NIHRDataInsights/HRCSData huggingface dataset:
Title: Development and validation of a Prediction model for Risk of complications in Early onset Pre eclampsia (PREP)
Funder: Department of Health (England)

Abstract: Pre-eclampsia is a disorder in pregnancy characterised by raised blood pressure and abnormal levels of protein in the urine beyond 20 weeks of pregnancy. The only known cure is delivery of the baby. Delivery before 34 weeks of pregnancy is premature. Current tests that are conducted in women with early onset pre-eclampsia include clinical history examination laboratory investigations and ultrasound. Women are often faced with making difficult decisions of early delivery of an extremely premature infant with a slim chance of survival and major neurological handicap compared to major concerns to their own health. Often the crucial decision of when to deliver is based on personal clinical experience of the clinician. This is due to a lack of sufficient evidence regarding the ability of tests to accurately predict the risk of complications to the mother or baby. PREP is a prospective cohort study of development and validation of prediction model for risk of adverse outcomes in women admitted with early onset pre-eclampsia before 34 weeks of pregnancy. The tests that will be assessed in the PREP study are those that are currently routinely performed in most units in the NHS. All women diagnosed with early onset pre-eclampsia will be eligible for recruitment. We aim to recruit 992 women from trusts within several of the Comprehensive Local Research Networks (CLRNs) throughout the UK


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR
Title: Trophoblast Microvesicles, Exosomes, miRNAs, Danger Molecules and Pre-eclampsia
Funder: Medical Research Council

Abstract: We will use placental perfusion to examine, (by proteomics and miRNA arrays), which danger molecules and miRNAs, shed from the placenta's syncytiotrophoblast surface, are soluble, and which are part of syncytiotrophoblast vesicles (STBM). As STBM comprise both smaller exosomes (STBex) and larger microvesicles (STBmic), with different possible biological functions, we will fractionate them (e.g. by nanofiltration) to determine their phenotypes and the differences between normal pregnancy and pre-eclampsia. To interpret our findings, the BeWo trophoblast cell line will be used to model the pre-eclamptic damage by exposing syncytialised BeWo to oxidative and inflammatory stress and inducers of apoptosis and necrosis. We will measure changes in soluble molecules released, proportions of STBex and STBmic and the molecules they carry, in response to each treatment to mimic the changes in pre-eclampsia. STBex and STBmic will be phenotyped using fluorescence Nanoparticle Tracking Analysis (fl-NTA - a technique we have pioneered) together with 6 colour flow cytometry. The further development of fl-NTA is a key part of this programme. We will then examine how STBex and STBmic and the miRNAs they carry are taken up by (using imaging flow cytometry, RT-PCR) and affect leucocyte and endothelial functions (cytokine/chemokine production and endothelial cell proliferation/permeability). Based on the danger molecules and miRNAs identified above, we will investigate their effect on syncytialised BeWo and placental explants to determine whether this triggers a vicious cycle of activation which could amplify the underlying problem. Our findings will be used to achieve our final aim, to characterize STBM from peripheral blood of normal pregnant and pre-eclamptic women, in samples from the Oxford Pregnancy Biobank, taken before and during active disease, to determine their use as diagnostic or predictive biomarkers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR
Title: Identification of normal and at-risk trajectories of blood pressure in pregnancy in relation to offspring perinatal health and childhood development
Funder: Medical Research Council

Abstract: Aim: To characterise patterns of blood pressure change in pregnancy which are associated with increased risk of adverse health outcomes in offspring. Objectives: 1. To develop normograms for blood pressure change across pregnancy based on pre/early-pregnancy maternal risk factors, and to assess the predictive ability of deviations from these trajectories to identify women at risk of pre-eclampsia, preterm birth and small for gestational age offspring. 2. To investigate whether particular patterns of maternal blood pressure change are associated with offspring perinatal outcomes and cardiovascular risk factors, growth and changes in adiposity in childhood and adolescence. 3. To identify maternal and fetal genetic variants related to patterns of blood pressure change during pregnancy. Methodology: The project will use antenatal blood pressure measurements (median 14 per woman) of ~13,000 women in the Avon Longitudinal Study of Parents and Children (ALSPAC). Early-pregnancy risk factors such as maternal body mass index, age, parity, smoking, previous hypertension, family history and markers of socio-economic position have been obtained via questionnaires. Genome wide SNP data is available for ~10000 mother-offspring pairs. The children have attended clinics between the ages of 7 and 18, in which cardiovascular risk factors and anthropometric measurements have been recorded. Statistical analysis will include multivariate multilevel models and Bayesian methods and validation, replication and pooling of results with a number of other similar pregnancy/birth cohorts will be undertaken. Scientific and Medical Opportunities: Recent findings have highlighted the potential for rates of blood pressure change in addition to blood pressure thresholds to be used to indicate high risk pregnancies. The development of normograms for blood pressure change could enable the identification of women at risk of adverse offspring outcomes earlier than current monitoring allows.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR
Title: Prediction and prevention of adverse pregnancy outcomes in women with chronic vascular disease
Funder: Department of Health (England)

Abstract: Chronic hypertension complicates 2% of pregnancies in the UK and is associated with increased maternal and perinatal morbidity. Recent NICE guidelines have highlighted the need to investigate the safety and efficacy of antihypertensive treatment in pregnancy. In women with a history of hypertension, blood vessel function is altered and in contrast to healthy pregnancies, the blood vessels do not relax during pregnancy. This abnormal adaptation is associated with an increased risk of developing pre-eclampsia and/or fetal growth restriction; both of which often necessitate a premature delivery. This prospective study, will investigate the clinical utility of measuring blood vessel relaxation using a highly sensitive blood pressure machine. The accuracy of blood vessel relaxation in the prediction of preterm pregnancy complications will be assessed and used to recruit women to a pilot randomised controlled trial. The trial will involve the prescription of a commonly used blood pressure tablet (nifedipine) to normalise blood vessel relaxation in women with chronic hypertension. Doses of nifedipine will be adjusted using the blood vessel relaxation values rather than conventional blood pressure targets in the treatment group. This pilot trial will assess the efficacy, safety and acceptability of targeted therapy. St Mary's hospital is a tertiary referral centre in central Manchester serving a diverse and high risk population. The Manchester Antenatal Vascular Service (MAViS) at St Mary's Hospital Manchester, is a unique specialist research clinic which has the necessary personnel, equipment and facilities to conduct this study.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR
Title: Nutritional, genetic and epigenetic contributions to blood pressure and cardiovascular disease.
Funder: Wellcome Trust

Abstract: 1) Investigate the causal relationship between dietary salt intake and high blood pressure to identify who is susceptible to hypertension and cardiovascular disease later in life. 2) Assess the mechanistic pathways underlying the known association between salt intake and blood pressure. 3) Examine how dietary salt intake alters epigenetic modifications. 4) Investigate whether these salt-induced epigenetic modifications alter gene expression and determine if these changes alter adverse cardiovascular health outcomes, specifically the risk of hypertension. 5) Identify whether maternal diet affects offspring BP through in utero mechanisms, and assess the challenges with this type of analysis. 6) Dissect the intergenerational transmission of salt-induced and nutritional effects on high blood pressure from parent to offspring.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR
Title: Role of Complement in Neural Crest migration and craniofacial development
Funder: Medical Research Council

Abstract: Collective cell migration is a widely recognized mode of migration during embryogenesis and cancer; however, it is not known how mesenchymal cells, which have reduced cell adhesion, are maintained as a cohesive group during migration. By using cephalic neural crest as a model for collective migration we will test the hypothesis that these cells are kept together by a mechanism of mutual attraction. Studying cephalic neural crest migration will also help to understand the origin of craniofacial abnormalities, a devastating phenotype that leads to birth defects and spontaneous abortion. In order to find novel molecular components implicated in neural crest migration we have examined molecular pathways that control migration in the immune system, where cell migration is better understood. We will focus on the complement system; central to this pathway is the C3 factor, a precursor of the chemoattractant C3a. We will analyze the cellular and molecular mechanisms by which C3a controls neural crest collective cell migration. We will test whether C3a is required for mutual attraction between cells; as alternatives we will analyze whether C3a controls cell adhesion or modifies the response of other known neural crest chemoattractant, Sdf1. The role of the complement cascade in neural crest development will be highly novel as no activity has been described for this system during early embryonic stages, before any blood or vessels are present. The results obtained here could be extrapolated to other migratory systems such as cancer and immune cells. In subsequent research we will use the information generated in this project to screen for craniofacial anomalies in human patients with complement deficiencies. Our hypothesis could have important consequences for human health, as it may suggest the avoidance of complement inhibitors to treat immune diseases during pregnancy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CONGENITAL DISORDERS
Title: Microtubule dynamics and age-related aneuploidy in mammalian oocytes
Funder: Medical Research Council

Abstract: Gain or loss of a chromosome (aneuploidy) in oocyte meiosis-I is the cause of developmental disorders such as Down's, is a major cause of unwanted pregnancy loss (miscarriage), and is the root of age-related infertility. Why oocytes from older females ('old oocytes') are more prone to chromosome segregation errors than young oocytes is unknown. In somatic cells the Kinesin-13 family of microtubule-depolymerising motors support faithful chromosome segregation by promoting spindle microtubule (MT) turnover, allowing incorrectly docked kinetochore microtubules to be corrected. Our hypothesis is that defects in MT dynamics defects predispose old oocytes to chromosome mis-segregation. We will address this hypothesis using a naturally-aged mouse model which exhibits age-related aneuploidy similar to humans. First, we will directly compare several aspects of spindle MT dynamics in young and old oocytes. We already have preliminary data that that spindle MT turnover is reduced in old oocytes. We hypothesise that reduced MT turnover in old oocytes correlates with failure to correct kinetochore-MT attachment-errors, thereby causing aneuploidy. Second, we will inhibit each of the three kinesin-13s in old and young oocytes, to establish which promote error correction, and whether the requirement for error-correction increases with maternal age. In addition, we will over-express kinesin 13s to directly determine whether increasing MT turnover can prevent chromosome segregation errors in old oocytes. Finally, we will use nuclear transfer techniques to determine whether a spindle constructed by a young oocyte is able to correctly segregate chromosomes from an old oocyte, and vice versa. This provides an alternative approach to assessing the impact of defective MT dynamics upon chromosome segregation in old oocytes. Together our experiments will establish how oocyte spindle MTs contrive to permit the chromosome segregation errors which lead to miscarriage and Down's.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CONGENITAL DISORDERS
Title: Molecular biology of cohesin in mitotic, postmitotic, and meiotic mammalian cells.
Funder: Wellcome Trust

Abstract: What is the cause of genetic disorders such as Down s Syndrome? What leads to spontaneous abortion? What is the cause of infertility in older women? What are the defects underlying devastating genetic diseases such as Cornelia de Lange syndrome or Roberts syndrome? How could one create plants whose seeds have the same genetic composition as their parents so that one could more easily propagate F1 hybrids? The answers to these questions lie in the mechanisms by which genetic information encoded b y the DNA of our chromosomes is passed from one generation to another (inheritance). A crucial aspect of inheritance is how sister DNAs produced during DNA replication are segregated to opposite sides of the cell before it divides. Work on yeast has identified the key part played by a large protein machine called cohesin that entraps sister DNAs inside a huge ring structure and holds them together until shortly before cell division. We wish to establish whether cohesin has a similar if not ident ical role in mammals and if so to elucidate the mechanical principles by which DNA enters into cohesin rings and is subsequently held inside them or released from them.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CONGENITAL DISORDERS
Title: Addressing the adverse impacts of domestic violence during pregnancy
Funder: The British Academy

Abstract: Domestic violence against women during pregnancy is a common problem, with an estimated 14% of women across the world exposed to physical abuse during pregnancy, 8% to sexual abuse, and 28% to emotional abuse by their partner or ex-partner. Exposure to this kind of violence can have significant adverse effects on both mother and child. For example, prenatally exposed children have an increased risk of being born too early and underweight and of later experiencing physical and mental health problems. The current project aims to inform the prevention of these and other adverse outcomes by examining the factors that predict domestic violence during pregnancy, the mechanisms that link prenatal violence exposure to adverse outcomes for mother and child, and the characteristics of individuals, families, and communities that either mitigate or exacerbate the negative effects of exposure to domestic violence during pregnancy.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;DISPUTED AETIOLOGY AND OTHER
Title: Enhancing Practice Around Reproductive Coercion within Reproductive Health Services
Funder: The British Academy

Abstract: Reproductive coercion and abuse (RCA) has been defined as attempts to control pregnancy through interference, abuse, threats and violence. Pregnancy is a recognised time for the initiation and escalation of domestic abuse, and thus interactions with reproductive healthcare providers are a key site for the identification and introduction to victim support services. This project aims to facilitate cross-learning, and build innovative responses to RCA by bringing together knowledge and understanding from the gender-based violence sector with reproductive health organisations. Working with BPAS, it aims to address specific concerns raised by policymakers and others around the identification of RCA and other forms of abuse during abortion consultations via phone or video call through engaging with existing academic and practice knowledge and relevant stakeholders. It also seeks to make a wider contribution by developing an ongoing network of expertise around RCA that can be utilised beyond the fellowship by healthcare organisations.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;DISPUTED AETIOLOGY AND OTHER
Title: Towards Better Pregnancy Monitoring: Miniaturised Tools for Non-Invasive Prenatal Diagnosis in Clinics and Hospitals
Funder: Royal Academy of Engineering

Abstract: The work achieved in my fellowship has confirmed the potential of microfluidics as a method to isolate circulating DNA from patient blood samples. The technology developed have the potential to greatly reduce the need for invasive biopsies making the care of patients both more reliable and cheaper, in a growing number of other medical applications. The project has provided a significant boost for the development of a Spin Out company funded by Scottish Enterprise, Natantis, which now has 4 staff and is developing a bedside device to rapidly capture novel biomarkers when they best reflect the health status of the patient.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;GENERIC HEALTH RELEVANCE
Title: A comparison in efficiency, supply and cost effectiveness between independent nurse prescribing and medication provision based on predetermined guidelines (patient group directions) in sexual health services.
Funder: Department of Health (England)

Abstract: This study explores how independent nurse prescribing compares with patient group directions (pre-determined medication guidelines) in sexual health. It investigates the appropriateness and safety of medication provision; cost implications and staff and patients’ experience. A mixed methods approach uses focus groups, questionnaires, a quantitative diary and structured observations of nurses’ consultations. Independent nurse prescribing is expected to provide more flexibility in practice than pre-determined guidelines. A health economics assessment will determine the extent to which investment in nurses’ independent access to medications creates benefits for patients and health professionals, and NHS cost savings in the delivery of sexual health services.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Improving women's health and pregnancy outcome: understanding the aetiology of ectopic pregnancy
Funder: Medical Research Council

Abstract: Ectopic pregnancy (EP) remains a common cause of pregnancy-related death and is a considerable cause of morbidity. Chlamydia trachomatis (CT) infection is the major risk factor for EP yet our knowledge of the pathogenic events that lead from CT to EP is unclear. We hypothesise EP is due to the result of: a) embryo retention in the Fallopian tube (FT) due to smooth muscle dysfunction and, b) changes in the phenotype/gene expression of the tubal epithelial cell that allow ectopic embryo implantation to occur. The endocannabinoids are multifunctional proteins that have a pivotal role in embryo transport due to their effects on oviductal smooth muscle. Silencing of the endocannabinoid receptor 1 (CB1) in the mouse results in tubal embryo retention (but not tubal implantation). Attenuated CB1 expression in the human FT is associated with ectopic pregnancy. Although this provides a plausible explanation for arrest of the embryo in the FT, the exact mechanism leading from tubal embryo retention to tubal implantation has hitherto been unexplained. We propose that CT infection causes changes in the tubal epithelial cell that make the FT receptive to ectopic implantation. The integrins, particularly alpha v beta 3, have now been largely accepted as markers of receptivity to the presenting embryo in the uterus, and functional blockout of alpha v beta 3 results in reduced implantation in the mouse. However, it is not known whether integrins have a similar expression in the FT to the uterus, or are aberrantly expressed in EP. The objectives of this project are to demonstrate that: 1) Endocannabinoids regulate smooth muscle contraction controlling passage of the embryo in the human FT in in-vitro models of tubal contractility and motility; and that CT infection results in aberrant integrin expression and embryo attachment in the human FT in an in-vitro model of tubal attachment. 2) Infection with Chlamydia in the CB1-knockout mouse causes altered tubal epithelial integrin expression and is the stimulus required for a retained embryo implant. 3) CB1 and integrin expression are different in the FT of women following EP in-vivo, and that these differences reflect CT infection. The delineation of role of CT infection in EP has significant public health implications, particularly in relation to the introduction of national Chlamydia screening programmes. An explanation of the aetiology of tubal ectopic implantation has potential to be translated into preventative health measures that could significantly reduce morbidity/mortality due to EP.


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