NIHRDataInsights/HRCSData huggingface dataset:
Title: ICT Solutions for Real-Time Electronic Monitoring of Antimicrobial Use & Resistance in the One Health Approach
Funder: Medical Research Council

Abstract: Adopting a ""One Health"" approach, this project will explore information and communication technology (ICT) solutions to create an electronic platform to holistically monitor antimicrobialuse and resistance in real time using ""big data"" from a range of surveillance systems on antimicrobial use and resistance in the human,(food) animal and environmental sectors in the UMgungundlovu district in KwaZulu-Natal, South Africa. The project will compare and contrast different surveillance systems in terms oftechnical feasibility and cost effective delineation of robust,representative surveillance data in addition to creating the electronic platform. The ""big data"" generated from the three sectors will be triangulated by adapting one or more of the open source software solutions: (1) WHONET and (2) ""Suite for Automated Global Electronic bioSurveillance"" (SAGES} which will allow analysis and visualization within and between sectors at district level. The real-time data on phenotypic trends in antimicrobial resistance (AMR) in correlation with antimicrobial use/exposure are expected to: 1. Assess the reliability, representivity and financial and technical feasibility of generating antimicrobial use and resistance data from: a. Point prevalence surveys,passive,laboratory-based,sentinel surveillance,and, active,disease-based, comprehensive surveillance in human health, b. The implementation of integrated,""farm-to-fork"" surveillance in animal health, and, c. Water-based surveillance systems in environmental health. 2. Allow early identification of emerging/escalating resistance within and between sectors, 3. Establish a database for evidence-based treatment guidelines and associated essential medicines lists for the optimal management of infections in humans and (food) animals, 4. Ascertain whether the surveillance of AMR in human sludge,animal manure-based fertilizers and water sources could serve as suitable proxies for AMR in human,animal and environmental health using Escherichia coli and Enterococcus spp. as indicator organisms,and, 5. Provide ""information for action"" by the various sectors and their regulatory authorities.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Using whole genome sequencing to develop Antimicrobial Resistance Reference Facility for One Health in South Africa
Funder: Medical Research Council

Abstract: Antimicrobial resistance (AMR) in human pathogens is reaching a crisis point with many pathogens becoming multidrug resistant and thereby untreatable. Although much work has been done to improve surveillance for AMR in nosocomial pathogens and sexually transmitted infections, surveillance for resistance in food and waterborne pathogens, with the exception of typhoid fever, remains problematic in the developing world. This is further complicated in that AMR may not be related purely to antimicrobial use in humans, but may also be affected by antimicrobial use in food and domestic animals and the persistence of antimicrobial in the environment. Whole genome sequencing (WGS) is proving to be a powerful tool in the identification of microbial evolution, including monitoring for the development of antimicrobial resistance. WGS is additionally the most exacting method to compare to bacterial isolates to confirm epidemiological linkage and has been invaluable in investigating food and waterborne outbreaks globally. International experience has shown WGS may be used as an alternative to conventional methods to characterise, serotype and define AMR in enteric pathogens. This project proposes to develop WGS techniques in South Africa to characterise enteric bacteria from South Africa human, animal and environmental sources to promote the rapid investigation of food and waterborne disease outbreaks in the country, which remain a significant public health burden. Experience gained from this work will be shared across the subcontinent and possibly the greater sub-Saharan Africa region. This project falls within: New technology innovations to improve surveillance. How can technology be used to improve and scale surveillance?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Human infection challenge vaccine (HIC-vac) network
Funder: Medical Research Council

Abstract: The Industrial Challenge Strategy Fund supplement is designed to bring diverse and flexible pump-priming activities to the Network with additional industrial involvement. This award will provide a support linkage, increasing UK Vaccine R&D activity around ‘proof of concept’ studies and can be used to support academic-industry partnerships and enhance academic and industry researchers' understanding of each other's needs and capabilities. This may be through people exchanges, creation of tecnology demonstrators, showcase events, workshops and pump-priming of grant activities.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);3.4 VACCINES
Health categories: INFECTION
Title: High Dose AMBISOME on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: A Randomized Controlled Trial
Funder: Medical Research Council

Abstract: Cryptococcal meningitis (CM) is associated with 10-20% of deaths in HIV-programmes in Africa. Ten-week mortality rates with current treatments range from 30-60%; novel treatments are urgently needed. Use of standard amphotericin B therapy is limited by side effects and the need for intensive nursing care and laboratory monitoring. Recent pharmacokinetic and clinical data show it may be possible to deliver safe and effective therapy for HIV-associated CM with very few large doses of Ambisome (liposomal amphotericin B, L-AmB). L-AmB has low rates of nephrotoxicity, long tissue half-life, and good brain penetration. The concept of single or intermittent dosing with very high doses is also established in prophylaxis in haematology patients and treatment of visceral leishmaniasis (VL). Single doses of 15mg/kg have been safely given, and 10mg/kg doses are routinely given for treatment of VL. We propose to determine whether short-course high-dose L-AmB is as effective as 14-day amphotericin B therapy (standard of care) in averting all-cause mortality in HIV-associated CM patients in a phase 3 clinical-endpoint trial. 850 patients recruited at 6 east and southern African sites will be randomised to either short course high-dose L-AmB (the shortest-course L-AmB regimen found to be safe and effective in an ongoing phase-II dose finding study) or standard 14- day amphotericin B deoxycholate, both given with fluconazole 1200 mg/d for the first 2 weeks. The primary outcome will be all-cause mortality within the first 10 weeks of treatment. Secondary objectives are to determine the fungicidal activity and safety profile of short-course high-dose L-AmB, and determine the health service costs of the two treatment regimens. If short-course treatment regimens were shown to be effective, the results of this study would lead to evidenced-based changes in treatment guidelines, and provide a practical treatment option with the potential to prevent many thousands of deaths.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Regulatory Genomics and System Biology
Funder: Medical Research Council

Abstract: The availability of completely sequenced genomes and genome-scale datasets provides us with a wealth of information and the opportunity to investigate fundamental problems of a different magnitude and kind that is complementary to conventional approaches. While much of this information is publicly available, one of the major challenges we face is to be able to mine this enormous amount of data and integrate them in a meaningful way in order to (i) generate experimentally testable hypotheses and (ii) uncover general principles that govern living systems. ||Research in my group aims to understand how regulation is achieved in cellular systems at three levels of complexity (Molecular, Systems and Genome level) and how they influence genome evolution. This area of research is important because many human diseases are a result of dysfunction of regulatory processes and understanding design principles of regulation can be exploited in biotechnology and medicine. At the molecular level, we investigate regulatory proteins that are involved in protein-protein, protein-nucleic acid and protein-small molecule interactions. In particular, we aim to gain an understanding of the proteins involved in the ubiquitin pathway, chromatin modification pathway and GPCR receptor signaling. At the systems level, we aim to gain an understanding of (a) how aggregation prone proteins are tolerated and regulated in cellular systems, (b) how pathogens could possibly exploit host machinery and signaling through molecular mimicry by secreting unstructured proteins that expose host-like peptide motifs and (c) understand the dynamics of regulatory proteins such as protein kinases, metabolic enzymes, etc within the context of their position in the various molecular interaction networks. Finally at the genome level, we investigate (a) the interplay between nucleosome modification and genome organization, (b) mutations and their impact on genome and transcriptome evolution and (c) the genetic basis of natural variation in specific behavioral traits.||To pursue these lines of research, we develop new computational methods that make use of the publicly available large-scale datasets. These include sequence, structure, expression and molecular interaction data from several different model organisms ranging from bacteria to fungi to humans. We also use newly available data on natural variation, cancer genome sequence and gene expression and nucleosome modification data, and information from genetic screens linking genotype with phenotype. The problems that we work on in my group have the ultimate objective of being able to identify new regulatory principles and features of regulatory systems, to exploit our findings and the general principles that we describe in specific applications such as genetic engineering, and to better understand regulatory dysfunctions leading to human diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: HIV Care Research Programme / Follow up of slow disease progressors and of individuals on long term ART
Funder: Medical Research Council

Abstract: In 2009, a well characterised cohort has been established at the MRC/UVRI Uganda Unit in Entebbe of about 700 HIV-infected patients who have been receiving anti-retroviral therapy (ART) for 5 years or more, with some on ART since 2003. Most of these patients had formerly participated in the international DART trial. Researchers from the DART research centres in Uganda and Zimbabwe agreed to maintain follow up of DART study participants and collect compatible data so that the various former DART sub-cohorts continue to provide good quality longitudinal data to inform ART treatment policy in Africa. Together they form one of the longest standing ART cohorts in the continent. The Entebbe project also comprises an additional group of about 100 infected individuals who have been diagnosed with HIV infection more than 5 years ago, but whose disease progression is very slow and who do not require ART yet. Patients in this population are seen at clinic every 3 months. For the long-term ART group, the objective is to study (i) the outcomes of 1st line ART up to 10 years, in terms of rates of treatment failure necessitating a switch to 2nd line ART (after 5 years, 19% of DART patients in Uganda had switched to 2nd line ART, how this proportion changes over time is important information for ongoing ART programmes); (ii) the possible long-term toxicities of 1st line ART in African populations; (iii) the medium-term impact of the boosted protease inhibitor class which is currently widely introduced in Africa as the mainstay of 2nd line ART (protease inhibitors may have a different toxicity profile in Africans compared to populations of industrialised countries, due to different dietary and other risk factors for the established cardiovascular and metabolic complications of this drug class; (iv) the durability of this 2nd line ART regimen; (v) the long term impact of initiating ART with a single class (3NRTI) regimen as used for many patients in DART (initiating therapy with a 3NRTI regimen was uniquely implemented in DART and has the advantage of preserving 2 ART drug classes; (vi) whether the good adherence to 1st line ART as observed in DART will be maintained outside of a trial situation and which factors are associated with good long term adherence; (vii) the development of viral resistance among patients who have not been managed using real time viral load; and (viii) the pattern of morbidity and mortality among patients with long term ART in Africa. Part of the cohort will provide a valuable resource for the MRC funded COSTP trial, that will investigate whether cotrimoxazole prophylaxis can be safely discontinued among patients who have regained their immune-competence on ART. The sub-cohort on long term progressors will continue to provide valuable data and blood specimens in support of the Units Basic Science Programme research on immunological characteristics that may be helpful for vaccine development.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Social Aspects of Health / Social and economic aspects of HIV care and support
Funder: Medical Research Council

Abstract: This research investigates the social and economic costs and benefits of HIV care and support. Many patients in need of ART live in rural areas from where it is not easy to access HIV care services. The necessary investment of time and costs to access ART may affect adherence to ART. Delivery of ART services close to patients residence may reduce this problem, but may lead to difficulties related to stigma and disclosure, as well as the standard of care provided. ||Three projects have been conducted on this theme. One provided a qualitative methodological perspective on adherence to ART by participants of the randomized controlled trial of home based versus facility based ART delivery strategies conducted in Jinja and to establish to what extent patients disclosure of HIV status to family members or significant others in the community influences social wellbeing; the second undertook a cost-effectiveness study of that care delivery. The first of the projects with the Jinja trial participants studied 40 clients purposively selected at enrolment of the Jinja Trial from three sample strata: trial arm (home vs. facility), disease status at enrolment (CD4 count over 150 cells/ul or WHO stage 1 or 2, versus CD4 count under 100 cells/ul or WHO stage 3 or 4), and gender. Consenting participants gave semi-structured interviews at enrolment and at 3, 6, and 18 months after starting ART and in the 3rd year of the trial. ||The third project studied whether the introduction of ART in the peripheral health centres had an impact on the health workers in the peripheral health centres. We focused specifically on whether the roll-out resulted in an increased work load; reduced work clarity for nurses as they are asked to carry out roles and responsibilities formerly carried out by doctors and clinicians; more strained relationships between health workers and their supervisors leading to reduction in social capital; an increase in work stress, reduced role clarity and reduced social capital will lead to reduced job satisfaction and reduced job satisfaction will lead to reduced organizational citizenship behaviour. Data were collected from health centre staff who both provided and did not provide ART and, in a second phase, from health centre clients.||The different components of this programme of work have been co-funded from different sources including the core budget of the MRC/UVRI Uganda Research Unit on AIDS, the US Centre for Disease Control and Prevention (CDC) and from the Ugandan Office of the Department for International Development (DFID).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: Social Aspects of Health/Social impact of the HIV epidemic
Funder: Medical Research Council

Abstract: As the HIV epidemic intensified in the 1990s, a growing number of studies documented aspects of its impact on households, businesses and national economies. However many of the initial studies of rural societies and of the impact of HIV and AIDS were essentially short-term cross-sectional views from which long-range conclusions and generalizations were made. The complexity of determinants of household vulnerability to HIV and the capacity to resist or recover from the impact of AIDS-related disease and the trajectories such recovery (or none thereof) take, remain unclear. Similarly, less is known about how the long term impacts of HIV and AIDS on agricultural practices and productivity and livelihood of households and how such impacts affect wider community relationships, operations, systems and structures. Five research projects have been conducted or are currently being executed under this theme. The first assessed the impact of HIV-infection on households over a 15-year period (1991-2006) in a rural setting in Uganda (identical with the study area of the General Population Cohort). The second examined the decisions around foster care for orphans and non-orphans within the extended family. It focused on the process leading to the fostering decisions in rural Uganda and the experience of children and families affected by this process. The third seeks to establish the relationship between orphanhood and education outcomes in a cluster of rural villages in Uganda; and to investigate the roles that parental characteristics, childrens attributes and fostering arrangements play in this relationship. The fourth focuses more specifically on the impact on agriculture and seeks to determine the impact of HIV and AIDS in Uganda on rural livelihoods for the past 20 years in order to understand the long-term impact of the epidemic and to contribute to the design of policies and programmes for impact mitigation. The fifth project is nested within the fourth, and examines household food production and consumption longitudinally and the impact on food security.| |The complementary components of this programme of work is funded by different sources which include the core budget of the MRC/UVRI Uganda Unit, the Economic and Social Research Council (ESRC) and the Food and Agriculture Organisation of the United Nations (FAO).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: Enveloped viruses and coated vesicles – cryo electron microscopy and tomography.
Funder: Medical Research Council

Abstract: The goal of this research programme is to develop and apply electron microscopy and tomography techniques to study the assembly and fusion mechanisms of enveloped viruses, as well as of coated trafficking vesicles. Enveloped viruses and coated trafficking vesicles are extraordinary self-assembling machines. The protein building blocks must interact with one another to collect all relevant components and/or cargo together at the assembly site, they must reshape a lipid bilayer to form the bounding membrane of the virus/vesicle, and they must drive a membrane scission process to release the virus/vesicle from the donor membrane. The virus/vesicle typically then undergoes a reassembly or disassembly proves to prepare for fusion with a target membrane. We aim to obtain a detailed, mechanistic understanding of these processes and of how they are regulated. To achieve this goal we need to obtain detailed structural information at different stages during assembly under close-to-native conditions. This is a challenge for conventional structural biology tools so we are developing and applying new approaches for cryo-electron tomography, correlated fluorescence and electron microscopy, and image processing. The main systems being studied are influenza virus, human immunodeficiency virus, clathrin-coated vesicles, and COPI-coated vesicles. For both influenza virus and human immunodeficiency virus, we will attempt to understand the mechanisms by which small molecules or antibodies can interfere with assembly, maturation or fusion.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: HIV Interventions
Funder: Medical Research Council

Abstract: Work under the HIV Intervention Programme has two broad aims. Firstly, to prevent acquisition of new infections, and secondly to improve survival and quality of life among people living with HIV. To address these aims several scientific projects will be undertaken partly by the Unit, and partly through scientific collaboration with our long-term partners and institutions in Europe, USA and Africa. Access to HIV prevention remains inadequate and does not necessarily prioritize key populations such as female sex workers (FSWs) and fishing communities (FC). Prevention of new HIV infections in such populations is a high priority for Uganda and elsewhere. We aim to conduct HIV intervention research in these populations by building on recent advances in biomedical interventions, some of which we participated in, such as oral and topical pre-exposure prophylaxis (PrEP), and HIV combination prevention. This programme of work builds on our past successes and expertise in conducting HIV epidemiological research in key populations and, work on designing and evaluating HIV prevention, treatment and care strategies in Africa. For example, we have been part of the work that recently showed efficacy of the Dapivirine vaginal ring in HIV prevention, and of the START trial that showed the benefit of initiating ARVs whenCD4+ count >500 cells above starting treatment in patients after the CD4+ count had declined to ≤350 cells/mm. The prevention research will include: i) continuation of research on evaluating HIV vaccines in early phase I and II trials, and new microbicides - especially combination and long acting products in collaboration with other research partners; ii) a pragmatic, randomized open-label wait-listed trial evaluating the effectiveness of tenofovir without the presence of a placebo-control to reduce the risk of HIV acquisition among high risk women, iii) assessing the long term safety profile and adherence of Dapivirine Vaginal Ring


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION