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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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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. 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In part this is because of institutional weaknesses at national and district level but the behaviour of global actors in the response has also attracted criticism. The situation has been particularly acute in Sierra Leone as many progressive reforms such as Free Health Care and other governance initiatives may have been undermined by the epidemic and the nature of the response. To date, the evidence on the impact of international Ebola-response assistance in Sierra Leone, and the way it has enabled or hampered local responses, is almost non-existent. For example, it is not known how, why and in what ways local health systems were used, or not used; and it is not at all clear whether international assistance has strengthened local health systems, or weakened them by building parallel structures and bypassing local institutions and relationships. The longer term implications of this kind of assistance, especially beyond the immediate crisis, are thus unclear. Documenting and understanding how and why national and international endeavours to care for the sick and interrupt the transmission of Ebola struggled to produce expected results, is paramount for improving future responses and ensuring health systems are not weakened by future emergencies. Our study will explore a range of factors including: the extent to which responses were informed by local concerns and perceptions of emergency-response systems; whether external interventions sought to work within or with local systems (and whether this resulted in the building of parallel response structures); whether external interventions ultimately weakened and made the health system less resilient by, for example, taking locally qualified staff away from public sector systems or by diverting resources from other ongoing health requirements (including routine maternal and child health and common preventable diseases). Specifically, we ask the following research questions: In what ways has the international Ebola-response affected Sierra Leone's health system and its ability to withstand future shocks? How can international, national and local emergency response mechanisms be utilised to build a resilient health system in Sierra Leone, and what lessons emerge? We bring together several different disciplinary and thematic perspectives, including health systems/systems strengthening, policy and implementation science; disaster risk reduction/emergency preparedness; and the anthropology of global health and medical humanitarianism. Explicitly bringing together these often separate bodies of learning will enable us to more fully and effectively answer our principal research questions, identify transferable lessons and contribute to generating substantive health systems research evidence relating to what promotes resilient health systems. Specific benefits of the project will include: * Identification of characteristics of resilient health systems that need to underpin health systems strengthening efforts, in Sierra Leone and other similar settings, and how these can be incorporated in national health systems development. * Identifying the key issues influencing village level responses to Ebola and reflecting on the implications of these issues for understanding and building more resilient health systems. * Suggestions for revising the existing guidelines for emergency responses, including those of the WHO drawing on the experiences of the recent Ebola epidemic in Sierra Leone.","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"], "participating_org_role":["1","2","3","4"], "participating_org_type":["10","15","15","80"], "participating_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY","MEDICAL RESEARCH COUNCIL","MEDICAL RESEARCH COUNCIL","LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE"], "activity_status_code":"4", "activity_date_iso_date":["2016-01-04T00:00:00Z","2016-02-01T00:00:00Z","2019-01-03T00:00:00Z","2019-04-30T00:00:00Z"], "activity_date_type":["1","2","3","4"], "contact_info_organisation_narrative":["Department of Business Energy and Industrial Strategy"], "contact_info_department_narrative":["General enquiries"], "contact_info_email":["enquiries@odamanagement.org"], "contact_info_website":["https://www.gov.uk/government/publications/beis-official-development-assistance-research-and-innovation"], "contact_info_mailing_address_narrative":["Department of Business, Energy and Industrial Strategy, 4th Floor, 1 Victoria Street, SW1H 0ET"], "activity_scope_code":"4", "recipient_country_code":["SL"], "recipient_country_percentage":[100.0], "sector_code":["12182"], "sector_vocabulary":["1"], "policy_marker_code":["1","5","6","7","8","10","11","12"], "policy_marker_significance":["0","0","0","0","0","0","0","0"], "policy_marker_vocabulary":["1","1","1","1","1","1","1","1"], "collaboration_type_code":"1", "default_flow_type_code":"10", "default_finance_type_code":"110", "default_aid_type_code":["D02"], "default_tied_status_code":"5", "budget_status":["1","1","1","1"], "budget_type":["1","1","1","1"], "budget_period_start_iso_date":["2015-04-01T00:00:00Z","2016-04-01T00:00:00Z","2017-04-01T00:00:00Z","2018-04-01T00:00:00Z"], "budget_period_end_iso_date":["2016-03-31T00:00:00Z","2017-03-31T00:00:00Z","2018-03-31T00:00:00Z","2019-03-31T00:00:00Z"], "budget_value":[39071.85,156585.66,188115.72,79341.56], "budget_value_currency":["GBP","GBP","GBP","GBP"], "capital_spend_percentage":0.0, "transaction_type":["3","3","3","3","3","3","3","3","3","3","3","2"], "transaction_date_iso_date":["2019-09-30T00:00:00Z","2018-09-30T00:00:00Z","2018-06-30T00:00:00Z","2018-03-31T00:00:00Z","2017-12-31T00:00:00Z","2017-09-30T00:00:00Z","2017-06-30T00:00:00Z","2017-03-31T00:00:00Z","2016-12-31T00:00:00Z","2016-09-30T00:00:00Z","2016-06-30T00:00:00Z","2016-01-04T00:00:00Z"], "transaction_value":[-5475.13,13223.6,13223.6,16612.25,16484.8,16484.8,13123.37,13123.37,13023.95,13023.95,26047.9,502785.54], "transaction_value_currency":["GBP","GBP","GBP","GBP","GBP","GBP","GBP","GBP","GBP","GBP","GBP"], "transaction_value_date":["2019-09-30T00:00:00Z","2018-09-30T00:00:00Z","2018-06-30T00:00:00Z","2018-03-31T00:00:00Z","2017-12-31T00:00:00Z","2017-09-30T00:00:00Z","2017-06-30T00:00:00Z","2017-03-31T00:00:00Z","2016-12-31T00:00:00Z","2016-09-30T00:00:00Z","2016-06-30T00:00:00Z","2016-01-04T00:00:00Z"], "hierarchy":1, "transaction_value_usd":[-6767.799411904153,17272.18924803812,17575.924814259113,23207.447912437485,22096.633580846446,21971.05665166011,16800.105859324896,16185.59242591052,16274.890256786874,17113.963414041144,37020.61444152637,724154.3433724258] },{ "default_currency":"GBP", "default_lang":"en", "iati_identifier":"GB-GOV-13-FUND--GCRF-MR_T038942_1", "reporting_org_ref":"GB-GOV-13", "reporting_org_type_code":"10", "reporting_org_narrative":["DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY"], "title_narrative":["SIPHRE Shock Index in Pregnancy: Haemorrhage Risk Evaluation. Shock index as a predictor of adverse outcome in maternal haemorrhage"], "description_narrative":["800 women die in pregnancy and childbirth each day, 99% of these occur in low-middle income countries (LMICs). Haemorrhage can cause death within a few hours if not recognised and managed quickly and is the leading cause of maternal death worldwide. Early detection and effective management rely on monitoring of vital signs , including heart rate and blood pressure. We have effective management to prevent death from bleeding, but most deaths or severe morbidities occur because of delayed or substandard care in the diagnosis and management; in many low- middle income countries (LMIC) vital signs are not measured due to lack of staff/ equipment or poorly functioning devices, leaving the recognition of compromised patients to crude visual estimation of blood loss alone or late signs such as collapse. Our project is a validation study of a vital signs ratio called shock index (SI)- a simple calculation using heart rate divided by blood pressure. Our previous work on SI in pregnancy and haemorrhage suggests it is a superior way of recognising compromised patients. Since SI is simple to measure and easy to apply to daily practice, we hope to demonstrate it is an effective tool for early recognition of bleeding patients at risk of poor outcome (major surgery, major blood loss or death) with the aim to reduce maternal mortality and morbidity in LMIC. The CRADLE VSA (CVSA) device accurately measures blood pressure and heart rate, displaying the results on a screen. It shows a red/amber/green traffic light warning system consistent with shock index thresholds to alert users to the patient's risk compromise, thus allowing prompt referral or escalation of management by even untrained health workers. The CVSA device has been designed and extensively validated by our team over 15 years to become the cheapest and most accurate device to measure BP at the high and low range we see in pregnancy. It is recognised as one of the top thirty high impact innovations in global health. It has been developed for use in LMIC being light, inexpensive, robust and easy to use. The use of the CVSA was extensively researched in the CRADLE 3 trial. In country data from Sierra Leone (SL) showed its implementation reduced maternal death rate by 60% (RR 0.37 CI 0.25 to 0.550). Following its success, the Department of Health in Sierra Leone are now rolling out the CRADLE VSA device nationwide, supported by DIFD, WHO, UNICEF and JICA. We propose a prospective validation study of shock index in Sierra Leone, where adverse outcomes are so prevalent, in order to obtain large data to support SI as a tool for earlier recognition of compromise in bleeding mothers. SL has the world's highest mortality rate (1,165 deaths per 100,000 live births. In the UK this is 9 per 100,000). Data including first and worst vital signs and clinical outcomes will be collected on all pregnant/postpartum women who suffer with haemorrhage (blood loss over 500mls). The performance of shock index to predict adverse clinical outcomes will be evaluated and compared to existing vital signs scores. A standardised early warning system for recognition of compromised patients does not exist for use in LMIC. Following validation on SI we propose a trial to evaluate the effect of SI in triage and management of bleeding patients in LIC. It is anticipated that a care bundle that incorporates SI as a triage/referral criteria will improve care. Since avoidable maternal deaths and near-misses are often related to delays in recognition of hemodynamic compromise this simple automated early warning system could be used in LIC worldwide.","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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COVID-19","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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