NIHRDataInsights/HRCSData huggingface dataset:
Title: Novel Applications and Refinements of Current Imaging Techniques in Perinatal and Childhood Death Investigation
Funder: Medical Research Council

Abstract: Objective: To develop a less invasive alternative to standard autopsy, thereby increasing parental acceptance rates of the post-mortem examination and information for causes of perinatal death. Outcomes: Technique optimisation and establishment of diagnostic accuracy rates in post-mortem imaging and ultrasound guided organ biopsies for perinatal death investigation. Methods: All fetuses referred for perinatal autopsy with tissue sampling will undergo a post-mortem MRI (if >500g) or micro-computed tomography (if <500g), and a comprehensive ultrasound study. The studies will be reported by radiologists specialising in post-mortem imaging, blinded to the results from the other modalities. After the initial radiology review, consensus imaging will take place and an ultrasound biopsy of target organs (liver, spleen, lungs, heart, and kidneys) will be performed. This will then be followed by the standard conventional autopsy (gold standard). Diagnostic accuracy rates for MRI, micro-computed tomography and ultrasound imaging, both alone and in conjunction, will be established. Results from the ultrasound guided biopsy relating to both tissue yield and pathological diagnosis will be compared to autopsy findings. Where tissue yield is insufficient, technique will be adapted with either differing organ approach or biopsy needle calibre to ensure best possible tissue samples. Scientific opportunities: If diagnostic accuracy and parental acceptance rates are high, medical opportunities will be created that allow increased monitoring of trends and explanation for causes of perinatal death. This raw data is currently lacking given the poor autopsy uptake rates. The long term aim is for image led perinatal autopsy to become the 'best practice' and promote widespread NHS adoption for service delivery. Our results could then contribute to epidemiological studies and inform future public health initiatives.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: A community-centered intervention to improve infant feeding practices among Pakistani and Bangladeshi families living in the UK
Funder: Medical Research Council

Abstract: Low rates of UK breastfeeding mean that infants and mothers are at risk of serious morbidity and mortality. Resources are targeted at mothers from white, disadvantaged communities who are considered the least likely to breastfeed, whereas mothers from ethnic minorities are considered to have relatively high breastfeeding rates. However, re-analysis of national data showed high heterogeneity in breastfeeding rates amongst South Asian mothers; Pakistani and Bangladeshi mothers are less likely to breastfeed exclusively at 6-8 weeks (17.5% and 21% respectively) than Indian mothers (32%). Mothers from these communities are vulnerable to infant feeding misinformation, and may participate in cultural practices which could be harmful to breastfeeding and/or result in early weaning. A culturally specific, sensitive approach is needed to facilitate infant feeding behaviour change in these communities. To achieve this, we will employ a four stage community-focussed methodology that has previously been applied to tackling FGM: (1) Community engagement via celebration events; (2) Recruitment of individuals from target communities to facilitate participation; (3) workshops with community members will address the specific problem areas identified by research (e.g. prelacteal feeds, discarding colostrum, early weaning), identify readiness to change, discuss acceptable key messages likely to be effective in behaviour change and appropriate behaviour change techniques and modes of delivery; (4) seminars with community and healthcare practitioners to understand resource needs. This will inform the development of a toolkit of resources including guidance on assessing readiness for change within local communities, key messages and delivery materials, and guidance for their use. Future research will examine the feasibility of the intervention (acceptability, uptake, recruitment and retention) before a trial of the intervention for increasing breastfeeding and age-appropriate weaning.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Exploration of the oogenic potential of putative germ line stem cells isolated from the ovaries of girls and adult women
Funder: Medical Research Council

Abstract: Cells with germ line potential have been isolated and purified from ovaries of a range of mammalian species including adult women. The ability to develop these cells into mature oocytes would have many applications in assisted reproduction and fertility preservation as well as being of great value as a model for the study of human oogenesis. However, questions still remain whether these cells are bona fide oogonial stem cells (OSCs) or the result of an in vitro transformation. In our previous MRC funded study, we developed a tissue dissociation protocol yielding a high number of viable cells amenable to FACS and molecular analysis without the need for expansion in vitro. The germ line marker DDX4 (at both gene and protein level) has been demonstrated in these freshly isolated cells and a FACS technique incorporating dual-detection of DDX4 with aldehyde dehydrogenase 1 (ALDH1) (marker of progenitor and stem cells) demonstrates that the putative OSC population in human ovaries can be divided into two sub-populations distinguished by expression of differentially spliced DDX4 transcripts and of DAZL, a major regulator of germ cell differentiation. The aim of this proposal is to determine the optimal sorted cell population to form human oocytes (determined by morphology and expression of oocyte specific genes) and to determine the somatic cell support that will facilitate this process. The function and developmental potential of the sub-populations of human OSCs will be tested by combine them with somatic cells from fetal and adult ovarian sources as well as injection of cells into ovarian cortex that can be developed in vitro. Once oocytes/follicles have formed we will be able to explore robustly the full meiotic and developmental potential of these cells and determine whether they are functional oocytes. These studies will provide the basis for exploring the therapeutic potential of these cells in areas such as Fertility Preservation and Infertility treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Scaling up the '24/7 BHU' strategy to provide round-the-clock maternity care in Punjab, Pakistan: A theory-driven, co-produced implementation study
Funder: Medical Research Council

Abstract: Pakistan's public-sector Basic Health Units (BHUs) are open for short times limiting access by poor and rural women to maternal healthcare. Punjab province's 24/7 BHU Initiative aims to scale-up a successful pilot to provide round-the-clock services. This 54-month project will co-produce a detailed analysis of the scale-up process, test plausible improvement approaches, and plan a longer-term strategy to enhance performance. We use socio-ecological systems theory to explore scale-up, examining the complex processes that emerge as the intervention encounters features in local settings, including gender and socioeconomic hierarchies. The range of system elements and processes is wide, so we also use an intuitive implementation framework to help stakeholders make sense of the complexity, determine critical factors and identify actionable strategies. We adopt a mixed-methods approach with two overlapping Work Packages. WP1 consists of three modules. First, policy document review and theory-driven interviews with policy makers explicate the 24/7 BHU Initiative programme theory and begin to build a system model. Second, patterns and predictors of performance are examined through three quantitative components: analysis of routine data, a new survey of 1,500 women/births in up to 50 BHUs, and BHU profiling. Third, institutional ethnographies in 4-5 BHUs in three districts describe the processes that ensue as the initiative embeds in local settings and provide detailed system understanding. WP2 includes two modules. First, two workshops and regular meetings with stakeholders integrate WP1 findings, identify feasible changes and establish priorities. Next, "change ideas" are selected for testing in one district and 2-3 BHUs through carefully documented pilots using the PDSA improvement approach. A variety of outputs for different audiences result, including a co-produced longer-term plan for the Punjab Health Department future strengthening of the 24/7 BHU Initiative.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Tommy's Reproductive Health Biobank
Funder: Medical Research Council

Abstract: The Tommy's Reproductive Health Biobank aims to facilitate researchers in reproductive health to move the field from one of excellent science and excellent pragmatic trials to a precision medicine focused field, where women at high risk of complications can be given appropriate care and new effective interventions can be developed. Tommy's four centres of excellence include research teams from Edinburgh, Manchester, King College London, Imperial, Birmingham and Warwick who all have the ability to obtain detailed mechanistic information from tissue samples using techniques including sequencing of DNA, RNA in whole tissues, RNA sequencing in single cells, DNA methylation gene reads, and proteomics. Clinical phenotyping in-terms of past history and importantly future pregnancy, neonatal and infant outcomes is needed to facilitate translation of this scientific excellence to patient benefit. Across the four Tommy's centres, a wide-ranging variety of samples are/will be collected including pre-conceptual endometrium, sperm, serum, plasma, serial samples in high and low risk pregnancy of plasma, serum, vaginal, dental microbiome, then at delivery adipose tissue, myometrium, placenta, membranes, cord blood, and after delivery neonatal brain. Currently these tissues are stored in six separate biobanks, all striving to achieve the same ideal situation. By combing these six into one virtual entity, it will allow us to ensure 1) quality and consistency of sampling and outcome ascertainment through unified SOPs for sample collection, 2) processing and tracking, 3) working with software engineers to link relevant clinical data and the development of a searchable database. The resulting biobank will have details of large numbers of women with diverse pregnancy problems, with high quality data collection and outcome follow up. This will ensure that samples are of maximum benefit to Tommy's researchers, as well as for others in the field and the wider research community.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: IMPC: Analysis of the novel craniocardiac malformation gene Rapgef5
Funder: Medical Research Council

Abstract: RAPGEF5 is a newly identified candidate birth defect gene, originally identified in a heterotaxy patient. Heterotaxy is a disorder of left-right development and is associated with a severe subset of congenital heart anomalies. Previous data using the frog Xenopus confirmed a requirement for RAPGEF5 in LR development, organ situs and craniofacial development. Establishing a regulator of nuclear accumulation of beta-catenin would transform our understanding of the Wnt pathway and facilitate the development of treatments for diseases such as cancer and cardiac ischemia. In order to investigate this promising congenital disease gene, we need to build on our work by using mammalian systems, which better represent human genetics, development and cardiac anatomy. In particular, we take advantage of powerful murine genetics and state of the art cell culture techniques and reagents available in the lab. We anticipate that this project will provide us with the tools to understand the role of RAPGEF5 in development as well as the biochemical role of RAPGEF5 and associated RAP proteins in signal transduction.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MICA: A Non-invasive Ultrasound-guided High Intensity Focused Ultrasound system for placental and fetal vascular ablation
Funder: Medical Research Council

Abstract: Approximately 4000 identical (monochorionic diamniotic-MCDA) twin pairs are born in the UK every year. Twin-Twin Transfusion Syndrome (TTTS) affects 10-15% of MCDA twin pregnancies in which it is a leading cause of mortality, premature delivery and morbidity. Fetoscopic laser ablation of placental vascular connections is an invasive procedure performed after 18 weeks gestation, with risks of preterm rupture of membranes or labour/miscarriage, infection and maternal complications. Hence management of TTTS is expectant, with monitoring for severe fetal compromise and intervention when the potential benefits exceed the associated risks of invasive treatment. Development of non-invasive alternatives would reduce these risks, allowing earlier treatment or treatment in less severe TTTS. High Intensity Focused Ultrasound (HIFU) is a licensed non-invasive therapeutic technique. It uses precisely aimed ultrasound beams generated using external sources to produce sharply delineated areas of ablation without damage to adjacent tissue. Our team has successfully demonstrated the use of ultrasound-guided HIFU to target, and selectively ablate, placental vessels in sheep, a recognised model of fetal physiology. The HIFU procedure was well tolerated without significant short or long term adverse effects (Shaw Sci Trans Med 2016). We will translate non-invasive HIFU vascular ablation into a first-in-human clinical trial by constructing a prototype ultrasound guided HIFU system and user interface, customised to ablate placental vasculature. This will be informed by market research involving interventional fetal medicine practitioners and patient-public groups, accessed through UK based patient support groups (TAMBA and MBF). Using advice from this advisory group and patient support organisations, we will conduct a Phase 1a safety/efficacy study of early gestation TTTS treatment with HIFU where other therapeutic modalities are severely limited.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: CRADLE-4: Can Reduction of Adverse pregnancy outcomes occur with planned DeLivery vs.Expectant management in pre-eclampsia?
Funder: Medical Research Council

Abstract: Pregnancy hypertension contributes 14% of deaths in pregnancy worldwide. This represents an estimated 60,000 deaths annualy worldwide. The WHO recommends that all women with pre-eclampsia at 37 weeks' gestation onwards are delivered. Experience from our work in eight LMIC countries has identified barriers in meeting this standard relating to detection and action. Prior to 34 weeks, expectant management is preferable as it reduces neonatal risk without increasing harm to the mother, although data for this comes mostly from a High Income setting. Guidance on the optimal timing of delivery for women between 34 and 37 weeks' is less clear. Early delivery would be beneficial to the mother and may also benefit the baby who is at risk of placental insufficiency resulting in unpredictable, rapid deterioration, e.g. placental abruption. However, the increased risk of neonatal morbidity associated with premature delivery needs to be defined and compared to the benefit of delivery. Especially in the context of LMIC settings with varying cultural and educational barriers to early delivery, compounded by challenges of resource availability. The trial is a multicenter, individual randomized controlled trial across India and Zambia. The aim is to determine whether accurate identification of pre-eclampsia with planned early delivery after 34 weeks' of gestation will reduce maternal morbidity without increasing neonatal morbidity compared to routine care. The impact of cultural, political and socio-economical context will be evaluated in each setting with a scoping review, questionnaires, interviews and focus groups with women, their families, stakeholders and health care providers. A cost effectiveness analysis will be also undertaken. Results will therefore be generalizable across many low and middle income settings and have the capacity to directly impact local, national and international guidance on the management of this common pregnancy condition.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Puberty health interventions to improve menstrual health and School attendance among Gambian adolescents (MEGAMBO).
Funder: Medical Research Council

Abstract: A systematic literature review we conducted in 2013 found there was good evidence that educational interventions can improve menstrual hygiene practices and reduce social restrictions but there was no quantitative evidence that improvements in menstrual knowledge and management methods reduce school absenteeism and urogenital infections. A recent study we are conducting among Gambian schoolgirls shows that students (boys and girls) had poor knowledge about menstruation. We also observed that lack of knowledge of menstruation led to embarrassment and fear of teasing, and this, together with pain and lack of effective materials and WASH facilities for MHM led to school girls absenteeism. Our study showed that there is an unmet need from girls, boys and parents for interventions to enable girls to better manage both the psychosocial aspects of menstruation (anxiety and distress) and the physical aspects (management of use of appropriate materials to eliminate leakage of menstrual blood and hygienic habits practices). One workshop with different stakeholders (parents, teachers, students, clinicians, education regional officer and NGOs) was held in Keneba in May 2017 in order to present the initial findings, discuss the problems and find possible solutions. After the workshop we all decided to create a 4 pack interventions that could be included in programmes already existing in these communities: Mother's club who will work with mums to inform about puberty, menstruation and absorbent and hygienic practices, Peers Education camps, which will involve girls and boys in schools to discuss puberty and menstrual management issues, Community meetings around puberty films and WASH improvements. The aim of our study is to test, refine and adapt the intervention packages suggested in the first study and to conduct a school-randomised controlled trial to evaluate the effect and cost-effect of an intervention to improve MH among girls to reduce school absenteeism in girls.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: From Stop to Go! Overcoming barriers to healthcare utilisation for high-risk adolescent mothers and their children in Southern Africa.
Funder: Medical Research Council

Abstract: Adolescent parents in Africa persistently under-utilise healthcare: antenatal care, PMTCT and child services. This increases maternal mortality and morbidity, birth complications, pre-term birth, neonatal and under-5 mortality, HIV-transmission, childhood illness and risk of developmental delay. Systematic reviews of African research find limited evidence of modifiable barriers or facilitators to healthcare utilisation in this group. There is no known research on potential impact of adolescent fathers. Policy partners have identified a need for high-quality research alongside cost-effectiveness models to inform programming. This study combines new data from maternal-child dyads in South Africa with prior data from pre-conception to pregnancy. It is powered to examine moderated and mediated pathways to healthcare uptake through multilevel structural equation models. It allows testing of combinations of interventions through marginal effect and propensity-score models. We will merge medical records, socio-economic surveys with standardised child developmental assessments from 450 mother-child dyads with service delivery information collected at 72 healthcare facilities. This complex multi-year dataset will be analysed using multi-level models to account for repeated measures and nested effects within facilities. After identification of facilitators (and potential interactive/additive effects), allocative efficiency analysis will compute the cost of these provisions under different budgetary models. Findings will be informed by qualitative research, by adolescent and policy advisory groups. Targeted activities will maximise ODA impact. The study was co-created with high-level policymakers at international and national level, and fills a clearly identified need in the Global South. Findings will be integrated into policies, programming and health facilities via a training module for healthcare practitioners delivered through our implementation partners.


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: UK Renal Imaging Network (UKRIN): Enabling clinical translation of functional MRI for kidney disease
Funder: Medical Research Council

Abstract: We propose an MRC Partnership to build on the UK's pioneering role in the development and standardisation of renal MRI. This will bring together MR physicists, radiologists, and nephrologists from major UK renal MRI research centres to create a platform for sharing expertise, building capacity, resolving challenges in data acquisition and analysis, and providing support for data sharing. Once established, this will provide technical support and shared databases of normative data to enable clinical validation through multi-centre studies. The Partnership Grant will allow us to: 1) Build capacity and enhance the UK's expertise in renal MRI, sharing expertise across the three main MR vendor platforms, and delivering a programme of network activities including Workshops and Symposia. 2) Produce a series of optimised and harmonized protocols for renal MRI comprising: (i) "standard" sequences (BOLD R2*, diffusion-weighted imaging, T1 and T2-weighted images, angiography and phase contrast MRI, T1 mapping); (ii) more advanced protocols (such as arterial spin labelling and magnetic resonance elastography); (iii) quality control protocols. 3a) Set up a Data Analysis Centre (DAC) to develop and validate a software framework for processing multi-parametric renal MRI data. This will support future clinical studies using renal MRI in study design and setup, and image quality assurance and processing. 3b) Develop a centralised platform for data sharing and analysis using the framework of the Dementias Platform UK (DPUK) national XNAT-based informatics platform. 4) Demonstrate the Partnership capability by performing a "travelling kidney" study and collecting a normative data set of subjects, providing data for testing within- and between-site reproducibility across the three MR vendors. 5) Ensure that the UK MR research community can exploit investment in renal MRI and provide sustainability through the establishment of the UKRIN Strategy Board.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH