B12, folate and homocysteine in stored maternal samples from a UK birth cohort which has measured body composition in the children, and carry out a case-control study of mothers with and without GDM in a UK population at high risk and with a high S Asian population (W Midlands) to determine whether UK women who develop GDM have low B12 status, or B12/folate imbalance, in early pregnancy. Samples taken in all studies will be used for genetic studies, and future epigenetic research, relevant to our objectives. We expect this unique research to have a major impact on future strategies to prevent type 2 diabetes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: The human fetal liver: development and response to maternal drug use.
Funder: Medical Research Council

Abstract: The human fetus is exposed to many potentially damaging chemicals, e.g. through maternal smoking and alcohol consumption. With large studies now linking such exposures with priority diseases (metabolic syndrome: cardiovascular disease, obesity and diabetes), accurate understanding of the underpinning pathophysiology is required. The human fetal liver has extensive metabolic and endocrine roles essential for normal growth and has been shown to be dysregulated by maternal drug use. This study will determine, for the first time, the exposure of the human fetal liver to maternal drug use and the effects that this has on liver function at the transcript, protein and cellular level. Understanding how maternal recreational drug use disturbs normal developmental pathways would represent a significant advance in our comprehension of mechanisms affecting fetal programming of adult health. Initially, 120 second trimester human fetal livers (a unique resource already collected) and 40 liver+placenta pairs (to be collected) will undergo analysis through collaboration with the National Institute on Drug Abuse to measure levels of over 20 drug metabolites (e.g. of cigarette, alcohol, cannabis, heroin). RNA transcript and protein levels will then be measured in a rigorously matched subset (60) of these samples to determine the effects of drug exposure on fetal liver function. Finally, stem cell culture models will be used to examine how exposure affects activity at the cellular level. The principal outcomes of the study will be: (1) to show what drug exposure levels are in the human fetus. (2) to demonstrate how these real-life exposure levels can alter fetal liver development and function, potentially affecting post-natal health and development. A secondary outcome of the project will be to establish whether the placenta is a reliable read-out of fetal exposures and, thereby, indicative of an increased chance of ill-health and dysregulated liver development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Functional studies of the ATP-sensitive potassium channel.
Funder: Wellcome Trust

Abstract: Type 2 diabetes is reaching epidemic proportions in Western societies and is predicted to affect 300 million people worldwide by 2025. A key element in development of the disease is the inability of the beta-cells of the pancreas to secrete enough insulin when the blood sugar concentration rises. Thus understanding how insulin secretion is controlled is of fundamental importance. Our studies focus on a protein called the KATP channel, which acts as a tiny, gated pore in the cell membrane. It plays a key role in insulin secretion: when the pore is open, insulin is not released and when it is shut insulin is secreted. Both glucose and the sulphonylurea drugs used to treat type 2 diabetes stimulate insulin release by closing the channel. We have shown that mutations in KATP channel genes cause neonatal diabetes (ND) because they are no longer closed properly by glucose. However, sulphonylureas are still effective, enabling most ND patients to switch from insulin injections to tablet therapy. This project aims to understand how ND mutations affect channel function; how sulphonylureas work; why some ND patients have remitting-relapsing diabetes, and why others may (in addition) experience developmental delay and epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: The role of DHEA sulfation in the pre-receptor regulation of androgen excess.
Funder: Wellcome Trust

Abstract: The human adrenal gland produces the hormone dehydroepiandrosterone (DHEA), which is a major precursor for the production of male hormones in both men and women. Too much androgen in women can cause irregular periods, infertility, acne and increases the risk to diabetes and high blood pressure, summarised by the term polycystic ovary syndrome. This condition affects 5-10% of all women. We have discovered a novel pathway that regulates the production of male hormones. Patients who have a mutation , i.e. a small spelling error in their genetic code, affecting the function of this factor, called PAPSS2, suffer from excess levels of androgens. Our research will aim to find out by what mechanisms disruption of PAPSS2 causes androgen excess. PAPSS2 also plays an important role in regulating the metabolism of drugs and hormones in the liver and thus our research will also give important insights in these mechanisms Clarification of this novel regulatory pathways in human physiology and diseas e comes with the possibility of applying new knowledge to the development of novel therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Do measures in cord blood predict long term offspring phenotype.
Funder: Wellcome Trust

Abstract: In the current study we will examine the extent to which the supply of sugar during pregnancy, the amount of fat a baby has when born and how much cholesterol and inflammation there is in its blood are related to how that baby then grows and develops as a child and to their likelihood of being obese and having high cholesterol in childhood and adolescence. We will use a large existing study of 2959 mothers and children. In this study we have detailed records of the mother s pregnancy and of the children s growth, development and health from birth to age 17. This work will provide unique evidence for how important pregnancy is for the long term health of the child and whether simple blood tests on cord blood collected at birth can be used to identify which children will be healthy and which more unhealthy later in life.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Genome-wide association study of maternal pregnancy phenotypes and later-life maternal and offspring vascular and metabolic phenotypes.
Funder: Wellcome Trust

Abstract: Our goal is to contribute to understanding mechanisms underlying the association of pregnancy phenotypes with future cardiovascular and metabolic phenotypes in women and their offspring. We will test genetic variation on the Illumina 660W-quad BeadChip for association with pregnancy and later-life phenotypes. Pregnancy phenotypes will include weight gain, blood pressure change, hypertensive disorder of pregnancy (HDP), cholesterol, smoking, diet and alcohol. Later-life phenotypes in mothers and offspring will include fat mass, carotid intima media thickness, blood pressure, glucose, insulin, lipids, smoking, diet, physical activity and alcohol. Our sample size of 7,500-10,100 will enable detection of quantitative trait loci responsible for small proportions of the variance in the continuous phenotypes we will examine: 80% power at = 10-7 to detect 0.35-0.58%. For HDP our study (N=1,950 cases) has 80% power to detect a 1.22 odds ratio at = 10-7. We have agreement to complete from se veral cohorts with relevant phenotypes in mothers and offspring and the ability to complete rapid genotyping to complete replication studies (N=44,900). With these additional 44,900 individuals and our contribution to an existing consortium examining genome-wide data in relation to HDP we will have considerable power to detect robust associations.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Defining the mechanisms by which maternal diet-induced obesity programmes central control of palatable food intake
Funder: Wellcome Trust

Abstract: In light of growing evidence for a transgenerational component in the current human obesity epidemic, it is important to understand how maternal environment affects the long-term health of the developing foetus. In animal models, maternal over-nutrition has been shown to programme a metabolic syndrome-like phenotype and hyperphagia in the offspring. In this project, we propose to use anestablished maternal diet-induced obesity (DIO) mouse model to investigate (i)whether exposure to a high fat, high palatable diet after weaning exacerbates the hyperphagia and increased adiposity previously seen in chow-fed offspring and (ii) how maternal DIO programmes hyperphagia in the offspring with a particular focus on the mesolimbic dopamine pathway involved in palatable feeding. For this, our key goals are to (a) characterise the behavioural phenotype of these offspring in terms of food preferences and motivated behaviours; (b) define the structural development of neural projections within the mesolimbic dopamine pathway; (c) to establish the effect of maternal DIO on gene and protein expression levels in this pathway to explore underlying biochemical mechanisms. Thes three levels of investigation will provide us with novel insight into the mechanistic and functional aspects of the developmental programming of the central control of feeding.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Novel mechanisms in adrenal and reproductive biology.
Funder: Wellcome Trust

Abstract: Disorders affecting the adrenal glands or gonads (testes, ovaries) have important clinical consequences. Children and adults with adrenal disorders can die from an adrenal crisis, or suffer long-term consequences following severe illness. Individuals with disorders (or differences) in sex development (DSD) may be born with atypical genitals where it is not clear if the baby is a boy or a girl, or have related disorders such as absent puberty, early menopause or even infertility. Understanding th ese mechanisms is important in planning the best counselling and treatment in the short- and long-term. In the past 5 years we have developed a detailed database of genetic events in human adrenal and gonad development. We will use this foundation to address several key biological and clinical questions. We will characterise 1) new mediators of testis development that are controlled by the key factors SRY and SOX9; 2) previously unknown regulators of steroid production; 3) factors regulating ova rian germ cell development; 4) new genes and pathways involved in adrenal failure and DSD; and 5) the long-term metabolic and reproductive effects of disruption of the master-regulator , steroidogenic factor-1. These studies would benefit patients with a range of conditions through better counselling, intervention and treatment.


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;RENAL AND UROGENITAL
Title: Longitudinal study of pelvic floor dysfunction, and its relationship with childbirth (ProLong20+)
Funder: Chief Scientist Office, Scotland

Abstract: Long-term consequences of childbirth on urinary incontinence (UI), faecal incontinence (FI) and pelvic organ prolapse (collectively, pelvic floor dysfunction, PFD) are poorly understood. PFD affects many women, causing distress and impaired quality-of-life. In 1993-94 we recruited 8000 women three months after giving birth (ProLong study). They completed a questionnaire at 6 years when 45%/10% had UI/FI, and at 12 years when 53%/13% had UI/FI. Prolapse was measured at 12 years and found in 24%. We now wish to contact ProLong women again, around the menopause when PFD may be even more common. Women would receive a questionnaire and be invited for pelvic floor examination. We would combine our questionnaire and examination data with women’s NHS data about PFD treatment received, to report how common PFD is, and how it relates to childbirth and other risk factors, particularly the menopause. The proposed research constitutes the longest ever prospective follow-up of post-natal PFD worldwide. Findings will inform estimates of future need for treatment and research, and ultimately improve women’s health during and after pregnancy.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;MUSCULOSKELETAL
Title: Ultrasound-Based Atlas for Longitudinal Analysis of Fetal Brain Maturation
Funder: Royal Academy of Engineering

Abstract: My primary objective is to develop computational techniques to enhance the diagnostic value of neurosonographic images. The contributions of the Fellowship are four-fold:1. Creation of a four-dimensional (temporal, 3D) probabilistic mapping of the fetal brain at different gestational ages, encoding US signal responses, and characterizing the developmental trajectory of the healthy brain during pregnancy.2. Development of automated algorithms for “individual-to-atlas” image matching and alignment. These tools will enable the extraction and quantification of structural differences between an individual and the population norm.3. Characterization of pathology-affected brain regions in US images. Applying the atlas as a reference for healthy brain maturation, I plan to identify affected regions and quantify pathological deviations caused by malnutrition across gestation. This will demonstrate the potential for routine longitudinal tracking of brain perturbations, in utero.4. Development of a multifactorial fetal health model that uses multiple biomarkers extracted exclusively from clinically-acquired US images, to quantify the extent of nutritional impairment.Unlike pre-existing atlases that map the brains of prematurely born infants, this Fellowship focuses on the development of the first atlas designed with a view for applications in early diagnostic screening and longitudinal monitoring of prenatal conditions, particularly those prevalent in the developing world.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;NEUROLOGICAL
Title: Investigating the impact of seizures on newborn brain
Funder: Wellcome Trust

Abstract: Seizures are a common manifestation of brain injury in newborn infants. Controversies still exist over whether seizures may themselves cause further damage to the developing brain, when to treat them, what drugs to use and how to improve detection. There is an urgent need for a better understanding of the pathophysiological changes to improve our management strategies. My key goal is to assess the impact of seizures on the newborn brain. I propose to use a new optical platform (combined broadband near-infrared spectroscopy and diffusion correlation spectroscopy) for a comprehensive real-time assessment of cerebral metabolism (using oxCCO and CMRO2), haemodynamics (using CBF and CBV) and oxygenation (using TOI) together with video-electroencephalography(EEG) at the cot-side to investigate seizure-induced changes inside brain. I aim to deliver a translational and clinical strategy to investigate these changes in healthy brains of an animal model and in a cohort of babies in neonatal intensive care who developed seizures after brain injury. I will further investigate the impact of phenobarbitone on brain metabolism and haemodynamics. Short and long-term impacts will be assessed with neuroimaging and neurodevelopmental outcome data. These findings will improve our understanding and will support an evidence-based approach for the management of neonatal seizures.

Lay abstract: Seizures or ‘fits’ are a common manifestation of brain injury in babies, but current treatments are poorly effective. To guide new treatments, we need to improve understanding of the effects of seizures on developing brain and their effects on outcomes. Using a new light-based technology (broadband near-infrared spectroscopy and diffusion correlation spectroscopy) together with electroencephalography (EEG), I will investigate the changes resulting from seizures in brain blood flow, metabolism, oxygenation and the brain’s ability to use oxygen for energy production. I will assess the impact of seizures in a laboratory model of an otherwise healthy brain and also in babies in neonatal intensive care who have brain injury, to understand how we might intervene. I will correlate the findings with changes seen in MRI scan and long-term neurodevelopmental outcomes. My research will enable us to understand the impacts of seizures better and modify our management strategy to improve neurodevelopmental outcome.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;NEUROLOGICAL
Title: Over 2.5 years for an analysis of volatile organic compounds (VOCs) emitted from the faeces of preterm infants as a predictor of preclinical necrotising enterocolitis (NEC).
Funder: Action Medical Research

Abstract: Necrotising enterocolitis (NEC) is the most serious gastrointestinal emergency of the newborn period. It can affect any baby but mainly occurs in infants born prematurely. This devastating condition affects around three per cent of newborns in neonatal units and up to 35 per cent of these babies will die. Infants with NEC often require emergency surgery to remove damaged intestines and complications are very common in survivors, including short gut syndrome, serious infections, liver damage and failure to thrive. Infants who survive after being severely affected have a greater risk of neurodevelopmental abnormalities. Recent evidence suggests that as more babies are surviving the early consequences of prematurity the incidence of NEC is increasing. Early diagnosis of NEC may help to avoid major problems These researchers have conducted a small study to look at the damage to the bowel through chemical changes in the baby’s faeces. They now wish to develop the work further and design a simple test of the babies’ faeces to identify those with NEC at an early stage. This could enable treatment to be given before irreversible damage occurs and the baby becomes very ill. If a baby is shown not to have NEC then this would also be useful as the infant would not be exposed to unnecessary treatments such as stopping normal feeding. The team plan to sample faeces passed by the baby and look for the chemicals it contains. Once they know which chemicals are clues to the diagnosis, they will develop a test to rapidly find them. The ultimate aim is to build a machine that can test for these chemicals for use within the neonatal unit and enable the diagnosis of necrotising enterocolitis at an earlier stage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;ORAL AND GASTROINTESTINAL