NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing a selection tool for Community Health Workers in sub-Saharan Africa
Funder: Medical Research Council

Abstract: There is good evidence that Community Health Workers (CHWs) can provide effective disease-specific care in their local communities. Recent scale-up of the role, tasks and workload of CHWs has however increased the job requirements of CHWs in terms of the knowledge, skills and attributes required to perform the job well, and there are now reports of difficulties in retaining CHWs, in their ability to perform all the tasks required of them and maintaining their diligence. An improved selection process for CHWs would mitigate these problems by identifying CHWs most likely to perform well and be retained in post. This project will use an existing selection tool (used by the charity Living Goods in Kenya and Uganda) and co-design appropriate versions of the tool for initial testing in two other local contexts, Mophor district in Ghana and Neno district in Malawi. We will start by establishing the predictive validity of the existing tool in use in Kenya and Uganda using previously-collected data on selection, training and job-performance. At the same time, we will review the CHW programmes in Ghana and Malawi to determine differences in required tool content (for example due to differences in the skills required to perform the tasks required in each programme). We will do this using task inventory analysis, observational job analysis of high-performing CHWs and job-element method-based semi-structured interviews with key stakeholders in each district. We will also establish 'design requirements' for tools such as format and maximum costs. We will use the results of these studies to co-design tools and undertake initial alpha and beta testing in Mpohor and Neno. Our final outcome will be a revised tool suitable for roll-out and summative evaluation in other areas.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Epidemiological Studies of the Porton Down Veterans: a ten-year update on mortality and cancer incidence, 2005-2014
Funder: Medical Research Council

Abstract: The Porton Down Veterans cohort comprises UK servicemen who took part in the 'human volunteer programme' of chemical warfare agent (CWA) research at Porton Down from 01/04/1941 to 31/12/1989. 18,276 Porton Down veterans had a small (6%) excess of deaths from all causes combined, compared to 17,600 veterans who did not visit Porton Down, taking follow-up until 31/12/2004. However, this could not be directly attributed to CWAs. They had no overall excess of cancer. Since 2004, there has been no further follow-up. Therefore, we propose to take follow-up to 31/12/2014. The additional ten years will add almost 8,000 further deaths and a proportionate number of additional cancer registrations, greatly increasing our statistical power. Updating this cohort to allow updated and new analyses to be undertaken represents a prudent and efficient use of public funds. We will update the standardised mortality ratios and rate ratios calculated initially. We will explore new questions e.g. the risk of neurological malignancy and non-cancer deaths with nerve agent exposure. We will also explore findings from the initial analysis e.g. the relationship between CS gas exposure and oesophageal cancer. Greater statistical power will allow us to study exposure-response relationships in more detail, e.g. for lung cancer and vesicants, and to study subgroups of causes of death, e.g. suicide. We will carry out a pilot study of the availability of smoking and alcohol information in the newly computerised military personnel archives and, if feasible, incorporate these confounding factors in nested case-control studies of suicide, oesophageal cancer, and lung cancer. We will also carry out a pilot study of data linkage to newly-available routinely collected datasets e.g. Hospital Episode Statistics.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Practices, regulation and accountability in the evolving private healthcare sector: lessons from Maharashtra State, India
Funder: Medical Research Council

Abstract: A case study of Maharashtra State, India, explores the changing face of private sector hospital care and related diagnostic services and the organised, and increasingly transnational, healthcare industry. Study questions are informed by the concepts of commercialisation; regulatory capture, social accountability and social regulation. a. What have been the key transformations in the private hospitals and diagnostics sector in Maharashtra state, and in India, since 2000 and what is the likely future trend? b. What have been the implications for medical and institutional practices, and how have the trends been experienced by medical practitioners and users? c. What has been the trajectory of regulatory mechanisms in this sector, whose interests have they articulated, and what are the regulatory implications of likely future trends? d. What could a social accountability approach to regulation look like in such a context? e. What lessons can be derived for India and for LMICs more broadly in order to facilitate universal access to quality healthcare? Methods include narrative literature review, collation of statistical data to map formal private healthcare sector; qualitative audio-recorded interviews with purposively sampled doctors, managers, administrators, owners, regulatory bodies, public health academics, specialist medical associations, GPs, patient advocacy groups. Thematic analysis will use NVivo software. Witness Seminars, an oral history technique, will explore i) corporatisation in healthcare and ii) the 1994 Act regulating private sector practice on sex-selection of foetuses. A stakeholder consultation with policy makers, professional organisations, regulatory bodies, facility owners, insurance bodies, patients' rights organisations, will examine regulatory challenges in the private healthcare sector. A modified version of the Clinical Establishments Act will be elaborated employing a social accountability framework.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: BIOS - Assessing the potential of wearable digital biosensors for health system strengthening in LMICs.
Funder: Medical Research Council

Abstract: Evidence shows that many low- and middle-income countries (LMICs) are experiencing a rising burden from non-communicable diseases (NCDs), mainly cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes. However, capacities of national health systems to address the challenges of NCDs are still inadequate. Structural gaps also remain in the ability of health information systems to collect and analyse pre-disease and clinical evidence on associated risk factors. The development of new wearable technologies for health monitoring is a promising technological innovation with potential to support health system strengthening in LMICs for the prevention and control of NCDs. Wearable digital health systems could be deployed, for example, to conduct regular surveys on risk factors for major NCDs and their distribution across socio-economic and demographic strata, informing policy development and resource allocation. In addition, wearable devices can deliver user experiences based on individual progress and health targets, contributing to behavioural change and improved data about the management of chronic conditions. Despite these promises, the public health potential of wearable digital health analytics has yet to be recognised and evaluated in systematic ways. This project aims to conduct a preliminary investigation of this potential, laying the conceptual and empirical foundation for a larger multi-country study. Key elements that will inform data collection and analysis include: (1) cultural relevance and appropriateness of the proposed technology; (2) ethical implications; (3) policy and regulatory barriers and opportunities; (4) health system support, capacities, and responsiveness; (5) usability and affordability. Empirical research will be conducted in Cambodia, where a prototype wearable device will be deployed for field assessment.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: Building an evidence base to support and enhance community health workers' (informal) use of mobile phones in Ghana, Malawi and Ethiopia
Funder: Medical Research Council

Abstract: CHW Questionnaire: 500 CHWs will be sampled in Ghana and in Malawi, using a multi-stage cluster sampling approach across all three regions in Malawi (Northern, Central, Southern) and three contrasting regions in Ghana (Central, Brong Ahafo, Northern), across urban, semi-rural and rural locations. In Ethiopia, with its much larger number of CHWs (38,000), 500 CHWs will be sampled in each of two regions (Oromia and Amhara). The sample size of 500 CHWs per sampling unit was determined envisaging 5% margin of error in estimation of level of work-related mobile phone usage and survey design effect of 25%, including missing data. In Amhara region in Ethiopia, for example, the first stage of our sampling scheme will be a random sample of 4 out of the 14 zones in the region. Then a random sample of 12 districts will be selected in each selected zone with an average of 10 CHWs per district: all CHWs in the selected district will be surveyed. A similar scheme will be used Ghana and Malawi, adapted to specific structure of each country's health system. Quantitative data will be analysed using survey methods in R, SAS9.4 and STATA. Descriptive analyses will be performed for each country to characterise 'informal mhealth'. To estimate level of CHW mobile usage, a survey logistic regression model will be used to account for survey design effects resulting from the multistage cluster sampling, with survey linear models used to analyse continuous data. A flexible mixed effects model will be used to perform "participant level" meta-analysis of data across countries. Focus group discussions with CHWs and patients in a sub-set of sampled clusters: each FDG will be facilitated by 2 RAs, one to manage the discussion and one to record. FGDs will be transcribed as soon as possible in the original language then translated into English, with a sample independently back-translated to ensure accuracy. Coding and thematic analysis will be performed using NVivo software or equivalent


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Human Developmental Biology Resource (HDBR): an embryonic and fetal tissue bank for functional genetics and cell-based research
Funder: Medical Research Council

Abstract: The Human Developmental Biology Resource (HDBR; www.hdbr.org) is a human fetal tissue bank that provides the scientific community with: (i) High-quality materials from embryonic and early fetal stages (4-22 post-conception weeks; PCW), including tissues for cell culture, sub-organ-specific dissected regions for 'omics analysis, and slides for spatial gene expression studies; (ii) An In-House Gene Expression Service that undertakes studies for registered researchers; (iii) A unique web-based database (HuDSeN) for dissemination of human gene expression data spatially mapped to 3D models. Since 1999, the Inst. Genetic Medicine, Newcastle and the Inst. Child Health, UCL have worked in partnership, developing the HDBR to support national and international research into human development. The 4-22 PCW period covers organogenesis when congenital disorders and many childhood/adult disorders originate. Research (e.g. 100,000 Genomes) is identifying ever-increasing numbers of disease-related genes and, while animal models can provide valuable mechanistic information, there is a growing need to access human fetal tissues for genetic and epigenetic research. Development of 'omics technologies, including at the single-cell level, and increasing use of stem and progenitor cell lines in tissue engineering, are further drivers for extending the HDBR tissue bank service. To meet these growing demands, the HDBR proposes to augment the value of its tissue supply particularly in the older fetal age range, as increasingly required for brain development studies. Systematic collection will begin of tissues from fetuses with prenatally diagnosed congenital anomalies to support research in these diseases. New dissection/tissue preparation methods will cater for single cell 'omics projects, while 'hotel' facilities will be offered to teams wishing to train in use of HDBR material. 'Omics data locations will be linked to HuDSeN to enhance usefulness of the gene expression database.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing a novel therapeutic to target endogenous stem cells to accelerate tissue repair and regeneration.
Funder: Medical Research Council

Abstract: Alarmins are passively released by dying or stressed cells after injury. We have found that the prototypical alarmin HMGB1, a highly-conserved molecule that forms a crucial part of the transcriptome, promotes tissue regeneration by transitioning stem cells from a wide variety of tissues, including blood, bone and muscle to G(Alert). This strategy to accelerate tissue healing and promote regeneration by targeting endogenous stem cells has significant advantages over treatments that rely on administration of stem cells that have been expanded in vitro. We found that only native HMGB1, which has no inflammatory action, transitions stem cells to G(Alert) and acts in conjunction with CXCL12 by forming a heterocomplex and inducing a conformational change in the receptor CXCR4. However, native HMGB1 has inherent limitations as it has LPS binding domains, nuclear localisation sequences and the C-terminus is toxic to bacteria. Furthermore, it can be oxidised in vivo to the disulphide form, which is pro-inflammatory. Our aim is to identify a truncated variant of HMGB1 which retains the key property of transitioning stem cells to G(Alert) without the unwanted characteristics of the native molecule and which can be expressed in E. coli and purified with ease. We have already successfully expressed truncated variants of HMGB1 in E. coli and are screening for biological activity using a high-throughput chemotaxis assay. Our truncated variants include forms where cysteines have been substituted with serine to prevent oxdisation to the pro-inflammatory form. We will generate further truncated variants, incorporating data from crystal structure determination of the heterocomplex with CXCl12 and assess the efficacy of the truncations that pass the chemotaxis assay using our well-established murine models of muscle, bone and haematological injury. This will allow us to proceed with development of a therapeutic that will be suitable for testing in early phase clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of CIZ1 in maintenance of epigenetic landscape in primary differentiated cells
Funder: Medical Research Council

Abstract: Inaccurate polycomb repressive complex 2 (PRC2) target gene selection and changes in PRC subunit expression have been linked with many types of cancer, particularly hematological malignancies where the data argue for both oncogenic and tumour suppressor function. Changes in CIZ1 are similarly emerging as widespread early events in cellular transformation, again implicating both oncogenic and tumour suppressor activity. Our analysis of CIZ1 null murine somatic cells at early passage (before immortalization) revealed widespread deregulation of genes that are normally under the control of PRC2, including those located on the inactive X chromosome (Xi). However PRC2 subunit levels are not themselves changed. This project will investigate how CIZ1 determines PRC target gene selection, and build on our recent evidence which suggests that PRC2 is normally attached to the core nuclear matrix, and that CIZ1 supports transfer of repressed chromatin toward the interior of the nucleus (likely visiting PRC2 bodies) specifically during S phase. We will use early passage WT cells because our data show that immortalized cells and tumour-derived cells have already sustained changes in PRC2 (release from the nuclear matrix) that facilitate bypass of the process we wish to study. We will use the Xi as a model to study template transfer (TT) because we can follow its movement, during DNA replication, from its typical position at the nuclear periphery into the interior and back again within a 30 minute window. Thus, this project will address i) the contribution of spatial immobilization of PRC bodies and associated TT to fidelity of PRC target gene maintenance in primary somatic cells and ii) whether the process is bypassed by reversion to a less spatially restricted, embryonic-like, process in transformed cells, and iii) the extent to which our common cultured cell models fail to report on what appears to be an unstudied mechanism that helps to maintain epigenetic fidelity in the body.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Organelle dynamics and function in the late endocytic pathway
Funder: Medical Research Council

Abstract: We will study organelle dynamics in the late endocytic pathway of mammalian cells, focussing on the reformation of lysosomes from endolysosomes. Endolysosomes, formed by endosome-lysosome fusion, are acidic, acid-hydrolase-active organelles from which neutral, acid-hydrolase-inactive, re-usable lysosomes are reformed. We will use small molecule inhibitors, rapid knocksideways inactivation and subcellular fractionation/proteomics approaches to identify protein machinery required for lysosome reformation from endolysosomes. We will investigate the role of the V-ATPase (vacuolar H+ ATPase) in the regulation of acidification during lysosome reformation and lysosome-endosome fusion and, using expressed fluorescent protein-tagged subunits, we will test whether regulation of lysosomal V-ATPase is regulated by the reversible dissociation of VO and V1 sectors, removal of the whole complex and/or binding of other proteins. We shall compare the machinery of lysosome reformation from endolysosomes with that used in lysosome reformation from autolysosomes and we will probe the relationship of intracellular positioning of endolysosomes/lysosomes to their state of maturation in the lysosome fusion and regeneration cycle. Throughout our study we will use confocal fluorescence microscopy, live cell microscopy, super-resolution microscopy, immunoEM and CLEM (correlative light and electron microscopy) of cultured cells to study lysosome reformation and as we uncover protein machinery involved in lysosome reformation and V-ATPase regulation we will use an integrated structural and cell biology approach to investigate protein interactions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structure and mechanism of the Swr1 histone exchange complex
Funder: Medical Research Council

Abstract: Chromatin is a compacted form of packing of DNA in cells that, although it promotes stability of the genetic material, causes problems with gaining access for biological processes such as replication and transcription. Access to the DNA is also required for repair. Cells contain a variety of protein complexes that remodel chromatin, to slide nucleosomes away from regions where access is required or to replace them after these processes have been completed. However, other complexes have different roles in signalling to recruit proteins for different functions. These include complexes that covalently modify histones (e.g.by acetylating lysines in histone tails) and others that physically exchange histones for other histone variants. The 14 protein (1MDa) yeast SWR1 complex (and its human equivalent SRCAP) catalyses the ATP-dependent exchange of histone H2A/H2B dimers for Htz1/H2B (or H2AZ/H2B) dimers. This acts as a signal for downstream processing and recruitment of DNA repair factors but also plays a poorly understood role in regulation of transcription. We have prepared milligram quantities of recombinant SWR1 (and SRCAP) complexes in insect cells and will use this material for high resolution structural studies by X-ray crystallography and cryo-electron microscopy. This structural information will suggest mechanisms for histone exchange that we will explore further using biochemical analysis exploiting a number of different tools we have prepared in the last few years. By combining these studies we hope to gain greater understanding of this important process in DNA repair.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: A molecular dissection of the interplay between diabetes and cancer: an integrated, multidisciplinary approach. II.
Funder: Medical Research Council

Abstract: The experimental paths are very different, due to diverse methodologies of the structural, chemical and cell biology. Receptors. The structural studies in York (IR-A,IR-B,IGF-1R) are re-focused due to gains achieved in the current MRC grant. Receptors and their constructs will be expressed only in the baculovirus system (yielding currently more reproducible/better crystals). Complexes with insulin/IGF1/2 will be expanded for highly specific analogues to decipher their structural signatures. Hormone receptor affinities will be evaluated by ITC & Novo Nordisk proprietary assays. TK protein expression/structural work will be carried in Cork, while TK crystal studies will be done with York. Frequent BAG beam access to DLS (Didcot), and remote data collection are well established. The exploitation of the larger constructs (i.e. IR ectodomains) by cryoEM is initiated, and it will be continued. However, when suitable grids:constructs are established, the cryoEM work will form a separate grant application. Hormones. Analogues of insulin, IGF1/2 will be semi-/fully-synthesised or expressed in E.coli; IOCB has key expertise here. The established wide range of analogue assays (receptor affinities and autophosphorylation, cell viability etc.), will be expanded for IGF-2R receptor essays; unique radio-active (125I, Eu) IGF2 tracers will be produced. All analogues with novel properties will be used in structural studies with the receptors, and optimised further in novel human muscle/fat-tissue cell-based platforms developed here. Cells. CRISPR-Cas9 will be used to knockout all IR isoforms individually (and IGF-1R), creating a novel insulin unresponsive cell line. This line will be transfected to express specific receptor(s) profile, then the insulin/analogues responsiveness of these cell lines will be characterised with respect to i) glucose transport, ii) the proportion of HA-GLUT4-GFP expressed/present at the cell surface, iii) IR downstream effectors activation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE