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London School of Hygiene & Tropical Medicine

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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.

Statistical methods for studying multidimensional mediators of genetic associations with chronic diseases. 27 May 2015

This project aims to develop methods to study mediation via high-dimensional OMICs biomarkers of genedisease associations, ie to identify which biomarkers lie on important pathways from genes to disease, with the ultimate aim of identifying therapeutic targets for new drugs, as well as new indications for existing drugs. The main challenge is coping with the high-dimensionality of the biomarkers. I will investigate novel and existing dimension-reduction methods on the mediators, and then use th e reduced set of mediators in a multiple mediators analysis, with appropriate allowances for the first step. Motivated by studies in which subjects are followed up for CVD (or other chronic disease) events, this will require extending methods for multiple mediation analysis to deal with time-to-event outcomes and time-updated biomarker data. As well as deriving the theoretical properties of the resulting estimators, I will investigate their performance (including robustness to modelling assumpt ions, measurement error, bimodal and truncated distribution of biomarkers) in simulation studies, and apply the most promising approaches to the analysis of several rich datasets, such as the UCLEB consortium of 15 British cohorts with access to 1H-NMR metabolomic data as well as genetic material and incident clinical events (totalling 35K participants with >7K CVD events).

Future diets and health: how will environmental changes affect food availability, food consumption and health 07 May 2015

This project aims to answer the primary research question: Will the projected impacts of environmental changes on terrestrial food production and food quality have a demonstrable influence on nutrition and health outcomes over the next 20-30 years? The project will establish an interdisciplinary approach encompassing environmental, agricultural, nutrition, health, mathematical and social sciences to enable the mapping and quantification of the multiple pathways between environmental change and population-level food availability, food quality, dietary intake, nutrition and health outcomes over the coming decades. By taking a broad, interdisciplinary analytical approach, and applying it to country case studies, this project aims to test whether current projections of changes in agricultural production, food availability and food quality are likely to result in quantifiable impacts on nutrition and health outcomes. Key goals: 1. Define an evidence-based analytical framework linking environmental change with nutrition and health outcomes. 2. Apply the framework to three countries (UK, Mexico and Ethiopia) to identify critical nodes where policy-level action may influence nutrition and health. 3. Establish a method and analytical baseline for future modelling and scenario testing and make an inter-sectoral dataset on agriculture, food prices, nutrition and health available for public use.

The 100 million Brazilian linked data and datacentre 16 Jun 2016

The proposed biomedical resource will be built around "CADASTRO-UNICO" a database of electronic records of over 100 million applicants to social protection programmes in Brazil. Records consist of detailed individual information on housing conditions, education and income, organized by household and by individuals. Our proposal is to link the individual social and benefits records to electronic health records including: births, deaths, hospitalizations, infectious disease notification and others. The size of the population will enable research on the interrelationships between social factors and health and on the impact of social protection policies on a large range of health outcomes on a degree of detail never done before. The datacentre will be high-powered, secure and have a public interface. This project is possible because Brazil has high quality records and an open, modern attitude towards use of data for research and policy, supported by a rigorous but enabling legal framework. We will create a unique international resource that will allow researchers and policy-makers to address questions that currently cannot be answered. The resource will serve as a beacon for methodological development and training. Our proposed resource has already attracted substantial interest from national and international scientists and policy makers.

(Pilot) InterTxt2Heart pilot: A trial to evaluate efficacy of text message to improve adherence to cardiovascular medications in secondary prevention. 16 Nov 2015

We plan to conduct a large international randomized controlled study that will evaluate the efficacy and safety of mobilephones short messages services (SMS) on adherence to cardiovascular disease (CVD) secondary prevention medications.For this funding call we are applying for the development phase of this study.Our specific objectives for this development study are :(1) Develop an appropriate content of mobile phone SMS addressing context-dependent causes of poor adherence and;(2) Develop the most appropriate trial design needed to evaluate the efficacy and safety of SMS to increase adherence tocardiovascular secondary prevention medications.The main research questions that we will address in this development grant are:1) What are the causes for poor adherence to CVD medications used for secondary prevention in each of the includedcountries?2) Which of these causes are likely to be modifiable by SMS delivery of effective behaviour change techniques (BCTs)?3) How can selected BCTs be operationalised as effective and simple SMS messages adapted to local context?4) How will the patterns of clinical care within each country impact on required sample size?5) What is the feasibility (and acceptability) of patient recruitment within selected centres?6) How suitable are the pre-selected e-platform (CommCare, Dimagi) and instruments for steps involved in the trial?

