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gen_42ecc64bc4961485414088e6bd111f13 | Strengthening the quality of adolescent primary healthcare in South Africa: preliminary work on a complex public health intervention | Medical Research Council | University of Cape Town | HRCS22_02513 | Over half the world's adolescents live in countries like South Africa, with high levels of communicable and non-communicable diseases, obesity, high adolescent fecundity and unmet need for contraception. Although at increased risk, adolescents are marginalised and face barriers in accessing healthcare. In South Africa many policies set out to right this, nevertheless, adolescent-specific service provision is lacking especially with regards to inter-sectoral collaboration. The Knowledge Translation Unit has developed a PACK Adolescent health systems strengthening intervention which covers the comprehensive and integrated primary healthcare of a 10 to 19 year old. At 6 clinics and 12 schools in South Africa, we will conduct a situational analysis of adolescent primary healthcare using observations of non-clinical healthcare processes and clinical consultations, interviews with policymakers and community-based organisations and focus groups with managers, clinicians and adolescents. Two theory of change workshops with key stakeholders will help adapt the intervention using minimum components that incorporate an understanding of adolescent health needs across clinics and schools. The customised intervention will then be piloted in 6 schools and 12 clinics. A parallel, mixed methods process evaluation will include observations of consultations and interviews with adolescents and clinicians. A survey questionnaire will be completed by end-users 6 months after implementation to assess the intervention's reach. Impact will be assessed through monitoring routine data of adolescents accessing healthcare in schools and clinics. We will engage with stakeholders in the design, adaptation, pilot and implementation phases through an advisory board of national and provincial stakeholders in health, education and social services, as well as adolescents themselves, to ensure that the study and the intervention speak to the needs of adolescents and their healthcare providers. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_e11c80763c6105790dbc691a3f47f4fd | Building a sustainable model to promote menstrual, sexual and reproductive health (MSRH) amongst secondary school girls in Tanzania | Medical Research Council | Mwanza Intervention Trials Unit | HRCS22_02514 | The project addresses a critical evidence gap in how to comprehensively address menstrual, sexual, and reproductive health (MSRH) challenges of adolescent girls in Tanzania. Poor MSRH is associated with subsequent psychosocial (high levels of shame, depression, anxiety) and physical (pain, increased risk of reproductive and urinary tract infections) ill health, and poor school outcomes (including poor performance, participation, and completion). Our Theory of Change builds on a model which was developed after a qualitative metasynthesis of 76 studies and over 6,000 women and girls. The model shows how the social and cultural context underpin social support, behavioural expectations, knowledge, and the physical and economic environment that affect elements of girls' menstrual experience, including practices and perceptions, confidence to participate, and menstrual-anxiety, all ultimately impacting on girls' mental and physical health and education. The project will be conducted in four phases. An initial inception phase (Phase 1) will be followed by a formative phase (Phase 2) to iteratively refine an existing MSRH intervention and collaboratively design strategies to embed the intervention into government structures thereby promoting scaleability. In Phase 3 we will pilot and evaluate the refined intervention and implementation strategies using a before-after mixed methods design to assess (a) feasibility (including cost per student, school and district), sustainability, and acceptability and (b) effect on MSRH practice and perceptions and the overall school climate. In the final phase (Phase 4) we will collaboratively synthesise the research findings. Our phased project approach will enable us to develop a scaleable MSRH intervention that fits within Tanzanian government structures to improve MSRH practices and perceptions and the school climate to ensure the psychosocial wellbeing and optimal school participation and performance of secondary school girls. | 3.2 Interventions to alter physical and biological environmental risks / Research Grant | 6project_grants_public |
gen_4dcac5332114637177cfc2c8bbc1f621 | Impact of prophylactic CPAP in the delivery room (DR-CPAP) on neonates <1500g in a low-resource setting: A feasibility trial | Medical Research Council | Mbale Clinical Research Institute | HRCS22_02591 | Complications of prematurity are the leading cause of deaths in children under the age of five and the majority occur in low income countries. The predominant reason for these preterm deaths is respiratory distress syndrome (RDS). In high-income countries (HICs), the use of early CPAP, within 15 minutes of delivery, can reduce the need for mechanical ventilation and surfactant in the treatment of RDS. In low-resource settings, where access to mechanical ventilation or artificial surfactant is limited, when CPAP fails there are limited options for care. We hypothesise that initiation of early prophylactic CPAP in the delivery room (DR-CPAP) will reduce the rate of CPAP failure and therefore the neonatal mortality rate in low-resource settings. This project will develop and test for feasibility, acceptability and safety a protocol for DR-CPAP, which if successful can later be tested for efficacy in a future trial. The feasibility of initiating CPAP in VLBW neonates within 15 minutes of delivery in this low-resource setting will be evaluated. The acceptability of administering CPAP in the delivery room will be assessed. The safety of DR-CPAP will be evaluated through adverse events. This project will ensure that deferred consent with prior assent is acceptable to both the mothers and the medical staff for a trial of neonatal emergency care. We will pilot low-cost third party randomisation and assess if neonates can randomised within 15 minutes of delivery to allow initiation of DR-CPAP within a suitable timeframe. This study will validate secondary outcomes for the future trial. The strong involvement of health leaders, medical staff, and mothers at all stages will ensure that if successful, the intervention will be both acceptable to the communities and more effectively scaled-up. Together these findings will allow us to design a large and robust multi-centre unblinded randomised controlled trial to evaluate the impact of DR-CPAP on mortality in VLBW infants. | 6.3 Medical devices / Research Grant | 6project_grants_public |
gen_3b0381a25647d59d20e3348aa3826957 | Patient-led support groups in the management of hypertension and diabetes in low-resource settings: mixed methods study of an innovative model | Medical Research Council | African Population and Health Research Center | HRCS22_02592 | The long term ambition of this project is to improve the lives of low and middle-income people living with untreated hypertension and diabetes across Africa through a patient-led model of care. Our work is motivated by the rising burden of hypertension and diabetes in a rapidly urbanising Africa and scarce public resources for managing patients. Patient support groups have gained considerable interest as a strategy to reach low-income patients, however, there is insufficient evidence to scale up such groups widely. We have seen a window of opportunity in long-lived experiences of 6 patient groups in the slums of Nairobi and we want to interview these patients and co-design a model of care and evaluate the feasibility of conducting a large trial. We plan to conduct this through three interrelated work packages. The first work package will be a mixed methods approach starting with ethnographies, focus group discussions, in-depth interviews and survey of patients in the groups. Key informant interviews of healthcare providers will also be conducted. A literature review to assess the adaptability of the models in Africa will follow. This formative work will inform the design of a model that we will pilot (work package 2) in two communities in Nairobi slums. The novel data from the pilot will inform design, sample size, logistical considerations for a multi-country trial. We have assembled a multi-disciplinary team to undertake this task. The last work package (work package 3) entails networking with stakeholders to disseminate findings and for investigators to plan the design of a large trial. We anticipate this work to be completed in 24 months. | 7.3 Management and decision making / Research Grant | 6project_grants_public |
gen_253df1104a294b0ad6fe2cecab7a29f4 | Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa | Medical Research Council | Wits Health Consortium | HRCS22_02609 | South Africa faces a complex health burden with rising non-communicable disease against a background of prevalent infection. Malnutrition, undernutrition alongside overweight/obesity, is widely prevalent, imposing risks along the life course especially among adolescent girls. We propose an intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition, using established research sites: rural Agincourt and Soweto. We hypothesise that, by optimising change in BMI of adolescent girls at-risk, we can realise a triple return on investment: improved nutrition, reduced metabolic risk, and moderated peri-conceptional exposures to offset transgenerational risk for metabolic conditions. We ask: 1. In high-risk nulliparous adolescent girls, can a community health worker-delivered intervention of nutrition (multi-micronutrient supplementation) and lifestyle change, with a conditional-cash transfer (i) achieve directionally-appropriate changes in BMI?, (ii) improve micronutrient status?, and (iii) influence individual behaviours? 2. Will these changes impact individual metabolic disease risk? 3. In those adolescent women who become pregnant, will reductions in variance of BMI from improved BMI status during the peri-conceptional period impact maternal glucose during pregnancy and new-born birth weight and adiposity? Further: is the intervention package cost-effective; can findings contribute to strategies to tackle the adolescent double burden of malnutrition and reduce trans-generational risk for metabolic disease? We will enrol 1248 underweight or overweight/obese girls 14-19y using age-/sex-appropriate cut-offs. After baseline assessment/randomisation, participants will be reassessed after 18-24 months follow-up. If a participant becomes pregnant, a reassessment will be conducted in pregnancy (<18weeks) and further measures collected during pregnancy and birth. We include both process and economic evaluations. | 3.1 Primary prevention interventions to modify behaviours or promote well-being / Research Grant | 6project_grants_public |
gen_833483a3b797d0af3da128dc5c173ac1 | Nutrition-sensitive epigenetic mechanisms in the early human embryo - developing insights from stem cell and organoid models | Medical Research Council | London School of Hygiene and Tropical Medicine | HRCS22_02610 | A seasonal 'experiment of nature' in rural Gambia has revealed the presence of DNA methylation (DNAm) hotspots sensitive to periconceptional environment. These are enriched for metastable epialleles, endogenous retroviruses and parent-of-origin-specific methylation (PofOm) suggesting establishment in the early embryo. This is further supported by analysis of public IVF and gametic DNAm datasets which show distinctive patterns of early embryo DNAm dynamics along with enrichment for regions hypomethylated in sperm. Several loci are linked to disease outcomes, including obesity, thyroid disease and cancer. Genetic analysis suggests the greater part of DNAm variance at many season-of-conception (SoC)-associated loci is explained by gene-environment interactions, suggesting they may have evolved to sense the environment, record the information and adapt the phenotype accordingly. Such 'programmed' epigenetic states would be maladaptive if there is a mismatch with the postnatal environment, with implications for the developmental origins of health and disease. This grant will allow me to gain a deeper understanding of early embryonic epigenetic processes and the techniques that are available to interrogate these, through joining a group at the University of Cambridge that has pioneered work in this area. I will use this knowledge and links with researchers working in the Department of Genetics to devise experiments to test key aspects of our nutritional programming hypothesis in developmental cell and gastruloid models, enabling me to probe the roles of specific nutrients, genetic variation, specific transcription factors (e.g. ZFPs), and chromatin remodelling via histone modifications. | 1.1 Normal biological development and functioning / Research Grant | 6project_grants_public |
gen_61e7ee6934863ca7044e0f6f5f26b569 | Duration of protection and density of colonisation following pneumococcal conjugate vaccination with a booster dose | Medical Research Council | London School of Hygiene and Tropical Medicine | HRCS22_02653 | Global control of pneumococcal disease is hampered by the cost of PCV. More than 20 countries are projected to 'transition' from GAVI vaccine subsidies in the next 5 years. Continuation of PCV programmes will require substantial increases in country expenditure on PCV. Gambia introduced a three-dose PCV schedule without a booster dose (a '3+0' schedule), with large reductions in vaccine-type (VT) invasive pneumococcal disease (IPD) and pneumonia. Now that VT IPD is controlled, a cluster-randomised trial has begun comparing the ongoing use of the 3+0 schedule with transition to a two-dose schedule with a booster dose at 9 months of age (a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection given its likely greater effect to prevent acquisition of pneumococcal bacteria. The ongoing study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures. Despite this and other studies of the 1+1 schedule that are underway, significant gaps in knowledge remain, and none of the current studies will determine the duration of the effect of the booster dose to prevent acquisition of VT pneumococci, the effect of the booster dose on density of VT colonisation, nor whether anti-pneumococcal IgG concentration or function are associated with rates of VT acquisition. The proposed study will extend randomised follow-up of 784 participants measuring VT acquisition with repeated nasopharyngeal specimens to 28 months of age, VT colonisation density at age 10 months by qPCR and pneumococcal microarray serotyping, and opsonophagocytic activity in additional participants to compare with the effect of IgG concentration on rates of acquisition. Our findings will inform WHO policy on PCV scheduling, allow mechanistic interpretation of the trial results, and provide duration of protection and force-of-infection inputs into mathematical modeling of the booster dose effect. | 3.4 Vaccines / Research Grant | 6project_grants_public |
gen_d3bd0c6fc044e0a3ea8d3c62db41f0ee | Doctors under siege: Making sense of the rising incidence of violence against doctors in India. | Medical Research Council | Gokhale Inst of Politics and Economics | HRCS22_02673 | Society grants medical professionals' status, respect, and privilege with the expectation that physicians would be competent, altruistic, moral, and conscientious. A well-functioning social contract and a harmonious relationship between the medical profession and the people it serves is essential for a country's health system to fulfill its mandate - in India this social contract seems to be breaking down. Globally, many societies have seen major transformations in their social contracts with the medical profession, however in India, this historically stable social contract is unraveling with a dramatic rise in violent attacks on doctors. We contend that this unraveling deserves critical examination to understand what underpins it - we argue that this understanding is an essential first step to inform changes to the nature of the medical profession's relationship with Indian society. This is the objective of our study. We will conduct an exploratory, qualitative study using in-depth interviews with purposefully selected participants to unpack how various societal actors experience and understand these acts of violence. Through comparing the understandings and experiences of different actors we will reveal the cleavages and disconnects in the current social contract, and the implications going forward. While the inquiry will be inductive, it will be guided by theoretical understandings around social conflict and foregrounded by the socio-economic-political processes shaping the society and the medical profession in India. Insights from our study will be of interest to social and health policy makers, and to the medical profession in India and beyond. We will share our insights widely within the medical profession with a view to trigger conversations and critical reflections about the state of social contract. We will also use study insights to work with stakeholders in India to inform the development of innovative and practical health system interventions. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_eedd5125a586004fada1a8fde287dcb5 | Developing an mHealth intervention to strengthen the community mental health system in the context of the COVID-19 pandemic in Peru | Medical Research Council | Cayetano Heredia University | HRCS22_02674 | The COVID-19 pandemic and the mandatory social distancing have made visible the challenges the Peruvian health system faces to provide remote care. People with mental disorders are particularly vulnerable in this context, due to the impact of the pandemic on their health, as well as the limitations in accessing services. As a result, the Ministry of Health in Peru published guidelines to providing mental health care through telemedicine. In this context, which is simultaneously a great challenge and opportunity for the community mental health system in Peru, we proposed a two-year project with the following objectives: (1) To assess the impact of the pandemic on the community mental health system in Peru, (2) To identify the strategies implemented to preserve the provision of mental health care during the pandemic and assess, using the Learning Health Systems framework, the readiness to deliver remote mental care, (3) To co-design and evaluate the performance of an mHealth intervention to deliver remote care within the community mental health system in Peru. To achieve this, the study comprises 3 phases: (1) the formative phase, centered around the first two aims, will involve the review of local and international guidelines and evidence produced during the pandemic and a qualitative study with stakeholders. (2) The intervention development phase to co-design along with stakeholders the mHealth intervention based on the formative phase. Finally, (3) the pilot of our intervention, assessing implementation and clinical outcomes. The pilot will recruit 60 participants (30 users and 30 relatives) who will receive the intervention delivered by 15 health providers. Recruitment will take place at 3 Community Mental Health Centers. Data will be collected at 3 different time points: (i) before starting, (ii) during and (iii) after finishing the intervention, through questionnaires, in-depth interviews, as well as data generated through the mHealth platform. | 2.3 Psychological, social and economic factors / Research Grant | 6project_grants_public |
gen_7bea01300256253bac06fc70ef3b2649 | Strengthening the health system for a people-centred community orientation in South Africa. A formative study. | Medical Research Council | University of KwaZulu-Natal | HRCS22_02675 | Health systems in sub-Saharan Africa are typically fragile, reactive and vertically organised - being ill-equipped to deal with multiple co-existing health problems, such as malaria, tuberculosis, HIV and non-communicable diseases; as well as emerging shocks such as COVID-19. The Lancet Commission on the future of health in sub-Saharan Africa identified health systems reforms towards people-centred systems as necessary for achieving longer and healthier lives in this region. People-centredness focuses on prevention and health promotion - empowering people to be more in control of their health and that of their communities. Strengthening of the community sub-system - a historically neglected component of the health system, comprising households, civic groups, community structures and other sectors - is central to strengthening a people-centred health system. While there is political will on the part of the South African Department of Health to make a shift towards a people-centred community-oriented health system, visible in policies promoting re-engineering of primary health care (PHC) in particular; there is a knowledge gap on how to implement these reforms operationally. To provide academic direction to closing this knowledge gap, the applicants have partnered with the KwaZulu-Natal provincial Department of Health and NGOs to provide strategic academic direction to achieve these reforms operationally. Through this foundation grant, we will conduct a formative investigation of the barriers, needs and opportunities for strengthening of the pillars of the health system as conceptualized by the Lancet Commission of Quality Health systems. Guided by Realist Evaluation (RE), this formative work will inform the co-development of Initial Programme Theories (IPT) which will provide logical conceptual models for strengthening of these key pillars, including multisectoral approaches.Testing and refining these models will form the scope of work for a full-stage proposal. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_3422cc2e13123f66fd290d014a5fb403 | Promoting Universal Health Coverage for Amputees through Social Enterprise and Engineering Innovation | Medical Research Council | Makerere University | HRCS22_02677 | In Uganda, as in many other LMICs, prosthetics services have been developed, and supported by international NGOs (e.g. ICRC), in humanitarian responses to conflict. When support is withdrawn, post-conflict, health systems struggle to integrate and maintain such services. Despite the government's commitment to universal health coverage, Ugandan citizens usually have to provide the cost of materials or devices. Local suppliers are scarce and orders from abroad are only made when a user has paid a percentage of the cost. This drives up costs, compromises quality, introduces delays, uncertainties and additional visit. It also makes maintenance a great challenge leading to poor device utilisation. In reality, many amputees do not have access to prosthetic services, although data on access is extremely poor. The Ugandan government adopted the Public Private Partnership (PPP) as a model for health system strengthening, where foreign partners make a significant contribution to public resources. Until now the PPP approach has only been utilised in the not-for-profit hospitals and large research institutions and has not been tested in public services. Our aim is to determine how engineering and social innovation can improve Uganda's ability to deliver universal health coverage in prosthetic services. We will integrate innovations in prosthesis design, coupled with fine-resolution modelling of demand, to pilot new, distributed prosthesis service models, characterised through our collaboration with Joint Medical Stores via a PPP model. To achieve our objectives, the following work packages are planned: (1) Promoting universal health coverage through health system strengthening and social enterprise; (2) Mapping clinical need, service distribution and quality, and scoping modelling of future services; (3) Evaluating the introduction of appropriate new technology into the Ugandan supply chain; and (4) Engagement and development of a proposal for a follow-on proposal. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_0b4fb628510513c6891cac82e4c03105 | Learning health systems: fostering participatory learning and action to equip rural health workers as change agents for maternal and newborn care. | Medical Research Council | South African Medical Research Council | HRCS22_02686 | Our study aims to create a culture of organizational learning within rural health facilities towards maternal and newborn health (MNH) care quality improvements. We will evaluate an innovative health system strengthening approach in rural KwaZulu-Natal, South Africa (SA) using participatory learning and action (PLA) groups. Evaluation sites are two rural districts, comprising 9 district hospitals and 2 community health centres. Districts were selected on the basis of low population density, long distances between levels of care, poor road infrastructure, lack of health resources, and poor MNH indicators. We will use implementation research methods to co-design and document intervention implementation via a mixed methods approach. A before-after evaluation design will assess the effect of PLA on organizational learning culture and person-centered MNH care. Pre-implementation, in-depth interviews with health personnel at all levels of participating districts exploring challenges of MNH care provision, and interviews with rural women as recipients of care, will inform the development of the intervention. Baseline and end-line cross-sectional surveys will measure facilities' performance as learning organisations, and womens' experiences of patient-centred MNH care. Two validated tools, 1) Dimensions of Learning Organisation questionnaire, will measure facilities' performance in terms of team learning, management support, and leadership, and 2) the Person-centred Maternity Care score (PCMC) will measure womens' MNH care experiences and their perceptions of newborn care in terms of dignity and respect, autonomy and supportive care. These will provide quantitative measures of change over the implementation period. A process evaluation using qualitative case study methodology will rigorously document the intervention implementation. An economic evaluation will determine budgetary implications of replicating this intervention routinely in rural districts in SA. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_91184a03ca8f605c6c98c39751790358 | Developing Strategies to coordinate HEalthcare provision between The GAmbia and Senegal (SHEGAS) | Medical Research Council | London School of Hygiene and Tropical Medicine | HRCS22_02688 | An increasingly mobile global population (there were an estimated 1 billion international and national migrants in 2019) poses challenges to policymakers, who must ensure their health systems can provide good quality healthcare to an increasing number of patients with diverse health needs. This is a particular challenge for policymakers in Low- and Middle-Income Countries (LMIC), particularly those in Africa, who already have over-stretched health systems, and who face fast-increasing rates of population mobility. This is particularly critical in the time of the Coronavirus Disease 2019 (Covid-19) pandemic. However, there is little relevant literature LMIC policymakers can draw on to inform their decisions. This research will adopt a participatory approach to co-develop a health systems strategy to coordinate people movement between The Gambia and Senegal - two countries with close political ties, a common pre-colonial history, and a different colonial and post-colonial history, leading to different political systems and official languages. We will adopt a mixed methods approach to first of all determine the volume of cross-border healthcare use, the influence of history on current population mobility and healthcare provision and use, to examine pre-exisiting formal and informal coordination mechanisms between different West African countries (including The Gambia and Senegal), and to explore the impact of the Covid-19 pandemic on cross-border health system coordination. We will use this information to co-develop a health system-wide strategy for responding to cross-border movement of patients between The Gambia and Senegal, in collaboration with policymakers from both countries, through the use of participatory multi-criteria mapping approach. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_34886efec3a32ee3dbdd9f49abb6cd8d | Gates Foundatoin | Arcady Group, LLC | INV-024993 | to improve the adherence to TB treatment, this grant will help address the market access, uptake, implementation, and utilization challenges of digital adherence technologies in low-middle-income countries | Agricultural Development / Global Health | 4other_research_funding | |
gen_14eb09d49c92711a1085bfafcccafa09 | SARS-CoV-2 infection, transmission dynamics and household impact in Malawi (SCATHIM) | Medical Research Council | University of Malawi | HRCS22_02717 | Sub-Saharan African countries have adopted prevention measures similar to those used in developed countries to combat the SARS-CoV-2 virus (COVID-19) pandemic, although their social, cultural and economic contexts are markedly dissimilar. Limited empirical data exist on SARS-CoV-2 transmission dynamics and the feasibility of prevention measures in diverse African households, to guide the adaptation of the preventive measures. We aim to determine the transmission dynamics, determinants and socio-economic impact of SARS-CoV-2 infection in households located in urban medium-density, urban high-density and rural-high density locations in Malawi, Africa. Our specific objectives are to (1) measure the secondary attack rates of SARS-CoV-2 infection within households of symptomatic and asymptomatic index cases, (2) assess how SARS CoV-2 susceptibility and clinical outcomes among household contacts of index cases are influenced by socio-demographic, nutritional and anti-SARS CoV-2 immunological status; co-infections (HIV, TB, malaria) and their treatments, and household environment, (3) assess the acceptability, feasibility, adoption and effectiveness of personal protective equipment among household members of index cases, (4) describe lived experiences of caregivers of SARS-CoV-2 index cases, and (5) estimate the direct and indirect costs associated with SARS-CoV-2 prevention and care in households of index cases. Through this study, we will generate contextually-relevant empirical data for identifying high risk individuals; predicting the intensity of SARS-CoV-2 transmission and the impact of preventive measures; and designing appropriate social safety nets for households affected by SARS-CoV-2. Our research team's existing engagement with policy makers and local health department will facilitate knowledge translation and enhance their pandemic response capacity. | 2.3 Psychological, social and economic factors / Research Grant | 6project_grants_public |
gen_d78cc0b99ed8b7ea24bef86ac7c48761 | To investigate the spectrum, determinants and long-term outcome of SARS-CoV-2 in African children, immune responses and protective role of prior sHCoV | Medical Research Council | University of Cape Town Lung Institute | HRCS22_02720 | To prospectively investigate SARS-CoV-2 in African children, we will leverage 2 ongoing cohorts: (i) the Drakenstein Child Health Study (DCHS), a birth cohort study with comprehensive longitudinal measurement of risk factors, a very well phenotyped population and large biobank of samples. Children will be followed for 3 study visits with repeated sampling through the epidemic and at any intercurrent illness. (ii) study of children hospitalized with pneumonia at the largest childrens hospital in Sub-Saharan Africa. Children will be tested for SARS-CoV-2 and for other viral pathogens by PCR of nasal samples. Clinical features, risk factors, nasal specimens and blood samples (serum, Paxgene, PBMCs) will be collected in children. PCR for SARS-CoV-2 and other respiratory viruses will be done on nasal samples. Serology for SARS-CoV-2 will be done in all children; in DCHS we will also investigate the role of prior seasonal coronavirus (sHCoV) infection using biobanked samples to investigate serological responses to sHCoV and potential cross protection for SARS-CoV-2. Immune markers, cytokines and RNA expression profiles will be measured to identify SARS-CoV-2 associated inflammation compared to other viral infections or asymptomatic illness. All children will be followed at 12 months for long-term health outcomes. This study design will enable us to investigate symptomatic and asymptomatic SARS-CoV-2 and serological responses, including cross-reactivity and cross-protection from sHCoV. We will also be able to compare clinical, immunological and inflammatory profiles and long term outcome of children with COVID, with asymptomatic infection, and with other viral-pneumonia, in a LMIC community and hospital setting. | 2.1 Biological and endogenous factors / Research Grant | 6project_grants_public |
gen_6859c540590f0117e2cd7e34b836b99a | Evaluation of low birth weight infant post-discharge outcomes and development of community-based follow-up and monitoring strategies in Africa | Medical Research Council | Aga Khan University, Kenya | HRCS22_02738 | Globally, every year 2.5 million newborns die. Low birth weight (LBW) infants (birth weight< 2,500g) who constitute 15% of all newborns, have the highest risk of mortality and adverse long-term growth, health and neurodevelopmental outcomes. They include both preterm and intrauterine growth restricted infants and majority are born in low-and middle-income countries (LMICs) in sub-Saharan Africa and Southern Asia. Over the past two decades, interventions to improve facility-based care in LMICs for LBW infants have been tested and implemented, but the scarcity of longitudinal data to determine the predictors of poor outcomes and inform the design and timing of interventions have hampered progress in improving their post-discharge outcomes. LBW infants in impoverished communities are particularly vulnerable and community-based strategies to monitor and address gaps in their care in a timely manner have the potential to improve their outcomes. Community-based peer support for mothers is effective in improving breast feeding practices in infants in low resource settings and has the potential to improve post-discharge survival outcomes for LBW infants. We propose to evaluate the predictors of stunting and neurodevelopmental impairment among LBW infants using a cohort of well-characterised mother-infant dyads recruited from one rural and two urban health facilities in Kenya and The Gambia over a period of 30 months. In addition, using a mixed methods approach, we will explore the feasibility and acceptability of embedding mother-to-mother peer support for LBW infants in community-level quality improvement strategies for maternal and child health in Kenya over a 12-month period. The data from these two studies will enable us to refine a community-based package of interventions for LBW infants and inform the design of a cluster randomised trial to rigorously evaluate the impact of these interventions on LBW infant survival, growth and neurodevelopmental outcomes. | 8.1 Organisation and delivery of services / Research Grant | 6project_grants_public |
gen_48d0cb4fdcb3cad21d7f47725486f2b9 | Host-virus interactions in KSHV-related malignancies: evaluating the role of STIP1 as a therapeutic target | Medical Research Council | Rhodes University | HRCS22_02739 | Molecular chaperones are essential for protein homeostasis. Hsp90 and Hsp70 function as broad host factors for viral protein folding and are essential for both KSHV latent and lytic replication cycles. As such, we believe KSHV is exquisitely sensitive to perturbations in molecular chaperone systems and inhibition of these pathways is a viable therapeutic strategy. However, targeting molecular chaperones directly is not without issue, due to cells having the ability to circumvent chaperone inhibition by activating alternative stress pathways. For example, resistance to the cellular stress response triggered by Hsp90 inhibition can be overcome by upregulating other chaperones, including Hsp70. To circumvent this issue, we will target alternative components of the stress complexes. Co-chaperones are accessory proteins that fine-tune the function of Hsp70-Hsp90 complexes. Specifically, the co-chaperone STIP1 (also known as HOP) couples the de novo and stress-related protein folding pathways of Hsp70, to the conformational regulation cycle of Hsp90. Therefore, inhibiting STIP1 function is a potential mechanism to simultaneously perturb both Hsp70 and Hsp90 function in viral infection. Our preliminary data suggest that STIP1 is required for survival of latently KSHV infected PEL cells and production of lytic virions. During lytic KSHV replication we determined that STIP1 become enriched in host networks regulating translation and ribosome biogenesis, cytoskeletal remodelling, and metabolism, all of which are necessary for KSHV infection. In addition, four KSHV-encoded proteins were associated with STIP1 during lytic replication. Based on this, this project will aim to understand the mechanisms by which STIP1 regulates the identified host and viral pathways, while concurrently extending the analysis of STIP1 as a therapeutic target in KSHV-infected cells and identifying hit compounds that inhibit STIP1 which could be developed into antiviral agents in future. | 2.1 Biological and endogenous factors / Research Grant | 6project_grants_public |
gen_bfc56ae67e7702f03548d849eb1652da | Development and pilot testing of an m-health intervention to reduce COVID-19 associated psychosocial distress among Nigerian healthcare workers | Medical Research Council | Obafemi Awolowo University | HRCS22_02740 | The advent of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) across the globe has brought severe disproportionate distress on individuals, communities, health resources, and nations. The distress is increasingly eroding the mental health and wellbeing of patients and caregivers in contexts with precariously fragile health resources. Nigeria with all health parameters below the WHO standard is no exception. COVID-19 related distress in Nigeria is rapidly jeopardising the mental health and wellbeing of health workers, especially doctors and nurses who spend relatively more time with patients. Doctors and nurses, hereafter referred to as healthcare workers (HWs), are brutally besieged by long working hours, psychological distress, fatigue, and occupational burnout. Also, the HWs' exposure to the virus is exponentially increasing while some of the control measures, like social distancing, imposed by the government are depleting their social capital and social connectedness, further undermining their mental health and wellbeing. However, m-health intervention is increasingly seen by some experts as a game-changer in the context of solutions to mental health and wellbeing challenges. Therefore, this project investigates COVID-19 associated psychosocial distress and evaluate the feasibility and pilot-testing of a guided m-health intervention among Nigeria's HWs. The study will use mixed-method to collect data for pilot-testing a guided m-health intervention to reduce Covid-19 associated psychosocial distress among the HWs in selected tertiary hospitals, Southwest Nigeria. The findings of this project would provide useful information on the feasibility of using such intervention for improving the psychosocial health of Nigerian HWs. | 7.1 Individual care needs / Research Grant | 6project_grants_public |
gen_676761ae23c8340d11d6169719025221 | Two-way risk communication mobile application versus traditional methods of adverse drug reaction reporting in Uganda: a randomized controlled trial | Medical Research Council | Makerere University | HRCS22_02798 | There is an urgent need to improve pharmacovigilance in Uganda. Despite efforts to improve reporting using web- and paper-methods, adverse drug reaction (ADR) reporting by healthcare professionals (HCPs) remains critically low. We aim to complete a cluster-randomised controlled trial to evaluate the effectiveness of a mobile application in addition to traditional web- and paper-based methods for ADR-reporting by HCPs. Our goal is to recruit 3820 HCPs from 382 ART-sites in Uganda to evaluate the Med Safety(R) mobile application, developed by the European Union WEB-RADR programme to embed digital PV in healthcare. Med Safety(R) is available in English and Luganda and has been implemented in limited settings in Uganda since February 2020. We aim to discover the barriers and facilitators to Med Safety(R) uptake, its effectiveness in improving PV, and the cost-effectiveness of rolling it out to HCPs at ART-sites. Our study will have two arms: HCPs enrolled at ART-sites in the intervention arm will be trained in the use of Med Safety(R), paper- and web-based ADR-reporting methods and those in the control arm will be trained in the use of paper- and web-based ADR-reporting only. HCPs will be encouraged to report ADRs through onsite awareness campaigns, reminder WhatsApp and mobile phone short messages. To-date we have enrolled 243 HCPs from 45 intervention sites and 386 HCPs from 41 control sites, using funding from Makerere University. We are requesting funds from the MRC to deliver the rest of this project. The work will deliver important insights into the practicality, acceptability and effectiveness of mobile application-driven ADR-reporting in a resource-limited setting and increase our knowledge of the safety of dolutegravir-regimens and isoniazid preventive therapy among people living with HIV in Uganda. This work underpins potential national roll-out of Med Safety(R) among HCPs in collaboration with Uganda's National Pharmacovigilance Centre. | 7.3 Management and decision making / Research Grant | 6project_grants_public |
gen_06c6ecea0ed0536adf1d12eef879141c | Healthcare and Socio-economic Impacts of COVID-19 on Patients with Diabetes in Tanzania and Kenya | Medical Research Council | Ifakara Health Institute | HRCS22_02810 | This project will provide much-needed, timely and unique evidence from rural and urban areas of neighbouring East African Countries (Tanzania and Kenya) with different approaches to the control of COVID-19. The project aims to explore the experiences of people with type 2 diabetes (T2D) and healthcare providers on managing T2D during COVID-19. Guided by the World Health Organization Social Determinants of Health and Wellbeing Framework [1] , it will focus on how the pandemic has impacted patients' and healthcare providers' ability to manage T2D, the socio-economic burden of T2D, and patients' response to COVID-19 itself. It will also identify policy gaps in each country in relation to health and social care of T2D during COVID-19. The study will foster multidisciplinary collaboration and capacity building by close working between scientists from Africa and UK throughout delivery of five interrelated workpackages (WPs). WP1 will employ questionnaires (N=500 in each country) and in-depth interviews (N=30 in each country) to explore patients' experiences of healthcare access, and T2D self management, socio-economic challenges and knowledge, attitude and practices related to COVID-19 in rural and urban settings in each country. WP2 will use a desk review and field research to estimate the individual and societal economic burden of T2D. In WP3, IDIs with local healthcare providers (N=15 in each country) will explore their perspectives on T2D management during COVID-19. In WP4, a policy landscape analysis in each country will employ a desk review and key informant interviews to identify policy gaps, priority setting and action for T2D during COVID-19. WP5 will use a multi-stage participatory process involving key stakeholders in which evidence from WPs 1-4 will be synthesised to develop context-specific national policy recommendations and health education messages for T2D management during COVID-19. | 2.3 Psychological, social and economic factors / Research Grant | 6project_grants_public |
gen_2c212af183572baecb85a93cdc6d40c7 | The Impact of COVID-19 Control measures on NCD risk factors and Metabolic health: A comparison of 3 Caribbean countries | Medical Research Council | University of the West Indies | HRCS22_02824 | Low and middle income countries (LMICs) have a disproportionate burden of noncommunicable diseases (NCDs) and limited resources for prevention and treatment. The COVID-19 pandemic has served to highlight and also exacerbate these disparities. With limited resources for tertiary level care and no evidence-based treatments or effective vaccines, LMIC governments employed a range of public health measures to control the spread of COVID-19, many of which interfered with daily routines and food systems. These control measure may have beneficial and detrimental effects on NCD risk factors, physical measurements (blood pressure and weight), mental & metabolic health. The Caribbean's high NCD burden and heterogeneity in COVID-19 incidence & implementation of COVID-19 control measures provides a unique opportunity to investigate the effect of specific policies on NCD health practices and explore differential effects by gender, urban/rural residence and socioeconomic status. We plan to administer a telephone survey to hospital out-patients who had blood taken for metabolic studies (glucose and lipids) at tertiary hospitals prior to the outbreak in three island territories -Jamaica, Barbados and Trinidad & Tobago (n= 1460) to investigate the effect of COVID-19 control measures on NCD risk factor practices and mental health. Participants will be invited for repeat laboratory testing to evaluate the effect of COVID-19 control measures on metabolic health. Blood pressure and weight will be abstracted from outpatient visit records prior to and following the epidemic. The effect of COVID-19 control measures on NCD risk factors, physical measures, mental and metabolic health has not been examined in the region. Through multi-island comparisons we can investigate the impact of specific government policies and help LMICs limit adverse outcomes in persons at risk of or living with NCDs while containing future COVID-19 outbreaks or other national disasters. | 2.4 Surveillance and distribution / Research Grant | 6project_grants_public |
gen_942fe357e14805c1a47cfa34a4a226d4 | HPV, STI and AMR in West Africa: estimating population burden and understanding exposures to accelerate vaccine impact and drive new interventions | Medical Research Council | London School of Hygiene and Tropical Medicine | HRCS22_02905 | This multi-stage, probability-based, cluster survey will be undertaken within an established Health and Demographic Surveillance System in The Gambia. It will generate key data on the population prevalence of human papilloma viruses - associated with cervical cancer, other sexually transmitted infections, viral hepatitis, and HIV; also, on associated risk factors in 15 to 49-year-old females. These data are expected to accelerate progress towards achieving the targets set out in relation to Sustainable Development Goal 3 - addressing health and wellbeing, in females in West Africa. Specifically, baseline prevalence data on HPV, at the point of national vaccine rollout, are essential if vaccine impact is to be predicted, measured, and maximized, through considering alternative vaccination schedules, and new vaccines as they become available. Data on sexually transmitted infections, important causes of neonatal death, stillbirth, and infertility and on their antimicrobial resistance patterns, will allow syndromic treatment guidelines to be adapted to the setting - thus reducing the drivers of further resistance. The data are also expected to provide advocacy for the implementation of strategies, such as for the prevention of congenital syphilis, which are known to be effective but not currently provided as part of antenatal care in The Gambia and other countries is West Africa. Quantifying the ongoing burden of hepatitis B in women of child-bearing age, despite a well-established vaccination programme, will determine progress toward elimination targets, and drive work to improve the timeliness of neonatal hepatitis B vaccination. Prevalence data on hepatitis C and HIV both amendable to prevention and treatment strategies, will be complemented by a study of health systems factors which aims to identify the barriers to implementation of proven interventions in The Gambia and sub-region. | 4.4 Population screening / Research Grant | 6project_grants_public |
gen_2497b399a10afd516fdcbb835051b1bc | C-it DU-it: Community Data Use for Integrated ANC | Department of Health and Social Care | LVCT Health Healthy Societies | HRCS22_05095 | Facility and community health data is rapidly changing from paper to electronic across Kenya. Multiple digital systems are being developed, but these do not link. Community health volunteers (CHVs) and facility staff need to work together using data to monitor and improve uptake of services. Antenatal care (ANC) is an example of a service where this is important as Kenya in adopting WHO’s ambitious target of 8 ANC contacts. This research will demonstrate how to link the data and use it, providing missing evidence on the impact, costs and scale-up of data linkage and use. Our intervention targets the interface between the community and the facility. Data linkage for data use is at its heart with ANC picked as an example of what is possible. Our short name C-it DU-it (pronounced “see-it; do-it”) is an acronym intended to convey ‘seeing’ linked data (C-it) and ‘doing’ or acting on the data (DU-it). Our aim is to strengthen community health systems in Kenya through ANC data linkage and use, learning lessons for other contexts. Our objectives are to: 1._x0001_To increase ANC uptake and quality in Western Kenya by a._x0001_linking community and facility digital ANC data systems, creating a system able to track an individual woman throughout pregnancy and schedule appointments (‘C-it’) b._x0001_strengthening the capacity of community work improvement teams to use ‘C-it’ data for quality improvement and of CHVs to deliver community-based ANC contacts (‘DU-it’). 2._x0001_To co-develop research strategies with county policymakers that address evidence gaps to scale-up community health systems strengthening through ‘C-it DU-it’: 3._x0001_To strengthen the capacity of communities, county managers, Kenyan researchers, and institutions to set the community health research agenda and deliver major implementation research. Our research will be conducted in 4 counties in Western Kenya. A realist evaluation will tell us how, why and for whom the approach worked or did not work. Understanding the relationship between the county context, how people responded and outcomes (e.g., political agendas; team working; motivation; local pregnancy beliefs) makes it easier to adapt the approach to other contexts. A pragmatic cluster-randomised controlled trial in Homa Bay will tell us the impact of linking digital data and the added value (if any) of combining this with training work improvement teams in data use. We will measure the impact on the number of ANC visits and the effects on pregnancy outcomes and quality of care. Health economic evaluation will identify whether C-it DU it reduces health expenditure for pregnant women accessing and engaging with ANC care and whether the intervention is cost effective. Scale-up We will adapt and scale-up the interventions using toolkits developed in the trial county to control clusters and 3 additional counties. There will be a chance to refine as results from our research emerge. Two Kenyan partners with excellent reputations and national influence are leading this study. LVCT piloted the approach and is a lead player in strengthening community health system and scale-up. KEMRI conducts large health systems trials in Western Kenya. Liverpool School of Tropical Medicine will support us in our research and our data digitisation experts will develop and test systems for data linkage adapted to each county. We will work with the county teams and hundreds of community health volunteers that identify pregnancy and refer women to ANC services. | 8.1 Organisation and delivery of services / GHPSR | 6project_grants_public |
gen_201c9a1786a10172416d9d284dcfc6e7 | Community Voices in Health Governance - Translating Public Participation Into Practice in a World of Pluralistic Health System | Department of Health and Social Care | University of Cape Town | HRCS22_05098 | India, Brazil and South Africa are countries with public health care systems, that assure some space, even if nominal, for citizen participation in its daily routines. This proposal focuses on ongoing changes in these systems, which increasingly rely on new ways of combining public and private provision, calling attention to the actual and potential role of institutionalized channels for public participation in contributing to system effectiveness. The central argument relies on the role of citizen participation in fostering the alignment of bureaucracies, politicians and health professionals around the goals of improving population health and wellbeing. The research program will produce a better understanding concerning: a) How citizen participation is working in these systems; b) How is it adapting to ongoing changes; c) What is needed in term of resources, institutional design, community involvement and public officials training to fulfill its potential contribution. Since the 2000’s, large cities in these countries began to expand access to health care based on models of purchasing public health care. These experiences are growing, with private and philanthropic providers hired to manage public facilities and deliver public services. There is preliminary evidence suggesting that under certain conditions these experiences are contributing to a quick expansion and improved access to care in peripheral and poor areas of big cities (Coelho et al 2019, Seem, & NandraJ 2021, Schütz 2020). Despite these initial positive results there is widespread resistance to this modality of pluralistic service provision, based on the idea that it introduces a private logic in the public system (England 2004; Witter et al 2012). Reynolds (2018) also caution that public servants lack the skills or experience to negotiate such contracts and that “unless substantial capacity is developed and mechanisms for monitoring — including by local health committees — established, the potential for dysfunctionality and fraud is great.” From our perspective, pluralistic modalities of public service provision may contribute to the improvement of public administration agility, but at the same time may create a coalition between state and private actors to the detriment of population health interests. For us, the strengthening of the public health care system in LMIC countries will need to address deficiencies related to the six building blocks of the WHO model: infrastructure, human resources, technology, medicines, financial resources, and evaluation systems and will be facilitated once community governance mechanisms crosscut all the building blocks providing glue to ensure community voice is harnessed for health system responsiveness to citizens needs and equity. In this scenario, we propose a multi country study focused on mapping and improving the state of community participation mechanisms in selected districts in the cities of Mumbai, Bengaluru, São Paulo, Fortaleza, Gqebhera and Cape Town, where pluralistic models of managing and providing services are either in place or in the making. This research seeks to understand the crucial role community participation can play in pluralistic health systems and how it could strengthen and enhance Universal Health System, helping to create an accountable health system with democratic governance. It seeks to identify a model for effective and meaningful participation within the pluralistic health system. | 8.1 Organisation and delivery of services / GHPSR | 6project_grants_public |
gen_b4d89fd8b4017aa8877611b42a46d9b1 | Implementation of the COmmunity HEalth System InnovatiON Project, COHESION - I | Department of Health and Social Care | Cayetano Heredia University | HRCS22_05108 | The COmmunity HEalth System InnovatiON (COHESION) project was a 3-year project that started in 2016 as a collaboration between research teams from Mozambique, Nepal, Peru and Switzerland. It enabled formative research to be conducted at policy, health system and community levels using tracer chronic conditions that included non-communicable diseases (NCDs) (diabetes and hypertension), and a specific neglected tropical disease (NTDs) (Schistosomiasis in Mozambique, Leprosy in Nepal and Neurocysticercosis in Peru). The results from this formative research were utilised as part of a process for identifying adequate interventions through a participatory approach with communities, primary healthcare (PHC) workers, and regional health authorities. Meetings with different stakeholders were carried out between 2017 and 2018 to propose context-relevant interventions oriented to address the challenges of providing care for people affected by NCDs and NTDs. During the meetings, participants provided feedback regarding problems and potential solutions for chronic care and health services in general and proposed possible areas of intervention. Upon completion of all the meetings, each country identified the main components to be included in their interventions that were focussed on communities, health workers and facilities. Taking the work forward, this proposed Project (COHESION-I) has two main objectives: first, the implementation and evaluation of the context specific co-created interventions in the three countries – Mozambique, Nepal and Peru (Component 1), and secondly, explore the possibilities to translate the experience and the lessons learnt to other countries (India) for adaptation of the COHESION approach in a different context (Component 2). 1.1_x0001_Component 1 We propose to work in six communities in Mozambique, Nepal and Peru. Two communities (A&B) where we worked as part of the formative research will receive the co-created/co-designed intervention encompassing activities with the community’s health service users and health providers. Two other communities (C&D) will receive a co-designed only intervention of the same duration, the idea is evaluate if interventions that were co-created in other communities will work in new communities with similar characteristics. Finally, two different communities (E&F) will receive no intervention (“usual care arm”) to enable meaningful comparisons between intervention arms and usual care. The current project will enable us to evaluate the impact of a co-designed strategy in terms of (a) improved responsiveness of PHC and patient satisfaction, and (b) improved health care provision for chronic conditions. We will compare the impacts of the co-designed intervention to those of the non-co designed intervention and usual care. 1.2_x0001_Component 2 In India, we will follow the approach taken in COHESION study and conduct a policy analysis, health system assessment and community perception study. A co-creation process will follow this to develop context-relevant interventions to improve the provision of care for people affected by NCDs and NTDs. The co-created interventions will be pilot tested in the field for feasibility, acceptability, and preliminary effectiveness. If the COHESION approach proved to be locally adaptable in India, a protocol for the COHESION methodology will be developed that can be adapted to different settings. | 8.1 Organisation and delivery of services / GHPSR | 6project_grants_public |
gen_faf16b0543fea2c65c533517eb6686c2 | Strengthening health systems by addressing community health workers’ mental wellbeing and agency | Department of Health and Social Care | BRAC James P. Grant School of Public Health, BRAC University | HRCS22_05118 | Community Health Workers (CHWs) are the backbone of the health system. In remote rural and slum settings, they are often the only point of contact with formal health services for many communities. COVID-19 has demonstrated how CHWs are critical in ensuring adaptability of health systems during crises. Supporting CHWs is fundamental to improve their resilience and agency, maintain trusting relationships with communities and the sustainability and responsiveness of the broader health system. Despite this, CHWs are under-prioritised and lack support. Limited available support focuses on additional service provision, often overwhelming CHWs and neglecting their wellbeing. Evidence across LMICs suggests that CHWs face many job related stressors: physical, including regular risks; and emotional, including trauma and pressure due to the scale of community demands for help in under-resourced contexts. Yet, these stressors remain invisible to health systems, which offer little or no support to preserve CHWs wellbeing, risking their effectiveness and retention. Our research aims to develop a holistic support package for community health workers (including training, supervision, physical and emotional support) to address a multitude of job-related stressors with a specific focus on psychosocial support to contribute to enhanced CHW wellbeing, agency and resilience. Our research will take a co-production approach, situating CHWs as peer-researchers who are central to data collection, analyses and co-designing of solutions with collaborators, working across sectors. We will: 1) develop an evidence base through analysis of existing policies and practices on support for wellbeing of CHWs; interdisciplinary research with CHWs to understand their experiences and challenges, including qualitative, participatory (photo voice, stepping stones, body mapping), quantitative surveys, and participatory evaluation methods; 2) utilize the evidence generated to co-produce a package of interventions with CHWs and key stakeholders, to support CHWs wellbeing, with a specific focus on mental wellbeing to promote agency of CHWs and resilience of health systems; and 3) pilot and evaluate interventions for cost, equity, feasibility and scale up. This work brings together global and national expertise in health systems strengthening, gender, mental health and participatory health research from Bangladesh (BRAC JPGSPH) and Kenya (LVCT Health, APHRC), and partners in the UK (LSTM) who have a proven track record of CHWs research and implementation. Collaborators include representatives from Community Development Organization, Associations of CHWs, Ministries of Health, National Institute of Mental Health, and the Divisions of Mental Health and Community Health Services at national and county levels. Capacity strengthening of CHWs and health systems actors will be embedded throughout. | 7.1 Individual care needs / GHPSR | 6project_grants_public |
gen_08506b1104dd062a5e75254e37b26168 | Calling time on avoidable morbidity from asthma in African children | Department of Health and Social Care | University of KwaZulu-Natal | HRCS22_05425 | Research question In a poor rural population in KwaZulu-Natal using a pragmatic adaptive randomised controlled trial in 2028 children and adolescents to answer the questions: a) Is a combination inhaled steroid/ fast onset long acting 2 agonist (ICS/LABA) clinically effective? b) Is the ICS/LABA cost-effective compared to standard of care as per South African Asthma Guidelines? I will establish an observatory for asthma in adolescents in Africa by answering the following questions: a) What is the prevalence and what are the risk factors for asthma in children and adolescents in Africa? Background In Africa, over 50 million children suffer from asthma. Mortality is unacceptably high and far exceeds that seen in high income regions of the world - for example the rate of asthma deaths is as high as 100 times that in the UK. A major contributor to the high and largely preventable morbidity and mortality from asthma in Africa is lack of access to effective and affordable inhaled therapies. Even the very first step of asthma treatment as recommended by the Global Initiative for Asthma -h; inhaled corticosteroid/fast onset 2 agonist (ICS/LABA) as required -h; is out of reach for the great majority in Africa. This global inequality has been ignored for too long due to a lack of high-quality burden of disease data and robust clinical and health economic data to guide policy. Aims and objectives To determine the clinical and cost effectiveness of ICS/LABA compared to standard asthma care The determine the prevalence and risk factors for asthma in adolescents in Africa To create an observatory for asthma for Africa To establish opportunities for early career researcher in Africa to strengthen research capacity To advocate for access and effective medications for asthma for African children and adolescents.Design and methods a) Individually randomised controlled adaptive trial of a single inhaler-based approach to asthma management. Population: Children and adolescents 6 -18 years, with 1 asthma exacerbation in the preceding 12 months.Intervention: A pragmatic strategy using an (ICS/LABA) inhaler for asthma exacerbations as well as for maintenance treatment. Control: Standard care for asthma.Primary outcome: Severe asthma exacerbations defined as events requiring treatment with systemic corticosteroids (oral or intravenous).Time: 12 months' follow-up. b) Multi-country cross-sectional study of three African countries to determine the prevalence and risk factors for asthma using standardised methodology from the Global Asthma Network (GAN) using self-administered written and video questionnaires. Additional questions on risk factors adapted to the African context will be included. Timelines: I propose to have relevant approvals/engagements (12 months), data collection (42 months), data analysis (48 months) and reporting/dissemination (60 months). Outputs and dissemination Effective and accessible asthma treatment Creation of an asthma observatory to improve the care of children and adolescents with asthma Masters and PhD opportunities for early career researchers Community engagement, publications and policy briefs Dissemination through Pan African Thoracic Society, Global Asthma Network and the International Union of Tuberculosis and Lung Disease through WHO engagement for access to affordable asthma therapy for all | 6.1 Pharmaceuticals / NIHR Professorships | 6project_grants_public |
gen_f1c6fda9cb13b725cb0fd1b713ed14f3 | Psychosocial, Pharmacological, and Legal Interventions for Improving the Psychosocial Outcomes of Children with Substance Misusing Parents | Department of Health and Social Care | Saint Louis University | HRCS22_09156 | Global estimates indicate approximately 5-10 per cent of children are raised in families where parents misuse alcohol or other drugs. Extensive research documents the adverse health, developmental and psychosocial outcomes for children raised in these families. Parental substance misuse also typically co-occurs with multiple family risk factors, including parental psychopathology and domestic violence. The prevalence and complexities associated with parental substance misuse has led to the development of a range of approaches that aim to improve child health and developmental outcomes. Estimates suggest that for every dollar invested into substance misuse treatment, there are significant cost savings. While there is a number of reviews on different interventions (~ 25), a critical limitation of the current evaluation and review literature is the lack of an updated integration and synthesis of the comparative effectiveness of intervention models. Without a clear understanding of the comparative effectiveness, practitioners and policy-makers face difficulties in making informed and reliable choices between interventions. This review will provide a comprehensive up-to-date review of psychosocial, pharmacological and legal interventions in the context of parental substance misuse and their impact on child psychosocial outcomes. The review will use network meta-analysis to synthesise the comparative effectiveness of different intervention approaches. | 6.1 Pharmaceuticals / ESP | 6project_grants_public |
gen_69c0a193ee13b6fb14ea87c8667f6fe5 | Physical interventions to interrupt or reduce the spread of respiratory viruses | Department of Health and Social Care | Cochrane Acute Respiratory Infections Group | HRCS22_09162 | Acute respiratory infection (ARI) is the leading cause of infectious disease morbidity and mortality and imposes a significant burden on healthcare systems. Viral epidemics or pandemics of ARIs pose a global threat, such as severe acute respiratory syndrome (SARS) in 2003, influenza (H1N1) in 2009, and the current coronavirus pandemic (COVID-19). ARIs are complex syndromes. Agent-specific interventions or preventive measures are seldom completely effective. Physical methods have clear advantages in reducing ARI transmission: they can be implemented quickly, independent of specific infective agents, at local, or wider geographic or social sectors, and are relatively cheap. This review assesses a range of interventions to prevent infection including physical barriers (e.g. masks), hygiene (e.g. handwashing), and distancing. For COVID-19, these are vitally important strategies that need a solid and reliable evidence-base. The previous update of the review in November 2020 was partly funded by the World Health Organization. It has been cited 740 times and has contributed to global decision-making. It has also been cited in a guideline.1 This review is amongst the most highly accessed during the pandemic, and it is imperative it is kept up to date with evidence from recent trials in the context of COVID-19, e.g. DANMASK.2 1. [S1-Guideline: Prevention of infection by wearing masks] Bartenschlager, Becker, Brandt, Dittmer, Eckerle, Liese, Mattner, Vogel, Wessels, Ziebuhr Deutsche Gesellschaft für Hygiene und Mikrobiologie, Gesellschaft für Virologie, Publication date: November 2020 2. https://clinicaltrials.gov/ct2/show/NCT04337541 | 3.1 Primary prevention interventions to modify behaviours or promote well-being / ESP | 6project_grants_public |
gen_a7e46f85eae7e2fb6d3fc75bf238e521 | Individual-level interventions for reducing occupational stress in healthcare workers | Department of Health and Social Care | AMC Medical Research B.V. | HRCS22_09169 | In the UK, one in ten workers are employed in health and social care. In 2020, 104,000 healthcare workers suffered from work-related stress, depression or anxiety. This is around half of all ill health among healthcare workers.(1) Financial and non-financial costs are high and quality of care is in jeopardy. Total economic costs are shared between individuals, employers and government/taxpayers. Preventing occupational stress among healthcare workers is therefore a priority. The review “Preventing occupational stress in healthcare workers” (2015; 41studies) found that cognitive behavioural therapy and mental and physical relaxation may reduce stress more than no intervention. This review has been used in WHO guidance (2) and also has the potential to guide future policy and practice. Its findings are dated and of low certainty, currently a major limitation. Therefore, this review needs to be updated, starting with individual-level interventions. We expect around 20 additional RCTs. The author team is experienced in conducting and updating Cochrane reviews in a timely manner and involves a representative of the population of interest. The lead author can dedicate working time when there is some funding available. References/Other: 1 Health and Safety Executive (HSE) (2020) Human health and social work activities statistics in Great Britain 2020. HSE. https://www.hse.gov.uk/statistics/ 2 World Health Organization, Wolf J., Prüss-Ustün, A., Ivanov I., Mugdal S. et al. ( 2018) . Preventing disease through a healthier and safer workplace. World Health Organization. https://apps.who.int/iris/handle/10665/272980. License: CC BY-NC-SA 3.0 IGO | 6.6 Psychological and behavioural / ESP | 6project_grants_public |
gen_fcad1299ca937d2d814e05a424d9ee70 | Semaphorin/plexin interactions in regenerative neurogenesis in zebrafish | Biotechnology and Biological Sciences Research Council | Technical University Dresden | HRCS22_10421 | Zebrafish, in contrast to mammals, show regeneration of neurons after spinal cord injury. The immune reaction to injury promotes regenerative neurogenesis in zebrafish, but how cross-talk between immune cells and neural progenitors occurs is poorly understood. We hypothesize that immune cells signal directly to neural progenitor cells via semaphorins to promote neurogenesis. In pilot studies using single cell RNAseq we determined that reactive macrophages show a 6-fold increase in sema4ab expression and that spinal progenitor cells express the receptors plexinb1a and plexinb1b after injury. We will determine spatiotemporal expression patterns of sema4ab and its ligands, and determine their functional roles by assessing progenitor cell proliferation and neuronal differentiation in mutants for ligand and receptors. To establish whether direct signalling occurs, we will expose neural progenitors to recombinant Sema4ab ex vivo and quantify regulation of neurogenesis-associated genes. To distinguish between effects in immune cell and neural progenitors, we will conditionally ablate plexinb1 function only in neural progenitor cells in vivo and determine regenerative outcome. This project will elucidate at the fundamental level if and how immune cells directly influence spinal progenitor cells after injury. This will provide targets for future interventions in non-regenerating mammals. | 1.1 Normal biological development and functioning / Responsive Mode | 6project_grants_public |
gen_114483ea722399c85085658dbff6b5fb | Demonstrating impact of mosquito-assisted larviciding (autodissemination) as a complementary malaria intervention in rural Tanzania | Wellcome Trust | Ifakara Health Institute | HRCS22_11808 | Long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS) have significantly reduced malaria burden across sub-Saharan Africa [1], but are increasingly threatened by challenges such as mosquito resistance against common public health insecticides [2]. This necessitates innovative complementary tools to sustain the gains [3]. Mosquito-driven autodissemination of pyriproxyfen (PPF) has previously been demonstrated to effectively reduce populations of the dengue vector, Aedes aegypti in field trials [4, 5]. In recent years, we have demonstrated similar potential against dominant malaria vectors, Anopheles gambiae and An. arabiensis under semi-field settings in Tanzania [6, 7]. This approach could potentially complement disease control by targeting mosquitoes in aquatic habitats [8]. However, it still needs field-validation and optimization for low-income endemic communities. Here, I propose to optimize the PPF-autodissemination technology and demonstrate its entomological impact as a complementary intervention in Tanzanian villages where malaria persists despite widespread LLINs use. I will also simulate potential epidemiological impact and develop practical community-engagement approaches for scaling-up the technology. Unlike most insecticides for malaria control, Pyriproxyfen has lower resistance risk [9], and can control both susceptible and resistant mosquitoes through adult emergence inhibition and sterilization [10]. This project will cost-effectively accelerate overall malaria elimination goals. | 3.2 Interventions to alter physical and biological environmental risks | 6project_grants_public |
gen_0ea836ee661b74669e424848b841d63b | OA fee for terminated award | Wellcome Trust | Stellenbosch University | HRCS22_11931 | In South Africa, where access to mental health services is poor, the risk of developing mental health issues among children and adolescents is high. Accordingly, there is an urgent need to implement cost-, and time-effective interventions to address these issues in child-friendly, and child-accessible settings. Evidence suggests that CBT-based interventions have potential to mitigate the onset of mental illness by addressing symptoms of anxiety and depression in younger children, and thus may be considered primary preventative interventions. We aim to determine the acceptability and feasibility of a culturally-specific and context-sensitive CBT-based psychoeducational programme to support psychological well-being amongst children and adolescents (11-14 years) in an impoverished area of the Western Cape. As such, our study seeks to develop (using core CBT principles of existing evidence-based programmes) a school-based universal intervention to reduce symptoms of anxiety and depression amongst adolescents and to determine if this intervention is acceptable and can feasibly be delivered by NGO school-based counsellors. We will: 1. Develop a CBT-based intervention programme for anxiety and depression. 2. Train NGO counsellors to deliver and pilot the intervention to primarily establish feasibility and acceptability, and, as a secondary outcome, preliminary effectiveness at reducing symptoms of anxiety and depression. | 6.6 Psychological and behavioural | 6project_grants_public |
gen_739095f6c25491109758813620f0670e | OA fee for Innovator Award | Wellcome Trust | Rare Partners (Italy) | HRCS22_11950 | The availability of funding will allow completion of a first exploratory clinical trial on sirolimus. This would be the first trial with the drug in thalassemia, will involve about 20 patients and will explore a surrogate end point known as an important point in thalassemia, namely HbF. The trial will also explore other end points, trying to evaluate meaningful clinical end points at a preliminary stage. The final goal of the project is a substantial decrease of the transfusion need, of great interest for the thalassemia patients. A reduction of transfusion need would dramatically improve the quality of life and reduce the iron overload, caused by repeated transfusions of red blood cells. The strategy for the future clinical development of sirolimus in thalassemia will be designed taking into account the results of this first pivotal trial. An additional important output of the study of particular significance would be the advancement toward personalised medicine (ex vivo test to predict in vivo results) and the possible combination of agents acting on HbF to improve treatment approaches. The available data, obtained so far in vitro on human preparations, strongly support this view and would be confirmed and expanded by the planned experiments. | 5.2 Cellular and gene therapies | 6project_grants_public |
gen_e86be71603b0f1c86b31a51e8b816180 | Open access for terminated award | Wellcome Trust | Fred Hutchinson Cancer Center | HRCS22_11959 | Oral cholera vaccines (OCV), administered in two doses, have emerged recently as a powerful tool for short-term outbreak control. When resources are limited, single-dose vaccination has been used as a way to stretch the supply, however, previous studies have shown that a single dose of vaccine is less effective, and wanes faster. In addition, studies have shown reduced effectiveness of the OCV in children under five years old, who are disproportionally affected by cholera. Determining who, how, and when to vaccinate are pressing decisions that public health officials usually take during an unfolding epidemic, often resulting in a sub-optimal use of resources. We will use mathematical models paired with optimization algorithms to determine optimal vaccine allocation, thereby providing public health officials with an evidence-based rationale for vaccine distribution. Our specific aims are: 1) To construct data-driven mathematical models of cholera transmission, infection and vaccination. 2) To determine optimal vaccine allocation strategies. 3) To develop and disseminate a free, user-friendly, decision-making tool to inform public health officials, in real time, about the best use of limited OCV supplies. This research will benefit countries with scarce resources for which making the best use of each dose of vaccine is a top priority. | 3.4 Vaccines | 6project_grants_public |
gen_c067ed8dbbb26d95c34f21714301083d | Identification of key immunogenic post-translational modifications in Trichohyalin: a potential major autoantigen in Alopecia Areata | Alopecia UK | University College Dublin | HRCS22_12096 | This project is aimed at discovery of HF-associated autoantigens in AA. Strong evidence for TCHH as a major AA autoantigen in humans as well as in several other mammals is intriguing. Given that TCHH is a substrate for immunogenic PTMs citrullination and deamidation, we speculate that there might be an abnormal immune response against normal antigens that becomes immunogenic at a certain stage of their maturation i.e., during early stages of anagen. We hypothesize that in the initial stages of TCHH maturation, either before or during loss of immune-privilege (IP), key PTMs in TCHH may prompt an active immune response against anagen HF in AA. The presentation of modified TCHH peptides on MHC molecules locally could be an initial activation event of the (auto)immune response in AA. To evaluate this hypothesis, we aim to address the following key questions in this proposal. 1. Which amino acid residues undergoes citrullination and deamidation modifications in TCHH during its maturation in the IRS during anagen? 2. Which post-translational modifications in THH could be potentially immunogenic? 3. Will theimmunogenic peptides identified(in 2 above)be able to induce cellular and antibody immunoreactivity in AA? | 1.1 Normal biological development and functioning | 6project_grants_public |
gen_dfe241ee3579ffe643c8a0f7dfa0c8c1 | HIGH PERFORMANCE POLYHYDROXYALKANOATES BASED PACKAGING TO MINIMISE FOOD WASTE | European Commission | BIOINICIA SL | CORDIS-773872 | The main objective of YPACK is the pre-industrial scale up and validation of two innovative food packaging solutions (thermoformed tray and flow pack bag) based on PHA, with active and passive barrier properties. New packaging will use food industry by-products (cheese whey and almond shells), assure the biodegradability and recyclability, and reduce food waste, in the frame of the EU Circular Economy strategy. YPACK will use a holistic approach and methodology involving different knowledge areas: Development of packaging solutions (Production of PHBV layers, compounding, prototyping, Industrial Validation), Product Validation (Quality / Shelf life), Social approach (Customer profiling, Dissemination, Policies & Regulatory) and Market Assessment (Business study and Risk assessment). YPACK is aligned with the EU Circular Economy strategy, including the use of raw bio-based food industry by-products, LCA studies, recyclability & biodegradability of packaging and trying to reduce Food Waste. The project is constructed in line with the Responsible Research and Innovation guidelines of the European Commission. The project has a total duration of 36 months. Several processes related to the production of multilayered passive and active systems based on raw PHBV will be optimised and scaled up to pre-industrial size to validate the production of the proposed packaging solutions for extend the shelf life of selected food products. They consist in: i) a multilayer tray involving an inner active layer, and ii) a multilayer flow pack with improved barrier properties. A consumer profiling and market study will be performed at the first stage of the project in order to identify consumers´ preferences, market needs and match them with the new EU regulations and packaging materials breakthroughs. | H2020-EU.3.2. / 3.2 Societal Challenges - Food | 0business_rnd_innovation |
gen_cbfad69536755c5eb5f0e3a0bfdaf899 | Motor and cognitive outcomes of non-invasive transcranial alternate current stimulation by entrainment of cerebellar oscillations | Ataxia UK | University of Brescia | HRCS22_12176 | Transcranial alternative current stimulation (tACS) is a non-invasive brain stimulation technique, which is thought to modulate physiologically relevant brain oscillations by a desired frequency. Cerebellar ataxias are characterised by loss of Purkinje cells, which have been shown to oscillate in the gamma frequency band (30-80Hz) (Zhurhaj et al., Eur J Neurosci, 2005). In this study, the Dr Borroni and colleagues will evaluate whether a single 60 minute session of cerebellar tACS at gamma frequency (50Hz) is superior to cerebellar tDCS or sham treatment at improving motor and cognitive outcomes. They will perform a triple-cross over study, with all patients receiving tACS, tDCS or sham treatment in a randomized order. The researchers will use two clinical rating scales to assess the treatments: the scale for the assessment and rating of ataxia (SARA) and the international cooperative ataxia rating scale (ICARS). They will also use wearable sensors so that they can measure more subtle changes in ataxia. In particular, they will look at changes in participant’s steps and the smoothness of movements. This study will help determine whether tACS could be a more effective brain stimulation technique for ataxia for use in future trials. | 6.5 Radiotherapy and other non-invasive therapies | 6project_grants_public |
gen_302bffaf5ea5325e4e91c04354d17b21 | Opinions of patients with psychosis, caregivers and key stakeholders on informed consent for research involving people with mental health conditions | Wellcome Trust | University of Botswana | HRCS22_12234 | Research involving people with mental health conditions (PWMHC) has its unique ethical challenges. Conducting research among human participants requires obtaining informed consent. However, PWMHC may have impaired decision-making capacity, which may invalidate consent. Often, surrogates are resorted to for consent which may undermine the autonomy of PWMHC. As a result, this study investigates participants' opinions from Low-and-Middle Income Countries (LMICs) on informed consent for research involving PWMHC. It is expected that the outcome will contribute to academic literature and discussions on this issue. This study will be in three stages. The first will be a systematic review of empirical studies on informed consent for research involving PWMHC. This will guide the second study, which will utilise qualitative methods to explore the views of patients with psychosis and their caregivers on informed consent for research involving PWMHC. In-depth interviews will be conducted among 15 patients and caregivers dyads who will be purposefully selected from Sbrana Psychiatric Hospital (SPH) in Botswana. The third will involve in-depth interviews with 15 key stakeholders involved in mental health research and policy. Data will be collected using an interview schedule developed and piloted by the researchers and analysed with the NViVo Software using the Framework Method. | 8.3 Policy, ethics and research governance | 6project_grants_public |
gen_66b93a78d1bdd82b873b841ca728e463 | NanoSCA3: Development of brain-targeted nanobodies for application in spinocerebellar ataxia type 3 therapy | Ataxia UK | i3S consortium | HRCS22_12235 | SCA3 is caused by the expansion of a polyglutamine segment in the ataxin-3 protein, which accumulates protein aggregates. Small variable domains of camelid heavy-chain-only antibodies, known as nanobodies, show promise as therapeutic anti-aggregation agents for other neurodegenerative disorders, such as Parkinson’s Disease, Huntington’s Disease and Alzheimer’s Disease. This group holds a collection of ataxin-3-targeting nanobodies, seven of which impact on pathogenic ataxin-3 aggregation in vitro. In this project, they will investigate the neuroprotective potential of these nanobodies in cellular and Drosophila models of SCA3. Promising nanobodies will be engineered for blood brain barrier transmission and optimised for safe use in humans. If this project is successful, then these optimised nanobodies would then need to be tested in SCA3 mouse models, before eventually being tested in a clinical treatment trial in people with SCA3. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_6fce11c9c8b47b6bee4d40bf4f715117 | Identifying ethical issues in conducting research with transwomen in India | Wellcome Trust | George Institute for Global Health | HRCS22_12258 | Research on trans communities including transwomen is extremely limited in India, inspite of the huge social and political injustices that they have suffered over ages. Trans communities are often a closed community and in India many of them become part of 'gharanas'. The gharana system is an institutionalized lifestyle, which defies the heteronormative idea of a family and is a place that makes transgenders feel safe and confident in their expression of identity. However, not everyone belongs to a gharana. In this project we will collaborate with a transwoman-led non-governmental organization in Kolkata, India. The main objective is to understand the ethical challenges of conducting research on transwomen and to develop a framework for undertaking ethical research with transwomen in India using qualitative research methods. We will interact with transwomen, understand ethical issues in conducting research with transwomen and identify and validate an appropriate ethical framework in consultation with transwomen using qualitative research methodology. We will use a feminist approach and the standpoint theory that postulates that an individual's perspectives are shaped by their social and political experiences. Narrative analysis of the qualitative data will be used to develop the final ethical framework in consultation with transwomen, prior to dissemination. | No Research Activity assigned | 6project_grants_public |
gen_ae0ace450b4fb3919b3389caaca3094d | The role of governance and ethical considerations of mental health research on children and adolescents: A pragmatic framework using mixed method Delphi process | Wellcome Trust | Jos University Teaching Hospital | HRCS22_12272 | The prevalence of children and adolescents (C&A) with mental health conditions is increasing globally. More attention is given to infectious diseases and a paucity of mental health research on C&A exists. This area remains neglected because of lack of effective governance, particularly in LMICs. Effective C&A mental health system is dependent on research governance structures, necessitating the need for an effective governance framework which guides ethical considerations in research and health systems for C&A. This study aims to assess the extent to which governance frameworks impacts mental health research on C&A, identify governance framework beneficial for C&A in LMICs and generate a consensus that examines indicators which guide ethical practice and good governance. A systematic review will be used to identify existing governance framework. Thereafter, a mixed method Delphi process comprising minimum 30 experts who meet the following criteria: diversity of expertise, independence, decentralization, and aggregation from LMICs and HICs across the six regions of the World Health Organization will be used to determine a consensus for effective governance for mental health research on C&A. Outputs generated from this study will be disseminated via seminars/ webinars conferences, publications, and academic and non-academic meetings to facilitate adoption by stakeholders and policymakers. | 8.3 Policy, ethics and research governance | 6project_grants_public |
gen_5d50dc46398fcdc8edba60e4878bece0 | A randomised, single blinded, prospective study to compare simulated daylight photodynamic therapy with natural daylight photodynamic therapy for treatment of actinic keratoses. | British Skin Foundation | St. Vincent's University Hospital | HRCS22_12286 | Actinic keratoses (AKs) are dysplastic epidermal lesions considered to be potential precursors of squamous cell carcinoma (SCC). Various studies have 2011 and 2015 inclusive there were 70 deaths per year attributed to keratinocyte cancers. Thus treatment of AKs prior to conversion to SCC is important. Photodynamic therapy (PDT) is a widely approved therapy for AKs. A protocol using daylight to treat AKs is widely practised. Daylight PDT (d-PDT) is very dependent on geographical location (latitude), weather conditions and time of year. It has to date been studied mostly in Nordic countries. In Denmark, a country at similar latitude to Ireland (55 degrees versus 53 degrees north) it is only possible to perform d-PDT from April to October due to low temperatures. Conventional PDT (c-PDT) is an alternative to d-PDT outside of these months but the main drawback for patients is pain. As a result, patients prefer d-PDT and in fact in Copenhagen, where they routinely offer d-PDT from April to October they have found that patients will frequently opt to defer their treatment until a time of year when d-PDT is an option. Artificial white light (AWL) has been investigated as an alternative PDT treatment to overcome this. We propose that a treatment room with 4000K white light LED flood lamps which would be orientated to provide uniform power distribution across treatment areas would mimic d-PDT and enable us to effectively treat AKs year round. | No Research Activity assigned | 6project_grants_public |
gen_22f090e2c04a8004ccaa0bc097434243 | Exploring the feasibility, acceptability and potential impact of an ultra-brief online well-being programme for caregivers of children with tuberous sclerosis complex (TSC) in South Africa and the United Kingdom | Tuberous Sclerosis Association | University of Cape Town | HRCS22_12292 | Background. To date, very little attention has been given to the mental health and well-being of caregivers of children with disabilities and chronic conditions, including caregivers of children with tuberous sclerosis complex (TSC). Acceptance and commitment therapy (ACT) has shown promise in improving the well-being of caregivers of children with complex needs. Objectives. Our pilot study will explore the feasibility, acceptability, and potential impact of a 3-session online caregiver well-being programme (Well-Beans for Caregivers Programme). Methods. Local TSC organisations and advocates will review the programme materials and protocol before the study commences. The identified community hubs will also assist with the recruitment of caregivers of children with TSC (aged 2 to 11), living in either South Africa or the United Kingdom. The programme will be delivered online by two trained facilitators to a group of 10 caregivers and two observer trainees. The group will meet once a week for 3 weeks. Using an electronic data collection platform, feedback will be sought from caregivers, facilitators, and observers after each session. Additionally, caregivers will complete a set of wellness forms (pre-, post, and follow-up). All participants will join a focus group after programme completion. To increase the scientific rigour of the study, the programme will be delivered twice, with the second group acting as the waitlist control for the study. Outcomes. We will use various measures and focus groups to gather quantitative and qualitative data from multiple informants. This small scale study is an important first step in finding scalable and sustainable ways to support the well-being of caregivers with children with TSC. Importantly, it addresses the following identified gaps in TSC research: (1) research from a low/middle-income country, (2) non-pharmacological intervention research focused on caregiver wellness, (3) qualitative research, and (4) utilising technologies to increase the accessibility of support to families. | 6.6 Psychological and behavioural | 6project_grants_public |
gen_9dea8c67c35d45933af769c06614fecc | Aetiologies, clinical presentation and neuro-cognitive outcomes of non-HIV associated encephalitis in Cameroon - exploring a neglected disease in a low income African country. | The Encephalitis Society | Filariasis and other Tropical Diseases Research Centre (CRFilMT) | HRCS22_12332 | Acute infectious encephalitis is a frequent infectious disease associated with high mortality rates. It is caused by different etiologic agents and manifests with a wide range of clinical signs. Encephalitis management guidelines in low- and middle-income countries (LMIC) are limited by the absence of local epidemiological data leading to delays or even absence of adequate treatment. Today’s empirical treatment based on non-specific signs and symptoms is a “blind” treatment strategy contributing to mortality. Therefore, there is an urgent need to identify the etiological agents of encephalitis in LMIC. We intend to investigate the aetiologies and pathogen-specific elements in the clinical presentation of encephalitis in HIV-negative adults from urban and rural areas in Cameroon. To achieve this goal, we will perform microbiologic analysis on cerebrospinal fluid, as well as inflammatory, biochemical, and cerebral imaging. Additionally, we will describe survival rates, and outcomes of encephalitis in terms of physical and neuropsychological sequelae. Finally, we will associate these clinical observations with the pathogen type, initial radiologic findings. The results will allow us to adapt diagnostic algorithms and treatment protocols to the regional variations in pathogen distribution. They will also emphasize the need for long-term follow-up and rehabilitation of survivors | 4.2 Evaluation of markers and technologies | 6project_grants_public |
gen_a14710be55e22900e602294257c2f45a | Getting ready to solve the unsolved for SLC26A4 | Royal National Institute for Deaf People | Radboud University Nijmegen Medical Centre | HRCS22_12333 | [none] | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_1397089b0e2f0dcf8974ad882f290bbe | Developing a novel host transcript-based test to diagnose scrub typhus in children with acute encephalitis syndrome | The Encephalitis Society | National Institute of Mental Health and Neurosciences | HRCS22_12359 | Encephalitis, swelling or inflammation of the brain, is a serious global health problem, leading to death of up to one-third of people affected by it, and around half of survivors not recovering fully. Recent research has shown scrub typhus as a major cause of encephalitis in children in India. Scrub typhus is an infection caused by bacteria that affects around 1 million people each year, especially in southeast Asia. Early diagnosis of scrub typhus encephalitis is important, as it is treatable, so starting antibiotics early can prevent death and long-term health problems. Currently, scrub typhus diagnostics have problems (such as delays in performing lumbar puncture) that can lead to results being slow and/or unreliable. This research will start to address these challenges. I will examine the body’s responses (host transcripts) in the blood of children with scrub typhus encephalitis. I will compare these responses to those of patients with other causes of encephalitis and clinically similar brain infections. I will identify patient transcript responses unique to scrub typhus brain infection and use these transcripts to begin to develop a fast and accurate diagnostic blood test for scrub typhus encephalitis This test will offer prompt and accurate diagnosis, leading to earlier appropriate treatment and improved patient outcomes. | 4.2 Evaluation of markers and technologies | 6project_grants_public |
gen_9f94ce80c375c26954cef1b127471e4a | Physiological characteristics of stimulation sites in auditory brainstem and cochlear implants | Royal National Institute for Deaf People | New York University | HRCS22_12365 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_c731116f5cb1d58c832f38a7ae8ca4a4 | Role of striatum in tinnitus pathophysiology | Royal National Institute for Deaf People | National University of Central Buenos Aires | HRCS22_12366 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_92401146eaf24fc58fdf847ced2d747f | iPSC-derived human spiral ganglion models: a pilot study | Royal National Institute for Deaf People | University of Zurich | HRCS22_12367 | [none] | 1.1 Normal biological development and functioning | 6project_grants_public |
gen_c71c4a42b096f7c7b55fbb36bf74de3a | Targeting cellular senescence to slow age-related hearing loss | Royal National Institute for Deaf People | University Medical Center Groningen | HRCS22_12368 | [none] | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_6c817fc243ef9a3f0cf66bdcfaff8b93 | Mechanism-based Approach to Optimization of Noise Reduction in Hearing Aids: Influence of Individual Traits on Outcomes and Preference | Royal National Institute for Deaf People | Purdue University System | HRCS22_12369 | [none] | 1.2 Psychological and socioeconomic processes | 6project_grants_public |
gen_d616e1269ff8fb481c15e8046e452221 | Study of otos genes expression and function in the zebrafish inner ear | Royal National Institute for Deaf People | Mount Desert Island Biological Laboratory | HRCS22_12370 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_6956ecca0f9c41477114e28cd48ac1cd | Assessment of hearing disability in children with auditory neuropathy using novel objective methods | Royal National Institute for Deaf People | Bionics Institute | HRCS22_12371 | [none] | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_be95528c11f43eec9c3d52fd6b91a711 | Investigating the dysregulation of cellular metabolism in hidradenitis suppurativa patients and whether metformin can reverse this altered metabolism | British Skin Foundation | Trinity College Dublin | HRCS22_12383 | Hidradenitis suppurativa (HS) is a chronic inflammatory disease affecting approximately 1% of the population. It is characterised by painful nodules and lesions in intertriginous areas of skin. Despite having similar prevalence to psoriasis, the disease is under-recognised, under-diagnosed and its pathogenesis is poorly understood. As a result, treatment options are limited and inadequate, and there is a pressing need for research into its pathogenesis to yield better treatment options. In recent years, immunometabolism has emerged as a major research field, since it became apparent that immune cell function is regulated via metabolic pathways. Although at the centre of other inflammatory diseases, no studies have investigated a dysregulated cellular metabolism in HS. Hence novel therapeutic targets may be uncovered. Furthermore, metformin, which can modulate cellular metabolism has demonstrated efficacy in treating HS. Our preliminary data showed that metabolism was dysregulated in the peripheral blood of HS patients. In addition, transcriptomic analysis of skin samples revealed striking differences in metabolic pathways in lesional HS skin compared with healthy skin. We will confirm our preliminary data showing dysregulated metabolism in peripheral blood of HS patients and identify the specific immune cell type/s responsible. We will then determine whether metformin treatment is associated with a reversal of the altered metabolism in HS. Finally, using available single cell RNA-sequencing data, we will further analyse altered expression of metabolic genes and pathways in HS lesional skin. This study will identify metabolic pathways that may be dysregulated in HS and represent potential therapeutic targets. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_b11ccc745636637bf2303c58b440e910 | Data-driven drug discovery for AT – interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids | Ataxia-Telangiectasia Society | QIMR Berghofer Medical Research Institute | HRCS22_12390 | Interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids | 1.1 Normal biological development and functioning | 6project_grants_public |
gen_17e5b3f919876a82f19877c0946da0d0 | Study of natural killer cells in AT pathogenesis and their therapeutic implications | Ataxia-Telangiectasia Society | University of Rome Tor Vergata | HRCS22_12391 | Study of natural killer cells in AT pathogenesis and their therapeutic implications | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_fb15e591049c7d9e4d03dacf038216bb | Implementing an hospital-based encephalitis surveillance in Senegal to decipher main causes of viral encephalitis in a West-African Low-Income Country. | The Encephalitis Society | Institut Pasteur de Dakar | HRCS22_12397 | The main objective of the project is to characterize the aetiology and the clinics of the encephalitis hospitalized in Senegal. To reach this objective, three specific aims have been identified: Specific aim 1: Detect and estimate prevalence of the different viruses associated to encephalitis. Specific aim 2: Describe the clinical features specific to each viral infection and the population under investigation | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_310f131b168c26beedde33e215fd4a0e | Genetics of Mitochondrial Diseases | Medical Research Foundation | Venetian Institute of Molecular Medicine | HRCS22_12411 | In “Mitofight” we are engaged in developing suitable therapeutic approaches against mitochondrial disorders in mouse models with a particular but not exclusive emphasis on Pearson syndrome and related conditions associated with instability of mtDNA. The creation of mouse models has to be followed by their characterisation in vivo and ex vivo, and eventually, to the evaluation of any beneficial effect induced by therapeutic strategies. In order to accomplish these goals Massimo Zeviani started his laboratory at VIMM dedicated to the investigation of our mouse disease models both in their behaviour (locomotor proficiency, orientation in space, cognitive functions) and after their culling (to study pathological changes in different tissues). In the frame of this project, we have characterized a knockin mouse reproducing the most common recessive mutation in the mitochondrial DNA Polymerase (POLGA467T). We demonstrated that the mutant POLG has severely impaired DNA binding, polymerase, and proofreading activities. In addition, mutant protein has reduced affinity for the accessory subunit POLG2, which makes POLG amenable of degradation by the LONP1 protease. This study highlights a new mechanism contributing to the pathogenesis of POLG-related disorders. In addition, we have produced a Y955C mouse model reproducing the most common dominant mutation of the patients. The initial characterization of this model showed that the mutant homozygous mice were embryonic lethal with complete penetrance. In contrast, the heterozygous did not show any obvious clinical phenotype. Post-mortem analysis showed only a partial increase of mtDNA content in skeletal muscle and liver in KI vs WT littermates. Older animals (around two years of age) showed spongiosis in several brain areas and inflammatory infiltrates in skeletal muscle. No major phenotypes were observed in other organs, such as liver, kidney and heart. No mtDNA 2 depletion or deletions were observed in any organ. In order to trigger a more severe phenotype, we challenged two-year old Y933C mice with a high-fat, ketogenic diet, for two months. No differences were observed between wild-type and mutant animals. We also tried to challenge the animals by administering AZT, a nucleoside analogue which causes mtDNA depletion in humans, in the drinking water, but again, we did not observe any obvious effect on the clinical phenotype or on mtDNA amount/quality. In collaboration with Maria Falkenberg, University of Gothenburg, we investigated the molecular pathogenesis of the mouse Y933C and humanY955C mutations in vitro. The data are clearcut and show that both mutant proteins have a DNA binding capacity similar to the wildtype counterparts, but that capacity to incorporate nucleotides is severely impaired. In addition, we demonstrated that the mutant protein has a dominant effect and inhibits the wild-type form. Future studies will be aimed at using additional challenges to trigger a more severe phenotype (eg: inducing fever by LPS administration) and in developing gene editing approaches to correct the mutation. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_6cd93e1b18f8fe31a7f5a127a050723e | The immunopeptidome of paediatric high-grade osteosarcoma | Myrovlytis Trust | St Anna Children's Hospital | HRCS22_12623 | Success rates in treatment of osteosarcoma (OSA), an aggressive cancer affecting children and adolescents, have not improved over the last 30 years. High-dose, multi-agent chemotherapy followed by radical surgery has remained the standard of care. Clearly, there is an unmet need for novel, personalized therapeutic approaches. OSA tumours feature hallmarks of immune recognition in the form of tumour infiltrating lymphocytes and a gradually increasing immunosuppressive tumour microenvironment. Personalized T cell-based cancer immunotherapy may very well exploit aberrantly expressed tumour-associated antigens (TAAs) as well as somatic protein-altering mutations, which are presented as “non-self” neoantigens (NeoAgs) to T cells in the context of MHC. Current TA mining efforts rely primarily on computational pipelines to define patient-specific TAs from next generation sequencing (immunogenomics). In silico methods only incompletely recapitulate all aspects of antigen processing and presentation. As a result, predictions often fail to reflect in vivo immunogenicity. Mass spectrometry-based HLA ligandomics is the only analytical method to directly identify the HLA peptidome presented on the surface of cells or tissue in an unbiased way. Our pilot study aims to generate the first HLA ligandomics dataset for human OSA. We will test promising candidate TA peptides for immunogenicity using T cells from healthy, HLA-matched, donors. In addition to classic peptides, derived from open reading frames, we will apply a novel methodology recently developed by the Schlosser group that allows the detection of cryptic HLA peptides. Cryptic peptides represent an underappreciated class of HLA ligands, deriving from supposedly noncoding regions (“proteomic dark matter”). Current evidence suggests that certain cryptic peptides are tumour-exclusive, thus representing attractive targets for immunotherapies. By mapping the bona-fide presented HLA ligandome in a cohort of OSA patients, we aim to uncover novel, clinically relevant, T cell epitopes. Additionally, our data may reveal an OSA-specific ligandomic fingerprint, applicable across patients. | No Research Activity assigned | 6project_grants_public |
gen_7cf4b35edcaf88ac9b516dfaec95e02f | Etravirine as a potential therapeutic for Friedreich's ataxia | Ataxia UK | University of Rome Tor Vergata | HRCS22_12661 | Friedreich’s ataxia is the most common inherited form of ataxia and is caused by a mutation in the frataxin gene, which decreases the production of frataxin protein. This group recently showed that etravirine, an anti-retroviral drug currently in use as a therapeutic for HIV-positive patients, is able to upregulate frataxin in different cell types derived from FA patients. Frataxin upregulation induced by etravirine could be therapeutically relevant, as it results in increased aconitase activity and protection from oxidative stress in cells derived from patients (Alfedi et al., 2019). In this project, they plan to test different etravirine analogues for their ability to increase frataxin levels in cells, with the aim to define the pharmacophore portion of the molecule that confers frataxin up-regulating properties. This could potentially lead to the identification of already existing and approved etravirine analogues with better efficacy and potency and inspire the design of new derivatives. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_5e78f61a4ae8293d85fd1130a4889e5a | Assessment of ataxia severity under real-life conditions with SARAhome: A multicenter study in spinocerebellar ataxia type 3 (SCA3) | Ataxia UK | Helmholtz Association of German Research Centres | HRCS22_12662 | The aim of the project is to study ataxia severity under real-life conditions in a large cohort of spinocerebellar ataxia type 3 (SCA3) patients. To this end, the researchers will employ SARAhome, a newly developed video-based digital assessment tool. The study will be performed as a substudy of the ESMI cohort. This study will allow for the first time to assess fluctuation of ataxia in SCA3 over a period of 14 days. Specifically, they wish to quantify the extent of fluctuations and identify causative factors. In addition, the study will give more information on the relation of SARAhome ratings to the conventional SARA obtained in the hospital, feasibility of SARAhome in a multicentre setting, and the minimum number of days of home assessment required to obtain a representative measure of ataxia severity. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public |
gen_983ac36f6dc1e6ea98a7b43ffb60db6d | AT cerebellar neurodegeneration and inositol phosphate signaling | Ataxia-Telangiectasia Society | University of Texas at Austin | HRCS22_12703 | AT cerebellar neurodegeneration | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_1e8da9d2a75074b0c084c310a2c457c2 | A-T cerebellar neurodegeneration and inositol phosphate signalling | Action for A-T | University of Texas at Austin | HRCS22_12704 | The project will aim to gain a high-resolution view of gene expression in A-T affected tissues and will test hypotheses about inositol phosphate_x0002_regulated calcium signaling and its functional relationship to A-T. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_dd3cc82d574c277aef5e636ec6423ba3 | Liraglutide: A phase II, randomized, double-blinded, placebo-controlled trial of Liraglutide in Parkinson’s disease (Extension 2) | Cure Parkinson's | Cedars-Sinai Medical Center | HRCS22_12746 | Extension to MT011. See above. | 6.1 Pharmaceuticals | 6project_grants_public |
gen_c3f3a3ffbeed13d44c6e039bc4884314 | The CRISTAL Index: Developing a combined response index for scleroderma trials assessing limited cutaneous systemic sclerosis | Scleroderma & Raynaud's UK | University of Michigan Health System | HRCS22_12773 | The project will establish a CRISTAL index which is defined as a combined response index for limited scleroderma, consisting of outcome measures and factors such as gut involvement, quality of life and Raynaud's. The purpose of the CRISTAL index is to create a tool of simultaneous parameters to better understand the effect of a drug to treat limited scleroderma | 6.9 Resources and infrastructure (evaluation of treatments) | 6project_grants_public |
gen_9f48c1b17ff96795154c39327bb7aabc | Non-invasive transcranial cerebellar stimulation: double blind, randomised, sham-controlled study followed by an open label extension phase | Ataxia UK | University of Brescia | HRCS22_12778 | Cerebellar transcranial Direct Current Stimulation (tDCS) is a non-invasive treatment which has been demonstrated to modulate cerebellar excitability and improve motor symptoms in patients with neurodegenerative cerebellar ataxias. In a previous study, this group showed that two weeks of tDCS improved symptoms, and this improvement could be seen for up to three months. These researchers now aim to study whether repeating anodal cerebellar tDCS for two weeks, after a three month interval, may prolong clinical improvement, and whether tDCS intervention might improve cerebellar cognitive-affective syndrome (CCAS; Schmahmann's syndrome). They will perform a double blind, randomised, placebo-controlled study with cerebellar tDCS (5 days/week for 2 weeks; anodal tDCS:placebo tDCS=1:1) in patients with Friedreich's ataxia (FA), spinocerebellar ataxia (SCA), or multiple system atrophy (MSA). Each patient will undergo a clinical evaluation, and cerebellar brain inhibition (CBI) connectivity assessment by Transcranial Magnetic Stimulation at baseline (T0), after tDCS treatment (T1), and at 3-months follow-up (T2). An open-label phase will follow, in which all included patients will receive anodal cerebellar tDCS stimulation (5 days/week for 2 weeks), and will undergo the same standardised assessment after treatment (T3), at 3-months follow-up (T4), at 6-months follow-up (T5), and at 12-months follow up (T6). They will consider clinical scales as primary outcome measures, and CBI assessment as secondary outcome measures. If the results are positive, tDCS would be envisioned as a promising rehabilitating approach in neurodegenerative ataxias. | 6.6 Psychological and behavioural | 6project_grants_public |
gen_5b9fc56da39af63d29fc61d37af8897a | Development of a selective high throughput screening assay for the discovery of compounds replacing frataxin in FA | Ataxia UK | University of Paris-Saclay | HRCS22_12811 | Friedreich’s ataxia (FA) is a neurodegenerative condition caused by defective expression of frataxin, a mitochondrial protein of elusive function. This group propose to explore new therapeutic approaches based on pharmacological replacement or enhancement of FXN function. They recently developed an assay which allows them to monitor the enzymatic activity of frataxin in vitro, which lead to better understanding of the role of frataxin. In this project, they plan use this biochemical assay to develop a cell-free high throughput screening assay of large chemical libraries for the identification of molecules mimicking or potentiating FXN activity. The main advantages of this assay compared to cell-based assays are to i) select molecules directly targeting the primary defect in FA, ii) circumvent cell-penetration, stability, toxicity and selectivity issues iii) reduce the time of screening to increase the number of conditions and compounds that could be tested. From this screen, they plan select a number of active compounds that will be further evaluated in animal models of FA, and modified by drug-design to improve their efficiency in vivo. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_871e421a7574f3817d303e62714ad477 | A translatable peptide reduces glial scar to repair chronic spinal cord injury | Spinal Research | Cleveland Clinic | HRCS22_12859 | Analysing the functional recovery of lower urinary tract assesed by urodinamic and EUS EMG recording and anatomical data. | HRCS Research Uncodeable | 6project_grants_public |
gen_b3a783dff988a34400715973859670c2 | Dissemination and Advocacy of COBRA-BPS Trial Findings to Improve BP Control and Reduce CVD Risk in Rural South Asia | Medical Research Foundation | Duke-NUS Medical School | HRCS22_12894 | Hypertension affects up to one in three adults in South Asia and less than 20% have controlled blood pressure, despite availability in treatment guidelines. Serious gaps in knowledge and practices of physicians in the management of hypertension exist in rural areas, and regular monitoring of BP in hypertensive patients is often not done during clinic visits. This is compounded by poor health literacy of the population, and limited services for counselling on risk factors and the importance of taking medicines. Thus, BP control is poor and death rates from cardiovascular disease are high. We conducted a 24-month randomized controlled trial among 2,645 hypertensive adults from 30 randomly selected rural communities (10 communities each in Bangladesh, Pakistan and Sri Lanka). Half the communities were randomized to multicomponent intervention consisting of home visits for BP monitoring and counseling by trained health workers and coordination with the public health care infrastructure. The other half received usual care. At the end of the study, the decline in mean systolic and diastolic BP was significantly greater by 5 mm Hg in the intervention group versus the usual care group. Blood pressure control (<140/90 mmHg) was better also for the intervention group, with 51.7% achieving control versus 42.5% for the usual care group. Scaling-up the intervention was projected to cost less than $2 per capita annually. Our findings demonstrate that home visits by government community health workers integrated with the existing health system led to reductions in blood pressure (BP) in rural Bangladesh, Pakistan and Sri Lanka. A low-cost program like ours could be adapted to many other settings globally to reduce the growing burden of uncontrolled hypertension and related morbidity and mortality. | 7.1 Individual care needs | 6project_grants_public |
gen_12847dc6df64e90bac7a7bb0d7a58588 | Testing the multimodal anti-depressant vortioxetine as a therapeutic strategy to mitigate SCA3 | Ataxia UK | University of Minho | HRCS22_12897 | Spinocerebellar ataxia type 3 (SCA3) is an inherited ataxia, caused by a mutation in the ATXN3 gene. This group previously demonstrated that modulation of serotonin (5-HT) signalling by the selective serotonin reuptake inhibitor, citalopram, suppressed mutant ataxin-3 aggregation and neuronal dysfunction in SCA3 in vivo models. In this work, they established the 5-HT transporter SERT as a novel therapeutic target for SCA3. Moreover, they identified a decrease in the expression of 5-HT1A receptors (5-HT1AR) in transgenic mice, which was restored to WT levels upon chronic citalopram administration. Direct targeting of the 5-HT1AR using a potent agonist (befiradol) also suppressed mutant ataxin-3 pathogenesis. Here, they aim to simultaneously target SERT and 5-HTRs, by using the multimodal antidepressant vortioxetine as a novel therapeutic strategy to mitigate SCA3, potentially increasing therapeutic efficacy previously obtained with citalopram and befiradolalone. They will test vortioxetine in a genetic mouse model of SCA3, and they hypothesise that vortioxetine will protect against mutant ataxin-3-induced neurotoxicity and stall disease progression. This pre-clinical study will inform prospective clinical trials targeting the serotonergic system. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_6b5b5a50c8cebbf9fe53593333396d74 | Development of a PRIME editing therapy for Ataxia-8 due to the c.121 A to T point mutation | Ataxia UK | Laval University | HRCS22_12954 | Spastic ataxia-8 with hypo-myelinating leukodystrophy is an autosomal recessive progressive neurodegenerative disorder, which has been described by Chelban et al. in 2017. It is characterized by onset of primarily motor dysfunction within the first year of life. The patients initially have hypotonia and later develop ataxia, spasticity, and a pyramidal syndrome with weakness and loss of ambulation. Other symptoms include dystonia, dysarthria, and abnormal eye movements. Imaging of the brain shows cerebellar atrophy and hypo-myelinating leukodystrophy. In a subsequent publication in 2019, Chelban et al. described various point mutations in the NKX6-2 gene in eight families. This project will focus, as an example, on the correction by the PRIME editing technique of the c.121 A > T mutation. However, the other point mutations may also be eventually corrected by a similar PRIME editing approach. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_d46055ffc83878a8becaaf368d2dc9b6 | Development and validation of a digital tool for identifying young people at risk for depression in South Africa. | Wellcome Trust | South African Medical Research Council | HRCS22_13062 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_66eaf0804ddc0271502b2b17c6b650f4 | Preclinical development of an amelioration therapy for Dentatorubro-Pallidoluysian Atrophy - FUNDING EXTENSION | Ataxia UK | Inserm | HRCS22_13114 | Dentatorubro-Pallidoluysian Atrophy (DRPLA) is a polyglutamine ataxia caused by mutations in the ATROPHIN-1 gene, for which no cure is available. This group have significant experience in models of ataxia and spastic paraplegia with ataxia, and in particular of DRPLA. Following the recent success of antisense oligonucleotide (ASO) approaches in Huntington’s Disease - a polyglutamine syndrome with many genetic similarities to DRPLA - this group plan to apply their expertise to this preclinical study aimed at developing an ASO therapy for DRPLA. This group will test a batch of ASOs designed against the Atrophin-1 mRNA. The efficacy of the two best performing ASOs will be further studied in a well characterised mouse model (ATN1-65Q-FL). They plan to measure changes in the behavioural, histopathological and transcriptomic hallmarks of DRPLA. The group hope that at the end of this project, it may be possible to translate this therapy into a clinical trial for DRPLA patients. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_0c60722e39d70c07595b9c6785f3858b | Advanced in Vitro Test Systems with Integrated Multi-"OMICS" to define Pathway Activation and Treatment Response Scores for Patient Stratification Towards Personalised Medicine in Systemic Sclerosis | Scleroderma & Raynaud's UK | Düsseldorf University Hospital | HRCS22_13174 | Develop a novel toolset for the molecular stratification of ssc patients to ensure they are put on the most appropriate therapies, therefore justifying the potential side effects of these therapies. Precision cut skin slices will be exposed to treatment candidates, monitored, and using biostatics an activation score for each treatment will be generated. Treatment specific signatures will also be generated to predict the likelihood of individual patients to respond to specific therapies. | 4.2 Evaluation of markers and technologies | 6project_grants_public |
gen_a4fc07539864a55f3175bbcb93799b2b | ROTA-biotic: measuring the impact of rotavirus vaccines on pediatric antibiotic usage | Wellcome Trust | Amsterdam Institute for Global Health and Development | HRCS22_13192 | Antimicrobial resistance (AMR) disproportionately impacts low- and middle-income countries (LMIC) and overcoming AMR requires public understanding and engagement (1,2). The ROTA-biotic project evaluates the impact of vaccines on antibiotic usage in Zambia and Ghana. Caregivers in Zambia and other LMICs are often insufficiently informed about the hazards of inappropriate antibiotic use and AMR (2). This public engagement proposal aims to increase knowledge and awareness of AMR among caregivers of children under-5 using school-going children. To achieve this goal, we propose a youth-led intervention in Zambia where high-school children educate primary caregivers of under-5 children about AMR using narratives and performing arts. Our work will demonstrate implementation and outcomes of a process by which children will: 1. Be engaged in the co-creation of a knowledge-based intervention with social scientists, local actors and artists, teachers of basic science, and community-based safe motherhood action groups (SMAGs) 2. Be included in a research process, specifically recruitment, data collection and interpretation of findings, and 3. Lead the implementation of intervention activities created by them and informed by caregivers and other stakeholders This will result in the production of visual materials and performing arts set/s aimed at educating caregivers on the concept of AMR and their role in controlling resistance in their children. Our work will facilitate broader dissemination of impactful AMR storylines within ROTA-biotic sites, schools, and ministries of health and education in both Zambia and Ghana. | 3.1 Primary prevention interventions to modify behaviours or promote well-being | 6project_grants_public |
gen_f0b14406d66dae8f03ac3598f60cdae5 | Improving care for Birt-Hogg-Dubé syndrome patients: clinical and genetic analysis of a unique cohort. | Myrovlytis Trust | Amsterdam UMC Location VUmc | HRCS22_13206 | We propose a clinical PhD project focusing on the risk of malignancies in Birt-Hogg-Dubé syndrome (BHD) and increasing awareness of BHD. Although the knowledge on the main features of BHD (skin, lungs, kidneys) has increased over the years, many unanswered questions remain that are highly relevant for diagnosis and management of BHD patients. Our large cohort of (>300) BHD patients allows us to study clinical aspects of BHD in detail. Furthermore, the size of our cohort and the frequency at which new families are diagnosed, indicates that BHD is an underdiagnosed disease. These issues form the basis of our two aims: 1. to evaluate the (individualized) risks for malignancies in patients with BHD, and 2. to increase awareness of BHD among other physicians. Our project is subdivided into four objectives. In the first objective, we will re-evaluate the lifetime risk for renal cell carcinoma (RCC) in patients with BHD along with possible additional risk factors for RCC, such as genotype, personal history of pneumothorax or fibrofolliculomas, renal cysts, family history of RCC, and lifestyle. In the second objective, we will focus on malignancies other than RCC, and compare their prevalence in patients with BHD, with their family members without BHD, and with general Dutch cancer statistics in a retrospective study. The results of these two objectives will provide important information for patients and physicians, and they will be used to re-evaluate the BHD guidelines. In the third and fourth objective, we aim to develop a website and an information leaflet for all Dutch pulmonologists, dermatologists and urologists to increase awareness of BHD among other physicians. The website will also provide patients with a source of information about BHD, and can be used to obtain informed consent for research. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_c729ab4e0d3a5bcef71160c02146301f | Enhancing sleep to delay the progression of tauopathy | Alzheimer's Research UK | University of Camerino | HRCS22_13250 | Not available | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_092d68c98ebdb8e2b59793a0c0a3fcf3 | Redenlab for the DRPLA Natural History Study (Speech and Dysphagia) | Ataxia UK | Redenlab | HRCS22_13317 | Speech directly effects quality of life (Impaired speech dramatically effects social relationships & employability). Communication typically worsens as disease severity increases in DRPLA. We aim to develop a DRPLA specific speech battery and exploratory measures of language function. | HRCS Research Uncodeable | 6project_grants_public |
gen_dd9af2893d470d77aaa73dd58a08d7ba | Aspartyl Protease Inhibitors as Antimalarials | Wellcome Trust | Walter and Eliza Hall Institute of Medical Research | HRCS22_13322 | Malaria is one of the world's most devastating diseases of humans and results in over 450,000 deaths annually. novel therapies are urgently required to populate the antimalarial clinical portfolio, as the current therapeutics that treat this disease are becoming less effective due to emerging resistance. A collaboration between Dr David Olsen from Merck & Co., Kenilworth, NJ USA (known as MSD outside the US and Canada) and Professor Alan Cowman from the Walter and Eliza Hall Institute (WEHI), has demonstrated that malaria aspartyl protease enzymes are an attractive drug target, as they perform essential functions for survival in blood, sexual and liver stages of the parasite life cycle. Through screening aspartyl protease inhibitor libraries, the collaboration has identified novel drug-/ike hit compounds that are potently active against the malaria parasite. The proposed research aims to increase potency against the parasite whilst maintaining selectivity, progressing to a lead optimisation stage discovery program." | 5.1 Pharmaceuticals | 6project_grants_public |
gen_d9382544a3478f9aae38a9b9b6fd02d2 | Study of the role of the NKG2D/NKG2D ligand axis in A-T pathogenesis and its therapeutic implications | Action for A-T | University of Rome Tor Vergata | HRCS22_13393 | Looking at whether NK cell dysfunctions, including defective NKG2D pathway, have a role in A-T disease progression and provide novel prognostic markers and therapeutic targets. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_2cbfbee88b8b5e5a75b81644f17415ff | Strengthening CAre in collaboration with People with lived Experience of psychosis in Uganda (SCAPE-U) | Wellcome Trust | George Washington University | HRCS22_13405 | Mental health services are most effective and equitable when designed, delivered, and evaluated in collaboration with people with lived experience of mental illness. Unfortunately, people with lived experience are rarely involved in health systems strengthening, and when they are, it is limited to specific components (e.g., peer helpers) rather than across-the-board collaboration in the continuum of health services. We are proposing a novel approach for collaboration with people with lived experience of psychosis that includes involvement at the primary care, community, and home settings. By collaborating on health systems strengthening across these multiple levels, we foresee a more in-depth contribution that can lead to rethinking how best to design and deliver care for people living with psychosis. We will pilot this multi-tiered collaboration with people with lived experience in Uganda because low-income countries represent the greatest gaps in access to evidence-based mental health care. We will conduct a pilot cluster randomized controlled trial of “Strengthening CAre in collaboration with People with lived Experience of psychosis in Uganda (SCAPE-U)”. We will train people with lived experience of psychosis using PhotoVoice and other methods to participate at three levels: primary health care, community and home level. The primary objective is to evaluate the feasibility and acceptability of SCAPE-U. This pilot will also be used to prepare a future grant in which we will conduct a fully powered cluster randomized controlled trial that will evaluate health systems outcomes and service user outcomes, including quality of life, lower symptom severity, less disability, lower rates of relapse, and less hospitalization. | 8.1 Organisation and delivery of services | 6project_grants_public |
gen_4138393929ff2d72e37478e3c24465c7 | Generating new Friedreich's Ataxia animal models for validating HSV-1 FXN gene therapy in Dorsal Root Ganglia | Ataxia UK | Autonomous University of Madrid | HRCS22_13428 | In a previous Ataxia UK-funded project, this group generated a novel HSV-1 vector, very similar to one already found to be safe in clinical trials for pain therapy (David Fink, Uni Michigan). They used the natural neurotropism of the vector to deliver a frataxin (FXN) transgene to deeply buried dorsal root ganglion (DRG) neurons after footpad injection. To translate this non-invasive gene therapy to the clinic, biodistribution, and efficacy studies in Friedreich's ataxia (FA) animal models are of high priority. However, current mouse models pose several obstacles: avoiding cardiac lethality, masking of localised vector effects by severe phenotypes, and the costly and labour-intensive process of crossing different transgenic mice and screening for desired genotypes. During this project, this group will aim to construct HSV-1 vectors to knock down frataxin in wild-type animals, or knock out frataxin in floxed FXN mice, to rapidly generate cell and animal FA models. This approach will complement whole animal models, eg by circumventing lethal cardiomyopathy, or by restricting pathology to localised tissues. Although primarily to advance translation of their gene therapy to the clinic, these tools will also facilitate the work of other groups needing FA models. | 5.2 Cellular and gene therapies | 6project_grants_public |
gen_2797be68bf3cad352c1cd8904c720625 | A real-time genome sequencing approach to the role of wildlife in transmission of animal trypanosomiasis | Wellcome Trust | International Centre of Insect Physiology and Ecology | HRCS22_13435 | Animal African trypanosomiasis (AAT) is a major livestock disease restricting economic development across Africa. AAT is caused by trypanosomes (Trypanosoma spp.), which are haemoparasites transmitted by blood-feeding flies; infection causes inflammatory anaemia, resulting in wastage and death if untreated. Prevention of infection depends on vector control and livestock management to minimise exposure. Therefore, improved epidemiological data are needed constantly to inform disease surveillance and intervention strategies. The role of sylvatic transmission to domestic animals from wildlife reservoirs is a key issue, which will be examined by tracking parasite genotypes across a national park boundary in southern Kenya. Using a third-generation DNA sequencing technology (Oxford Nanopore MinION), I will produce real-time transmission data with greater precision than ever before. I will produce transcriptomes for parasites isolated from vectors, wildlife and livestock over one year, extracting single nucleotide polymorphisms to track genotypes through space and time. This will test the hypothesis that sylvatic transmission from wildlife inside the park sustains AAT in livestock outside. This project will show how new sequencing technologies can enhance parasite epidemiology, while elucidating the importance of sylvatic transmission to AAT, so enabling animal health agencies to better manage disease risk and better localize and prioritize control strategies. | 2.2 Factors relating to physical environment | 6project_grants_public |
gen_cba64ae81392b6f17e9788311da8168d | Examining the implementation of the Kenya Community Health Strategy in urban informal settlements | Wellcome Trust | KEMRI Wellcome Trust Research Programme | HRCS22_13436 | The Kenya Community Health Strategy (CHS) is a plan of action to expand community access to health care using - amongst other measures - community health volunteers (CHVs). The CHS has had varying degrees of success with ongoing discussions on how to strengthen it. There is limited information on implementation of the CHS in urban informal settlements (‘slums’) such as those located in Nairobi, Kenya. This is despite such areas accounting for a high burden of disease. Focusing on four large slums within Nairobi County and utilizing a qualitative exploratory approach, this study seeks to understand what influences the performance of CHVs. Individual and group interviews will be conducted with various cadres of health staff at sub-national and community level. These will be supplemented with observations and document reviews. Data will be analysed using framework analysis. The findings from this work will have direct relevance on ongoing policy discussions and strategies on how to strengthen the role of CHVs to attain universal health coverage (UHC). Findings will also inform potential future intervention studies on the effectiveness of CHVs to support the recovery of ill children post hospital admission. | 8.3 Policy, ethics and research governance | 6project_grants_public |
gen_a1c001dced8681de828355a3a462dc1c | Using economic modelling to determine the optimal package of services against non-communicable diseases (NCDs) in South Africa | Wellcome Trust | University of the Witwatersrand | HRCS22_13438 | The goal of this study is to use economic analysis and disease modelling to determine the economic impact of non-communicable diseases (NCDs) in South Africa and to establish how to optimally allocate public-sector resources across NCD interventions. Under this project I will construct a multi-disease health state transition model and use it to establish healthcare costs of and needs for different interventions (including preventative measures for distal risk factors such as smoking and alcohol intake) and packages of interventions targeted at the prevention, early detection and management of NCDs at baseline and over the next 20 years. Ingredients-based costing and micro-costing will be used to augment available data on intervention costs. Using an established epidemiological model parameterised to South Africa based on large surveys and routine data, I will then establish the incremental cost-effectiveness of individual interventions and intervention packages, allowing for downstream health benefits. Finally, I will test different combinations of interventions to identify the optimal package and service delivery platforms that will result in the most cost-effective programme to reach the country’s NCD policy goal, a reduction of premature mortality due to NCDs by 25%, under both the current budget and a budget increased by up to 50%. | 8.1 Organisation and delivery of services | 6project_grants_public |
gen_3c9da12b6eebf62ec08823b39bdf6f59 | Antimicrobial Resistant Enterobacteriaceae: Dairy production systems as potential sources of infection for humans in Kenya | Wellcome Trust | International Livestock Research Institute | HRCS22_13441 | Antimicrobial resistance (AMR) is a global health threat, associated with increased morbidity, mortality, and financial costs. Identifying the potential reservoirs of antibiotic resistance and resistance mechanisms is an important task to tackle AMR. Klebsiella pneumoniae and Escherichia coli which can cause severe and often fatal infections such as septicemia and pneumonia are among the identified priority antimicrobial-resistant pathogens by the World Health Organization in 2017. Cephalosporins and Carbapenems are considered critically important antibiotics in the treatment of Gram-negative infections however their resistance has been reported in clinical settings. The contribution of livestock as potential reservoirs and source of resistance genes to humans, which can be acquired by direct contact or through the environment and food-chain in Kenya is not known. This study will investigate antibiotic usage, knowledge and practices amongst farmers and levels of AMR in different cattle dairy production systems to give an insight to Antimicrobial Usage and AMR, in particular focusing on the carriage of Cephalosporins and Carbapenem-resistant Enterobacteriaceae (E. coli and K. pneumoniae). Moreover, we will investigate the genetic determinants conferring resistance and mobile genetic elements harboring resistant genes. Additional information on AMR would aid further research focused on combating AMR in developing countries. | 2.2 Factors relating to physical environment | 6project_grants_public |
gen_416e83bfc002c40f3399df896d2a4255 | Identifying Community Pharmacists Preferences for Attributes of Public Health Interventions Delivered Through Private Retail Pharmacies: A Discrete Choice Experiment | Wellcome Trust | KEMRI Wellcome Trust Research Programme | HRCS22_13442 | Private retail pharmacies are the first point of contact for most people seeking treatment for minor illness in LMICs. They play a significant role in delivery of public health interventions (PHIs). In Kenya, for example, retail pharmacies are involved in the provision of family planning services, HIV counselling and testing services and malaria treatment. Despite the role private retail pharmacies play in delivering PHIs, there is limited evidence on the attributes of PHIs that community pharmacists (pharmacists working in private retail pharmacies) value and the trade-offs they would be willing to make. Moreover, private retail pharmacies have competing interests aimed at maximizing profits. It is therefore essential that the contracts policy makers design for them are aligned with their incentives. The proposed study aims to elicit the preferences of community pharmacists for attributes of PHIs in Kenya, utilizing a discrete the choice experiment (DCE) approach. A DCE is a stated preference method used to elicit individuals’ preferences for goods and services using hypothetical scenarios. The mixed-method study will involve 350 participants from 4 counties. Data will be analyzed using thematic analysis and conditional-logit model. Findings will inform policy makers in design and implementation of PHIs through private retail pharmacies. | 8.1 Organisation and delivery of services | 6project_grants_public |
gen_4fb79fecbe459c5fd62d7a5e92465aae | Identification and stratification of Parkinson’s patients lacking | Cure Parkinson's | St Vincent's Hospital Sydney | HRCS22_13497 | GBA mutations, which impact lysosomal enzyme GCase activity, are numerically the most significant genetic risk factor for Parkinson’s disease (PD). However, the incomplete penetrance of Parkinson’s amongst GBA carriers is surprisingly low and raises the possibility of genetic modifiers that influence GBA expression and GCase activity. This prospect is supported by reports that patients with idiopathic PD lacking GBA mutations have also been found to have reduced levels of GCase levels. To investigate this idea further, a genome-wide search was conducted of >31million common SNPs for trans-eQTLs (Expression quantitative trait loci) for GBA expression in either the substantia nigra or the cortex identified significant distal SNP-GBA associations for two loci in the substantia nigra and four loci in the cortex, with the six loci located on different chromosomes from each other and GBA. Importantly the variants either increase (SN 1; cortex 2) or decrease (SN 1; cortex 2) GBA expression. Therefore, independent assortments of these common regulatory variants could result in combinations of variant haplotypes that produce a range of GBA expression levels in the SN and/or cortex that could modulate the phenotype of GBA carriers. These consequences of regulatory variant combinations would also modulate GBA expression in individuals lacking GBA mutations, with the prediction that reduced GBA expression is a significant disease contributor in specific PD patients. If identifiable, these idiopathic patients would be best suited to benefit from GBA therapeutics. It is predicted here that haplotype combinations of the 3 regulatory variants that decrease GBA expression in the SN (rs1A) and/or cortex (rs3C & rs4D) will: 1. be over-represented in patients relative to healthy individuals 2. have earlier disease onset of movement and cognitive impairment respectively 3. have elevated disease progression in motor and cognitive symptoms. Conversely, haplotype combinations of the 3 regulatory variants that increase GBA expression in the SN (rs2B) and/or cortex (rs5E & rs6E) will be over-represented in healthy individuals. This project aims to validate these variants using larger datasets (the NIH Accelerated Medicine Partnership PD (AMP PD)) and assess the clinical outcomes of individuals carrying the variants. The ultimate goal is to apply the knowledge gained in patient selection practices for future clinical PD trials of therapies targeting GBA (such as ambroxol). | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_28c6383f963a3d412e18f6b1628cfc1b | Investigating the use of the Ataxia Instrumented Measure – Spoon (AIM-S) in measuring upper limb function in Dentatorubral-pallidoluysian atrophy (DRPLA). | Ataxia UK | Murdoch Children's Research Institute | HRCS22_13553 | Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disease caused by an expanded CAG repeat in the ATN1 gene, resulting in a mutant protein (atrophin-1) with a polyglutamine expanded tract. DRPLA is an ultra-rare disease and information regarding its natural history is very limited. To better understand upper body function in an objective manner the Ataxia Instrumented Measure – Spoon (AIM-S) will be used to quantify upper limb motor control in the study participants. This work will be part of a larger project that aims to collect longitudinal data in the study participants and investigate a comprehensive set of biomarkers. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_bd030eb973789159b51b9b54d10d4f5a | MicroRNAs in dystrophic epidermolysis bullosa fibrosis: expression profiling, activity and therapeutic perspectives | DEBRA | Istituti di Ricovero e Cura a Carattere Scientifico | HRCS22_13625 | we hypothesize that: (i) miRNAs exert a role in injury-driven fibrosis of RDEB, and (ii) deregulated miRNAs and their targets can be exploited for the design of novel therapeutic approaches to limit RDEB fibrosis. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_d7a5f621235fc08dca67a50bd5389493 | Learning Data Driven Medical Checklists For Multi-Disciplinary Consult Scheduling | Wellcome Trust | University of Toronto | HRCS22_13646 | Checklists are simple tools that are often used to promote safety in clinical applications, because they can easily be integrated into a clinical workflow deployment without the need for extensive training or additional technology. Currently, machine learning in health focuses on large, complex deep neural networks. In comparison with deep neural networks, checklists are far easier to use, understand, and scrutinize. In practice, checklists are difficult to develop, and the vast majority of real-world checklists are hand-crafted by panels of experts. Given the widespread integration of electronic health data over the past decade, our goal is to learn checklists from data for clinical tasks. The main application of our method, in partnership with Dr. Leo Celi at Beth Israel Deaconess Medical Center (BIDMC) in Boston, is to predict mortality in patients eligible for Continuous Renal Replacement Therapy (CRRT). A generated checklist for CRRT is clinically desirable in the intensive care unit as a mechanism to trigger a multidisciplinary discussion with the patient’s family, to consider the value of the treatment weighed against the physical burden and cost. Thus we include operational considerations such as number of items in the checklist, the false negative/positive rate tradeoff, and fairness across protected groups. | No Research Activity assigned | 6project_grants_public |
gen_4a44bfe786db86d2da7f9103b025fb74 | Investigating the interplay between early life factors, the genome and childhood cancer risk | Children with Cancer UK | International Agency for Research on Cancer | HRCS22_13649 | The causes of childhood cancer are still largely unknown. Dr Natália Spitz Toledo Dias and her team will investigate whether environmental exposures during a baby’s life in the womb can cause changes to gene activity that may be associated with childhood cancer risk. The ultimate aim is to provide an evidence base for cancer prevention and discover the cancer’s molecular origins which could serve for targeted therapy. Dr Spitz Toledo Dias’ research is funded by Children with | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_68b442c8034acef7d390305f3b569551 | Hearing loss and dementia: uncovering the mechanisms of accelerated cognitive decline using comorbid preclinical models | Royal National Institute for Deaf People | Western University | HRCS22_13650 | Hearing loss is one of the most prevalent, chronic health conditions worldwide. In addition to age-related hearing impairment, excessive noise exposure is a leading cause of hearing loss. Beyond the devastating effects of hearing impairment itself, there is epidemiological evidence linking hearing loss to an increased risk for dementia, including Alzheimer’s disease (AD). At present, however, we lack a full understanding of the cellular mechanisms responsible for the relationship between hearing loss and dementia, which has hindered our ability to intervene effectively. Although neuroinflammation, as evidenced by activated microglia, has been identified as a key pathological correlate of both noise-induced hearing loss and age-related cognitive decline, its role as a common mechanistic link between hearing loss and dementia has not been elucidated. To that end, we will noise expose young adult male and female wildtype (Aim 1) and transgenic rats that represent a model for prodromal AD (Aim 2), and use a novel combination of (1) PET/MRI scans for neuroinflammation, (2) blood biomarker assays of pro/anti-inflammatory cytokines, (3) cognitive behavioural testing, and finally (4) post-mortem neurohistological analyses of microglial activation and AD-related pathology. By correlating these complementary results from the same rats, we will gain crucial insight into the cellular mechanisms underlying how hearing loss alters cognition throughout aging, and affects the susceptibility to AD-related pathology. Furthermore, our innovative proposal will establish a preclinical model capable of capturing the earliest interactions between hearing loss and dementia; a translational platform which could further inform future clinical investigations. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_f38d111c6b0fc173d666e5d7549ffb1a | Hearing loss and dementia: uncovering the mechanisms of accelerated cognitive decline using comorbid preclinical models | Alzheimer's Research UK | Western University | HRCS22_13652 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_25de19256a03b75a85a8d650655edc32 | The cerebrovascular system: the missing link between hearing loss and dementia? | Royal National Institute for Deaf People | Institut Pasteur | HRCS22_13666 | Dementia is a major health challenge, as it is predicted to affect 100 million people by 2050. Hearing loss was recently shown to be a major risk factor for dementia. However, the biological mechanisms underlying this correlation are unknown. The neurovascular system plays a crucial role in the neurodegenerative pathophysiological process of dementia. Based on our ground-breaking preliminary results showing that i) the central auditory system is highly vascularised and ii) this vascularisation is strongly remodelled following peripheral hearing loss, we aim to determine whether hearing impairment increases the risk of dementia directly by affecting the vascular organisation of the central auditory system. Using mouse genetic resources for hearing impairment and 3D whole-brain imaging methods for analyses of the brain microvasculature, we will assess the impact on the cerebrovascular system of (1) peripheral hearing loss and (2) central auditory deficits in genetic forms of deafness. We will also determine (3) whether changes in the auditory neurovascular system as a result of auditory deficits are associated with an increase in the levels of markers of neurodegeneration and (4) whether hearing restoration in a genetic form of deafness rescues auditory system vascularisation defects. By characterising the cerebrovascular system as a key player in the mechanisms linking hearing impairment to dementia, our work will provide a scientific basis for evaluating the potential contribution of hearing rehabilitation to decreasing the risk of dementia, whilst identifying the cerebrovascular system as a promising therapeutic target for preventing and delaying dementia. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_4ac5b4661b7450d0d1e7ac25c0dc14f8 | The cerebrovascular system: the missing link between hearing loss and dementia? | Alzheimer's Research UK | Institut Pasteur | HRCS22_13671 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_86a474b5bc5dc91c9644ec105a616eaa | Functional and metabolomic analysis of iPSC-derived Purkinje neurons from AT patients | Ataxia-Telangiectasia Society | FIRC Institute of Molecular Oncology | HRCS22_13676 | Functional and metabolomic analysis of iPSC-derived Purkinje neurons from AT patients | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_76eb404c41ef2e6002fa0a5e13a57299 | Multicenter, randomised, placebo-controlled, double-blinded, parallel arm proof-of concept trial of Lixisenatide in patients with early Parkinson’s disease (LIXIPARK - Extension) | Cure Parkinson's | Centre Hospitalier Universitaire de Toulouse | HRCS22_13683 | Extension to WM011. Please see above. | 6.1 Pharmaceuticals | 6project_grants_public |
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