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Improving diagnosis and treatment of TB meningitis 30 Sep 2018

Tuberculous meningitis (TBM), the most severe form of TB, affects the brain and spine. Over 100,000 children and adults suffer from TBM yearly, of which up to a half die and a quarter are left disabled. These appalling outcomes are driven by: Delay in diagnosis - there is no reliable test; Suboptimal antibiotic treatment – rifampicin, the key antibiotic, doesn’t reach therapeutic levels in spinal fluid. I will address these challenges through TBM research based in Uganda. We will perform lumbar puncture (spinal tap) on ~240 people presenting to hospital with symptoms of meningitis. We will evaluate an exciting new test ‘Xpert MTB/Rif Ultra’ on spinal fluid, potentially a fast and reliable fully-automated way of diagnosing TBM. Persons with TBM will be invited to join a clinical trial (RIFT trial). Participants will be randomly allocated to one of three groups receiving different rifampicin doses. We will then measure levels of rifampicin in blood, spinal fluid, and brain tissue (among deaths) to determine whether target levels are reached. We will also study other important clinical factors.

Using linked electronic health data to improve eczema diagnosis and outcomes 10 Jul 2018

Eczema effects 10% of adults. Despite this, and although eczema is visible, there is limited public awareness of either the existence of eczema in adults or its effects on the individual. This awareness includes the impact of eczema on a person’s physical and mental health, social lives, educational attainment and economic prosperity. In this project I will engage with adults with and without eczema in a highly interactive way to understand why adult eczema remains an "invisible visible" disease and how people perceive the impact of eczema on health and social outcomes in the long-term. This programme of work will involve six workshops around the UK using digital storytelling, art and photography to tell real stories and start conversations about eczema. Stories from the workshops will drive the content for a theatre production about eczema. The digital storytelling and art will be added to an interactive, curated website to broaden and continue the discussion around the socio-cultural aspects of adult eczema. Using a variety of creative and engaging approaches, these activities will develop a discussion about the broader consequences of having eczema, including increasing awareness and changing perceptions amongst those with and without eczema. This public engagement work will enrich research conducted in my Wellcome fellowship, using electronic health records to answer questions about long-term outcomes in eczema by understanding impacts beyond health outcomes that would present for medical attention. It will also help me and my attendees understand barriers to visibility and awareness of eczema amongst adults.

Developing and piloting an interventional bundle to reduce mortality from gastroschisis in low-resource settings and identifying priority congenital anomalies for further interventional studies. 30 Sep 2018

Birth defects have risen to become the 5th leading cause of death in under 5-year olds across the globe. Due to a lack of newborn care facilities and surgery for babies in low- and middle-income countries, hundreds of thousands die or are disabled every year from conditions that are operable and survivable in high-income countries (HICs). This research project has two main goals: To undertake a clinical study in seven centres across four countries in sub-Saharan Africa (SSA) with the aim of improving the survival of infants born with gastroschisis. This is a condition where the baby is born with their intestines protruding through a hole in the abdominal wall; it is one of the commonest birth defects and has a great disparity in survival across the world. Above 75% die in SSA compared to less than 4% in HICs. The intervention will include training and resources that may help to improve the survival of infants born with other birth defects too. To undertake the first global study into infants born with a birth defect to determine differences in management and survival in low-, middle-, and high-income countries and to identify areas of greatest need for future interventional studies.

Institutional Translation Partnership Awards 'London School of Hygiene & Tropical Medicine' 30 Sep 2018

The LSHTM Institutional Translation Partnership Award (iTP A) aims to explore and stimulate translational research, enabling our researchers to progress their research along the translation pipeline, and crucially embed and incentivise a culture of innovation. A translational facilitator will liaise with researchers to identify appropriate projects, develop funding strategies, provide project management support, and coordinate industrial collaborations. Flexible seed funding for pilot projects and access to relevant training programs will ensure that researchers across career stages can confidently explore and contribute to the translational research landscape. Researchers will also have access to translational expertise through experts in residence, while challenge led workshops will bring together researchers with industry experts to address key translational challenges. Finally, a translational culture will be firmly embedded by rewarding and celebrating translation as part of research excellence through the development of Innovation awards which will be launched at a new showcase during the annual LSHTM week.

Using mathematical modelling to re-think global pneumococcal immunisation strategies. 18 Oct 2017

Despite the success of pneumococcal conjugate vaccines (PCVs) two major challenges remain. First, serotype replacement has mitigated PCV impact and pneumococci remain a predominant cause of child death. Second, PCVs are among the most expensive vaccines, which threatens sustainability in low income countries as they transition from Gavi support. The fellowship addresses those issues using a combination of epidemiological, statistical and modelling techniques and the collection of key data that leverages ongoing studies. I plan to use machine learning to unravel drivers of heterogeneity in the global serotype distribution of pneumococci, which will enable inference of pneumococcal epidemiology in settings with limited data. I will then use constrained optimisation on models that include the dynamics of serotype replacement into their predictions to inform design of more efficient PCVs that can further reduce the global pneumococcal diseases burden. I further plan to use a set of novel models to estimate who infects infants, a key knowledge gap in the assessment of reduced dose PCV schedules, an approach being pursued as a potential cost saving strategy. Phylogenetic inference in combination with mathematical models will be used to identify common transmission pathways to infants and risk factors associated with them.

Amount: £1,097,366
Funder: The Wellcome Trust
Recipient: London School of Hygiene & Tropical M...

Open Access Awards 2017/18 30 Sep 2018

Not available

Unravelling the intracellular interactions and signalling of Apical membrane antigen-1 (AMA1) in malaria parasites. 24 Apr 2018

Apical membrane antigen-1 (AMA1) is a type-I integral membrane protein of malaria parasites, required for host cell invasion. Invasion requires phosphorylation of the AMA1 cytoplasmic domain (CD), suggesting a signalling role. Exactly what process(es) the AMA1 CD regulates, and how it does so, is unknown. This project will examine the role of the AMA1 CD in regulating cellular events during invasion, using the recently culture-adapted malarial species Plasmodium knowlesi. A conditional mutagenesis system (DiCre) will be used to switch expression of wild-type AMA1 to mutant alleles (e.g. non-phosphorylated forms) to examine the role of the CD in invasion. The impact of mutagenesis on discharge of secretory organelles containing invasion ligands will be examined using immunofluorescence and electron microscopy. Proteins that interact with the AMA1 CD will be identified using directed biotinylation by an APEX2 tag fused to the CD, followed by pulldown and mass spectrometry. The role of interacting proteins in invasion will then be explored using DiCre-mediated knockout. A high-throughput Cas9 mutagenesis screen of the AMA1 CD will also be performed to identify crucial residues involved in mediating interaction of partner proteins with the AMA1 CD. This project will elucidate the long-hypothesised signalling role of AMA1.

Optimising health with gender equity: a missing piece in nutrition programme planning 24 Apr 2018

The nutritional status of populations is a marker of societal development and realisation of human rights. Worldwide, pervasive gender inequity in nutritional outcomes reflects structural disparities in the rights, freedoms, and welfare of men and women. My doctoral research in Nepal found that women are strongly discriminated against in the intra-household allocation of foods, especially during pregnancy. Yet, the health and economic implications of this are unknown. This project aims to estimate the health, mortality, and economic costs of gender-based dietary inequity, and identify policy-amenable determinants of intra-household food allocation. I will collate 11 datasets from eight low- and middle-income countries (n=27,660 households). To estimate health impacts of inequity, I will re-allocate foods under different ‘equity’ scenarios and predict the health and mortality outcomes from these scenarios. I will then use microeconomic models to predict household-level economic costs of inequity, and the ‘PROFILES’ tool to estimate population-level economic costs of equity. A multi-level determinants analysis will identify factors that affect intra-household inequity. This will be the first analysis to address health, mortality, and economic effects of diet-based gender inequity, and will provide critical information to transform national and international policy and programmes so they can protect women and save lives.

Lancet Series on 'Environment, Agriculture, Food and Health 30 Sep 2018

We have been invited by the Lancet to write a new series of articles that will draw on a critical and under-researched area of planetary health, namely the interactions between the environment, food systems and population health. The series will draw on some of our existing interdisciplinary WT-funded research and also expand with new partnerships into issues of infectious disease and equity. The cross-sectoral policy opportunities that emerge from the novel analysis will be drawn out and engagement activities are planned to maximise the impact of the series. Following meetings with the Lancet we have identified five papers for the series: Problem statement: outlining the critical interplay between the environment, agriculture, food and health. Scenario analysis: novel analysis of possible future agriculture and food scenarios under environmental change with a particular focus on non-communicable disease. Expanding the focus: including agriculture-related infectious disease outcomes and how these might be affected under environmental change. Inequality: taking a specific equity lens to the debate with a focus on LMICs. Solutions: identifying potential cross-sectoral policy options to safeguard human and planetary health. The series is due in late-2018.

Exposed to MDR-TB, what happens next? A multi-national observational cohort e-registry to study natural history and improve outcomes 30 Sep 2018

Multi Drug Resistant Tuberculosis (MDRTB) it is difficult to diagnose and treat. Globally 50% of diagnosed cases do not successfully complete treatment. Currently there is no treatment for MDRTB-exposed contacts (people who have spent > 8 hours/week with an MDRTB patient). Exposed contacts of MDRTB who could develop disease and lead to ongoing transmission need to be identified, diagnosed and treated early. Contact tracing helps us identify people with early TB or asymptomatic latent TB infection (LTBI). Our aim is to improve and harmonise processes used to identify MDRTB contacts who are most likely to be reservoirs of infection. We will recruit longitudinal cohorts in two countries using a mobile application (app) for TB nurses to enable care and follow-up of contacts. The app will populate a registry of contacts to be followed up for two years at six monthly intervals. This will create a data set allowing me to answer questions around the likelihood of MDRTB exposed contacts developing secondary disease and the risk factors involved. A registry automatically generates a list of eligible contacts to receive a preventive treatment once one is available. A second study at one site will explore risk factors associated with progressing to active disease.

Immune activation in HIV-exposed uninfected Zimbabwean infants 30 Sep 2018

Most children born to HIV-positive mothers do not get infected with HIV because of effective preventive medications. However, children who are exposed to HIV but not infected (HIV-exposed uninfected children) are more likely to be hospitalised or die due to serious infections than children born to HIV-negative mothers (HIV-unexposed children). The reasons for poorer health outcomes are unknown. It is possible that HIV-exposed uninfected children have problems with the immune system (the part of the body that fights infections), leading to more infections. The immune system of HIV-exposed uninfected children may be too overactive but ineffective at doing its job of fighting infections. We call this immune activation. I will investigate this in Zimbabwe. First, I will use laboratory experiments to compare immune activation in HIV-exposed uninfected children and HIV-unexposed children using stored blood samples. Next, I will investigate if immune activation in mothers during pregnancy leads to immune activation in their children soon after birth. Finally, I will investigate if these immune problems in HIV-exposed uninfected babies are associated with more infections in early life. Through this work, I hope to identify immune problems that can be targeted with new treatments to try and reduce deaths in HIV-exposed children.

Real-time modelling for forecasts during infectious disease outbreaks 10 Apr 2018

Local and international public health bodies often face difficult decisions during infectious disease outbreaks. Limits on human resources or logistics, for example in the speed and scale of vaccine production and delivery, require prioritisation of areas or population groups when rolling out an intervention. It is now possible to collect a wealth of epidemiological, genetic, spatial and behavioural data during an outbreak and make it available immediately for analysis. It remains an open question how these data are best combined for forecasts that can inform decision making. My fellowship aims to systematically investigate and improve the predictive capabilities of mathematical models during outbreaks. In particular, I will develop methods to combine different data sources in order to analyse an outbreak in real time. By testing these methods on a range of recent epidemic datasets, I will assess the predictive capabilities of models using different amounts and types of data. A particular focus will be on translating forecasts into recommendations for decisions, and on how the accuracy of forecasts affects the quality of these decisions. All the work will be conducted with the aim of generating a computational platform that is readily deployable in an outbreak situation for meaningful decision support.

Amount: £1,614,694
Funder: The Wellcome Trust
Recipient: London School of Hygiene & Tropical M...

A Quantitative Analysis of the Health Extension Program to Inform Human Resource Policy Interventions in Ethiopia 08 May 2018

In 2004, Ethiopia launched the Health Extension Program (HEP) - a primary health care delivery strategy focussing on the delivery of 16 essential health services, targeting the rural poor. Health Extension Workers (HEWs) were employed as key vehicles for delivery of HEP. Though their deployment was in large numbers, current policy initiatives towards HEP are hampered by the dearth of empirical, quantitative data on HEW behaviours; the determinants of their job choices and the implications of these dynamics on retention policies for this workforce. This project proposes to investigate the labor market response to changes in wages, working conditions, and training opportunities of HEWs, using a discrete choice experiment. Additionally, this will be the first study to undertake an economic evaluation of available health workforce policies to provide critical insight on which policies to pursue for better retention of HEWs, as well as using mathematical modelling techniques to ascertain the causal impact of HEP on the equity of health service delivery in Ethiopia. With these three research packages, the project aims to create pioneering evidence that fills critical gaps in literature to inform human resource policy interventions in the context of HEP, leading to improvements in population health in Ethiopia.

Designing fit-for-purpose regulation for evolving healthcare systems 30 Nov 2017

Healthcare markets in low- and middle-income countries (LMICS) are undergoing dramatic change, with private sector expansion, emergence of new organisational forms and business models, and growing foreign investment. The regulation systems in these countries are inadequate and ill-suited to manage these challenges and future market evolution, and rarely incorporate modern perspectives on regulation which highlight the need for "responsive", "smart" and risk-based regulation, drawing on an expanded range of regulatory strategies, tools and actors. We aim to understand the challenges that recent developments in LMIC healthcare markets pose for effective regulation. We will review recent trends in private sector development and regulation systems in 3 LMICs with rapidly changing healthcare markets. We will assemble a group of scholars and policymakers with expertise in regulatory theory and implementation in a set of middle- and high income countries. We will debate appropriate theoretical frameworks and methods for studying regulatory developments, and consider what concepts and lessons might be relevant to LMICs (taking into account differences in resources, institutions, health systems, and history) and identify critical research questions. Outputs will be a network of scholars, an agenda setting paper, and a proposal for a larger scale project to take these ideas forward.

Measuring mental capacity: a history 23 Jan 2018

This project will develop a history of the medico-legal concept of mental capacity in Britain and Ireland over the twentieth century. It will use under-explored sources from civil court proceedings alongside medical, legal, and advocacy material to explore how mental capacity was assessed, defined, and understood by doctors, the judiciary, and lay observers, including those whose capacity was called into question. By taking a comparative approach to the four jurisdictions under examination, I will draw out the origins and effects of different approaches to mental capacity. A focus on the twentieth century will examine the impact of changing medical knowledge and methods, shifts within social provision for people with disabilities, and broader social attitudes regarding age and dementia, mental illness, and developmental disability. My goals are to discover how medico-legal thought regarding mental capacity changed across the period in question and varied across the four jurisdictions; and to analyse how these changes and differences came about. This will pay particular attention to ideas that remain contested in current law and practice, such as consent, medical ethics, vulnerability, autonomy, and rights, as well as the changing medical knowledge, legal practice, and social contexts that affect assessments of mental capacity.

MSc Public Health 11 Jul 2018

This MSc covers the whole breadth of public health, encompassing high-, middle- and low-income countries. The aim of the programme – consistent with LSHTM’s mission to improve health worldwide – is to provide students with the knowledge and skills necessary to improve the health of populations, communities and particular groups within them. The emphasis is on the use, development and critical evaluation of conceptual models, evidence and methods of analysis, and on effective interventions and policies at local, national and international levels. On successful completion of the programme, students will receive a Master's degree in Public Health. Students can follow a general public health course or concentrate on one of five more specific streams: environment and health; health economics; health promotion; health services management; health services research. In addition to choosing a stream, students holding the Wellcome Trust Studentship will follow a humanities and social science ‘pathway’ through the programme. This will involve taking specialist modules in humanities and social science subjects (such as history, anthropology and sociology) and producing a dissertation rooted in one of these disciplines. The students will be guided along this pathway by a personal tutor with a background in the humanities or social sciences.

Which maternal infections are associated with stillbirths and early neonatal deaths, in East Africa? 06 Dec 2016

Reducing neonatal deaths and stillbirths is an international public health priority, yet the contribution of vertically-acquired infection, potentially amenable to intervention, is unclear, with essentially no data from the highest mortality settings. I propose to provide a robust description of the association of maternal infection with stillbirths and early neonatal deaths by studying mothers delivering in a moderate mortality setting in Kilifi, Kenya, and in Harar, Ethiopia, where the under-5 mortality ratio is three-fold higher than in Kilifi, Kenya. I will begin by investigating mothers in Kilifi County Hospital, Kenya, from a well-characterised existing maternal cohort (2011-16) in a case-control design (n=700). Laboratory investigation using nucleic acid detection on stored blood samples will be done at the internationally accredited KEMRI-Wellcome Trust Research Programme laboratories. Then, in a prospective study in Hiwot Fana Hospital, Harar, Ethiopia, I will recruit and investigate mothers (2017-19) in the same case-control design (n=700). Laboratory investigation on site will include both conventional and nucleic acid detection methods. This study utilises a new site for the Child Health and Mortality Prevention Surveillance (CHAMPS) network. As this network extends, it will create the opportunity to use this work to design community studies and large scale intervention trials.

STRONGER-SAFE: Understanding transmission and optimising interventions for an enhanced S.A.F.E. strategy for trachoma elimination 05 Apr 2017

Trachoma is the leading infectious cause of blindness worldwide. It is intrinsically linked to poverty in both cause and effect. Preventing blindness from trachoma has broad and profound impact on health and well-being. It is caused by repeated infection with Chlamydia trachomatis (Ct). The WHO-endorsed SAFE-Strategy aims to control infection through annual, single-dose, community-wide azithromycin treatment coupled with Water/Sanitation/Hygiene (WASH) and fly-control measures to suppress transmission. However, particularly in hyperendemic regions, the current approach is not having the anticipated impact. There are two critical issues. Firstly, current azithromycin schedules appear insufficient. Secondly, transmission routes are poorly defined and the very limited evidence-base makes it hard to focus WASH interventions and guide programmatic decisions. We propose the following: 1) Conduct intensive observation of human behaviour and hygiene practice, and fly behaviour, combined with Ct infection mapping, to identify major routes of transmission. 2) Develop and test contextually appropriate, practical, targeted WASH and fly-control approaches to interrupt Ct transmission. 3) Our modelling work indicates double-dose azithromycin two weeks apart is much more effective in controlling Ct. In a cluster-randomised trials we will test whether intensified double-dose treatment coupled with targeted transmission-interrupting strategies can control trachoma more effectively.

Amount: £3,785,335
Funder: The Wellcome Trust
Recipient: London School of Hygiene & Tropical M...