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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. 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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. 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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. 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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. 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Worldwide, about ten million people are killed or hospitalised because of a head injury every year. Most head injuries are caused by road traffic crashes, and because car use is increasing, the number of people suffering a head injury is increasing. Amongst those who survive a head injury, many are left severely disabled for the rest of their lives. For example, there is a high likelihood that Michael Schumacher will be permanently disabled as a result of his recent head injury. Most victims of head injury are young adults living in low and middle income countries. Because many of the victims are also breadwinners for their families, head injuries can also result in loss of income which, along with medical costs, can increase household debt and lead to a fall in living standards for the whole family. When the head is injured there is often bleeding inside the brain, which can continue for some time and worsen after hospital admission. This bleeding increases pressure inside the skull causing further damage to the brain, which can be fatal or result in serious disability for the patient. We think that we can prevent some of these deaths and disability by reducing the amount of bleeding in the brain after head injury. Tranexamic acid is a cheap drug that reduces bleeding in other conditions. A large trial in accident victims (other than those with head injury) found that it reduces the chances of bleeding to death. If this drug also works in patients with head injury and bleeding into the brain, this would be important to know because it could save lives at a very low cost. We have already done two preparatory studies to see if tranexamic acid can help people who have bleeding inside the brain because of a head injury. Together, the results of the studies suggest that tranexamic acid should reduce the amount of bleeding inside the brain and could reduce their chances of dying or being disabled. However, because these studies were small, we are not very certain about the accuracy of their results. Also, they were not designed to find out whether tranexamic acid reduces disability. Because doctors are still unsure about whether tranexamic acid works, it is not given to patients with traumatic brain injury. But if a new clinical trial showed that it worked, this would change very quickly. We want to find out if tranexamic acid saves lives and reduces disability in people with traumatic brain injury. We plan to study 10,000 patients with traumatic brain injury in countries throughout the world. We will give half of them tranexamic acid and the other half a dummy medicine called a placebo. To make sure that the two groups are the same apart from tranexamic acid, we will decide who gets tranexamic acid and who gets placebo using the modern equivalent of the toss of a coin (this is called randomisation). Everyone will of course get all the treatments that doctors usually give to traumatically brain injured patients. At the end of the trial we will see if giving tranexamic acid on top of all the usual treatments improves survival and other patient outcomes. The study will be carried out by a team of researchers with lots of experience in doing clinical trials. In fact, it will be the same team that did the successful study of tranexamic acid in accident victims. The trial will cost several million pounds but if it shows (as we hope it will) that tranexamic acid works, we will have a very cheap way of reducing the number of people who die and are disabled after a head injury. The start up phase of trial is underway and over a thousand patients have been recruited. The trial procedures work well. This application is for funds to continue recruitment to 10,000 patients.","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. 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However, among patients receiving first-line ART, 20-30% will have a detectable viral load after 12 months. The long-term success of ART programmes is heavily dependent on accurate, available and timely viral load monitoring to document viral suppression or indicate the need for second line ART switch. Existing HIV viral load assays require significant infrastructure and highly trained personnel to perform, thus only a few centralised laboratories are capable of viral load testing in most developing countries. Centralised testing leads to poor access to those in need, long turn-around times, delay of results and subsequent loss of patients, all of which lead to sub-optimal ART treatment outcomes, which can cause significant morbidity and mortality. The University of Cambridge, in partnership with Diagnostics for the Real World, has developed an innovative point-of-care nucleic acid amplification test for the diagnosis monitoring the efficacy of HIV treatment by determining of the amount of circulating virus is above or below the threshold for treatment failure. The SAMBA HIV-1 Semi-Q Test allows the patient to be tested and treated in the same visit, thus improving access and treatment outcomes. The plasma-based semi-automated (SAMBA I) assay has received product approval in Malawi, Kenya, Zimbabwe and Uganda and has been used for testing of over 35,500 patients at Médecins sans Frontières (MSF) sites in Malawi and Uganda to date. The SAMBA HIV-1 Semi-Q Test has recently been improved to enable the use of small volume whole blood, using a patented method of filtration. This removes the need for plasma separation, thus increasing utility at lower cadre health clinics and reduces the time to result. In addition a fully automated SAMBA instrument system has been developed, called SAMBA II. The key aims of this proposal are: 1) integrate the whole blood SAMBA HIV-1 Semi-Q Test onto the fully automated SAMBA II instrument, 2) perform an evaluation in house, in Africa and in Europe to evaluate its perforce compared to another CE-marked test and 3) submit for CE-mark. Although the SAMBA test will most likely be used in Africa, a CE-mark is required to allow it to be procured by NGO's.","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. 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Nearly half a million people died from the disease in 2015, the majority of deaths being in children under the age of five. The malaria parasite is spread by infected mosquitoes and the most effective way to monitor the disease is to monitor populations of these mosquitoes. However, current tools for sampling malarial mosquitoes are time-consuming and labour intensive, making them expensive and difficult to standardize. Accordingly, data between countries and regions cannot be reliably compared. To solve this problem, we have developed a mosquito trap that exploits the blood-seeking behaviour of mosquitoes by mimicking the sensory stimuli that a mosquito follows when searching for a person to bite. These include the look, smell and temperature of warm-blooded hosts. We have incorporated these stimuli into a trap that lures mosquitoes towards it and then captures them when they land. Our project will test this \"Human Decoy\" Trap against current methods used in mosquito monitoring to determine whether the Human Decoy Trap can overcome the limitations of existing tools. We will evaluate if Human Decoy Trap catches are suitably similar to those of current traps in terms of numbers of mosquitoes and other important data related to malaria that can be extracted from mosquitoes caught by traps, such as the proportion of caught mosquitoes infected with malaria parasites. Over 90 countries, mostly low and middle income, are malaria-endemic. We will work in Burkina Faso, Benin and Cameroon, three West African countries where malaria causes thousands of deaths every year, but differing in intensity and seasonality of transmission and with different mosquito species involved. This will help us to understand whether there are differences in trap performance in a wide range of malaria settings. In addition, we will work with end-users of the trap, namely local communities, public health operatives and field technicians, to better understand their perspectives and needs regarding mosquito sampling and control. During the course of the project, we will use data we collect to optimize and improve the trap's performance and design. This will help us to develop a commercial prototype that is effective and acceptable to end-users, maximising the likelihood the trap will be adopted into the communities and sectors that need it the most. Longer-term, we envision a version of the Human Decoy Trap that can be deployed as a mosquito control tool. The most effective way of controlling malaria is to reduce the number of infective mosquito bites a person receives. This is currently achieved by providing people with insecticide-treated bed nets to protect them from bites whilst they sleep and spraying the walls inside houses thus killing mosquitoes that rest there. However, neither of these options protects people from mosquitoes that may bite them outdoors during the day or just before they go to bed at night. Data from this current project will be used to provide preliminary evidence for the suitability of the Human Decoy Trap as a control tool that is specifically targeted at malaria mosquitoes biting outdoors, which may also be effective against other species of mosquitoes that can carry other infectious diseases, such as dengue fever, chikungunya and Zika viruses. Such an improved sampling method would enhance the quality of data necessary for efficient targeting and evaluation of malaria control intervention activities and reduce the cost of collecting it. A successful outdoor mosquito control device would help to reduce the population of infected mosquitoes that cause malaria. Ultimately, the combined effect of these tools would be a reduction in the human suffering and death caused by malaria to millions of people every year and an improvement in the social and economic prospects of the 3.2 billion people living at risk of malaria.","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. 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This involves instances where funding can be utilized to 9 original grant objectives affected by the ODA review, or opportunities for new follow-on, knowledge exchange or impact activities. 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