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      "title_narrative":["Pest Risk Information Service (PRISE)"],
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      "title_narrative":["Rational Design, Synthesis and Biological Evaluation of Benzimidazoles; Towards a Novel Therapy Selectively Targeting C. neoformans beta-tubulin"],
      "description_narrative":["The Need:  Cryptococcus neoformans (C. neoformans) is a yeast like fungus which manifests as meningitis and less frequently pneumonia within the human body. In sub-Saharan Africa C. neoformans causes more deaths annually than tuberculosis. C. neoformans is the most common cause of fungal infection in patients with AIDS and there are an estimated 1 million cases of cryptococcal meningitis worldwide each year. The current drugs used to treat this disease are a 2 week course of amphotericin B and 5-flucytosine followed by a long term course of fluconazole. Amphotericin B  and 5-flucytosine are associated with toxicity and fluconazole suppresses the growth of the fungus but does not completely remove it from the body. There is a therefore a great need for new drugs to treat C. neoformans infections. These drugs must have less toxicity and work better against the disease. The aim of this proposal is to complete the early stage drug discovery activities required to ultimately develop new drugs for cryptococcal meningoencephalitis that can be used in sub-Saharan Africa.  The Concept:  It has previously been reported within scientific papers that a class of compound called the benzimidazoles (widely used to treat worm infections in humans and as fungicides in agriculture) have good activity against C. neoformans in a laboratory and this has subsequently been confirmed by work here at the University of Liverpool (UoL). Benzimidazoles have been shown to interfere with cell division in C. neoformans through binding to beta-tubulin. Beta-tubulin is a protein that is essential for cell division and growth, when benzimidazoles bind to beta-tubulin the fungal cell can no longer grow. More recently, unpublished studies carried out at UoL have shown flubendazole to be active against C. neoformans in the mouse model. Humans also have beta-tubulin so it is essential that any new drug developed against the beta-tubulin target is selective for C. neoformans beta-tubulin. Medicinal chemistry (modification of the chemical structure of a drug) can be used to improve both selectivity for beta-tubulin and activity against C. neoformans.  The Solution:  Identification of an active class of compound, against a known target, with established whole cell C. neoformans and animal model activity provides an excellent starting point for medicinal chemistry modification. To date benzimidazole compounds have never undergone medicinal chemistry optimisation to establish beta-tubulin selectivity or to improve C. neoformans activity. The two most commonly use benzimidazole drugs (Flubendazole and albendazole) are extensively metabolised within the body and have a limited ability to move from the stomach into the blood stream. New compounds will be designed using information from computer models to predict how they are likely to behave within the body.  In order to improve the safety profile of the newly designed compounds their selectivity for C. neoformans beta-tubulin over human beta-tubulin will be measured in the laboratory (alongside activity against C. neoformans) and computer models of the binding sites of the two tubulins used to look at how new compounds are likely to bind better with C. neoformans beta-tubulin. Once C. neoformans activity, selectivity for beta-tubulin and improved levels of circulating drug have been established the compounds will move into a mouse model of C. neoformans infection.   Impact:  The long term aim is to develop a single therapy that does not require subsequent long term treatment with fluconazole and that can be given both orally and by injection. Given the number of patients affected by C. neoformans this project has the potential to have a dramatic beneficial impact on individuals and societies.  Development:  Compounds demonstrating activity in the mouse model will form the basis of further funding applications to progress the new drugs through the drug development pipeline.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world."],
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      "title_narrative":["The Role of Nutrients, Gut Dysfunction and the Gut Microbiome in Determining Health Outcomes in Undernutrition"],
      "description_narrative":["Undernutrition affects 462 million people world-wide with 165 million children having stunted height and 52 million children are wasted (very thin).  Both acute and chronic malnutrition ('stunting') are associated with significant health and economic burdens in low and middle income countries (LMICs). In acute malnutrition, little progress has been made in the management of severe acute malnutrition (SAM) in children, where mortality (death) remains high.  The factors underpinning SAM are complex and multifactorial, ultimately resulting in disruption of the normal gut bugs (or microbiota), reduced ammounts of vital nutrients being available, the barrier (mucosa) of the gut breaking down causing altered function such as impaired mucosal immunity and leakiness of the bugs from the gut (gram negative bacteria) into the body causing septicaemia and high risk of mortality.  On top of this, poverty and the lack of foods causing undernutrition there is also poor quality water and increased environmental pathogen burden (worms and poor sanitation) all leading to an increase the gut not being able to absorp protein and vital nutrients. These form a vicious cycle and contribute to the poor outcomes in undernourished children. .  Rather than just increase the amount of proten and energy giving in refeeding programmes, which have failed to tackle the underlying problems of the poor gut barrier function and pathogenic gut bacterial (microbiome) we plan to take an alternative approach. Our overarching strategy is to develop a programme of work to understand the relationships between undernutrition, pathogen burden, gut barrier function, the gut microbiome, and health outcomes, and to develop nutritional strategies that are context-specific to overcome nutritional challenges at key stages of child development in LMICs. The nutritional feed we propose will focus upon legume (pulses) based proteins and carbohydrates since the latter are metabolised in the gut to produce fatty acids which can help repair gut barrier function and alter the micriobiome into a more 'healthy' one, with less loss of vital nutrients. Ultimately improving nutrition statue and reducing the risk of septicaemia.  Research Questions: We have six priority research questions which underpin our long-term research plans. These are: 1. To understand the role of gut barrier dysfunction in both acute and chronic malnutrition?  2. Do the use of legumes feeds help repair the gut barrier and promote a healthy gut microbiome and lead to improved health outcomes in malnutrition? 3. What are the protein requirements of malnourished children under high pathogen burden? 4. In order to help farmers in low middle income countries (LIMCs) can locally-produced legume crops help meet the protein and vital nutrients at key stages of life? 5. What intervention studies are needed to generate evidence of the benefit of legume pulses in the management of undernutrition in LMIC populations? 6. How can legume consumption be increased sustainably across LMIC populations? To begin to achieve this we will bring the research community together with the long term aim of developing, revisit and refine current recommendations of macronutrient feeding regimens to reduce morbidity and mortality associated with gut barrier dysfunction in LMICs.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world."],
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      "reporting_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY"],
      "title_narrative":["Interdisciplinary interventions for stunting and wasting in Zimbabwe, Zambia and Pakistan"],
      "description_narrative":["Undernutrition underlies almost half of all child deaths and has far-reaching educational, economic and health impacts. We focus on stunting and wasting, the major forms of undernutrition, which are not explained simply by shortage of food. Stunting, or reduced height, impairs long-term educational attainment and earning potential in adulthood and has multiple underlying causes, but few effective preventive strategies. Wasting in its most serious form presents as severe acute malnutrition (SAM) and children have a high risk of dying in hospital or after discharge home. For children to survive, thrive and lead prosperous lives, we need new ways to tackle undernutrition. We aim to strengthen partnerships, draw on expertise beyond traditional nutrition disciplines, and conduct a long-term programme of research in three countries with a high burden of child undernutrition - Zimbabwe, Zambia and Pakistan. Our ambition is to improve child survival, health and potential by finding new ways of preventing stunting and treating wasting, to help reach the Sustainable Development Goals.  Our long-term research programme has three aims. Our first aim is to understand the network of environmental, social and biological factors that interact to cause undernutrition so we can find the most promising targets for intervention. Our second aim is to use this learning to evaluate new strategies for undernutrition. We will design packages of interventions that are often not used together, and test their effectiveness, first in small pilot studies and then in large clinical trials aimed at preventing stunting and treating wasting. Our third aim is to use the findings we generate to influence policy and development programmes so that new interventions are scaled up effectively to reduce undernutrition.  We plan to use this current grant opportunity  to strengthen links with each country, build more south-south cooperation through collaborative meetings and a shared programme of work, and engage new investigators from outside the nutrition field. We will conduct four pilot projects to identify new approaches to undernutrition, which will start to inform our long-term programme. First, we will bring together experts in human, animal and environmental health to discuss the risks and benefits of livestock ownership for stunting and start to design a future intervention that increases the positive effects of livestock ownership whilst mitigating the negative effects. Second, we will work with social scientists to evaluate the attitudes and behaviours of mothers whose children are recovering from SAM. Strengthening the capacity of mothers to look after their children might help to deliver a package of care after discharge from hospital to improve the long-term outcomes of children with SAM. Third, we will explore whether giving high-dose vitamin D is a promising strategy to improve recovery of children with SAM in Zambia and Zimbabwe, as we recently found in Pakistan. We will measure vitamin D in our laboratory using blood samples collected from children with SAM during hospital admission and at discharge, to see whether vitamin D deficiency partly explains their poor outcomes. If so, high-dose vitamin D should be evaluated in a future trial. Finally, we will conduct a pilot study to treat maternal depression as a way of improving child growth. Poor maternal mental health can compromise caregiving and feeding practices and increases the risk of child stunting. Treatment of common mental disorders using a community-based intervention based on problem solving therapy, delivered by trained lay workers, is highly effective but is mostly used in urban areas currently. We will conduct pilot work to see if this intervention works for mothers in rural Zimbabwe, and whether it is a promising approach to improve child growth and development.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world."],
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      "participating_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY","MEDICAL RESEARCH COUNCIL","MEDICAL RESEARCH COUNCIL","QUEEN MARY UNIVERSITY OF LONDON"],
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      "title_narrative":["MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases"],
      "description_narrative":["Neuromuscular Diseases (NMD) affect at least 17 million children and adults globally. They cause either premature death or are chronic diseases causing lifelong disability with economic impact. They include many different disorders affecting muscle and nerve function and account for ~20% of all non-infectious neurological diseases. Examples include muscular dystrophies, congenital myopathies, neuropathies, motor neuron diseases, muscle channelopathies and mitochondrial diseases. Advances in genetics have improved our ability to diagnose patients in the UK, and this has resulted in improved patient care and enabled clinical trials. However the benefits of genetic advances have not been realised in Official Development Assistance (ODA) defined Lower and Middle Income Countries (LMICs), partly because of a lack of neurologists trained specifically in genomic NMD medicine.  NMDs are commonly genetic and are inherited. Identifying genetic pathways and applying genetic testing has led to some of the most important advances in disease understanding alongside patient management plans and the development of new therapies. Many of the key interventions involve the inexpensive practical applications of widely available medical technology (e.g. low-cost off-licence medication, targeted vaccination, cardiac monitoring and respiratory care), but their application is contingent on making a precise diagnosis. For example, a precise genetic diagnosis can lead to a personalised and often simple management plan following established care guidelines that includes basic screening for known complications (e.g. cardiac, respiratory, gastroenterological and metabolic) and often simple interventions that improve health outcomes - interventions that could be implemented easily in LMICs providing an accurate genetic diagnosis is made. In the UK, a muscle biopsy has been the mainstay in the investigation algorithm in many patients, but this requires a specialist laboratory equipped for frozen section analysis with a growing panel of diagnostic antibodies. However, recent advances in genomics provide the opportunity to diagnose with high precision based on a DNA sample and clinical data collected remotely.  Our central objective is to build ethnically diverse cohorts of children and adults with NMDs and undertake genomic analysis to find known and identify new disease genes. We will increase the number of patients with a precise genetic diagnosis to both improve patient care and to increase knowledge on the comparative genetic architecture of NMDs across four continents.  This is a brand new transcontinental programme led by UK professors at UCL, Newcastle and Cambridge Universities. The research programme will train a new generation of academic doctors, generate the world's largest cohort of 15,000 ethnically diverse NMD patients and will investigate the causative genes. We will work with five LMIC clinical and academic centres in: India, Turkey, South Africa, Zambia and Brazil. The trained doctors will be the future clinical academic leaders to undertake research and improve NMD patient care in these countries. The fellows will already be fully trained in neurology and will spend a year in the UK for specialist training in NMD genomic medicine and spend three years in their country building NMD patient cohorts that will be assessed in detail clinically and will undergo full genetic analysis to achieve a precise diagnosis and optimise patient management. All data produced will be anonymised and shared by all researchers. Importantly, we have access to several thousand ethnically matched control DNAs already and will build this control resource further, complementing those available through the Genomics England 100,000 genomes project, the NIHR BioResource and international collaborative resources. We will train a new generation of NMD doctors who will pursue their research career in their own country, discover new genes and improve patient care.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world."],
      "participating_org_ref":["GB-GOV-13","GB-COH-RC000346","GB-COH-RC000346"],
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      "default_lang":"en",
      "iati_identifier":"GB-GOV-13-FUND--GCRF-MR_N020618_1",
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      "reporting_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY"],
      "title_narrative":["Can community-wide active case finding for tuberculosis and universal testing and treatment for HIV control the African tuberculosis epidemic?"],
      "description_narrative":["Tuberculosis (TB) is an infectious disease, which is spread when the bacteria causing TB is released into the air by TB cases when they cough. Globally one third of the worlds population is infected with TB and 9 million new cases of disease, with 1.5 million deaths occurred in 2013.  Only 1 in 10 individuals infected with TB goes on to develop disease but the risk is much higher in individuals who have a weakened immune system such as those infected with HIV. Because of the overlap between HIV and TB, sub-Saharan Africa has the highest rate of TB disease. But, with increasing globalisation and travel, this has also translated into increasing rates in other parts of the world such as the UK. Therefore preventing TB in sub-Saharan Africa helps countries devastated by this disease, and also decreases the risk of TB worldwide. To control TB a consistent decrease in the number of new cases and improved TB case outcomes (e.g. less deaths) are needed in the whole population.  There is no effective vaccine against TB. However, if TB cases are identified earlier and started on effective treatment, before they normally present to healthcare, TB spread to others could be reduced. Active case finding for TB (ACF) involves systematically screening the whole population for TB disease and starting cases on treatment. This benefits the individual and should decrease the number of new cases by decreasing the spread of TB. Antiretroviral therapy (ART) improves a HIV-infected person's immune function and decreases their susceptibility to TB. Therefore if rolled-out widely to those who need it, ART should decrease the number of new TB cases. However to date, we don't have any strong evidence to show that ACF and ART can control TB in populations.   HPTN071 is a large trial being conducted in 21 Zambian and South African communities, two countries devastated by TB and HIV, by the London School of Hygiene and Tropical Medicine in the UK, Zambart in Zambia and the Desmond Tutu TB Centre in South Africa. In this trial 14 intervention communities receive a HIV prevention package administered to the entire population and 7 control communities receive usual care. In the intervention communities, from 2014-2018, all adults and children are tested annually for HIV (\"universal testing\"). ART is started immediately in 7 communities (\"universal treatment\") and according to national guidelines in 7 communities. The trial will determine if new HIV infections can be decreased by this strategy of universal test and treat. To measure this, the study will follow 52500 adults aged 18-44 years for 3 years from all 21 communities, and compare the number of new HIV infections in the intervention and control communities. Given the TB problem in these communities, all individuals in the intervention communities are also asked about TB symptoms (e.g. cough, night sweats etc). If symptoms are reported, sputum is collected and tested for TB, with referral to local TB clinics for treatment.   HPTN071 therefore combines community-wide ACF for TB and ART for HIV. It provides a unique opportunity to study if these interventions together can decrease the number of new TB cases and improve the clinical outcomes of TB cases. This proposed project will use information from the HPTN071 trial as well as the national TB records for these communities to see if the number of new TB cases have reduced in the intervention communities compared to the control communities, and also what the clinical outcomes for these patients are. A mathematical model will be used to better understand and tease out the effects of the two interventions.   This project has the potential to change our approach to TB prevention in sub-Saharan Africa. It is an important study, which will make a major contribution in the fight against one of the most important diseases in the world.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world."],
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      "participating_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY","MEDICAL RESEARCH COUNCIL","MEDICAL RESEARCH COUNCIL","LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE"],
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