NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the effect of folic acid on the neural tube defect methylome
Funder: Medical Research Council

Abstract: This project sets out to investigate the effect of embryonic folate status on DNA methylation in wild type and mutant mouse embryos susceptible to NTDs. To do this, we will use the recently developed high throughput, bisulphite-sequencing (BS-Seq) method. We will use both diet and supplementation methods to restrict or increase intake of folic acid. Neurulation stage embryos from wild type or NTD mutant animals will be investigated for locus specific, genome wide effects on DNA methylation (epigenome). Male and female animals will be analysed independently in order to investigate sex specific differences. Candidate regions undergoing treatment specific epigenetic effects will be independently verified and investigated in additional mouse strains with different NTD causing mutations (e.g. Curlytail) or down regulation of the folate cycle (Mthfrnull). Global gene expression changes will be evaluated using RNA-seq and gene specific changes of interest confirmed using RT-PCR and in situ hybridization. Our experiments have been designed to generate the most reliable data possible by ensuring we use appropriate intra-experimental controls, e.g. wild-type animals versus mutant animals and using an appropriate number of samples in each arm of the experiment, e.g. 2 wild-type DNA samples and 2 mutant DNA samples. Experiments will be performed according to protocols we have already standardized. We have developed the appropriate expertise in our labs at ICH and KCL to be able to effectively carry out each of the techniques described for this project. The use of animals to achieve the objectives is necessary as there is no alternative way to reproducibly study the developmental time points in known affected and unaffected human samples. The mouse is a validated and widely used model for the study of human embryology. We aim to use as many animals as needed to achieve a robust data output and will consider in vitro alternatives where appropriate.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Centre for Reproductive Biomedicine Fellowship Award 1
Funder: Medical Research Council

Abstract: Reproduction is a fundamental feature of all life, essential for the continuation of our species. The remarkable integrative biology of human reproductive tissues is responsible for their outstanding resilience, characterised by long-term maintenance of stem cell populations and repeated episodes of regeneration and scarless healing. In Edinburgh there is now an exciting opportunity to understand the fundamental mechanisms responsible for the resilience and repair of reproductive tissues by bringing together, under new leadership and in a new Centre, outstanding strengths in reproductive health and tissue biology, the stem cell niche, resolution and repair of inflammation, developmental programming by steroids, epigenetics, systems and computational biology and tissue and organ imaging. The added value delivered will enable investigators and trainees in the proposed Mr.C/University of Edinburgh Centre for Reproductive Health (CRH) to address three linked questions of crucial importance in reproductive health and beyond: [1] What mechanisms deliver the optimal tissue niches for repeated regeneration of reproductive tissues? [2] How do reproductive tissues normally achieve scarless healing and what goes wrong when this fails? [3] How is reproductive resilience programmed by developmental effects of steroids? The proposed research strategy will offer unparalleled opportunities to understand fundamental processes with implications for resilience and repair in many organs. We will exploit this knowledge to develop novel treatments for the major unmet clinical challenges in reproductive health, to exploit this for impacts across medicine and to provide a rich environment for interdisciplinary research training.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: iNKT cells as drivers for preterm labour
Funder: Medical Research Council

Abstract: The purpose of this work is to characterise invariant (i) NKT activation at the maternofetal interface during labour in women, and test the efficacy of iNKT directed therapies. 1. To determine the key changes in the transcriptome of the human decidua at the onset of labour, we will obtain decidua from the Edinburgh Reproductive Tissue Bank from women in labour at term or preterm and undertake microarray analysis, followed by a combination of statistical and network analyses using Bioconductor and Biolayout Express3D respectively. 2. To determine evidence of iNKT cell activation at the maternofetal interface during human term and preterm labour, we will use flow cytometry to quantify and determine activation status of the cell types involved, including iNKT cells and their downstream effector cells. Additional analysis will be performed using a match-configured LSRFortessa, and FACSDiVa or FlowJo. 3. To determine if iNKT activation is sufficient for the onset of preterm labour in a mouse model, we will use our mouse model of preterm birth. On day 17 of gestation CD-1mice will receive an intrauterine injection of the iNKT cells activator alpha GalCer or PBS. We will measure time to delivery and fetal viability at birth. 4. To determine the timing of activation if iNKT and downstream effector cells in infection induced preterm labour in the mouse, we will use the model described in (3) followed by FACS of decidua from mice harvested 1 or 6 hrs after injection. 5. To determine whether iNKT inhibitor drugs prevent preterm labour, we will use di-palmiotoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1 binding lipid antagonist to prevent preterm delivery in our mouse model of LPS induced preterm birth and record outcomes as in (3). 6. To determine whether iNKT activation is amplified by progesterone withdrawal, we will incubate FACS sorted decidual iNKT cells with increasing concentrations of progesterone, and measure functional read outs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Developmental and meiotic potential of oocytes derived from human ovarian germ line stem cells (OSCs) in vitro.
Funder: Medical Research Council

Abstract: Cells with germ line potential have been isolated and purified from adult mouse ovary and from human ovarian tissue obtained from adult women. These cells, termed oogonial stem cells (OSCs) have been characterised in mice and after in vivo transplantation they form functional oocytes that can be matured, fertilised and form embryos. The equivalent human cells that have been isolated have been much less fully characterised. Yet the ability to develop these cells into mature oocytes would have many potential applications in assisted reproduction and fertility preservation as well being of huge value as a model for the study of human oogenesis. This project aims to confirm the isolation of this cell population from ovaries of adult women of varying ages and to determine the developmental potential of oocytes derived from human OSCs. To test the developmental potential of human OSCs we will combine them with a multistep culture system recently developed in our lab that supports development of human oocytes from the most immature stage (primordial) to fully developed stages with some being capable of undergoing meiotic maturation to Metaphase II. Using this system our preliminary data show that OSCs form follicles when injected into human ovary tissue, with confirmation that they can undergo the initial stages of folliculogenesis. By combining these two technologies we will be able to explore robustly the full meiotic and developmental potential of these cells, and provide a basis for future studies exploring their therapeutic potential.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The intrauterine environment and human early placental development; a new paradigm for the pathophysiology of complications of pregnancy
Funder: Medical Research Council

Abstract: This programme investigates the initiation of the pathophysiology of common complications of pregnancy that have profound effects on neonatal and long-term health. There is strong evidence that poor placental development is a unifying feature, but virtually nothing is known regarding how early placental growth is regulated. Our previous research showed that contrary to textbook accounts, the maternal blood supply to the placenta is not established until 10-12 weeks gestation, and that until then the conceptus is supported by secretions from the endometrial glands. Extending data from domestic species, we hypothesise the conceptus signals to the glands to up-regulate secretion of nutrients and mitogenic growth factors that stimulate proliferation of the placental tissues through a feed-forward mechanism. To test this, we will first identify the transcriptional networks that maintain stemness within a proliferative trophoblast progenitor niche we have identified. Secondly, we will use RNA-Seq to generate a comprehensive catalogue of the potential gland secretome in early pregnancy. The importance of specific growth factor-receptor pairings will be tested in vitro using co-cultures and in vivo using temporally regulated tissue-specific knock-out mice. Clinical correlates will be sought by assessing gland function in pre-conception endometrial biopsies from a high-risk population and linking to pregnancy outcome. Having identified the relevant pathways, we will test susceptibility to perturbation by metabolic stresses known to increase risk of the complications. This will be achieved by a combination of cell cultures in vitro, mouse models in vivo, and human clinical correlates. Finally, we will test whether uterine architecture is affected by developmental programming, leading to intergenerational effects. By elucidating these regulatory pathways, we aim to identify new approaches for the development of therapeutic interventions to optimise early placental development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving neonatal health in remote rural areas in China and Vietnam
Funder: Medical Research Council

Abstract: Objective: Assess the feasibility of a participatory problem-solving intervention to improve use of available practice guidelines to improve neonatal health in rural China and Vietnam Design: Qualitative Methods: Stage 1:Conduct 3 desk-based reviews: global neonatal health (NH) practice guidelines; challenges and methods of monitoring NH impact in remote rural areas; and cost-effectiveness of NH interventions. Stage 2:Conduct 3 national key informant interviews (KIIs) in Beijing. Stage 3:In Guizhou, China collect data on health service management practices, community actions to support improved NH outcomes, health service information systems, costing, and assess the feasibility of larger full-scale intervention. This uses 4 methods: (i) 12 KIIs: community level representatives e.g. community workers, local health committee members [n=3]; local health service managers [n=3], frontline health workers [n=3] at primary and referral levels; and policy makers [n=2] and senior health service officials [n=1] at provincial level; (ii) 2 focus group discussions: 1 with mothers who have delivered in the past 2 years and 1 with community members; (iii) Document review of local community action agreements and provincial and national policies and plans to assess policy space to implement the full scale intervention; and (iv) Observation of systems practice in the local health management office and 3 health facilities: review health management information systems (HMIS) to identify potential for monitoring NH outcomes and accounting systems to identify cost data. Stage 4: Repeat the data collection protocol in Tay Nguyen, Vietnam. Data analysis & outputs: Analyse country data using framework based on the questions and emergent themes. Produce outputs on global review of monitoring NH services in remote areas; briefs on a) practicalities of monitoring NH in remote areas of China and Vietnam and b) national policy space and local decision making freedom to improve NH services.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Remifentanil intravenous patient controlled analgesia (PCA) versus intramuscular pethidine for pain relief in labour, a double blind, randomised controlled trial.
Funder: Department of Health (England)

