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gen_ec33874896cf02db1d51094d23840e04 | Women in Bioinformatics and Data Science Latin America: Conference and Boot Camp | Wellcome Trust | Open Collective Foundation | HRCS22_12441 | No abstract available for this analysis. | 1.4 Methodologies and measurements | 3networking_collaborative
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gen_2f112de7778e16039c77e1d5927ab477 | Reducing meat intake to mitigate climate change and improve health | Wellcome Trust | University of North Carolina at Chapel Hill | HRCS22_12601 | Black, Indigenous, and People of Color (BIPOC) suffer most from the consequences of broken food systems (Petersen et al., 2019) and climate change (Morello-Frosch et al., 2009) yet are underrepresented among research leaders working to address such issues (National Science Foundation, 2018; Pearson & Schuldt, 2014). The Nutrition Research Scholars Program (NRSP) aims to build a pipeline of BIPOC scholars to become leaders in food, health, and climate research to inform policy. Our activity will involve implementation of the pilot NRSP providing BIPOC students interested in nutrition and climate with research experience and mentorship from leaders in nutrition and food policy. We will implement a 12-week summer NRSP for two BIPOC undergraduate students to build research and professional development skills and prepare for matriculation in a PhD program. Short-term indicators of success will include objective measures (e.g., total professional development workshops and networking meetings attended) and subjective measures (e.g., satisfaction with the NRSP). Long-term indicators will include continuation of an annual NRSP, total scholars matriculating in related PhD programs, and development of a network of BIPOC scholars working with our research group. Upon successful completion of the pilot, we will expand the program to other research groups within the UNC Department of Nutrition; disseminate program findings at nutrition conferences; and build sustainability by incorporating funding for NRSP scholars in grant proposals. With time, the NRSP will foster a pipeline of BIPOC nutrition scholars pursuing graduate training to work as researchers at the nexus of food policy, health, and environmental change. | No Research Activity assigned | 1fellowships_scholarships
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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
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gen_a27969be2b8166cb3ff41bb9d0b3e737 | Leveraging PHFI’s networks to disseminate recommendations from HCN policy briefs | Wellcome Trust | Public Health Foundation of India (PHFI) | HRCS22_12636 | The proposed work aims to convene stakeholders-health professionals, academia, civil society organisations, think tanks and policy makers to disseminate the recommendations from the policy brief on climate resilient health systems developed by the Health and Climate Network(HCN). The Public Health Foundation of India(PHFI) and its sister organisation- Centre for Chronic Disease Control(CCDC) are strategically poised to deliver the stated objectives given the extensive networks and collaborations already existing as a platform for transformative work with the health systems in India. PHFI's Centre for Environmental Health , recognised as a Centre of Excellence by the Government of India's Ministry of Health and Family Welfare within its National Program for Climate Change and Health, is engaged in providing technical inputs for development of an implementation framework for green and climate resilient health systems which will be customised for use across every state in India. CCDC's Health and Environment Leadership Platform(HELP), established collaboratively with Health Care Without Harm works with private hospitals to commit to decarbonisation as part of the Race to Zero initiative of UNFCCC for COP 26 and beyond. The team will leverage recommendations from the specific brief and related briefs on energy, transport and nutrition to enhance uptake and implementation. | 8.3 Policy, ethics and research governance | 3networking_collaborative
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gen_2a23239f5c7123679116cdedaf3c847e | ECFS & CFE Post-Doctoral Research Fellowship | Cystic Fibrosis Trust | European Cystic Fibrosis Society | HRCS22_12654 | The European Cystic Fibrosis Society (ECFS) is an international societyof researchersand clinical professionals committed to improving survival and quality of life for people with cystic fibrosis (CF)by promoting high quality research, education and care.Cystic Fibrosis Europe (CFE) is the federation of national CF Associations in Europe. CFE represents persons with CF and their families in Europe. CFE aims to promote investment and progress in CF research in Europe, to promote the best care from a patient perspectiveand represent and defend the interests of people with CF.With aim to foster basic and translational research on CF, the ECFS and CFE have joined forces to support a number of European Post-Doctoral2-year duration Research Fellowships. It is likely that a call for this 2-year support will be launched every 2 years. | HRCS Research Uncodeable | 1fellowships_scholarships
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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
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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
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gen_a3552c65356b76d4f064500a82416327 | INGSA learning & outreach | Wellcome Trust | University of Auckland | HRCS22_12667 | This proposal repurposes funding that Wellcome had intended for use to support LMIC delegate travel to the INGSA biennial conference. It would now enable acceleration of our Online Outreach and Training Strategy. Our current funding envelope pre-dates the pandemic, and did not anticipated the extent of online delivery now required. We have tried hard to transform programming with existing resources, but gaps remain. Will now focus on delivery of accessible, inclusive and interactive capacity-building online. We have content that can be turned into pedagogically-robust modules and made available via a reputable learning platform. Deliverables include: 1. “INGSA Shorts” series of 2-3 minute videos which condense learning/wisdom from the 2021 conference (estimated cost: $12,000 NZD) 2. Minimum three MOOC-style courses, framed around the conference's themes: Science Advice in Crisis (i.e. lessons learned from the pandemic); Science advice for complex/long-term issues (i.e. foresight/resilience; Evidence/democracy. Content drawn from 2021 conference and other Wellcome/IDRC funded programming including past LMIC workshops, the Covid-19 comparisons, Knowledge Associates projects. This approach leverages the full complement of INGSA programming (estimated cost: $28,000 NZD) We will work with new INGSA Board and LMIC partners to co-design, contextualise and field-test material, ensuring that content and format is robust and appropriate to context. | No Research Activity assigned | 3networking_collaborative
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gen_0156c211d89e7df794009e4f72a4c246 | Expanding the Health and Climate Network agenda in Latin America | Wellcome Trust | Brazilian Institute for Consumers Defence | HRCS22_12672 | Considering the current discussions on the urgency for food systems transformation and climate change mitigation, in view of the UN global events Food Systems Summit and COP26 and their outcomes, Idec proposes to articulate partners and deepen discussions at national and regional levels, influencing the political agenda. The proposal's objectives are: 1) To translate and disseminate the four Health and Climate Network (HCN) briefings in order to expand dialogue with strategic partners in Latin America involved in COP26; 2) To promote discussions to deepen connections on current food systems and their outcomes on the people's and planetary health in Brazil and Latin America. Proposed activities are: a) To translate to Portuguese and Spanish and disseminate the four briefings in Idec's own media and explore other media and share them among strategic partners in Latin America; b) To present the HCN Briefing 1 on Food Systems in strategic meetings, to discuss its recommendations in Brazil; c) To fund investigative journalism from a well-recognized journalism agency to further deepen the discussions raised in Briefing 1, producing in-depth materials about food systems and climate agenda; d) To develop podcast episodes on topics related to Briefing 1 targeting key stakeholders on the climate agenda. | No Research Activity assigned | 3networking_collaborative
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gen_94c9f3f1fe55efecd470fc80f847a9f4 | Health - Climate - Transport Nexus: Dissemination of Policy Messages | Wellcome Trust | SLOCAT Partnership on Sustainable, Low Carbon Transport | HRCS22_12676 | Tackling transport emissions has positive impacts. The benefits of transforming mobility paradigms spans across the notion of planetary health that includes human health and the health of our planet. Whether it is curbing emissions, reducing deaths in road crashes, enabling healthy lifestyles, supporting mental health with reclaimed streets or better integrating spatial and transport planning; the transport-air pollution-health-climate nexus is a multiplier. Aim: Strengthening the nexus to advance two complementary objectives by March 2022: • Capitalise on the interdependence between the enablers and disruptors of transport systems transformation and health to influence climate action policy and investment frameworks. • Facilitate medium-, long-term strategic collaborations beyond the transport community. Intended Outcomes • Mutually-reinforcing benefits of transport, health & well-being and climate action better understood. • Economies of scale and costs of inaction soundly established and clearly communicated. • Structured collaboration between a diverse group of experts, thought leaders and policy-makers. • Transport policies and investments defined with an integrated look at health implications and vice-versa. Target Audience • Policy makers, sectors associations, knowledge and academia, governments, multilateral organisations, NGOs, philanthropy and industry • Global, national and local level actors engaged in the international processes on climate change and sustainability (e.g. COP26 and the Second UN Conference on Sustainable Transport). | No Research Activity assigned | 3networking_collaborative
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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
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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 phosphateregulated calcium signaling and its functional relationship to A-T. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_f61d546a52309f738eb0d085334bac7c | AREF Training Programme Grant 2019/20 | Medical Research Foundation | Atlanta Research and Education Foundation | HRCS22_12723 | The aim of the Research Development Fellowship (RDF) Programme is to provide opportunities for talented health researchers based in Africa, so that they can lead research that is responsive to its African settings and can contribute to reducing the burden of disease. During the fellowship Fellows will have developed their skills, experience, confidence and research outputs to help them progress towards becoming an independent researcher and leading their own research programme | No Research Activity assigned | 1fellowships_scholarships
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gen_791d00f0a2befa415a32b50f5c8380b3 | Inclusion and Equity in Humanitarianism: A Fellowship with Médecins Sans Frontières (MSF) | Wellcome Trust | University of Cape Town | HRCS22_12728 | During my secondment with MSF, my project will focus on equity in humanitarian responses to global health emergencies. Humanitarian organisations such as MSF are a critical part of the international response to global health emergencies. Increasingly humanitarian organisations are required to reflect on equity within their work. Questions of equity relate to, amongst others, how MSF works with other actors such as governments, engagement activities with affected communities, provision of health care services, the role of technology and research-related activities. This project has three objectives: 1. Policy review: I will conduct a review of policies that guides the response of MSF with a specific focus on how equity is operationalised. 2. Critical review and analysis: I will conduct a review and critical analysis of literature related to equity in humanitarian responses in global health emergencies. This review will summarise normative and empirical accounts, frameworks, and considerations of equity, including research as part of the humanitarian response. 3. Recommendations: Based on insights gained from objectives 1 and 2, I will develop targeted recommendations regarding equity for relevant stakeholders involved in MSF's work. I will also facilitate interactive sessions with MSF staff about their experiences of equity, which will also inform recommendations. | 8.3 Policy, ethics and research governance | 1fellowships_scholarships
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gen_f5881f08bcf0d430dc159c88d893d7a3 | The inflammatory response as a targetable pharmacodynamic parameter of antileishmanial drugs | Wellcome Trust | Centro Internacional de Entrenamiento e Investigaciones Medicas | HRCS22_12729 | The radio drama: “Myths and Realities of Cutaneous Leishmaniasis” will consist of 6 episodes of 10 minutes each in Spanish language and it will be a co-created product of the interaction with the inhabitants of the municipality of Tumaco, particularly with local health workers and patients. The creation and dissemination of the radio drama will be carried out in collaboration with the local community broadcaster: Tumaco Stereo, and through it, the importance of early and timely treatment in the management of cutaneous leishmaniasis (CL) will be promoted in Tumaco, a municipality that is endemic for CL and that is affected by socio- economic exclusion, and an intense armed conflict, which make accessing health education difficult. | No Research Activity assigned | 5out_of_scope
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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
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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
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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
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gen_105ac4a8599abbddd8205e7b8b1f8e02 | David Hague Early Career Investigator of the Year Award | Alzheimer's Research UK | New York University | HRCS22_12780 | No abstract available for this analysis. | No Research Activity assigned | 1fellowships_scholarships
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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
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gen_b97197473c4327059aa487a4a0b6a241 | Metaphoric Stammers and Embodied Speakers: Connecting Clinical, Cultural and Creative Practice in the area of Dysfluent Speech | Wellcome Trust | University College Dublin | HRCS22_12816 | Stammering is a complex, fascinating phenomenon that involves 70 million speakers worldwide, with a ratio of approx. 4 men to 1 woman (Stuttering Foundation). Attended by a history of problematic medical/clinical intervention (Shell 2005; Eagle 2014), it continues to challenge neuroscientists exploring its causes (Per Alm 2006), clinicians developing treatments, and (most of all) the individuals who stammer across the borders of class, culture and ethnicity. Despite the profound significance of cultural responses to the experience of dyslfuency and its expression, the humanities have remained sidelined from mainstream scientific/clinical practice (e.g., Oxford Dysfluency Conference 2017). The present project proposes the first humanities-led network in the area, one in dynamic conversation with clinical/scientific voices around concepts of 'normal' speech and the tenacious alignment of fluency with social 'health' and cultural authority. Building upon presentations/discussions from the recent 'Metaphoric Stammers' conference (2018), three workshops (Clinical, Cultural and Creative) will identify a shared agenda and a series of key objectives, along with the practical structures necessary for delivery. Overall aim: development of a transformative approach to dysfluency with the interdisciplinarity and flexibility necessary to respond to its complex, highly individualised nature, ultimately informing and reshaping public debate/policy around clinical practice and resourcing. | No Research Activity assigned | 3networking_collaborative
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gen_427e5eaa9889a0def189f78b4b87a741 | To develop affordable medical technologies | Wellcome Trust | Biotechnology Industry Research Assistance Council | HRCS22_12857 | No abstract available for this analysis. | No Research Activity assigned | 0business_rnd_innovation
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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
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gen_127d4dbf6d07e9a8bf9eb2559f1545a9 | FOSTER (Fight Osteosarcoma Through European Research) consortium - Website Creation and maintenance | Myrovlytis Trust | Institut Gustave Roussy | HRCS22_12888 | The FOSTER consortium (Fight Osteosarcoma Through European Research) proposes to connect multidisciplinary and patient/parent advocate expertise, at a Pan-European level to improve biological, translational and clinical research on osteosarcoma, to ultimately improve survival. With 265 members from across 19 countries, and 8 work packages from biology to late-effects, FOSTER consortium work is overseen by an Executive Committee, with the help of a project manager: to implement a strategic research plan agenda with regular meetings where knowledge sharing can be freely developed; to pursue the aim of gaining a comprehensive overview of current osteosarcoma biology knowledge and trial situation, and thus tackle the current gaps and remaining challenges in osteosarcoma. The FOSTER consortium WEBsite purposes will be improve communication toward professionals from every discipline from biology to clinic, especially young in career investigators, patients and parents whom life have been or are impacted by osteosarcoma and general public. It will communicate on the FOSTER consortium activities, meetings and events, increase visibility of FOSTER consortium, favour multiprofessional European collaborations on osteosarcoma, attract new members to further develop FOSTER consortium activities, seek funding for the operation of the consortium and the studies that will result from its work. | 7.4 Resources and infrastructure (disease management) | 3networking_collaborative
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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
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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
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gen_a677ddbf2e3bbb32da540bce99ada42a | COVID Kurakani (Covid Conversations): understanding stakeholder perceptions of COVID-19 sequencing in Nepal | Wellcome Trust | BNMT Nepal | HRCS22_12925 | The Wellcome Trust funded Epidemic Intelligence project has implemented large scale genome sequencing for SARS CoV-2 at the only functioning sequencing laboratory in country, and stimulated discussion on the future role of pathogen sequencing and approaches to build capacity in Nepal. COVID Kurakani (Covid Conversations) will engage stakeholders to stimulate increased understanding of the role of pathogen sequencing, allow researchers to listen to, be informed by and respond to community perceptions and concerns around sequencing, build trust between participating communities and the researchers and facilitate capacity building for genome sequencing in the country. Our key goals are: 1. Build capacity among the epidemic intelligence team to develop and deliver high quality public engagement activities surrounding pathogen sequencing for epidemic response. 2. Conduct an EDGE analysis of public engagement status at BNMT. 3. Conduct an internal workshop to design the public engagement strategy, including the senior management team. 4. Utilise media expertise among the research team to develop and deliver a series of panel discussion programmes for national broadcast with three participatory target audiences. 5. Understand community and stakeholder perceptions of COVID-19 sequencing. 6. Address knowledge gaps and concerns among stakeholders to build trust and inform the dialogue surrounding pathogen sequencing. | No Research Activity assigned | 3networking_collaborative
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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
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gen_3e8466ca82dfc9dc5e2bc2f83c4724a0 | Development of MyoDys45-55, a gene editing therapy for Duchenne muscular dystrophy | Duchenne UK | Myogene (US) | HRCS22_13024 | No abstract available for this analysis | 5.2 Cellular and gene therapies | 0business_rnd_innovation
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gen_3ae32202ad3b332e0a3cdff1338c0c98 | Human Cell Atlas 2021 Meetings | Wellcome Trust | Human Cell Atlas | HRCS22_13039 | This year’s Human Cell Atlas General Meeting will convene our community virtually to share updates and insights on new HCA research and initiatives, as well as to highlight the work of the HCA Biological Networks and continue to build on progress from the HCA Biological Network Seminar Series. Key outcomes of this meeting will include a shared appreciation for recent advances and future needs that will facilitate the construction of an integrated atlas; progress toward strategic roadmaps for different organs, tissues, and systems; and an enhanced understanding of how the Human Cell Atlas will provide a healthy reference for the understanding of disease. Event Overview Day 1: Plenary talks and networking opportunities.Themes: HCA Overview, Computational Advancements and Cross-Cutting Approaches Day 2: Poster viewings, biological network interactive sessions, and breakout sessions.Theme: HCA Biological Network updates, and plan to organize to build out roadmaps. Day 3: Plenary talks, panel discussions and networking opportunities.Theme: HCA and Disease Impact, and Defining 10-year plan. A portion of the requested funds will also provide partial support for the 2021 HCA Asia General Meeting, to be held in November or December 2021. | No Research Activity assigned | 3networking_collaborative
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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
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gen_aa9fba53fa1552ac043aadb5699d8508 | Environment-Health Nexus in the Asia-Pacific Region | Wellcome Trust | International Institute for Sustainable Development | HRCS22_13073 | The objective of this project is to reverse the current trends towards environmental degradation while reducing the vulnerability of regional populations to environment-related health impacts in the Asia-Pacific region. Towards that objective, this initiative will aim toward increasing political commitment in the Asia-Pacific to strengthen both environmental and health policy via mainstreaming the environment-health nexus, as well as increasing uptake and capacity to operationalize the environment-health nexus in public policy in this region. This work aims to target the barriers to engagement on nexus issues, and support UN Member States in taking an interdisciplinary approach to intergovernmental exchanges on the environment-health nexus. We will collaborate in developing new policy products and knowledge tools on the environment-health nexus shaped to the Asia-Pacific context. In addition, we will partner in, and inform, a high-level regional dialogue on the environment-health nexus in the Asia-Pacific region. Uptake of health issues in non-health ministries through these knowledge and capacity building tools will serve to elevate health and wellbeing in intergovernmental decision-making, particularly to the desks of the negotiators making environmental decisions, at national, regional and global levels. | No Research Activity assigned | 3networking_collaborative
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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
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gen_643f0a3583539aa5e1e88dcc568069b0 | AP-001 for the Prevention of Hearing Loss | Royal National Institute for Deaf People | Anida Pharma | HRCS22_13132 | Anida Pharma is developing AP-001, in the scientific literature referred to neuroprotectin D1 (NPD1), for the prevention of drug-induced hearing loss with the further potential expansion into hearing regeneration. AP-001/NPD1 is an endogenous lipid-derived pleiotropic G protein-coupled receptor agonist with high potency that can best be described as a homeostatic regulator which is upregulated during stresses to control excessive inflammation, accelerate inflammation-resolution while controlling apoptotic events in affected host tissue cells, as well as stimulating tissue repair, and repeatedly confirmed in various CNS and ocular models. AP-001 was then investigated in the cisplatin-induced ototoxicity model in the rat and shown, when injected transtympanically, to dose-dependently and completely prevent ABR threshold shifts. Pharmacokinetic observations from perilymph sampling further corroborated the effect data. A novel finding in this context was the inhibition of NOX3 and iNOS resulting in no ROS formation, and of high relevance for the prevention of ototoxicity. AP-001 has the confirmed prerequisite physiochemical characteristics to become a drug candidate and has entered drug product development to identify a suitable formulation for transtympanic delivery for prolonged action to meet clinical needs: rapid onset action yet release drug for sufficient duration to meet practical clinical needs. | 5.1 Pharmaceuticals | 0business_rnd_innovation
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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
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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
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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
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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
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gen_ae319340aeaa8cc0de8022cec702bf56 | World One Health Congress 2022 | Wellcome Trust | SingHealth | HRCS22_13301 | The World One Health Congress (WOHC) is the world’s premier congress that takes place biennially for the worldwide One Health community. It aims to profile and advance trans-disciplinary efforts that further our collective understanding of animal-human disease transmission alongside their social and environmental determinants. This Congress is hosted by the SingHealth Duke-NUS Global Health Institute (SDGHI) with organisational support from the SingHealth International Collaboration Office (ICO). Other collaborating agencies include the Ministry of Health, Ministry of National Development, National University of Singapore, Nanyang Technological University, Singapore Management University, Saw Swee Hock School of Public Health, Duke-NUS Medical School and more. WOHC 2022 will serve to increase awareness and understanding of the drivers and global risks of a pandemic threat and ensure that these stay high on the agenda of governments and institutions in the region. The Congress will ultimately help countries to decrease risk by fomenting better surveillance and boost pandemic preparedness. The WOHC 2022 anticipates more than 1,500 professionals from international academic institutions, civil societies, national governments and multilateral organisations. At least 750 participants will attend the face-to-face Congress in Singapore, and another 750 will participate virtually. | No Research Activity assigned | 3networking_collaborative
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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gen_a64bb96b00caa1d9655b742d09ad1e93 | BHD Expert Patient Training | Myrovlytis Trust | BHD France | HRCS22_13534 | The Paris School of medicine offers a 8 months training course destined to people who wish to become expert patients in a given field of illness. This training will provide methodology and expertise of how to deal with the BHD syndrome’s various backgrounds. The aim is to gain credibility and experience as an expert patient in BHD, in order to be fully accepted by the medical world and user representation bodies both in France and abroad. 4. I expect this training will enable me to take part in various actions in the future ie funding, congresses, symposiums in order to help research. | 7.1 Individual care needs | 4other_research_funding
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gen_93df995adac20092f68f9eae4cfa783d | ReAct Africa Annual Conference 2022. Theme: "Africa’s response to Antimicrobial Resistance: Accelerating One Health National Action Plans implementation for the next 5 years." | Wellcome Trust | ReAct Africa | HRCS22_13541 | ReAct Africa and South Centre Annual Conference 2022 Theme: "Africa’s response to Antimicrobial Resistance: Accelerating One Health National Action Plans implementation for the next 5 years." Antimicrobial resistance is a significant global threat to public health, food security, and development today. In Africa, AMR has been documented to be a problem exacerbated by a high burden of infectious diseases and weak healthcare systems. The existential COVID-19 pandemic has further complicated the situation. The conference comes at an opportune time in July 2022. The conference offers an opportunity for retrospection where experts and key multisectoral stakeholders convene to reflect on lessons learned. The setting allows for context-specific discussions on challenges that are relatable across the region. The conference also provides a forum for sharing best practices across sectors with a one-health approach. The conference will be an opportunity to present the GRAM report results. Leveraging on experience, insights, and tools from countries, NGOs, academia, UN agencies, continental and regional agencies, CSOs, and the private sector, the conference will explore what can be done differently in the subsequent years. Presentations will include scientific poster presentations on diverse research and exhibit best practices that contribute to catalytic action for the next five years. | HRCS Research Uncodeable | 3networking_collaborative
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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
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gen_e52b4b32e7dfd0a623e23c4c6a1cdc3e | Research on Research Institute Extension - CTWS-Leiden | Wellcome Trust | Leiden University | HRCS22_13616 | No abstract available for this analysis. | No Research Activity assigned | 2institutional_funding
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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
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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
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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
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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
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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
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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
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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
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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
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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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gen_0be1c7ae5c3aa742530fb52e2d396b03 | Contribution of fatty acid metabolism to the advanced and metastatic phenotype of pancreatic cancer | Worldwide Cancer Research | Instituto de Investigación Sanitaria Aragón | HRCS22_13690 | Pancreatic Ductal Adenocarcinoma (PDAC) is an extremely lethal disease due to the current lack of effective therapies and extreme malignancy of the tumours once diagnosed. We have recently shown that PDAC is hierarchically organised with Cancer Stem Cells (CSCs) constituting a major source for disease progression, including metastasis and relapse following chemotherapy. Interestingly, increased lipid scavenging and aberrant fatty acid metabolism have been linked to pancreatic tumour progression and poor prognosis in PDAC patients. We have recently reported that, in contrast to differentiated tumour cells, pancreatic CSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS, Sancho et al, Cell Metabolism 2015). This metabolism confers the ability of using a wider range of substrates able to feed the TCA cycle, including fatty acids. Now, our preliminary results indicate that: 1) CSCs store and metabolise fatty acids for full tumorigenic capacity; 2) Energy deprivation promotes a highly dedifferentiated and aggressive phenotype through PPARdelta. We hypothesise that CSCs are able to modulate lipid storage/utilisation conferring them with high resilience and plasticity to adapt to the changing and challenging conditions during tumour progression and metastasis. Thus, in the present project we aim to analyse the specific role of fatty acid metabolism in the advanced and metastatic phenotype of PDAC by addressing the following three aims: 1. To study the role of lipid uptake and storage in CSCs to cope with situations of metabolic stress. 2. To investigate the role of PPARd in the acquisition of an advanced/metastatic phenotype in pancreatic cancer 3. To validate new therapeutic strategies targeting lipid metabolism Our ultimate aim is to identify and validate most effective CSC-targeting strategies with great translational potential, to improve the still miserable prognosis of PDAC patients. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_f462b3222300687a05103720cf36dea8 | LMICSS - Wellcome Centre for Infectious Diseases Research in Africa | Wellcome Trust | University of Cape Town | HRCS22_13694 | Total number of current applications in progress for LMICSSs by Administering Organisation (for all Programmes they administer): 1Total number of current applications in progress for LMICSSs to be held at the AAP/Centre to which the application relates: 1 | No Research Activity assigned | 2institutional_funding
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gen_635bd8cd7972480f4c0ea93ac63abafb | Tools to Highlight Impact and Aid Curation of Scholarly Outputs | Wellcome Trust | American Society for Cell Biology | HRCS22_13707 | The proliferation of scholarly content and implementation of transparent peer review are creating challenges for readers and evaluators to assess research significance and review outcomes, and for journals to curate field-specific content. We propose controlled experiments in which we test the utility of badges and impact statements to signal the significance of articles published by the American Society for Cell Biology (ASCB) in its research journal, Molecular Biology of the Cell (MBoC). We will devise badges that alert readers to article attributes such as new concept, broadly relevant, technical advance, teaching resource, etc. We will also experiment with new peer review processes, including a streamlined process designed to concisely identify points of significance and key issues, and one in which authors, reviewers, and editors work together to craft concise impact statements for display on articles. The effects of these innovations will be assessed relative to traditional practices by comparing article-level metrics including article views, downloads, and Altmetrics attention scores and by surveys. We will then use these innovations and the expertise of ASCB members, including early career scientists, to curate preprints and articles in other venues with the goal of providing standard, portable tools for use by other publishers. | No Research Activity assigned | 6project_grants_public
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gen_2fd8b1bedcd8851386a3bf43a9a4b34a | Filling in the gaps during a crisis of care: social and political constructions of lay care work during the HIV/AIDs epidemic and the Covid-19 pandemic in South Africa. | Wellcome Trust | University of the Western Cape | HRCS22_13713 | The project aims to explore the various social and political constructions of lay care work during the Covid-19 pandemic and the early stages of the HIV/AIDs epidemic in Cape Town. It will analyse the tensions and possibilities that arise when informal, self-organised and localised care work done by ordinary people interacts with the formal health system, considering how this represents a potential for social change in the health system and broader society. Analysis will draw on Feminist care theory and De Certeau's concept of "tactics" and "strategies", situating the project in a broader critique of the ways in which the dominant neoliberal and capitalist order produces a "crisis of care" that marginalises care work and stifles possibility for meaningful collaborations between the formal health system and ordinary people doing this work. Research will involve archival and document-based data such as meeting recordings, media pieces, policy documents, academic and NGO reports, and documentary films regarding lay care work and community-based care during Covid-19 and the early stages of the HIV/AIDS epidemic (90s-early 2000s). It will also draw on in-depth interviews with participants who were actively involved in and/or able to reflect on the provision of place-based, lay care during both cases. | No Research Activity assigned | 6project_grants_public
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gen_a28a2a61df4ddf5ff668aaa10e4dbf46 | Advancing the global health agenda with the Paris Peace Forum | Wellcome Trust | Paris Peace Forum | HRCS22_13758 | The Paris Peace Forum will host a series of discussions to maintain the partnership developed by ACT-A (Access to COVID-19 Tools Accelerator) and the governance of global health at the top of the political agenda and further deliver concrete solutions while contributing to the construction of an overall governance framework in the sector. The proposal includes hosting discussions taking place in the framework of a pilot, year-long partnership between the Forum and Wellcome Trust. These discussions would mobilize stakeholders of the Forum’s community and beyond. The Forum would naturally seek Wellcome’s guidance and advice on the scope, topics, invitees, and outputs of these discussions. Stakeholders would be invited to participate in each discussion based on their institutional focus and expertise and on the basis of their capacity to contribute to and implement the desired outcomes. With the support provided by the Wellcome Trust, the Forum could convene two roundtables in 2021, to provide for sufficient time for preparation, eventually for follow-up actions in between and potentially to leverage to key moments in the annual Forum cycle: the Spring meetings of the Paris Peace Forum (May 2021) and the fourth edition of the annual event (11-13 November, 2021). | No Research Activity assigned | 3networking_collaborative
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gen_ee8f01dd9c1ef3bd9097c8ce4b50a15d | PRECISION - supplementary award | Cancer Research UK | University of Texas MD Anderson Cancer Center | HRCS22_13775 | Background Ductal carcinoma in situ (DCIS) now represents 20-25% of all breast neoplasia. This is due to large-scale detection by widely adopted population-based breast cancer screening programs . As a result, thousands of women are confronted with DCIS each year: more than 8,000 in the UK, 2,300 in the Netherlands, and over 50,000 in the US. Conventional management includes surgery, supplemented by radiotherapy and/or endocrine therapy, but overtreats the majority of DCIS as ~1% recur annually and breast cancer mortality is ~3% at 20 years. Uncertainty as to which DCIS lesions will progress to invasive cancer or, after excision, which will return with recurrent DCIS or invasive breast cancer drives this overtreatment. Distinguishing DCIS that may progress to lethal disease from the majority of harmless DCIS is therefore an urgent need to save thousands of women with low risk DCIS the burden of radical treatment without any survival benefit. Aim We aim to reduce the burden of overtreatment of DCIS (surgery, radiation therapy, hormonal therapies) through the development of novel tests that promote informed and shared decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS management presently achieved. Methods First, three large retrospective DCIS cohorts (and supplementary sources) will be collected enabling subsequent in depth molecular studies. Second, extensive genomic characterisation, immune profiling and imaging analysis will be performed. In vivo and in vitro modelling will be performed to study the biology of DCIS in detail. Finally, all clinical, immune, and molecular data will be incorporated into a clinical risk prediction model. This risk prediction model can be validated in three prospective DCIS trials. Specifically, in the current project we will a.) collect tissue and blood samples from these trials and b.) start validation of the biomarkers detected in the retrospective series. How the results of this research will be used The discoveries from our laboratory studies, including a risk stratification model, will be cross-validated in prospective trials of DCIS active surveillance versus conventional treatment (the LORIS, LORD and COMET trials). As such, the main result of this study will be that we can identify a group of women for which active surveillance for DCIS could be a safer alternative to intensive treatment. Ultimately, this may also contribute to a more reassuring perception of risk regarding non-life threatening precancerous lesions in general, reducing anxiety and preserving quality of life. | 2.6 Resources and infrastructure (aetiology) | 6project_grants_public
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gen_cee277dd4d3fff26bd3c01a14f1b1071 | Social security for children with disabilities in rural South African communities: family caregiver, health worker, civil society, and policy implementer perspectives on access to and the use of the Care Dependency Grant in the Cape Winelands | Wellcome Trust | Stellenbosch University | HRCS22_13786 | In South Africa, state-funded social protection for disabled children has primarily been through the Care Dependency Grant (CDG). The CDG is distributed to the caregivers of these children and provides important financial assistance, but it is under-researched. Little is known about caregivers’ access and utilisation of the CDG, what the value of complementary interventions might be, how doctors assess need and deservingness, and how government agencies conceive of and communicate about the CDG. The proposed study will investigate these and other questions in a qualitative study using ethnographic and participatory methods, with a specific focus on the Cape Winelands district. Participants will include caregivers of children with disabilities, assessing doctors, South African Social Services Agency (SASSA) staff members, and organisations working with disabled children. Findings will be discussed with reference to broader debates around social protection, development, poverty alleviation, and access to health and education for disabled children. A better understanding of how this grant is conceived of, used, and distributed from the perspective of different stakeholders will build knowledge in this underdeveloped area. It will also produce important initial evidence for potential future interventions to improve the social protection of disabled children and their caregivers in South Africa. | 8.1 Organisation and delivery of services | 6project_grants_public
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gen_f550a07b390fe0c9a67f2758d61bf665 | Improving the prediction of endometrial cancer risk using genetics | Worldwide Cancer Research | QIMR Berghofer Medical Research Institute | HRCS22_13825 | Endometrial cancer (cancer of the uterine lining) is the most commonly diagnosed gynaecological cancer in developed countries, including Australia. Its incidence is rapidly increasing due to the ageing population and rising rates of obesity, the strongest known risk factor for endometrial cancer. This is a global problem, with a recent study reporting increased incidence rates of endometrial cancer in 26 of 43 countries studied. Unlike many cancer types, endometrial cancer-specific mortality has increased approximately 2% each year since 2008, in part due to its increased incidence. Whilst the link between obesity and endometrial cancer risk is well-recognised, the mechanism for how this occurs is unknown. Understanding which characteristics of obesity are responsible for this relationship would provide vital information not only for informing endometrial cancer risk but also understanding the biology of this disease. How to use the information from obesity and other risk factors effectively to identify women at very high risk of endometrial cancer is not available. Harnessing these data would provide avenues for personalised risk prediction and targeted prevention interventions, including bariatric surgery. Our research team leads the world’s largest genetic study of endometrial cancer through co-ordination of the Endometrial Cancer Association Consortium and identifying several genetic variants associated with endometrial cancer risk by genome-wide association study. We will use these genetic data to explore the relationship between endometrial cancer and specific obesity-related traits. We will construct endometrial cancer genetic risk scores, integrating genetic data from endometrial cancer risk factors to improve predictive capacity. Finally, we will assess the effect of intervention strategies on reducing endometrial cancer risk, providing essential data for clinical implementation of genetic risk scores for endometrial cancer prevention. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_b7217427976bbf234e2b66a35b98bc13 | Assessment of the impact of mycotoxins on the epigenome and their synergistic role with EBV in endemic Burkitt lymphoma in African children | Children with Cancer UK | International Agency for Research on Cancer | HRCS22_13849 | Chronic exposure to toxins (Mycotoxins) produced by moulds (Fungi) and infection with oncogenic viruses have been shown to increase a person’s chances of developing cancer; for example, the synergy between Aflatoxin B1(AFB1) and Hepatitis B virus infection have been shown to increase the development of Liver cancer 1. Burkitt’s lymphoma (BL) is a childhood cancer of the lymphatic system that is known to occur when the B-lymphocyte is infected with Epstein Barr virus 2, endemic Burkitt’s Lymphoma variant (eBL) occurs mostly in African regions prone to EBV and malaria infections 3. In addition, persons living in African regions are faced with unavoidable mycotoxins exposure. Mycotoxins are problematic in terms of acute exposure in staple crops especially in low- and middle-income countries (LMICs), leading to mycotoxicosis outbreaks (e.g. aflatoxicosis) 4. A recent study estimated that about 60 to 80% of world’s food crops are contaminated with mycotoxins, meaning that dietary mycotoxins’ exposure is unavoidable 5, 6, 7. Generally, mycotoxins have caused both economic 8, 9, 10, 11 and health problems 12 such as carcinogenicity, hepatotoxicity, and genotoxicity. Therefore, chronic exposure to mycotoxins coincides with higher incidence of eBL across regions of Africa. Previous studies within our branch demonstrated that exposure to certain mycotoxins promotes EBV infection, and children in regions of Africa with high mycotoxin exposure and high incidence of BL also have higher EBV infection levels | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_fb0bf5f01ec0788f101a2c66dc7a95a8 | Liraglutide: A phase II, randomized, double-blinded, placebo-controlled trial of Liraglutide in Parkinson’s disease (Extension 1) | Cure Parkinson's | Cedars-Sinai Medical Center | HRCS22_13854 | Extension to MT011. See above. | 6.1 Pharmaceuticals | 6project_grants_public
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gen_cd0d1462819e5d8ae760e511ee9978c2 | Silence, solitude, and serotonin: how hearing loss and social isolation converge to influence serotonergic regulation of the auditory midbrain | Royal National Institute for Deaf People | Indiana University | HRCS22_13910 | The social isolation that often accompanies hearing impairment in older adults co-occurs with other health concerns, including depression, anxiety, and cognitive decline. A contributing factor to these negative outcomes may be dysfunctional communication driven by deficits in auditory processing and perception. We will assess whether noise-induced hearing loss and social isolation additively influence regulation of the auditory system by serotonin. To test this hypothesis, we will noise-expose CBA/CaJ mice in young adulthood, resulting in exaggerated age-related increases in auditory thresholds. Noise exposure or sham treatment will be factorially combined with a one-month period of individual or social housing in postbreeding mice, to create four treatment groups. Three different outcome measures will be assessed: 1)The density of axons labelled with an antibody to the serotonin transporter will assess plasticity in serotonergic projections to the inferior colliculus (IC). 2)The numbers of neurons in the dorsal raphe nucleus (DRN) that double-label for antibodies to tryptophan hydroxylase and the immediate early gene product cFos will assess the functional activation of serotonergic neurons during a social encounter. Analysis will focus on DRN subregions that project to the IC. 3)Anxiety-like behaviors in the elevated plus, open field, and social encounter tests will be used to assess the engagement of broad mechanisms regulating affective behavior. The predicted additive effects of hearing loss and isolation on serotonergic axons in the IC, and isolation-only effects on the activity of DRN neurons, could create dysfunctional regulation of auditory processing during social encounters. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_63a21e7a089e8aa4079861a955044896 | The development of a best-in-class iron chelator to prevent oxidative stress, iron regulated cell death (ferroptosis) and synucleinopathy as a treatment for Parkinson’s Disease, to-gether with the integration of biomarkers of target engagement and efficacy. | Cure Parkinson's | Centre Hospitalier Universitaire de Lille | HRCS22_13946 | Excessive labile iron in the Substantia Nigra pars compacta (SNpc) is a pathognomonic hallmark of PD and leads to increased production of noxious reactive oxygen species. Alpha-synuclein regulates dopamine and iron transport, with PD associated mutations in this protein causing functional disruption of these processes. It has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell death pathway with unique lipid peroxidation signatures called ferroptosis. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher-affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials have led to several current large randomized clinical trials (FAIR PARK II) that aim to demonstrate the concept of conservative iron chelation. A new iron chelator, SP-420 (invented by Prof. Ray Bergeron, University of Florida, and in clinical development by AbFero Pharmaceuticals) has significant advantages over deferiprone, including superior potency, tolerability, and safety (lack of neutropenia/agranulocytosis). A European consortium has been set up to launch the preclinical validation of SP420 in PD models and is funded by the European Commission (Eurostars program). The Eurostars work package will allow definition of 1) the pharmacokinetics (Pronexus AB, Dr. Kehr, Sweden), the in vitro molecular mechanisms (CHUL, Prof. Devos, France) 3) the in vivo validation in the subchronic MPTP mouse, 6-OH dopamine rats and in the preformed fibrils of the alpha synuclein mouse model (Erasmus University, Prof. Mastrobaradino, The Netherlands). Despite the quality of the Eurostars initiative, additional challenges to the success of a P2 trial remain. Indeed, while the concept of effective neuroprotection in PD has continued to excite interest, there has been more than 40 years of failure in neuroprotection. A key solution to overcome this major challenge is to better characterize the best population and the best doses, thus enhancing the chances of a successful clinical trial. Thus, the goal of this project is to validate neuroprotection induced by SP-420 in two additional pivotal in vivo PD models (i.e. the subchronic MPTP-treated aging mouse and the Thy1-a-syn mouse model, not funded by the Eurostars program) and associated with target engagement and the theragnostic biomarkers (not studied in the Eurostars program). Several new dry and wet biomarkers will be additionally be assessed including: MRI sequence of magnetization transfer associated with the T2* sequence (i.e. iron in and outside neuromelanin), PET scan [64Cu]-ATSM (i.e. lipid peroxidation preceding cell death) associated with GFAP (i.e. astrocytosis) associated with light chain neurofilament (i.e. axonal destruction), selenium (i.e. selenoprotein GPX4 = major antioxidant enzyme for lipid) associated with 4-HNE, MiRNA involved in ferroptosis associated with ferritin and alpha synuclein. The results will further validate the potential of SP-420 as a viable PII PD candidate, allowing AbFero to facilitate regulatory interactions necessary to support clinical trials in patients with PD, and increasing confidence in the investor and clinical community who will be key partners for AbFero as the substantial financial commitments are sought for PII and PIII studies. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_7a22b8bf23c4f9bddc1d26b78136023e | Enteric Pathogens and Post-discharge Outcomes among Children in sub-Saharan Africa and South Asia (The EPPO-SASA Study) | Wellcome Trust | KEMRI Wellcome Trust Research Programme | HRCS22_13957 | Enteric pathogens are a major cause of hospitalisation among children and are associated with diarrhoea, enteric dysfunction, dysbiosis, and increased risk of mortality and readmission especially in low- and middle-income countries. When admitted to hospital, treatment failure may occur despite following guidelines. Furthermore, carriage of pathogens or disturbance in the intestinal microbiome may be hospital-acquired and/or resistant to first-line antimicrobials potentially increasing the risk of readmission. I aim to determine whether molecular evidence of enteric pathogens and gut dysbiosis at hospital discharge, when children were judged as clinically well, is associated with readmission post-discharge among children across the nutritional stratum. This case-control study is nested within the completed CHAIN cohort study (six countries) that aims to characterise demographic, clinical, and social risk factors for mortality among children <2 years old, with an extensive nested case-cohort systems biology sub-study targeting mortality. Cases will be children readmitted to hospital within 6 months of index discharge and controls will be age, nutritional stratum and site matched children who were not readmitted. I will utilise targeted faecal TaqMan multiplex PCR (Kilifi, Kenya), culturomics and metagenomics (Sanger Institute, UK). Findings may support policies for post-discharge screening, prophylaxis, targeted diagnostics, and revision of treatment protocols. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_57027a0cb8aef15033ac39477a2a5a07 | RECOVER (Real World Clinical Outcomes with Novel Modulator Therapy Combinations in People with CF) | Cystic Fibrosis Trust | Children's Health Ireland at Crumlin | HRCS22_13961 | Triple combination CFTR modulator therapy (TCMT), has shown promising results on important health outcomes in clinical trials in PWCF and has been approved in the US for use in people>12 years of age with one or more copy of F508del. Approval in Europe is pending, subsequent to which the drug will be provided for use in PWCF in Ireland as part of a pre-existing agreement with the manufacturer. Clinical trials are highly monitored and tightly controlled, and regulators understand the importance of 'real world' data to ensure they help patients as they are supposed to and are safe when widely used. We have designed a real-world study involving children and adults with CF across eight paediatric and adult CF centres in the UK and Ireland in collaboration with CF registry of Ireland and the UK CF registry. We will be examining a wide range of well-established tests in these people, as well as some newer, more sensitive tests looking at how this new treatment might affect health and quality of life in PWCF. We will be looking at how PWCF feel about this new treatment, how it affects their quality of life and whether it affects their need for, or ability to take, other CF treatments. One of the key strengths of RECOVER will be the direct comparison of a 'control' group in UK centres (who do not yet have access to treatment) with an on-treatment group in Ireland. With a point of care 'registry style' database and data management by CFRI we will be in a position to produce real time data on the effectiveness of TCMT in the real world and hopefully, convince reimbursement agencies of the benefits of therapy. | No Research Activity assigned | 6project_grants_public
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gen_cfca34f1f6fde4ffb411423bce3e59d1 | Developing native strains of insect-killing Metarhizium spp. fungi to prevent malaria transmission in Burkina Faso | Wellcome Trust | Institut de Recherche en Sciences de la Santé | HRCS22_13969 | Despite efforts developing entomopathogenic fungi as biocontrol agents against disease vectors, expectations have not been met due to their relatively poor efficacy compared to cheaper chemical insecticides. The vast majority of mosquito control studies have focused on a single fungal isolate. However, the recent discovery that native strains of entomopathogenic fungi in Burkina Faso confer exceptionally high virulence against Anopheles gambiae provide new evidence that could transform the effectiveness of these biocontrol tools. These strains showed LT80 as low as 7 days, which is an unprecedented improvement over previous studies where LT80 values are ~10 days. The proposed research will investigate new ways to exploit local fungi strains for sustainable vectors control solutions. Specifically, using a combination of laboratory assays, semi-field experiments, and hut trials, I will investigate the practical utility of the native strain of Metarhizium from Burkina Faso for malaria vector control. This project will tackle the current challenges in the implementation of biocontrol strategies and will overcome the ecological barriers that have prevented the use of fungi for mosquito control and develop an effective entomopathogenic approach, which will be 1) applicable to other settings, 2) low-cost and biological, and 3) complementary to current vector control interventions. | 3.2 Interventions to alter physical and biological environmental risks | 6project_grants_public
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gen_567f6468ad03f1e0e112c724db15378a | A digital dashboard to support institutions implementing open science: Establishing a core set of open science metrics to track | Wellcome Trust | University of Ottawa | HRCS22_13974 | The completion of the proposed research program will result in two key outputs: 1) a core outcome set of open science (OS) metrics relevant to, and developed by, the biomedical community; and 2) a usable flexible, tailorable, and automated tool, developed using user-centred design best practices, that reports on these core OS metrics. Establishing a core outcome set of OS metrics is a vital step to move forward discussion around how to measure research(er) quality. Without consensus on what to measure, or how to measure it, even well intended institutions can’t easily consider incorporating metrics beyond those traditionally used (i.e., journal impact factor or number of publications). A core outcome set does not limit organizations from tailoring the collection of OS metrics, but ensures a standard set across organisations to enable national and international standardisation and comparison. By engaging with the research community at the onset of this program and throughout via an integrated knowledge translation approach, we can ensure that the tool we develop to report on the established core OS metrics meets the needs of the community and considers their concerns. Doing so ensures greater uptake. Further, through embedding considerations of equity, diversity, and inclusion in our design of the OS dashboard, we intend to create a tool that is globally relevant in biomedicine. This will ensure that our impact is as broad as possible and serves the entire biomedical community. By meeting our proposed aims, we will have achieved a ready to implement publicly available OS dashboard. | No Research Activity assigned | 6project_grants_public
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gen_cb46733854f3ce314377df6c2c11a4c3 | Accelerating Drug Discovery with Symbolic-Numerics in SciML | Wellcome Trust | Boston University | HRCS22_14003 | Pharmaceutical companies understand the need for modeling stochasticity, by which we can improve the reliability and effectiveness of drugs across the whole population. Our 2020 review in Trends in Pharmacological Sciences, one of the highest impact journals in pharmacology, argued that deterministic models that ignore stochasticity bias clinical and pre-clinical trial analyses. The quantitative systems pharmacology (QSP) groups within drug companies are the core units that model and predict patient outcomes, dramatically reducing the research and development timeline by predicting which drugs will fail before clinical trials begin. These groups have recently adopted stochastic dynamical models in order to better achieve their goals. Discussing with CJ Musante, Global Head of Pharmacology at Pfizer, the main reason that stochastic models are not more widely used is due to a lack of software that addresses the needs of QSP modelers. Stochastic models are more predictive of patient outcomes, but computationally expensive. Moreover, turnaround times needed by QSP teams are too short to make use of stochastic models with current software. This proposal addresses this problem, proposing to build software tooling which automates the construction and solution of stochastic models in a way that is orders of magnitude faster than what exists today. | No Research Activity assigned | 6project_grants_public
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gen_ae2f6e346919a1ebe8bf8a7b8b18f1a9 | Public and Population Health Open Research Ecosystem in Africa (P2HOREA) | Wellcome Trust | University of the Witwatersrand | HRCS22_14017 | This project seeks to address existing data sharing concerns of African public and population health researchers. It also motivates for the implementation of Africa-led initiatives for data sharing. Using acquired knowledge on global best practices and regional concerns, the project will design sustainable mechanisms to incentivise data sharing. This will involve leveraging our strategic partnerships and adopting artificial intelligence (AI) tools to implement solutions to some of the concerns. We will improve data sharing value chain; simplify access and utilization of data; and strengthen capacity and advocacy towards incentivised data sharing. Using AI tools, we will develop a virtual and physical environment for active and passive identification and curation of a list of publicly funded research data in public and population health in Africa; link researchers and research institutions to reusable publicly funded data; increase awareness and address fears and misconceptions about data sharing; and advocate for institutions to provide best practice rewards when data is shared. These activities will result in improved knowledge, attitude, and practices on data sharing by researchers, institutional data custodians and institutional management; increased collaboration and knowledge generation among researchers; and incentivisation of data sharing at institutional level. The project will promote scientific data findability, access, and reusability while simultaneously addressing data governance and trust concerns, fear of data misuse and exploitation, and ensuring compliance with privacy, security, and ethical standards on data sharing. | 8.3 Policy, ethics and research governance | 3networking_collaborative
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gen_d6179e7774b38ede89a677d01cdb127a | Data-driven drug discovery for A-T – interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids | Action for A-T | QIMR Berghofer Medical Research Institute | HRCS22_14090 | Using a data-driven approach, informed by single-cell sequencing of a large cohort of ATMdeficient cerebellar brain organoids - the hypothsis is that computational prediction of drugs will allow selective, positive modulation of aberrant pathways and behaviour in the team's in vitro model of the A-T cerebellum. Further, the team will democratize this research space by sharing their data, placing the building blocks for expansion of this project to grow globally. | 1.1 Normal biological development and functioning | 6project_grants_public
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gen_a4d8dad4026b2da9b5bc8fe060a0d402 | Innovative methods for gene therapy in A-T | Action for A-T | University of Granada | HRCS22_14091 | This project will be looking at Innovative methods for the potential of delivering gene therapy in A-T | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_0a6ad8a2d5b65b37a12332585eff8573 | Discovering new aminoglycosides to alleviate inner ear toxicity | Royal National Institute for Deaf People | Stanford University | HRCS22_14099 | Aminoglycosides are a class of widely used, broad spectrum antibiotics that cause hearing impairments in upwards of 20% of treated patients and even higher percentages if repeated treatments are needed or susceptible genetic mutations are present. Although aminoglycoside ototoxicity is a well-documented side-effect, there is still no FDA-approved treatment to prevent it. Despite the availability of newer, less ototoxic and nephrotoxic antibiotics, aminoglycosides are still among the most commonly prescribed class of antibiotics worldwide because of their efficacy, low costs, and low rates of antibiotic resistance. Indeed, aminoglycosides are designated as one of the critically important antimicrobials for human medicine. In the US, it is the first line of treatment for neonatal and peripartum sepsis and complicated urinary tract infection. In cystic fibrosis patients who are prone to recurrent sinopulmonary infection as most patients now survive into adulthood, repeated treatment with aminoglycosides is common with resulting hearing loss at rates up to 47%. There is clearly a pressing need to reduce aminoglycoside ototoxicity. Aminoglycosides cause permanent hearing loss resulting from the irreversible loss of cochlear hair cells. We have made significant progress in designing aminoglycosides with differential effects on the prokaryotic and eukaryotic ribosome to reduce ototoxicity while preserving antimicrobial activity in vitro and in vivo, devised novel chemical synthetic pathways, identified target sites on the aminoglycoside backbones to modify, and generated several lead compounds. The current proposal aims to: 1)test and optimize lead compounds in in vivo ototoxicity and infection models 2)test additional novel aminoglycoside analogues in vitro for ototoxicity and antimicrobial activities and ability to permeate hair cells. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_5e6a6863485bf426599a7c8bfd7e5f86 | Preclinical development of an amelioration therapy for Dentatorubro-Pallidoluysian Atrophy | Ataxia UK | Inserm | HRCS22_14108 | 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
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gen_e66e9a14bf4e0ce08475d64afdb3f836 | IMAXT : imaging and molecular annotation of xenografts and tumors | Cancer Research UK | Memorial Sloan Kettering Cancer Center | HRCS22_14116 | We propose to develop an entirely new way for scientists and physicians to understand cancer and predict its clinical behaviour. Our integrated approach will produce faithful three-dimensional representations of tumours and their host environments, wherein each cell is identified and molecularly annotated. These models will be presented in an interactive, virtual reality (VR) framework. Investigators will literally be able to walk inside a tumour, visualize the arrangement of tumour cells in relation to each environmental cell type, and perform interactive comparative molecular analyses in real time. We call this project IMAXT, Imaging and Molecular Annotation of Xenografts and Tumours. This approach harnesses our innate pattern recognition capabilities while maintaining the statistical rigour of molecular measurements. We wish not only to provide research tools that allow us to better understand how cancer develops and responds to therapy but also to transform the way that patients are diagnosed and treatments planned. Though this approach will be applicable to nearly all tumour types, we will begin in breast cancer, where both inter- and intra-individual heterogeneity are apparent and inform treatment decisions and prognosis. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_f2561d7710182e99085e9e0bd76ba12c | Preclinical programme evaluating antioxidant drug | Duchenne UK | MetrioPharm (Germany) | HRCS22_14142 | No abstract available for this analysis | 5.1 Pharmaceuticals | 0business_rnd_innovation
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gen_e2c9ce9a8c9b6ecfb8ff9188983bb500 | Intimate partner violence against women in low- and middle-income countries: associations with parenting practices and early childhood development. | Wellcome Trust | Associação Brasileira de Saúde Coletiva | HRCS22_14182 | The 2030 Agenda for Sustainable Development highlights the need to prevent and respond to violence against women and girls. It also affirms the need to invest in early childhood care for the promotion of sustainable development in low and middle-income (LMICs). Intimate partner violence (IPV) is one of the most common and extreme manifestations of gender inequality worldwide, and has a higher prevalence and more severe consequences for women and children living in LMICs. I aim to examine the association of IPV with parenting practices and early childhood development in LMICs. This will be done using data from nationally representative household surveys (DHS) carried out since 2010 in at least 10 LMICs, and a large population-based prospective cohort study in Brazil, following over 4,000 children born in 2015. A key objective of the project is to explore whether women´s mental health mediates the proposed associations, and the role of women’s empowerment levels in the associations under study. The empirical evidence generated from this project will contribute to increasing visibility of the intergenerational consequences of IPV on children and provide guidance for the direction of global resources to prevent gender-based violence. | 2.3 Psychological, social and economic factors | 6project_grants_public
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gen_17dfd315c8331f2682f3cea00fe55c68 | Identifying innate and adaptive immune mechanisms associated with fibrosis in animal models of RDEB | DEBRA | New York Medical College | HRCS22_14225 | We recently demonstrated that TGFβ signaling is activated in RDEB (col7a1-/-) mice as early as a week after birth in the interdigital folds of murine paw skin. At the same time, many critical genes involved in wound healing and fibrosis are significantly upregulated. In preliminary studies, we also observed infiltration of significant levels of neutrophils, macrophages, T cells and mast cells in the dermis of newborn and a week-old RDEB mouse skin. This inflammatory response is likely initiated by damage-associated molecular patterns (DAMPs), also known as sterile inflammation, as there is no apparent microbial-associated infection. Sterile inflammation has often shown to result in chronic inflammation and fibrosis. Surprisingly, all these immune cells are later (in two weeks) clustered around hair follicles. Such tropism of T cells to hair follicles resembles the features of skin resident memory T (TRM) cells, which provide rapid immune protection, however, when dysregulated, result in unwanted inflammation and fibrosis. Investigating the early events of sterile inflammation with subsequent microbialassociated infection is critical to understand the mechanisms of chronic inflammation and fibrosis in patients with RDEB. These results will facilitate the development of effective therapeutic strategies to prevent chronic fibrosis in patients with RDEB. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_2a72ff736c62a437f0eb41c40b425fe1 | NT3 treatment for brain coding restoration after cochlear synaptopathy | Royal National Institute for Deaf People | University of Michigan Health System | HRCS22_14228 | After noise-exposure that produces TTS, and thus clinically ‘normal’ audiograms, there is nonetheless permanent damage to auditory nerve (AN) - hair-cell synapses. 'Hidden' hearing loss is a potential major health issue, as temporal bone and ABR studies suggest it is common in humans, causing difficulties understanding speech in noise. These deficits reflect temporal-coding problems likely due to loss of high-threshold, low-spontaneous rate ANFs, which are preferentially affected after TTS. The primary central targets of high-threshold ANFs reside in the small cell cap (SCC) of the cochlear nucleus (CN), which is prominent in humans. SCC neurons display large dynamic ranges and superior suprathreshold tuning and temporal coding, which are essential for speech perception in noisy environments. The SCC is a recipient and projection area of medial olivocochlear (MOC) neurons which minimize threshold shifts after noise damage, and thus likely also play a role in SCC circuits in hidden hearing loss. The overall hypothesis of this proposal is that the SCC plays a major role in suprathreshold sound coding and that this coding is highly susceptible to degradation by hidden hearing loss. We will elucidate the cochlea-SCC-MOC circuit in normal and noise-damaged animals with hidden hearing loss, using optogenetics, physiology and tract tracing. Furthermore, we will determine whether NT3 restoration of ANFs affects auditory processing in the SCC after noise damage. Cochlear delivery of neurotrophins in humans is easily achieved via trans-tympanic injections, suggesting a possible clinical intervention. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_02b25c3c8618bbd1d4d9caef16e1fe17 | GHIAA MAPGuide: creation of access resources and guidance for funders | Wellcome Trust | Global Healthcare Innovation Alliance Accelerator | HRCS22_14254 | The GHIAA MAPGuide enables users to explore a range of approaches used to address key issues in global health agreements. As of 1 November 2021, the MAPGuide contained analysis of 387 provisions from 59 agreements, and our team is constantly working to expand on this. An important next step in widening the impact of the MAPGuide is to create educational resources that present key information and best practice recommendations in a format that can be easily understood by all stakeholders. The objective of this application is to develop materials that provide guidance to global health funders, PDPs and government ministries as they work to develop equitable access policies and ensure that they are translated into actionable agreements. The materials will draw on the agreements and provisions in the MAPGuide to examine the key pillars of equitable access and how they can be achieved through meaningful and enforceable contract terms. This information will be presented on the MAPGuide website in an easy to use format using a combination of infographics and a series of ‘plain English’ articles that explore key topics in more detail. | No Research Activity assigned | 3networking_collaborative
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gen_cbf4e4602db01f5942203dae6a9108c4 | Accelerating the development of lorlatinib to improve cure rates for patients newly diagNOsed ALK-driven high-risk neuroblastoma | Solving Kids' Cancer | Children's Hospital of Philadelphia | HRCS22_14317 | Neuroblastoma, the most common solid tumor malignancy of childhood, encapsulates the full spectrum of cancerheterogeneity. This cancer of the developing peripheral sympathetic nervous system shows widely divergent clinical manifestations, with approximately half of patients exhibiting explosively malignant disease with high risk for fatality. Genetic interrogation of neuroblastoma has demonstrated that this observed clinical heterogeneity is molecularly driven. However, current therapy consists of a largely empiric selection of cytotoxic therapies followed by targeted immuNOtherapy used to prevent relapse once remission is achieved. Despite this intensive therapy, cure rates for patients with high-risk neuroblastoma have been stalled in the 50% range and those surviving often suffer lifelong toxicities including deafness, growth and skeletal deficiencies, hormonal dysregulation, learning disabilities and second malignant cancers. The disproportionately high mortality rate for patients with high-risk disease mandates a need for the development of molecular targeted therapies that will ultimately improve survival while minimizing the risk of late effects. Activating mutations in the ALK oncogene are the cause of the hereditary form of neuroblastoma, and importantly these mutations are present in 14% of patients newly diagNOsed with high-risk neuroblastoma, representing a tractable therapeutic target. In addition, emerging data have demonstrated that many newly diagNOsed patients have a hidden small percentage of ALKmutated neuroblastoma cells that ultimately lead to disease relapse, explaining the observation that ALKmutations are more common at relapse compared to diagNOsis. These finding led to our initial study of crizotinib, a first-generation inhibitor of ALK, as a potential treatment for neuroblastoma, and led to the current investigation of crizotinib in patients with newly diagNOsed high-risk neuroblastoma within the Children’s Oncology Group(COG). More recently, through a partnership with Pfizer Pharmaceuticals, we have discovered a highly specific and potent ALK inhibitor, lorlatinib, that has improved anti-neuroblastoma activity and provides a unique opportunity to achieve significant impact in neuroblastoma patients. The successful completion of this project will result in the dramatic transatlantic acceleration of lorlatinib use in parallel Phase 3 trials within COG and International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) that seek tosubstantially improve the event-free survival for patients with newly diagNOsed high-risk neuroblastoma whose tumors harbor an activated ALK gene mutation. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_3d3fc267fa17ce3a91f59793045f055e | Extreme dose rate proton therapy - reducing side effects for brain cancer treatments. | The Brain Tumour Charity | Harvard University | HRCS22_14355 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_7bd2a94c34c915271a4d213bd6be0888 | Establishing the content coverage of available Patient-Reported Outcome (PRO) measures used in neuro-oncology and provide recommendations on the use of these PRO measures: part of the Response Assessment in Neuro-Oncology – Patient Reported Outcome (RANO-PRO) initiative | The Brain Tumour Charity | Leiden University Medical Center | HRCS22_14356 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_d69dffa1dd0d98448682a573eae8353f | Unveiling mechanisms of tumor formation linked to BRCA2 mutation | Worldwide Cancer Research | Spanish National Research Council | HRCS22_14389 | Inactivating germline mutations affecting a single copy of BRCA2 are associated with an increased risk of breast and ovarian cancer. However, what drives tumorigenesis in carriers of heterozygous BRCA2 mutations remains elusive. Moreover, BRCA2 deficient breast tumors lack a clear pathological phenotype that distinguishes them from sporadic cancers so the identification of a molecular signature of tumor formation associated with BRCA2 deficiency remains a challenge. Over recent years, many mutational signatures have been generated corresponding to different types of tumors including BRCA1/2 associated breast cancer. However, a defective BRCA2 gives rise to at least five mutational signatures and although they have been associated with homologous recombination (HR) deficiency, not all HR deficient genes lead to the same outcome. Furthermore, BRCA1 and BRCA2-mutated tumors can be discriminated against using these mutational signatures suggesting that mechanisms specific to each gene might be acting as potential cancer drivers. This is perhaps not surprising given the number of functions the two proteins exert in cells. As these different functions are mapped to distinct regions in the protein, we argue that different mutations in a single gene could reveal different mechanisms of tumor formation. Thus, by focusing on BRCA2-mutated tumors bearing a common pathogenic mutation we may unveil new mechanisms of tumor formation that would otherwise remain “hidden” in the population of BRCA2-mutated tumors. In addition, by recreating these mutations in relevant breast epithelial cells in heterozygosis we will be able to confirm which of the deregulated pathways observed in tumors are specifically due to BRCA2 mutation. Our preliminary results reveal a substitution signature prevalent in tumors bearing a specific pathogenic mutation and a deregulated pathway that was confirmed in our heterozygous cell system expressing the same mutation thus supporting this hypothesis. If confirmed, this project will have important clinical implications for prevention and treatment. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_7660412b1b4180e3050e0bcf9461fda7 | The Research Software Alliance (ReSA) | Wellcome Trust | Code for Science & Society | HRCS22_14399 | Research software is a critical component of open research, and an increased focus on research software challenges will further the objectives of Wellcome Trust’s Open Research programme to maximise research impact. The Research Software Alliance (ReSA) advances the vision that software is valued as a fundamental component of research. This proposal will support ReSA to bring research software communities together to collaborate on the advancement of research software, utilising application of the FAIR principles as a catalyst for this global endeavour.This project seeks USD$157,250 to engage the research software community to apply the FAIR principles to research software. to achieve three aims: 1. FAIR4RS WG project direction to develop agreed FAIR for research software principles 2. FAIR4RS Roadmap leadership to map FAIR for research software projects into a longer-term strategic framework 3. People Roadmap to support the development of career paths and reward structures to complement the FAIR4RS Roadmap This proposal will accelerate the development of an open research system that recognises and supports research software. This will provide researchers with the skills and resources to fully utilise research software, in a system where policy makers and funders value research software, and where organisations adequately reward staff with software expertise. | 1.5 Resources and infrastructure (underpinning) | 3networking_collaborative
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gen_3d7a488a964f455d75f7e6a9d1587f75 | Baseline pathology image analyses by deep learning approaches to predict the onset of ESR1 mutations, an exploratory study on samples collected in PADA-1, a UCBG/GINECO phase 3 trial | Worldwide Cancer Research | Institute Curie | HRCS22_14403 | Background Pathology image analysis by deep neural networks has been successfully applied to the detection of numerous mutations (EGFR in NSCLC, BRCA…) already present in tumor cells; these approaches have however never been used to predict whether a resistance mutation will appear later during therapy. Mutations in ESR1, the gene encoding for estrogen receptor (ER) alpha, are rare (<5%) in untreated ER+ HER2- metastatic breast cancers before therapy but are “acquired” in ~40% of cancers as a mechanism of resistance to aromatase inhibitors (AI). Interestingly, these mutations are sensitive to selective ER degraders (SERDs). Predicting which cancer is more likely to develop an ESR1 mutation could transform ER+ breast cancer care, as it will allow targeting high-risk patients and even guide the use of SERDs before ESR1 mutations become detectable. Challenge We hypothesize that digitalized and combined hematoxylin-eosin (H&E), ER and PR (progesterone receptor) immunohistochemistry (IHC) analyses of pre-treatment tumor tissue by deep neural networks could accurately predict the later onset of ESR1 mutations during AI-based therapy. Methods 588 tumor samples, obtained with each patient consent before the start of first line AI + palbociclib therapy, have been collected as part of the PADA-1 trial (PI: FC Bidard; NCT03079011). These samples are fully annotated: patient and tumor characteristics, treatment response, PFS, OS and ESR1 mutation status by ctDNA analysis collected every 2 months during therapy, until tumor progression. Centralized H&E stained slides, ER and PR IHC slides will be digitalized and then processed by our deep learning Multiple Instance Learning workflow, based on tiling, encoding, attention scoring, tile aggregation, and slide classification. Deliverables We will establish validated algorithm predicting the individual risk to develop an “acquired” ESR1 mutations while on AI + Palbociclib. The prediction of treatment outcomes (PFS, OS) will also be assessed as a by-product of this analysis. | 6.1 Pharmaceuticals | 6project_grants_public
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gen_3c1cbabc32df15e653615eae23137b22 | Exploring the use of CDK4/6 inhibitors in combination with classical chemotherapy | Worldwide Cancer Research | Spanish National Cancer Research Centre | HRCS22_14416 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_9e61d146a48b9c42163a5f163a14e969 | Modelling neuroblastoma - immune cell interactions in a tissue- engineered 3D platform | Neuroblastoma UK | Royal College of Surgeons in Ireland | HRCS22_14420 | Combining 3D printing with cancer research | No Research Activity assigned | 6project_grants_public
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gen_d0acd25723dd0053dcc54bafa035ce92 | Making the invisible visible: In vivo mapping of molecular biomarkers in adult diffuse glioma with CEST MRI | The Brain Tumour Charity | Erasmus MC | HRCS22_14464 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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