Examining health system performance for indigenous people in the Peruvian Amazon through the lens of tuberculosis control. 15 Mar 2016

What are the key features that are required to strengthen the health system to improve the the detection, diagnosis, and treatment of tuberculosis for Peruvian Amazonian indigenous peoples (IP) and guarantee theprovision of high-quality health services?The secondary questions are: (a) What are the barriers, enablers and/or facilitators for appropriate TB detection?; (b) What are the barriers, enablers and/or facilitators for appropriate TB diagnosis? and (c) What are the barriers, enablers and/or facilitators for appropriate TB treatment? In each of these questions we will use the World Health Organization's building blocks approach to health systems (14) that looks into six major dimensions: leadership and governance, financing, health work force, information system, service delivery and medical products and technology.We will capture views and information from three key scenarios: i) community organizations, including indigenous federations; ii) health facilities, including users and providers; and, iii) health managers, and decision makers.We will have three phases: Phase 1 will address all three secondary questions; Phase 2, will assemble all information gathered and, design/prepare a proposal of TB health system's strengthening; and, Phase 3, will address a wider consultation with key stakeholders to validate the proposal.

Social, behavioural and economic drivers of inappropriate antibiotic use by informal private healthcare providers in rural India. 15 Mar 2016

This is an exploratory study of the social, economic and behavioural drivers of antibiotic use in informal providers in rural areas of the state of West Bengal in India. In pluralistic health systems of low and middle income countries (LMICs), including in India, the bulk of healthcare at first contact is delivered by providers who may not have a formal medical qualification but practice a range of biomedical treatments, including treatment with antibiotics. They are known by different names such as drug sellers, village doctors or rural medical practitioners and are found all over Asia and Africa. Evidence suggests that their antibiotic use is high and irrational, and interventions that have focused on training and recognition of IPs have not succeeded in lowering their antibiotic use. Antibiotic use is one of the most critical components of IPs' quality of care that needs to be addressed urgently. Excessive dispensing/prescription of antibiotics by healthcare providers including IPs in LMICs is one of the reasons for overuse of antibiotics in humans leading to increasing antibiotic resistance which is a major global health threat today. We will conduct structured interviews with a sample of 100 IPs each in two districts (total 200), selected through stratified random sampling, followed by in-depth interviews and observations at 30 IP clinics, focus group discussions with community members and key informant interviews with government, pharmaceutical and formal medical sector representatives. In small group workshops with IPs, communities, and with the other stakeholders, we will present ideas for different interventions and seek feedback from participants on what they think would be the most effective and feasible. This will help us develop a plan for implementing and evaluating a comprehensive intervention in future.

Understanding and enhancing approaches to quality improvement in small and medium sized private facilities in sub-Saharan Africa 15 Mar 2016

Innovative approaches are needed to assess quality and institutionalize quality improvement in private facilities, but rigorous evaluation of such interventions is very limited, with a particular lack of controlled designs. This study will provide new evidence on the PharmAccess model of quality improvement. The research is based on a well-articulated theory of change, linking PharmAccess activities to outputs, outcomes and impacts, and draws on both quantitative and qualitative data:- to examine changes in adherence to SafeCare standards in participating facilities to date, we will analyse the PharmAccess database which contains SafeCare scores across multiple dimensions, facility characteristics and implementation measures for at least two time points for 300 facilities in Kenya and Tanzania, using panel regression methods to identify factors associated with improvements in scores.- to evaluate the impact of PharmAccess on process quality of care we will conduct a prospective randomised controlled trial in Tanzania. Intervention facilities will receive the full PharmAccess package, while control facilities receive SafeCare assessments only with no further action. The primary outcome will be technical process quality at follow-up, with secondary outcomes of SafeCare scores, perceived quality, and business performance. The primary outcome will be measured using standardised (covert) patients and clinical role-playing vignettes.- to understand experiences and perceptions of participating facilities we will conduct in-depth interviews with staff from 30 purposively selected intervention facilities, and 8 implementing staff.- In addition to improving quality in participating facilities, PharmAccess aims to make the broader market and policy environment more conducive to the operation of a high performing private sector. We will investigate these potential effects through 30 key informant interviews with stakeholders in Kenya and Tanzania

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.

Provision of Seed Grants for Supporting Research in the Ebola Epidemic Region 15 May 2017

These funds will support a research-funding budget, for smaller scale researchon the ground in the epidemic zone. This would be able to cover 3-6 local projects under the guidance of Professor James Grover Whitworth. (Any proposals that are larger in scope or cost should be referred to the Trust to consideration for funding). Following the initial period, the team will ensurethat research can continue along with surveillance as the health systems are rebuilt in the region.

Ethnic inequalities in trajectories of cardio-metabolic risk factor control and outcomes of type two diabetes 19 Apr 2016

Type 2 diabetes increases the risk of vascular disease, with co-morbid hypertension and hyperlipidaemia increasing risk further. UK studies have identified substantial ethnic differences in the risk of vascular outcomes amongst individuals with type 2 diabetes. Whether these inequalities stem from differences in healthcare usage, quality of care, or differences in treatment efficacy remains unknown. The aim of this fellowship is to identify modifiable determinants of ethnic inequalities in vascular outcomes of type 2 diabetes in order to generate an evidence base for clinical management of diabetes tailored to the UK population. Objectives: 1. To identify determinants of ethnic differences in access to health services and quality of preventive care for patients with type 2 diabetes using electronic health databases. 2. To examine whether patients identified as having uncontrolled cardio-metabolic risk factors are treated appropriately and equitably across ethnic groups. 3. To identify ethnic differences in trajectories of risk factor control following initiation of treatment and achievement of control to recommended targets. 4. To explore whether pharmacological treatment reduces the risk of vascular events equally across ethnic groups. 5. To develop recommendations for treatment strategies based on real world evidence of ethnic differences in risk factor profile and pharmacological treatment.

Defining reservoirs and transmission of antimicrobial resistant Escherichia coli using a One Health approach. 11 Nov 2015

Escherichia coli is a leading cause of infections in hospitals and the community. The increasing global prevalence of E. coli producing extended-spectrum beta-lactamases (ESBL-EC) represents a major public health challenge. ESBL-EC infections are associated with excess morbidity, mortality, longer hospital stay and higher healthcare costs. I aim to define the source(s) of ESBL-EC acquisition in a defined hospital population, in which I consider other patients, the hospital environment, food and water as potential sources. I will test the hypothesis that genome sequencing of ESBL-EC from these sources will define the major reservoirs for these strains and transmission pathways between them. I will place this genome data into a clinical context through a prospective longitudinal cohort study of ESBL-EC in hospitalised haematology patients. The most probable source(s) of new ESBL-EC acquisition in this cohort will be determined using epidemiological and whole genome sequence data on ESBL- EC from patients entering and leaving hospitals (n=975), the hospital environment (n=150), livestock (n=425), wastewater (n=425), a nearby nursing home (n=427), and bloodstream infections in the UK and Ireland (n=1519). Using mathematical modelling, I will infer transmission routes and predict the likely impact of different interventions on antimicrobial resistance reservoirs and transmission events

Palm Oil: Sustainability, Health and Economics (POSHE) 15 Jun 2016

Palm oil, a ubiquitous food ingredient, has brought economic benefit to Asia, but has been linked with negative health and environmental outcomes. Previous research has found strong associations between palm oil intake and mortality from cardiovascular disease, and between oil palm production and environmental degradation. Given consumption trends in the region, potential health impacts flowing from careful policy development to restrict intake are substantial. The proposed work will break new ground in terms of (i) investigating health, economic as well as environmental aspects of palm oil, and (ii) integrating health as well as environmental aspects with a whole-economy macroeconomic model. We propose a pilot project for Thailand to (i) examine interconnections between economic, health and environmental dimensions of palm oil production and consumption. (ii) Identify and simulate the impacts of a set of policy-relevant scenarios, and (iii) test methods and data assimilation procedures, preparing the ground for a follow-on regional project. Our modelling approach involves integration of data and combination of Thailand-specific macroeconomic and health/demographic models with an environmental module. Policies will be simulated, and economic, health and environmental impacts estimated. Trade-offs and synergies will be examined, and policy recommendations made.

Characterisation of immune responses to novel malaria pre-erythrocytic stage antigens 01 Apr 2016

The feasibility of malaria vaccination was initially established in mouse models 45 years ago by multiple immunisations of irradiated Plasmodium berghei sporozoites (gamma-PbSpz), which completely protected against parasite challenge. The elicited protection targets the pre-erythrocytic stages of the parasite, i.e. sporozoites and exo-erythrocytic forms (EEFs or liver stages), and is mediated primarily by cytotoxic (CD8+) T cells and neutralising antibodies. However, the paucity of endogenous antigenic targets for recognition by these immune effector mechanisms has limited in-depth characterisation of the mechanisms underlying sporozoite-induced protection. The circumsporozoite protein (CSP), the basis of the most advanced malaria vaccine candidate to date, is an immunodominant antigen only in the BALB/c immunisation and infection model. However, several lines of evidence suggest that protection against pre-erythrocytic stages can be independent of CSP-specific immune responses. These findings warrant the search for other antigenic targets against malaria pre-erythrocytic stages. The Hafalla group has made considerable advances in identifying novel targets of T cells and antibodies against malaria pre-erythrocytic stages. My goal is to characterise some antigens using defined immunological assays. This research endeavor will contribute to a comprehensive understanding of immune responses to malaria pre-erythrocytic stages and will reveal correlates of protection against this infection.

Bridging the Gap Between Community-led Initiatives and Humanitarian Agencies to Meet Refugees’ Health Needs in Lebanon: A Feasibility Study 10 Nov 2016

Seed funding is requested to conduct a feasibility study that will explore to what extent humanitarian agencies can build on initiatives led by refugee health professionals to pilot public health interventions for refugees (registered and unregistred) in Lebanon. The process by which displaced health professionals provide health services to refugee communities is poorly documented and understood. Our main goals are to identify initiatives led by Syrian displaced health professionals to meet refugees' health needs in Lebanon, and determine whether identified initiatives could benefit from international support to implement public health interventions. We will conduct an ethnographic study in the Bekaa Valley which is the home of the vast majority of Syrian refugees in Lebanon to gain a better understanding of the grassroots response led by Syrian health providers, along with a clearer appreciation of its structure and financing. We will also explore interactions between Syrian health providers and other agencies and organisations. Our findings will contribute to current humanitarian debates and will be used to inform a large-scale collaborative research proposal.

Community-level fatal and non-fatal stroke surveillance: providing the tools for evaluating interventions in hypertension and stroke in sub-Saharan Africa. 12 Mar 2014

It is thought that stroke is particularly common in sub-Saharan Africa (SSA), possibly due to a high prevalence of hypertension, but there is remarkably little accurate data. Determining and evaluating optimal strategies to reduce the burden of stroke in SSA requires validated tools to assess incidence, mortality and the contribution of modifiable risk factors. In a recent national survey in Malawi 1/3 of adults had hypertension, 94% previously undiagnosed. We have already shown, in the rura l demographic surveillance site (DSS) that is one of the settings for this study, that stroke was a leading cause of adult mortality, at 9%. I will: 1) Undertake a detailed assessment of, immediate and delayed mortality from stroke and the relative importance of risk factors for stroke mortality (including hypertension) by linking data from multiple settings in SSA. 2) Provide the most accurate estimates to date from SSA of the age specific incidence of transient ischaemic attacks, fatal an d non-fatal stroke, recurrent stroke and the short- and longer-term mortality from stroke by establishing and evaluating the validity of community and health clinic stroke surveillance at the rural DSS and urban site (where only hospital surveillance will be implemented) in Malawi.

THRIVE to Research Excellence (THRIVE-2) 05 May 2015

THRiVE (hereafter called THRiVE-1) was established in 2009 with the underlying10-year vision of developing a regional network of research excellence, including some of the best universities and research institutes in East Africa(EA) with support from two leading UK universities (LSHTM and UC). Our currentvision is that by 2030 Africa will lead research that has a major impact on health in the region and make significant contributions to world health. In five years, we have built a robust network that has led to strong and productive multidisciplinary collaborations in training, research, supervisionand mentorship. We recruited the best applicants and linked them with leading research groups in EA, a strategy that has spawned more than 400 publications between THRiVE-1 partners since 2010. The excellent PhD and post-doctoral fellows we recruited are emerging as potential research leaders. We made significant efforts to improve institutional capacity in research management and public engagement. Building on this successful research training and mentorship platform, our strategy in THRiVE-2 is to significantly and rapidly enhance the transformation of East African universities into world class research hubs, byspearheading the transition of PhD and post-doctoral fellows into health research leaders. We aim to continue strengthening the THRiVE-1 network to harness synergies to groom and mentor the most promising young scientists trained in THRIVE-1 and others selected in THRIVE-2 to become independent, internationally-recognised research leaders doing excellent research that addresses EA's priority health problems. We will continue to support the uptake of research findings and innovations into policy and practice. We will focus our strengths that have emerged in the past 5 years in key areasof infectious diseases/neglected tropical diseases (IDs/NTDs), maternal, neonatal and reproductive health (MN/RH) and non-communicable diseases (NCDs) (Figure 1): all of which are major and priority and emerging health problems in the region. We have identified more than 300 potential supervisors and mentors across the Consortium, including world leaders, doing cutting-edge research in these themes. To ensure a continuing pipeline, we will continue to seek out, recruit and mentor the best young scientists in EA who have creative and bold ideas at undergraduate, Masters, PhD, and post-doctoral levels and provide them with training, supervision, mentorship and excellent research environments. We willensure that women scientists make up a significant proportion of those recruited through our established merit based recruitment process. We will provide protected research time to successful applicants and use the mentoringand personal development planning tools developed during THRiVE-1, in collaboration with the Malaria Capacity Development Consortium (MCDC) and the UK Academy of Medical Sciences, to facilitate their transition into research leaders who will, in turn, mentor a new generation of researchers. We will continue to take advantage of the LSHTM and UC's staff development programmes to provide training in leadership skills and public engagement and also continue to benefit from the expertise of the MUII consortium in immunology and bioinformatics to produce the world-class scientists that will rise to the current and future health challenges in EA.

Estimating the burden of dengue, chikungunya and Zika in Latin America 19 Apr 2017

Since the mid 1990s, Latin America has seen a resurgence of arboviral disease. All four serotypes of dengue are now endemic and recent invasions of chikungunya and Zika viruses threaten to also persist. New strategies are urgently needed to combat co-circulation of arboviruses and the diseases they cause. Estimates of arbovirus burden are crucial to ensure these new strategies are optimally prioritised, targeted, measured and evaluated, however traditional passive surveillance suffers some key systemic biases. This research aims to improve the estimates of arboviral burden in Latin America by quantifying the main biases and gaps in passive surveillance data. This will be achieved by comparing passive data to equivalent metrics generated from applying mathematical and statistical models to community-based seroprevalence and routine laboratory testing data. Final burden estimates disaggregated by virus, disease severity, country and year since 2010 will be generated by leveraging information from multiple data types and propagating their uncertainty. Engaging Ministries of Health to explain, investigate and ultimately improve these estimates will be an important final output to achieve impact. Beyond the project, these burden estimates can be used to design rational strategies against what is rapidly becoming the biggest public health priority in Latin America.