Abstract: The provision of pain relief during labour is a vital component of a positive maternal experience. Opioid drug-based pain relief is the most common method with intramuscular injections of pethidine being most used (>40% of women). However, pethidine is not always effective and in more than a third of cases women go on to require an epidural. Although epidurals provide excellent pain relief, they increase the risk of a forceps or suction delivery; which is more traumatic for the baby and mother. An alternative opioid drug is remifentanil, this is administered on an “as required basis” where a small dose is given via an intravenous drip each time a woman presses a button. This method of administration gives the woman control over her own pain relief and means that the drug is administered in direct response to pain, with a safety mechanism to avoid overdose. The research hypothesis is that remifentanil leads to lower conversion rates to epidural and thereby increases the likelihood of a spontaneous vaginal birth. This study is designed to compare remifentanil to pethidine in a robust scientific trial to generate evidence to support or reject our hypothesis. Our primary aim is to determine whether remifentanil reduces the number of women who subsequently require an epidural. We will also record pain relief effectiveness, sedation, any effects on the baby at delivery. The study will be conducted and supervised by researchers experienced in the care of women in labour. The results will be published in a high impact scientific journal and used to make recommendations on the use of remifentanil in childbirth.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Induction of labour versus expectant management for women over 35 years of age
Funder: Department of Health (England)

Abstract: Background The average age at childbirth in the UK is rising. The proportion of women giving birth over the age of 35 years was 12% in 1996 and 20% in 2006. Women over this age are at a higher risk of perinatal death. Many obstetricians respond to this by suggesting labour induction to forestall some of the risk. In a national survey 37% already induce women aged 40-44. A substantial minoity of parents support such a policy, but others do not on the grounds that it might increase caesareans. However trials of induction in other high risk scenarios have not shown any increase in caesareans, rather the contrary. Aims 1. To test the hypothesis that a policy of induction of labour at 39 weeks for women over the age of 35 years reduces the rate of emergency caesarean deliveries. 2. There is also a need for a much larger trial to answer the question, does induction of labour improve perinatal outcomes. This would be a large and costly trial, involving approximately 10,000 women. We will pilot this larger study, and measure: The recruitment rate per hospital. The age distribution of participating women. Compliance with the treatment arms of the trial. The overall gestational age distribution of the two groups. Completeness of outcome data Plan of Investigation We will set up a randomised controlled trial and recruit women over 35 years of age in 3 centres with a total maternity population of 28,000 for 24 months. Participants will be randomised to induction of labour between 39 + 0/7 and 39 + 6/7 weeks or expectant management. We will recruit 336 women per group. The primary end point is caesarean section. Secondary end points will include: operative vaginal delivery, perinatal mortality, neonatal mortality, serious neonatal morbidity and maternal delivery expectation/experience measured by questionnaire. We will invite a sample of participants to join focus groups to explore in-depth their views. We will also collect data to test the feasibility of a larger trial to test the effect of induction of labour on perinatal outcomes. Potential Impact How best to manage pregnancy in women aged over 35, or other age thresholds, is an important question for modern obstetrics. Many consultant obstetricians already induce pregnant women over a certain age threshold at term, although the threshold varies. There is little hard evidence to support such a policy. 42% of women over 35 years of age would consider having their labour induced at term based on their age alone. A trial which showed a reduction in caesareans from such a policy would likely in itself increase the use of induction and prevent many stillbirths. If a larger trial to show an effect on stillbirths directly were found to be feasible, it would provide a more precise estimate of the risks and benefits and, depending on the results, either expand the policy or curtail it.


Research activity codes: 6.4 SURGERY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving implantation rates and reducing loss of early pregnancies by measuring serum endocannabinoids at the time of embryo transfer (The IMPLANT Study)
Funder: Department of Health (England)

Abstract: Background 1:6 couples suffer from infertility. For most of these, procedures such as IVF-ET or ICSI-EToffer their only hope. The success rates following these procedures, however, has remained around 25% after embryo transfers in the UK over the last decade. Failure to significantly improve pregnancy rates from these procedures is due largely to poor understanding of the precise physiological mechanisms regulating implantation. Endocannabinoids have recently been demonstrated to be the crucial regulators of the synchronous development of the fertilised ovum to an active blastocyst for implantation and transformation of the early endometrium to one receptive of the blastocyst. We have shown that a fall of >= 40% in anandamide levels from egg retrieval to ET is associated with a successful pregnancy. Aims The aims of this randomised controlled tiral are (1) to demonstrate an improvement of at least 15% in the successful pregnancy (take home baby) rate over currently achievable rates following IVF-ET and ICSI-ET (2) to determine cost benefit of introducing an anandamide (AEA) test prior to embryo transfer in an assissted reproduction programme. Plan of Investigation Women attending for IVF-ET and ICSI will be recruited into the study when they attend for their first visit. Those agreeing to participate will be randomised into timed embryo replacement (ET) or standard ET(>48hrs) . For the timed group, blood for AEA will be at oocyte retrieval (OR) and then 48h (d2), 72h(d3) and 120 (d5)h later. ET will proceed if levels fall by >= 40% from that at OR on days 2 or 3. Where the drop is less on d3 but embryo quality is poor, ET will proceed. Where embryo quality on d3 is good and AEA does not drop significantly, the measurement will be repeated on d5 and replacement undertaken irrespective of changes in AEA levels or embryo quality. Evidence has shown that delaying ET does not affect pregnancy rates and may even improve themif embryo quality is better. Potential Impact IVF treatment is not only expensive, costing £4500-£6000 per cycle but failure can be devasting for couples. Although the NHS sometimes pays for the first cycle for couples who have never had a child and are below 40 years, with a pregnancy rate of about 25%, three out of every 4 couples attending for IVF will suffer disappointment and have to bear the incremental cost with subsequent treatment. The consequences of failed IVF include a feeling of regret, feeling of emptiness, loss of self esteem, depression, stress and breakdown of relationships. An improvement in the pregnancy rate for these expensive procedures will therefore significantly reduce not only the enormous financial but enormous psychological and health (especially psychiatric) burden on couples and the NHS.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Attitudes of teenagers towards unprotected sex and pregnancy
Funder: Division for Social Care and Health Research (Wales)

Abstract: The UK has the highest rate of teenage pregnancy in Western Europe (UNICEF, 2001) and in Wales the rates are higher still (Statistics for Wales 2008). The Welsh Assembly Government’s Strategic Framework for Promoting Sexual Health in Wales (2000) aims to reduce rates of teenage conceptions as one of its three key objectives. Teenage pregnancy is linked to social disadvantage, it occurs in response to social disadvantage and it also perpetuates social disadvantage for the teenage parent and their child (Lemos 2009). A review of the literature on teenage pregnancy (Swann et al. 2003) states that research is required to build a better understanding of issues that have an impact on teenage pregnancy rates so that future interventions can be designed to address these issues. Criticisms made in the review include: the lack of studies carried out in the UK; a shortage of studies using qualitative methods and including input from teenager themselves; a lack of understanding of ‘what works’ in reducing teenage pregnancies and limited research on the motivations for teenage unprotected sex. For instance: why are some pregnancies unplanned and unwanted, some unplanned but wanted, and some planned and wanted. The aim of this PhD is to examine the views and experiences of teenagers themselves and their families. This is in line with both the Fulfilled Lives, Supportive Communities (Wag 2007) strategy for social services which aims to ensure that: “people who need services will have a far greater say over what they need and how it is provided” and also with Rhondda Cynon Taf Teenage Sexual Health and Teenage Pregnancy Strategy (www.fframwaith.org). A mix of qualitative and quantitative methods will be utilised to explore the attitudes and beliefs towards unprotected sex and pregnancy of male and female teenagers and their families. Teenagers from a broad range of backgrounds will be involved to enable the identification of factors that discriminate between different groups of teenagers. Furthermore, the study will access the views of those who have experienced a teenage pregnancy and those who have not. The project will identify factors that influence the behaviour of teenagers, and which can be used to help design innovative strategies to reduce teenage pregnancy.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH