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      "title_narrative":["Unveiling the protein landscape of the African trypanosome cell surface and chasing down potential targets for therapeutic intervention"],
      "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":["Understanding and enhancing approaches to quality improvement in small and medium sized private facilities in sub-Saharan Africa"],
      "description_narrative":["The private sector is a major and growing source of treatment in low- and middle-income countries (LMIC), but there is considerable concern about the safety and quality of care. Recent years have seen fast growth in small and medium sized private clinics, but their regulation is often poor, and relatively little is known about the effectiveness of interventions to improve the quality of care they provide. This project aims to address this evidence gap.   The research takes place in the context of an innovative intervention developed by the international NGO PharmAccess that extends the benefits of clinical standards and stepwise certification to small and medium-sized facilities in LMIC, using standards developed with international accreditation bodies. The PharmAccess model seeks to improve the quality of care that facilities provide as well as to shape the broader healthcare and finance markets and policy environment. There are several components to the model. Health facilities are assessed on a set of \"SafeCare\" structural quality standards, trained on quality improvement and business skills, and assisted in the development of a quality and business improvement plan. They receive regular mentoring visits and are also connected with the PharmAccess Medical Credit Fund, a social investment fund which facilitates access to bank loans to finance implementation of the plan. The aim is to create a series of virtuous circles, with improvements in SafeCare assessment scores signalling improved quality of care to individual and institutional purchasers, thus increasing demand for health services; and improved business performance ensuring further access to credit, and the sustainability of quality gains.  The research will begin with an analysis of secondary data collected routinely by PharmAccess in Tanzania and Kenya to date to examine changes in the SafeCare assessment scores over time and factors associated with these changes. We will then undertake a randomised controlled trial to evaluate prospectively the impact on quality of care of the roll out of the PharmAccess model to additional private for-profit and faith-based facilities in Tanzania. The trial will assess the effects of the intervention on the quality of care received by patients through comparison of 120 intervention and 120 control facilities after 2 years of implementation. These data will also be used to assess the relationship between SafeCare assessment scores (which measure availability of inputs such as infrastructure, technology and standard operating procedures) and measures of technical and perceived quality of patient care (which concern the interaction between caregivers and patients). Technical quality will be measured through standardised patients (covert actors) and clinical vignettes (overt role-playing), with perceived quality measured through patient interviews. In addition, in-depth interviews will be conducted in 30 intervention facilities and with 8 implementing staff in Tanzania to assess the perceived benefits and costs of participating in the PharmAccess model, and factors affecting quality improvement and business performance. Finally, 30 national level key informants will be interviewed to explore how the PharmAccess model shapes the market for healthcare and healthcare finance, and the policy environment in both Tanzania and Kenya.  The results are expected to make an important contribution to the evidence base on improving private sector care and to the literature on measuring process quality of patient care. The findings will be of substantial benefit to national and international policy makers and programme managers who are interested in private sector healthcare and health systems strengthening more generally, with important implications for all organisations within the health system that require adherence to quality standards (eg, social health insurance programmes, social franchising programmes, regulatory agencies)","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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