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      "description_narrative":["GCRF Health and Context award - The Problem Globally 1.7 billion diarrhoea episodes result in approximately 2 million deaths in 2010.1 Regionally, Africa has the greatest burden. Alongside poor infant feeding, diarrhoea diseases also contribute to infant malnutrition.2-4 Despite new vaccines, treatments and public health measures,3 diarrhoea and malnutrition remain considerable public health problems in low- and middle-income countries (LMIC). The period when a child starts eating solids (usually 6-24 months called complementary food (CF)), is associated with the highest rates of diarrhoea: over 50% of all diarrhoea deaths occur at 6-11 months.1 Most low-income households in LMIC cook ingredients at home or obtain food from informal street food-sellers who prepare the goods in their homes. Therefore home food handling, preparation and storage determine the scale of food contamination.  Although many studies explore the effects of improved water supply, hygiene and nutrition of infant diets on infant diarrhoea and growth development, much less attention paid to studies of food safety remain scarce. Research in this area has been too general to reduce diarrhoea through food contamination. The World Health Organisation (WHO) advocates targeted interventions to support CF safety and hygiene. Ideally CF safety needs to be accompanied with achieving optimal dietary intake for young children, which also remains a challenge in LMIC. Research shows that infant health and safety advice has limited impact on behaviour change unless accompanied by means to motivate and empower mothers in the community. Yet previous interventions targeting diet or diarrhoea have seldom drawn on cultural dramatic arts and community assets to motivate behaviour change. African communities have a particularly strong cultural heritage to underpin such potential impact.  Our Aim We propose a low-cost, scalable, and adaptable community intervention to reduce diarrhoea and improve the growth of young children in urban-poor and rural Mali. We will assess the effects in both settings, to inform replication and scaling of the intervention, because the dynamics of community life vary in each.  Our Previous Work We combine two complementary interventions shown to be effective elsewhere in LMIC. A trial in the Gambia (developed through former work in Bangladesh, Nepal and Pakistan) evaluated efforts to improve hygiene and safety of CF, while a trial in Kenya evaluated a community programme to improve breastfeeding and weaning food content.  Our Plan After adaptation with communities, our intervention will empower local families to implement behaviour change. It will include campaign-like activities such as culturally relevant dramatic arts (drama, songs, stories), public meetings, certifications, and home visits, delivered by a small team: 5 days of community campaign visits dispersed during 35 days and including home visits by trained female volunteers, plus a reminder campaign day at 9 months. We will allocate 120 urban and rural sites in Mali by chance to receive the intervention, or not, and assess 27 households in each site after 15 months.   The study is designed to quantify the influence of urban vs rural context, and to examine other societal influences (e.g. household poverty, women's work, and education, etc). Using observations, interviews, discussion groups, surveys and laboratory tests we will compare the implementation of the intervention in urban-poor and rural settings. Importantly, the intervention is designed to be sustainable through peer-education among mothers and older female volunteers (demonstrated after 32 months in Gambia), thus requiring only small levels of coordination resources from central government.","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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      "description_narrative":["Neglected tropical diseases are a diverse group of diseases that thrive mainly among the poorest of the world's populations. Three of the World Health Organisation's 10 most significant neglected tropical diseases - African trypanosomiasis (also known as sleeping sickness), leishmaniasis, and Chagas' disease - are caused by closely-related single-celled parasites. Human infection with African trypanosomes is brought about when an infected tsetse fly takes a blood meal. Without treatment the disease progresses through general ill health to coma and death. Current drugs in use against trypanosomes are old, toxic and failing due to emergence of resistance. Urgent new research is needed to identify potential new therapeutic options.  An unusual aspect of African trypanosomes is that they multiply in the human blood in full view of the body's defence systems. They do this by periodically changing their cell surface to escape recognition by the host. However, many molecules on the parasite surface perform essential functions and cannot be changed. Trypanosomes place these in a special, protected domain on the cell surface. Identifying surface-exposed invariant molecules and understanding how this protective segregation is maintained are of major scientific interest, as well as of practical utility in uncovering ways in which trypanosomes may be vulnerable to new therapies.  Using a combinatorial approach funded by the MRC, I have previously identified the composition of the African trypanosome cell surface. I now aim to exploit this knowledge to single out those invariant surface molecules that are essential to the survival of the parasite during infection. For this, I propose to harness some of the power of modern DNA sequencing technologies to test which cell surface genes, when silenced, cause the parasite to die inside the host. A similar method will be used to identify not only cell surface genes, but any genes that the parasite uses to maintain the cell surface organisation, which is so critical to escaping the host immune attack.   Finally, I propose to test those surface-exposed molecules for their potential as vaccines. My pilot experiments show that I can use genetically-modified parasite to screen for molecules on the parasite surface that are accessible to the immune system. I propose to develop this assay and test the most promising candidates in an animal model of human disease. The proposed work will increase our understanding of the fundamental biology of a significant human parasite, and also, by exposing essential surface molecules, provide the first steps in developing new treatments.","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":["A mathematical modeling framework for tuberculosis burden estimation and economic evaluation of pharmaceutical interventions"],
      "description_narrative":["Tuberculosis (TB) is a major cause of disease and death globally. In 2015, WHO estimated there were 9.6 million TB cases and 1.5 TB deaths. Nearly 500,000 of these cases were resistant to two or more of the main drugs used to treat TB. New drugs, and combinations of drugs, are being developed to treat tuberculosis, as are new vaccines that may protect against disease in adults.  Quantifying the burden of TB is fundamental to understanding its global epidemiology and for making appropriate resource allocation decisions. Most estimates of new TB case numbers each year rely strongly on the number of cases reported by countries in that year to WHO. Unfortunately, one in three TB cases are thought to go either undetected or unreported, so the number of cases reported underestimates the number of new cases. While one can correct for this, it is hard to know exactly how much to adjust the reported numbers. Some countries have good systems for recording causes of deaths, which can be used to estimate the number of deaths caused by TB. Increasingly, large and expensive prevalence surveys are being used to estimate the number of people with active disease in a population. These estimates are less subject to bias, but measure a different quantity. Little work has explored the best way of combining these three data sources.  A major goal of this work is to use mathematical transmission models for burden estimation and provide a unified framework for all data. These models yield the number of new cases, deaths, and also the prevalence of disease. They explicitly represent disease transmission and so introduce a dependence between the number of new cases in different years. These models involve parameters evidenced from previous epidemiological work, but must be calibrated to learn from data on TB reports, deaths and prevalence. Calibration means adjusting imperfectly known model parameters in order to match observed model outputs to the data. This process provides a model that may be used to make predictions about burden, but may also teach us something about the underlying processes. Many of the parameters concerning the epidemiology and disease course of TB are quite uncertain, and this uncertainty is rarely represented fully in models needing calibration, but will be done in this project using statistical techniques that also allow comparison of different models' performance.   TB burden estimation and calibration of transmission models are almost always carried out on a country-by-country basis. Many parameters describing disease progression are likely to be similar in different countries, even if their exact values differ for unknown reasons. Hierarchical modelling techniques allow such parameters to be correlated between countries. This can improve precision, particularly for countries with little data, as estimates can be informed by data from neighbouring countries. I will explore these techniques for the transmission model, and also in statistical modelling aiming to account for the observed patterns of drug-resistance. The transmission model will ultimately be extended to include different types of drug resistance.  As new treatments and vaccines emerge, those with responsibility for public health will want to understand the potential impact these new technologies can have in terms of gains in health, and changes in spending. Producing cost-effectiveness and budget impact evidence requires a model that includes transmission, in order to account for indirect benefits accrued by avoiding secondary cases. We will use our model to provide guidance to decision-makers seeking to maximise health gain with limited resources. We will also analyse sources of uncertainty in the model to identify future research that would have most value in increasing the precision of burden estimates and in reducing decision uncertainty around the introduction of new interventions.","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":["MICA: Development of new agents for the treatment of cryptosporidiosis"],
      "description_narrative":["A recent clinical study in Africa and South Asia has found that cryptosporidiosis is one of the most significant causes of death and illness from diarrheal diseases amongst children in the developing world. Cryptosporidiosis is caused by a single-celled protozoan parasite; the predominant species infecting humans are called Cryptosporidium hominis and Cryptosporidium parvum. This parasite mainly lives in the cells in the gut wall and has a complex life-cycle. Infection occurs due to consumption of water or food contaminated with the parasites. Parasites are spread from an infected individual through their faeces. In people who are healthy and well nourished, the disease clears naturally within a couple of weeks. However, in people who are malnourished (particularly in young children) and people with an immune system that is not functioning properly (for example HIV/AIDS victims), the disease can have a much more significant impact. It is the major contributor to life-threatening diarrhea in young children, with 2.9-4.7 million cases in children under 24 months in sub-Saharan Africa and the Indian sub-continent, leading to more than 200,000 deaths per year. Cryptosporidiosis is also associated with malnutrition and stunted growth in children and probably causes chronic infections, which last for weeks or months. The only drug registered for the treatment of this disease is nitazoxanide, which is not very effective, especially in those patients who are most severely affected due to a weak immune system and/ or malnutrition.   Therefore there is an urgent need for the development of new drugs to treat: (1) children <24 months, especially those that are malnourished and with chronic diarrhea; and (2) immunocompromised children and adults with advanced AIDS and chronic diarrhea. Cryptosporidium may be the cause of as much as 75% of chronic diarrhea in this patient cohort.   We have discovered some chemical starting points that can be used for a drug discovery programme. We have a series of compounds that kill the parasites and also are very effective in clearing the parasites from rodent models of cryptosporidiosis. The compounds are thought to work through preventing the parasite making proteins. The aim of this project is to take these starting points and optimise them to make a molecule which has the potential to be a drug. This will require us to optimise multiple features of the molecule: its ability to kill the parasite, its ability to reach the sites in the body where the parasite resides without being broken down, and its safety. At the end of this project we hope to have a \"preclinical candidate\". This is a compound that we think should be suitable to enter human clinical trials. The steps after this project, prior to human clinical trials will be to make the compound on a larger scale under properly defined conditions and to carry out formal safety testing.","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":["A comparative trial of seasonal vaccination with the malaria vaccine RTS,S/AS01, seasonal malaria chemoprevention and the two interventions combined"],
      "description_narrative":["There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2015 there were still 438 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment: new tools and approaches are needed. In the African Sahel and sub-Sahel, the risk of malaria is concentrated in the few months of the rainy season, although some transmission continues during the rest of the year.  The seasonality of malaria in this part of Africa has allowed the development of a control measure called seasonal malaria chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarials sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season, a regimen which is very demanding on health care givers and recipient children.   The malaria vaccine RTS,S/AS01 has been in development for over 20 years. A recent trial conducted in 15,439 children showed that when three doses of the vaccine were given to children aged 5-17 months, followed by a fourth dose a year later, the vaccine provided 37% protection against clinical attacks of malaria over a period of 4 years, and a similar level of protection against severe malaria. The vaccine caused febrile convulsions in about 1% of children and there was a small, unexplained, increase in the incidence of meningitis in  vaccine recipients.  These findings were reviewed by the European Medicine Agency in July 2015 and, based on the balance of benefits and risks, the Agency gave the vaccine  a positive opinion. WHO has subsequently recommended that several large pilot implementation studies should be done before the vaccine is deployed more widely and that alternative approaches to its delivery should be explored.  A characteristic feature of the vaccine is that it produces high levels of protection in the first few months after vaccination but that this subsequently wanes. Vaccine efficacy of 86% (26/30 subjects protected) was obtained in a recent trial in USA military volunteers challenged shortly after three doses of vaccine had been given,  the last dose at a lower concentration than usual. The aim of this study is to take advantage of the high initial efficacy of RTS,S/AS01 to investigate its potential to provide protection to children exposed to malaria for just a few months each year.   A three arm trial is proposed which will compare  (a) administration of three doses of RTS,S/AS01 to young children followed by a fourth  and a fifth dose at the beginning of two subsequent malaria transmission season (b) administration of SMC with SP + AQ  as recommended by WHO (c) the combination of these two interventions. The main objectives of the trial will be to determine  whether  RTS,S/AS01  provides a similar level of protection to that of SMC and is equally cost effective as SMC but is easier to administer and whether combination of the two interventions provides an added, cost effective benefit.  The trial will be conducted in 6,000 children (2,000 in each arm) in Hounde, Burkina Faso and Bougouni, Mali where a trial of adding the antibiotic azithromycin to the anti-malaria treatment regimen used for SMC is currently under way and due to finish at the end of 2016.  The study team and many of the techniques needed for the new trial are, therefore, in place.  The main end-point of the new trial will be the incidence of episodes of clinical malaria severe enough to warrant treatment. Other end-points will be the incidence of severe malaria, hospital admissions with malaria and anaemia. The safety of the two interventions will be monitored, with a focus on meningitis. The costs of the two approaches and of the combination will be measured and the preference of the local populations for each intervention will be determined.","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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