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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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      "description_narrative":["Almost half of the world's population, including 700 million people in Africa, relies on biomass fuels (animal dung, crop residues, wood) for their everyday fuel-energy requirements. These fuels are typically burned in open fires, often indoors, that emit smoke into the household environment and lead to high levels of household air pollution. Women and children, especially young children, experience high exposures to air pollution in the home; this has been linked to a range of adverse health outcomes including non communicable lung diseases like chronic obstructive pulmonary disease (COPD) and lung cancer in adults and asthma in children. It is now recognised that household air pollution from biomass smoke is the third leading cause of global disability and death with 4 million deaths attributed to this exposure annually. This burden, much of which is represented by non-communicable respiratory disease, falls hardest on poor populations around the world and in countries in sub-Saharan Africa in particular.  To build the foundations for work to tackle this issue we have bought together a network of investigators from ten African countries (Cameroon, Ethiopia, Ghana, Kenya, Malawi, Nigeria, South Africa, Sudan, The Gambia and Uganda) underpinned by support from the Pan African Thoracic Society (PATS), American Thoracic Society (ATS) Methods in Epidemiologic, Clinical and Operations Research (MECOR) programme, MRC BREATHE-Africa partnership, Malawi Liverpool Wellcome Trust (MLW), Burden of Obstructive Lung Disease (BOLD) Centre, Spirometry Training Services Africa, Global Asthma Network (GAN), and Collaboration for Applied Health Research and Delivery (CAHRD). This proposal offers an unprecedented opportunity to create a multi-site multi-disciplinary pan-African platform for clinical, epidemiological and applied health research underpinned by regional and international collaborative research and delivery networks that will allow us to conduct research into the causes, prevention and treatment of non-communicable respiratory disease across the life course. By addressing a major cause of morbidity and mortality across the life course of children and adults living in low or middle-income countries in Africa the proposal is fully aligned with the overall principle of Official Development Assistance (ODA) to promote welfare of developing countries.   Within the two years of this foundations-building grant we will work hard to create a thriving partnership whilst delivering on two specific research aims: to 1) develop and share methodology for the measurement of non-communicable respiratory disease exposures and outcomes tailored to the challenges of conducting research in resource-constrained African environments and 2) use this methodology to generate and share high quality preliminary data from multiple African sites.","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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      "description_narrative":["More than a third of adults around the world live with more than one chronic condition. This accumulation of diseases is otherwise known as multimorbidity. Existing studies of multimorbidity have identified that the number of people living with multimorbidity in communities is similar between High (HIC) and Low- and Middle-Income Countries (LMICs). However, very fewer studies have been carried out in LMICs. Not everyone who has multimorbidity share the same diseases, and several different possible patterns are thought to exist. These patterns are normally referred to as clusters, as they represent the clusters formed by different diseases. Most of the research on clusters has been carried out in HIC, with very few studies being conducted in LMICs. Some existing studies carried out in HIC have showed that when a person has both physical and mental disorders, their quality of life is lower, their risk of dying is increased, and their economic burden is higher, compared to a person who only has physical illnesses. This area of work has however been largely under-researched in LMICs, partly for the following reasons: a) analysing multimorbidity clusters is challenging and requires advanced training in data analysis; b) lack of suitable and up-to date data; c) neglect of LMICs mental health research more generally, and d) lack of interdisciplinary researchers trained with appropriate skills to address this complexity, especially in LMICs. With MUTUAL we will develop a platform for high-quality, LMIC-led research to investigate knowledge gaps in our understanding of multimorbidity associated with both mental and physical illnesses (MPM) in LMICs. This will be done by creating a capacity building programme taking place across three countries, in three continents, and with different levels of economic development: Brazil, Ethiopia and Malaysia. Training will be delivered by tutors and mentors in 3 areas of need: a) advanced statistical methods and epidemiology; b) health economics; and c) evidence synthesis. This will be further enhanced by training in transferable skills (e.g. research dissemination, public speaking, leadership, impact, data security). Training resources will be made available outside of the network so that other researchers interested in the training will be able to access it. Early career researchers across the three countries, with support of both UK and in-country tutors, will then work mutually to advance our understanding of multimorbidity using existing datasets of people living in the three countries, with detailed information of health status. This will be carried out using advanced statistical analysis. Health economics techniques will also be used to understand the economic impact associated with specific clusters, to assess which are the most burdensome. Our final objective is to create a network and platform for future training and for further research activities around the topic of multimorbidity. We hope that this project will have a direct impact on people's lives, both individuals living with multimorbidity, but also on early career researchers.","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":["Developing an innovative primary health care system for pastoralist community"],
      "description_narrative":["Joint HSR Initiative 1 Development award to develop an innovative primary health care system for pastoralist community in Ethopia\n\n","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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