NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural changes to host and parasite during malarial egress from the human red blood cell
Funder: Medical Research Council

Abstract: This project has two objectives related to egress of merozoites from the Plasmodium falciparum-infected erythrocyte: (1) to determine the structural consequences and function of PfSUB1 protease-mediated proteolytic processing of the major merozoite surface protein MSP1, occurring in the early stages of egress; and (2) to define what cellular and molecular changes occur in the parasitophorous vacuole and red cell membranes leading to their rupture and merozoite release. For objective (1) we will use single particle cryo-electron microscopy (cryo-EM) analysis and biophysical methods to establish the conformation of the merozoite surface protein MSP1 before and after proteolysis by PfSUB1. The findings will be related to merozoite infectivity. For objective (2) we will use existing and novel pharmacological tools combined with state-of-the-art cryo-EM cellular tomography to characterize membrane changes and other structural alterations that lead to their rupture, in normal cells and under experimental conditions that stall egress at different stages. To achieve our aims we have formed a collaborative partnership between groups with complementary strengths in malarial ultrastructure, single-molecule and cellular cryo-EM, malaria parasite biochemistry and cell biology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Structural and Functional Investigation of Meningococcal TonB Dependent Transporters
Funder: Medical Research Council

Abstract: Neisseria meningitidis (the meningococcus) is a human host specific pathogen and a major cause of bacterial meningitis and sepsis. Meningococcal septicaemia develops rapidly and is fatal in about 10% of cases with survivors facing the possibility of permanent disability. There is currently no approved vaccine that protects against all circulating meningococcal strains. An essential feature of meningococcal survival and replication is its ability to extract iron from the human iron transport proteins transferrin and lactoferrin. The mechanism of this iron extraction is unknown but the key players are the outer membrane TonB dependent transporters (TBDTs) TbpA and LbpA (Transferrin/Lactoferrin binding protein A). Other interesting meningococcal TBDTs studied herein include the siderophore receptor FetA, a potential vaccine candidate, and NMB1829, which has an unidentified transport substrate but aids host colonisation. This project will investigate the structural basis of iron uptake from host proteins by TbpA and LbpA. Initial investigations will study the formation of complexes between the TBDT, its target host protein and secondary lipoprotein with the aim of establishing a stable, monodispersed complex suitable for structural studies. The ultimate aim of this part of the work is to elucidate a high-resolution structure of binary or tertiary complexes to explain the iron uptake mechanism. This project also aims to solve the structure of FetA to aid its development as a vaccine component. A collaborating meningococcal vaccine consortium has incorporated FetA into a vaccine formulation due to enter Phase I clinical trials and are therefore interested in its structure. An additional TonB dependent receptor (NMB1829) has been identified as important for meningococcal colonisation of the nasal pharynx and will also be targeted with the aim of not only solving its structure, but more importantly revealing its target molecule by analysing protein expression and bacterial survival in the presence or absence of potential nutrients. The same screen that identified NMB1829‘s role in colonisation also identified three soluble proteins as being important colonisation factors. This project will also structurally characterise these virulence factors and use the resulting structures and specific mutations to test predictions of their functions using biochemistry and microbiology experiments. Deciphering the roles of these proteins and other uncharacterised virulence factors is an important goal as it could lead to the identification of new virulence pathways and antibiotic targets in the meningococcus and potentially in other bacterial pathogens.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Reducing Hospital Acquired Infections Due to Antibiotic Resistant Gram Negative Organisms
Funder: Department of Health (England)

Abstract: Infections caused by multi drug resistant (MDR) gram negative bacteria lead to poor clinical outcomes and high rates of mortality. They represent an increasing challenge to the current healthcare system by limiting the antibiotics available to treat infections and by placing increasing pressure on the isolation facilities that prevent cross transmission. In order to respond to this clinical need it is essential to be able to judge when cross transmissions have occurred, in order to evaluate containment effectiveness. Current typing methods utilised for this purpose have limited access and are expensive, technically difficult and slow to deliver results. What is needed is a rapid typing technique that can be used responsively to inform infection control practice and to aid in making clinical decisions.This project aims to control the spread of MDR gram negative bacteria by focusing on rapid diagnostic techniques, improving control mechanisms by examining isolation policies and finally identifying factors that lead to poor clinical outcome when colonisation occurs.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Nutritional Genetics
Funder: Medical Research Council

Abstract: Nutritional genetics covers research on the role of genetic variation on dietary responses as well as evolutionary aspects of nutritional regulation of gene expression. We employ genetic and epigenetic tools to explore critical pathways that underpin or modulate nutritionally-mediated health and disease outcomes. The key driver of the Nutritional Genetics theme within the ING is the need to provide mechanistic insights into the underlying processes. The Keneba Biobank, a repository of biological samples involving the whole of the rural population of West Kiang (N~12000), presents a resource and major platform for our genetic research. Due to its tight integration across the other ING areas of research, Nutritional Genetics is a cross-cutting theme; we concentrate on the following two sub-themes: 1) Genetics and epigenetics of growth and development. Over several decades our group has collected DNA, birth size and child growth records on individuals living in rural Gambia. This is being used to understand which genes affect growth trajectories employing multi-generational, cross-sectional and longitudinal study designs in combination with high-throughput genome-wide association study (GWAS) and ExomeSNPChip genotyping arrays. Our epigenetics studies test the hypothesis that differences in maternal nutritional status during the periconceptional period influences the establishment of epigenetic signatures in the next generation. Our results on pre-natal supplementation and seasonal differences in dietary intakes demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic DNA methylation changes in their offspring postnatally. 2) Genetics of nutrition-mediated infection. Our past and ongoing research demonstrated that viral, bacterial and host genetic factors modulate iron homeostasis and hence the pathogenesis of infectious diseases. Our future work focuses on seeking to identify genetic variants that affect phenotype variations of iron absorption and metabolism in Gambians. Risk alleles associated with iron deficiency and anemia will be ascertained in a first stage and in a second stage their potential functional effects on phenotypic outcomes including infection will be evaluated.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Investigating temporary relocation of Female Sex Workers: Implications for Health, Care, and Trials
Funder: Medical Research Council

Abstract: Background In many low-income settings the burden of HIV falls disproportionately on female sex workers (FSW). Recent innovations in interventions for FSW use community-level approaches to tackle HIV and related issues. Interventions that improve treatment access and adherence among FSW may contribute to ART coverage targets, and may reduce incident infections. While migrant status and the movement of clients have been studied, the phenomenon of relocation for work temporarily (TR) has not been researched. TR may have implications for community-based interventions, social cohesion, adherence support, and evaluations of intervention effects. Purpose To investigate the causes and implications of TR among FSW living in Karnataka and Zimabwe between 2006 and 2015, and implications for intervention planning. To improve evaluations of interventions for FSW, and pragmatic cluster randomized trials (CRT), by investigating the implications of TR on CRT. Methods (1) KHPT collected three rounds of cross-sectional survey data from FSW between 2006 and 20011. CeSHHAR collected cross-sectional data from 2,800 FSW in 2013, and will collect data on approximately 5,000 more in 2015. (2) The names of places worked other than the sampled location will be geo-located using GIS software ARC GIS, with assistance from local researchers in Karnataka and Zimbabwe. (3) Potential causes of TR will be explored using multilevel modelling and pathway analysis. HIV and ART-use implications of TR will be analysed similarly. (4) A model FSW population will be simulated in R. Parameters will be derived from data. CRT will be simulated with a range of parameters, including: number and distance between clusters, extent of TR, typology of FSW. Scientific developments Quantitative characterization of TR in FSW in variety of settings; implications of TR for intervention planning; risks associated with TR; estimation of risk of bias in impact evaluations.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Menstrual hygiene and school absenteeism among Gambian schools: Preparatory phase for a RCT.
Funder: Medical Research Council

Abstract: Menstrual hygiene interventions may improve girls' school attendance. A systematic review we conducted in 2013 identified 7 interventions studies of menstrual hygiene education which show some evidence that educational interventions can improve MHM practices and reduce social restrictions but the studies had methodological issues(9). A recent qualitative study we carried out among Gambian schoolgirls showed that girls had a poor knowledge about menstruation and that some of the reasons why they miss school were association with menstrual hygiene management (8). Achieving higher levels of education are correlated to important public health outcomes, including reduction of early pregnancies, risk of HIV infection infant and maternal mortality as well as improvements in the nutritional status of children. The aim of this research will be: 1)to test different methods to measure outcomes and collection of basic epidemiology data, 2)understand the intervention needs of the target population,3)to refine the intervention, 4)to assess acceptability and feasibility of the intervention among schoolgirls, parents and teachers.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Combating drug resistance through better governance of unregulated antimicrobial sellers in Cambodia: addressing stakeholder connections & perceptions
Funder: Medical Research Council

Abstract: This Foundation grant addresses the intersection of two 'wicked problems' - antimicrobial resistance and governance of unregulated for-profit healthcare providers. These are challenging to tackle owing to the number and complexity of stakeholders involved who have conflicting interests, as well as the critical role of how the problem is framed in driving responses. Our research will identify the diverse providers that sell antimicrobials in urban Cambodia, and use a political science based social network analysis methodology to investigate power relations and networks between unregulated drug sellers (UDS) and local stakeholders that influence policy. Our analysis will apply the Social Construction Framework for Public Policy to systematically investigate how power relations and social construction reinforce or weaken support for alternative governance measures around antimicrobial selling by UDS, thereby identifying strategies that are likely to be supported by local policy actors and implemented at scale. Cambodia serves as an important case study with wider relevance because, like many other countries in the region and those whose health systems have been weakened by conflict, it has experienced massive growth in for-profit healthcare providers. Research will generate: a) understanding of the social and geographical spread of UDS dispensing antimicrobials in urban Cambodia, b) an analysis of stakeholders that are critical to governing UDS and access to antimicrobials, their networks and power relations and c) on this basis, develop a governance intervention to reduce inappropriate access to antimicrobials through UDS. This knowledge and intervention developed will inform a larger research proposal testing the intervention on national scale in Cambodia and provide timely information for policymaking on UDS in other low and middle-income countries that are currently developing health systems strengthening plans under the International Health Regulations.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Understanding health system linkages: Formative research to develop strategies to support quality improvement in treatment in the private sector
Funder: Medical Research Council

Abstract: Qualitative research with a specific focus on antibiotic treatment will be used to shed light on broader processes affecting quality of care in private clinics and drug shops in Uganda. Through improved understandings of how health system factors can be instrumental in shaping treatment practices by small-to-medium sized private providers (SMPPs), the study will generate novel insights on how health system levers could be used more effectively to (i) support and improve quality of care in the private sector, and (ii) promote responsible prescribing and use of antibiotics in Uganda and other low income settings. The study aims to provide evidence relevant for strategy development in four main areas: 1) Regulation of SMPPs, and improved understandings of the opportunities, challenges, and consequences for the health system. 2) Design of interventions to improve quality of care in SMPPs (provider training/CPD, accreditation, social franchising) 3) Strengthening of linkages between private providers and public health workers, public health officials and regulators to foster partnership, oversight and knowledge exchange 4) Refinement of Uganda's first National Action Plan for Antimicrobial Resistance, and development of specific policies and interventions deriving from the Plan. This knowledge will be timely for strategic planning by the Ministry to Health to develop its national plan to counter antimicrobial resistance. The study will also identify opportunities to build synergy across sectors, inform current debates on the role of the private sector in healthcare provision in Uganda, and help shape models for future implementation. The findings will be used to engage with local stakeholders to co-design a comprehensive strategy to promote responsible prescribing and use of antimicrobials, and support quality improvement in health care services in SMPPs in Uganda. Evaluation of this intervention strategy will form the basis of a future grant application.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: MICA:Development of new paradigm in differentiated care for HIV patients; Community pharmacy drug refill using the ARTAccess Mobile phone application.
Funder: Medical Research Council

Abstract: Can a set of interlinking mhealth technologies integrated into existing health systems improve and expand the care and treatment of people living with HIV in order to achieve the 90:90:90 UNAIDS goals? Technologies based on cheap widely available mobile phones (mHeath) provide an opportunity to support health systems, but are so far understudied. In Uganda we have developed a range of models of care that have helped to differentiate care for people living with HIV (PLHIV). These allow intensified support for those who need it whilst safely reducing interactions with stable patients. We are now starting to evaluate mHealth interventions that will allow further streamlining of these models of HIV care delivery, so that more people can access ART within our limited resource envelope. We are working with community pharmacies to deliver anti-retroviral drugs (ART) with additional nursing support. This foundation grant will allow us to pilot the use of mHealth tools to link patient information on ART and viral load to an algorithm which guides a community pharmacy on ART delivery without additional staff needs. We ultimately aim to evaluate a complex intervention based on interlinking mHealth tools which support health service delivery, logistics and information management to improve outcomes in PLHIV whilst reducing the burden on human and financial resources. This will require a large multi-site research trial using creative approaches and development of new research methodologies. In this foundation grant we will conduct preliminary studies including feasibility, acceptability and evaluation of the impact of introduction into the health systems of 2 novel mHealth innovations. We will use descriptive, qualitative, quantitative and cost analysis methods to evaluate the effect of the pilot on the health system. We will develop methods to enable a multi-site trial of a complex intervention with multiple mHealth technologies supporting different health system functions.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Non-adherence to treatment: a methodological approach to compensating for its impact in chronic infections, using tuberculosis as a model disease.
Funder: Medical Research Council

Abstract: Non-adherence to treatment costs hundreds of billions of dollars globally per year and is particularly problematic in chronic diseases, which require lengthy treatment. In addition to persistence of symptoms and increased disease severity, poor adherence in communicable chronic diseases risks the development of drug resistance, jeopardising both individual and population-level health. Adherence guidelines frequently tacitly assume that all doses must be taken for successful treatment. Clinical trials often set simple thresholds- e.g. 80% of doses taken- to define adherence. The reality is complex; granular analyses of the relationship between adherence (percentage of overall duration taken, patterns of missed doses, percentage of doses taken) and treatment outcomes are critical for effective translation of trials into clinical guidance. This study aims to utilise different methodological approaches to assess the impact of evidence-based adherence patterns on treatment outcomes and inform how this should influence our approach to treatment. A model disease (tuberculosis) has been chosen on the basis of its global importance and the need for improved regimens. The Objectives and methods are: 1) Describe statistically how, when and why non-adherence occurs and the relationship between adherence and outcomes across different settings. 2) Determine how adherence patterns influence the temporal development of drug resistance. 3) Use an adaptable reaction kinetic model to assess the impact of treatment adherence on optimal dosing. 4) Draw together these strands of evidence to determine how adherence should influence our approach to treatment. This work will advance the scientific community's thinking when designing future clinical trials. The disease-adaptable approach to determine how adherence influences a drug's 'operational efficacy' will change how guidance is written. Its methodologies will be usable for a wide array of chronic diseases.


Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Development of two community-based interventions targeting inappropriate antibiotic dispensing and use behaviours in rural Vietnam
Funder: Medical Research Council

Abstract: Between 2000 and 2010, worldwide antibiotic consumption increased by 35%, including large rises in use of last-resort antibiotics, and particularly in middle income countries. Reducing inappropriate antibiotic use has been shown to reduce the prevalence of antibiotic resistant bacteria at population-level in high income countries, but few population-level interventions aiming to reduce antibiotic use have been evaluated in low and middle income countries with higher burdens of infectious disease and antibiotic resistance. This development grant will inform the design of two community-based interventions aiming to reduce inappropriate antibiotic use and resistance. One intervention will target the supply of antibiotics through private pharmacies, the major source of treatment for minor illness, where antibiotics can easily be obtained without a prescription. Introducing rapid diagnostic tests would help pharmacists to differentiate between bacterial and non-bacterial infections, and reduce inappropriate antibiotic dispensing. The other intervention will tackle the demand for antibiotics in communities by using participatory action research to improve understanding of the problem of antibiotic resistance, and develop appropriate strategies to address at community-level. To inform the design of the interventions, we will conduct a literature review, and qualitative and economic interviews with providers and consumers of antibiotics. We will use a community-led media approach to develop messages and content for the community group intervention. During the development phase we will also develop a probabilistic mathematical model to explore the potential impact of community-based, pharmacy-based, and combined approaches.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION