NIHRDataInsights/HRCSData huggingface dataset:
Title: Urban violence and pacification in Rio's favelas: innovative approaches to measurement and quantifying health system impacts
Funder: Medical Research Council

Abstract: Evidence gaps relating to health system functioning in areas of high urban violence are inhibiting progress towards universal health coverage (UHC) and the Sustainable Development Goals. This is particularly the case in cities in low- and middle-income countries in Latin America with high homicide rates and large urban slums. This study aims to address important research gaps by exploring innovative approaches to measuring urban violence and quantifying health system impacts. The research will be based in the city of Rio de Janeiro where there are large challenges from urban violence, and recent interventions aiming to address urban violence (a pacification programme) and expand primary healthcare. It will build on strong collaborations between Imperial College and Brazilian-based investigators and advance existing research on this globally important topic. Four specific areas will addressed in the research: i) multiple data sources, including policing data, geocoding homicides, app-based reports, and school closures, will be used to explore different approaches to measuring local exposure to urban violence; ii) the impact of urban violence on clinic roll-out as part of a major investment in PHC between 2008-16 will be examined. Regression modelling will be used to adjust for other local factors; iii) quasi-experimental fixed effects panel regression will be used to understand how episodes of local violence impact health service functioning, with metrics such as clinic closures, opening times, home visits used a proxies for healthcare access and quality; iv) the pacification programme's impact on health system functioning will be evaluated using quasi-experimental method such as interrupted time series and event studies.

Lay abstract: Note - this award is managed by MRC but funded via Foreign, Commonwealth & Dev Office

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Balancing safety and good care in the context of infectious disease outbreaks: learning health systems for infection prevention and control in Uganda
Funder: Medical Research Council

Abstract: In resource-poor health systems experiencing infectious disease (ID) outbreaks including Coronavirus disease, health care workers (HCW) negotiate globalised standards for infection prevention control (IPC) under locally specific conditions and constraints and balance the need to care alongside that to protect. Set in Uganda, a country that has experienced multiple ID outbreaks in recent decades, this project applies a relational approach to the study of IPC measures in the context of care provision in health facilities and communities. Using methods drawn from policy research, anthropology and geography, our analysis of IPC measures is grounded in a broader mapping of temporal, geographic and social distances that characterise the material realities and practices of care in health facilities and communities of two contrasting regions (South-Central and West Nile). First, we employ documentary analysis methods, key informant interviews and life histories to elucidate path-dependent influences of past ID outbreaks on current discourse and practice of IPC. Second, interviews, observations, and participatory mapping techniques will examine how current implementation of IPC physical barrier and distancing measures relate to social, professional, and geographic hierarchies of care provision. We will further elicit how formal and informal caregivers attend to care needs and mitigate risk and safety in the context of ID outbreaks including COVID-19. Third, data will be synthesised and shared in consultation workshops to assess where and how health care workers and communities experiences of providing care in the context of ID outbreaks can be usefully integrated into current IPC and health systems strengthening initiatives. Our project aims to deliver findings that can inform health protection practices and protocols, optimise safe and compassionate care for vulnerable populations, and strengthen learning systems for epidemic preparedness within and beyond Ugandan borders.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Development of miDOC: an expert system and methodology for multiple imputation
Funder: Medical Research Council

Abstract: Missing data are common in health research, increasingly addressed by multiple imputation (MI). There are unresolved methodological questions around how to choose the best imputation model for each incomplete variable. Application of MI can be complex and involve multiple decisions which are rarely justified (e.g. which variables to include in each imputation model, how to specify the functional form of each imputation model, diagnostics for the MI procedure, etc). We will tackle these outstanding issues, and combine our insights with current knowledge into a new automated expert system, the 'multiple imputation Doctor' (miDOC). MiDOC will guide researchers through their analyses, and by providing documented decisions and code, will increase reproducibility and transparency of analyses. Objectives: 1-3: Resolve outstanding questions around bias due to incorrect specification of the imputation model (even when compatible with the analysis model), and bias due to including variables that are strongly predictive of missingness, or due to over-fitting of the imputation model 4: Develop methodology and an associated algorithm to identify the optimum choice of variables to include in an imputation model, for imputation of different types and roles of variables 5: Extend diagnostics to address issues in (1), including diagnostics for over-fitting of imputation models. 6: Incorporate the results of (1) - (5), together with current knowledge, into an expert system, miDOC, developed in R. miDOC will take the scientific model and data, then (i) identify whether MI is likely to be biased, (ii) implement a sensible MI strategy and (iii) provide diagnostics , including a summary of the MI assumptions. 7: Apply miDOC to exemplar analyses 8: Disseminate the results through conference presentations, research articles, workshops, courses and guidance for researchers, our established website, www.missingdata.org, and the next edition of Carpenter & Kenward.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing and Testing Participant Information Leaflets (PILs) that Inform and do not Cause Harm (PrinciPILs)
Funder: Medical Research Council

Abstract: Presentation of potential trial participation harms and benefits in PILs varies, with trial benefits sometimes not being mentioned. This can waste scarce resources (with every PI having to negotiate their own method) and can cause information-induced adverse events ('nocebo effects'). Our aim is to develop and test PILs that help solve these problems. This will be achieved in 5 steps: 1. Obtaining stakeholder views: We will obtain participant, clinician, ethicist, medico-legal expert, research nurse, and trial manager views about how to balance information about trial harms and benefits within PILs. 2. Identify Principles: Based on (1), develop principles to guide PIL design. 3. Development: Based on (2), design PILs for three trials. We will call these 'PrinciPILs'. 4. Testing: Set up five studies within a trial (SWATs). The SWATs will involve randomising participants to receive 'standard' PIL (developed by host trialists), or a PrinciPIL. We will analyse early results (recruitment and retention rates, AEs) ease of recruiting host trials; facilitators and barriers to PrinciPIL-testing and acceptance. We will also set up an infrastructure for embedding results of future PrinciPIL SWATs in a meta-analysis, should this be required. 5. Generating guidance and a resource for designing and testing PrinciPILs: We will produce guidance for producing and testing PrinciPILs. We aim for this resource to be become part of the package supported by the HRA and therefore may result in changes to their templates for PILs. Importantly, PrinciPILs are valuable even if they do not reduce information induced AEs. This is because PrinciPILs will be generated using the transparent methodology described above, whereas the way in which trial benefits and harms are presented in current PILs which do not seem to be based on an ethically justified rationale.


Research activity codes: 6.8 COMPLEMENTARY;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Reporting of randomised factorial trials: development of extensions to the CONSORT 2010 and SPIRIT 2013 guidance statements
Funder: Medical Research Council

Abstract: Reporting standards for protocols (SPIRIT) and results (CONSORT) of randomised trials improve completeness and transparency of research. Randomised factorial trials require additional methodological complexity in design and analysis not included in standard SPIRIT and CONSORT statements. This study aim is to improve reporting of randomised factorial trials by developing extensions to CONSORT and SPIRIT statements. We will: (1) complete a scoping review of the literature; (2) conduct an online Delphi survey and (3) consensus meeting of stakeholders including trials researchers, knowledge users, research funders, journal editors, and PPI (patient and public involvement) representatives; (4) produce and disseminating extension checklists and associated explanatory documents. We aim to complete the scoping review by end of 2020, prior to commencing funding for this study. The output from the review will be a list of items (approximately 40) related to reporting design, conduct and analysis of factorial trials. Phase 2 of the study is an online Delphi survey. Participants will rate importance of each item on the provisional list for inclusion in guidance statements. We anticipate inviting around 100-130 participants. We will conduct two survey rounds. In round 2, participants will see their own round 1 responses and a summary of all other participants' responses. Following completion of round 2, items will be categorised as 'consensus in', 'consensus out' or 'no consensus'. 'Consensus out' items will be discarded and all other items taken forward to a consensus meeting of around 30 participants. Each item will be presented and voted on for inclusion in final checklists for SPIRIT and CONSORT extensions for factorial trials. We will produce and disseminate the extensions and supporting materials widely through publication, presentation at conferences and workshops, and free availability on the Equator Network and CONSORT and SPIRIT websites.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploiting instrumental variables to estimate the effects of time-varying treatments using routine data
Funder: Medical Research Council

Abstract: Decision makers are increasingly using routine data to evaluate health interventions when evidence from clinical trials is limited or unavailable. This has been particularly relevant to the evaluation of treatment strategies sustained over time due to the limitations of trials regarding the duration of follow-up and treatment adherence. The ability to derive valid estimates of sustained treatment effects from routine data critically depends on adequate control of both measured and unmeasured confounding, at each point in time. Instrumental variable (IV) methods have been widely used to address the confounding by exploiting sources of variation, known as 'instruments' (e.g. genetic factors), that explain treatment assignment but have no direct effect on outcomes. However, existing IV methods are not appropriate for addressing the time-varying nature of the confounding in the estimation of sustained treatment effects. This research considers a novel approach that incorporates IV analysis into the marginal structural model (MSM) framework, which can adjust for the time-varying confounding. The project tackles outstanding methodological and practical issues that must be addressed before this combined IV-MSM approach can be adopted to derive valid inferences from routine data. We will achieve this in four related work packages: 1) To assess the validity of time-varying instruments through the use causal diagrams, graphical tools and falsification tests. 2) To address the recurrent issue of 'weak instruments', by exploring matching approaches and multiple robust estimators to improve the strength of time-varying instruments. 3) To extend the standard IV-MSM approach to deal with continuous instruments, as these are often considered in studies using routine data. 4) To translate the proposed methods to a broad audience by illustrating substantive applications of these across different clinical settings, and by providing software tools and practical guidance.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulating e-pharmacy: challenges and opportunities for access and quality of care in LMIC health systems
Funder: Medical Research Council

Abstract: E-pharmacy is a growing phenomenon in low and middle-income countries. It has the potential to improve accessibility, reduce prices, and enhance quality assurance, yet public health concerns abound. Inappropriate use of prescription-only medicines purchased online is argued to lead to increased morbidity and mortality, antibiotic resistance and controlled prescription drug use disorders, with cyber-security threats also a significant risk. Regulation of the sector has not kept pace with these rapidly evolving, dynamic markets which operate with ease across national boundaries. This study will provide new evidence on the performance and regulation of e-pharmacies in Kenya and India- two countries at very different stages of e-pharmacy development and with contrasting political and regulatory settings. We will characterise the e-pharmacy markets in both countries in terms of their scale, scope, business models and website regulatory compliance, using a mix of internet scraping, website review and in-depth interviews. The performance of e-pharmacies will be assessed using standardised patients (online mystery clients) to measure the proportion of cases managed in line with recommended care and government regulations, and prices charged. A sub-set of medicines purchased will be tested for quality through package inspection, and analysis of available active pharmaceutical ingredient and dissolution. We will conduct a critical appraisal of e-pharmacy regulation in each country, and assess options for amendments, drawing on document review and in-depth interviews with staff from regulatory, professional, industry and patient bodies. Finally, we will study the policy processes influencing the design and implementation of the regulatory environment, drawing on the '3I+N' framework of interests, ideas, institutions and networks.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Reducing the Burden of Serious Health-related Suffering: An evidence base to close national divides in access to palliative care and pain relief
Funder: Medical Research Council

Abstract: Lack of palliative care is a global health and equity imperative that will prevent LMICs from achieving the target of Universal Health Coverage (UHC) in SDG3. The raging of COVID-19 in Latin America (LA) demonstrates the weakness of health systems that lack universal access to palliative care and pain relief (PCPR). The Lancet Commission (LC) identified essential research - which this programme will take forward by focusing on LA and projecting regionally and globally. We hypothesize that prioritizing and investing in universal access to appropriate PCPR can improve the quality of life and of dying, free scarce resources and strengthen health systems overall by improving balanced and safe access to pain relief medications. Potential impact on indicators such as opioid availability and use of tertiary beds for end-of-life care will be used to test the hypothesis. Our research intervention uses DCP3 models to design PCPR packages, based on the UHC frameworks of progressive universalism and structured pluralism. Progressive universalism is a pro-poor, equity enhancing, preferred pathway to UHC through public financing of an initially limited set of high-quality, cost-effective interventions for population-wide delivery. The structured pluralism model builds on LA health reform experience on benefit packages as explicit entitlements to realize the right to health. Research activities include: 1. Determine the optimal mix of medicines, equipment and human resources to design essential packages for children and expanded PCPR packages for adults and children. 2. Match packages to conditions requiring PCPR using LC methods. 3. Cost packages by country and compare to international prices. 4. Model additional cost-saving opportunities and identify opportunities in the packages to promote gender responsiveness. 5. Propose national PCPR performance indicators, and monitor against COVID-19 tracked data. 6. Convene virtual trainings focused on PCPR and health systems.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the multigenerational link between sperm RNA content and birth defects caused by abnormal folate metabolism
Funder: Medical Research Council

Abstract: It is becoming clear that environmental stressors (e.g., poor diet) experienced during our lifetime increases disease risk in our children and grandchildren. While the mechanism is unclear, the inheritance of epigenetic 'information' via gametes is likely. Persistence of a disease phenotype beyond the F2 generation in the absence of stressors and genetic mutation is called transgenerational epigenetic inheritance (TEI). Though TEI in humans is becoming evident as a contributor to the increasing prevalence of cardiovascular and metabolic disease, our mechanistic understanding is limited to exciting work in plant and invertebrate models. However, we recently generated a robust mouse model of TEI (Mtrr model) whereby disruption of folate metabolism in the F0 generation is sufficient to cause congenital malformations (e.g. neural tube defects) up to the F4 generation. Our unpublished data in the Mtrr model indicate epigenetic instability in spermatozoa of F0 males including genome-wide alterations in DNA methylation and small tRNA fragments (tsRNA) content. tsRNAs were recently implicated in direct epigenetic inheritance of metabolic disease. If and how gamete epigenetic instability is recreated in each generation to perpetuate TEI is uncertain. We hypothesize that epigenetic instability in gametes escapes reprogramming to influence development and metabolism in the next generation. Sequentially, this forms an environment that creates germ cell epigenetic instability, thus propagating disease risk over multiple generations. Our goal is to explore whether alterations in sperm tsRNA content sufficiently phenocopies epigenetic instability and multigenerational inheritance of congenital malformations in the Mtrr model by influencing metabolism in the F1 generation. Overall, we aim to tease apart general and paradigm-specific mechanistic effects of TEI to gain a greater understanding of the long-term measures required to prevent non-communicable diseases and birth defects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: High-fidelity epigenetic maintenance in somatic cells: CIZ1 assemblies as molecular shield
Funder: Medical Research Council

Abstract: CIZ1 forms large RNA-dependent assemblies around the inactive X chromosome, and smaller assemblies throughout the nucleus. Deletion of CIZ1 deregulates approximately 2% of genes in primary fibroblasts, causes loss of H3K27me3, H2AK119ub1 and H4K20me1, and predisposes mice to lymphomas and leukemias. We can model de novo formation of CIZ1 assemblies, and acquisition of histone post-translational modifications (PTMs), by adding ectopic CIZ1 to genetically null cells. This shows that a prion-like polyglutamine domain in the N-terminus of CIZ1 is essential for assemblies to form. Crucially, CIZ1 protein fragments encoding this domain (but lacking other essential elements) can also destabilize endogenous CIZ1 assemblies, leading to loss of histone PTMs. For H2AK119ub1, this is abrogated when deubiquitinylases are chemically inhibited. This suggests a novel function for CIZ1 as a molecular shield that promotes epigenetic stability by protecting chromatin from deubiquitinylases. It is important to understand this because truncated isoforms of CIZ1, similar to those with dominant negative assembly-dispersal capability in our assays, are evident in early stage common solid tumours, and possibly also mimicked by polyglutamine fragments derived from the Huntingtin protein. Here, we ask whether CIZ1 assembly destabilization by dominant negative fragments impacts on gene expression using a transcriptomic approach, and also ask how it affects the location and behaviour of the inactive X chromosome during its replication. We also seek to understand a normal biological context in which alternative splicing appears to modulate assembly formation and dissolution. An independent strand will compare histone PTMs in WT and CIZ1 null fibroblasts, then tissues, to establish the breadth of CIZ1's influence over chromatin state.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using structural and chemical biology to understand the roles and mechanisms of CDKs: generating hypotheses for drug discovery
Funder: Medical Research Council

Abstract: This programme will exploit our collaborations and strengths with CDK reagents, biochemical/biophysical assays, structural biology and small molecule and peptide chemistry to dissect the mechanisms by which CDKs regulate the cell cycle and transcription. Our first aim is to advance understanding of the activity of CDK-containing complexes. To this end we will: (i) Continue crystallographic and cryo-EM studies of CDK9-cyclin T-containing and p27KIP1-CDK2-cyclin A-containing complexes (ii) Initiate crystallization trials of CDK11 and CDK11-cyclin L/D3 complexes. (iii) Use structural and biophysical techniques to define the cyclin K-SETD1A interaction. (iv) Carry out crystallographic fragment ("FragLite") screens against (i) CDK4/6-cyclin D1/3 complexes and (ii) CDK2-cyclin E. We will assess the functional significance of hotspots identified in this way by directed mutagenesis followed by cell free (SPR, ITC, HTRF) and cell-based assays for known protein partners. We will use affinity purification mass spectrometry to identify new interactors and initiate structural studies for tractable and biologically significant protein interactions identified. Our second aim is to exploit structural insight into CDK-cyclin complexes to develop hypotheses for allosteric and PPI approaches to drug discovery. To this end we will: (i) Exploit our FragLite map of cyclin T to generate molecular and chemical tools to dissect the impact of specific cyclin T interactions on P-TEFb-dependent transcriptional programs. We will compare the effects of this approach to that of conventional CDK9 inhibitors and use this workflow to guide studies to follow up our FragLite screen of cyclin K. (ii) Carry out mRNA-display screens to identify potent CDK11 and cyclin L, CDK4, CDK6 and CDK-cyclin D3, and cyclin K-specific cyclic peptides. This work will enable functional studies to identify and characterise CDK and cyclin protein binding sites and roles.


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