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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
University of Oxford
Amounts:
£500 - £1,000

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Results

Chloroquine/Hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis study (COPCOV) 30 Sep 2020

There is no proven treatment, chemoprophylaxis or vaccine for COVID-19. This is the most serious pandemic emergency for 100 years. Healthcare workers are being affected disproportionately in the continuing epidemic threatening an imminent breakdown of health services. Chloroquine and hydroxychloroquine are safe and well-tolerated medications which can be taken for years without adverse effects.Both have significant antiviral activity against SARS-CoV-2 and there is emerging evidence from China and Europe of efficacy in treatment. Unfortunately there is also premature recommendation from countries such as India which now recommends low dose hydroxychloroquine for prophylaxis in health care workers. We propose conducting a multi-centre, multi-country randomised, double blind, placebo controlled assessment of the prophylactic efficacy of chloroquine (Asia) or hydroxychloroquine (Europe) in preventing COVID-19 illness in at-risk healthcare workers and other frontline staff. At least 40,000 participants in Asia and Europe will be randomised 1:1 to receive chloroquine or hydroxychloroquine or a matched film coated placebo as daily prophylaxis for three months. The study’s objectives are the prevention of symptomatic coronavirus disease (COVID-19) and the attenuation of the clinical severity.

Amount: £6,920,135
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation of pre-existing immunity to coronaviruses; implications for immunopathology and pathophysiology of COVID-19 disease 30 Sep 2020

Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2. Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses. Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.

Amount: £1,217,834
Funder: The Wellcome Trust
Recipient: University of Oxford

Neural mechanisms of learning, planning, and decision-making 31 Mar 2020

This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.

Amount: £2,580,251
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms of reading development in deaf children 31 Mar 2020

Many severely and profoundly deaf children struggle to learn to read because written text is a visual representation of spoken language, to which they have limited access. I have shown that speechreading (lipreading) relates to deaf children’s reading development. Fully understanding the mechanisms underlying the speechreading-reading relationship is fundamental to harnessing speechreading as a tool to improve deaf children’s reading. My goal is to investigate this mechanism in 1) a longitudinal study, to determine the relationships between speechreading, phonological skills, language skills and reading over time and 2) in neuroimaging studies with deaf children and adults to investigate neural representations of visual speech and written text and the relationships between them. All deaf participants involved in the studies above will use speechreading. A subset will also have learned British Sign Language from an early age. Good quality early sign language exposure is beneficial to reading development in profoundly deaf children. However, the mechanism underlying this relationship is unclear. I will employ parallel methods to those used in the speechreading studies to examine 1) the longitudinal relationships between sign language, fingerspelling and reading and 2) the neural representation of these visual language inputs in deaf children and adults.

Amount: £1,580,335
Funder: The Wellcome Trust
Recipient: University College London

Circuit mechanisms that command and pattern behavioural sequences 31 Mar 2020

Animals accomplish goal-directed behaviours by performing sequences of motor actions. A central goal of neuroscience is to understand how neural circuits regulate behaviour in accordance with external events and internal drives and precisely choreograph diverse actions for a successful outcome. To meet this challenge, I will exploit the unique accessibility of the larval zebrafish and focus on a conserved behaviour – hunting – in which a sequence of discrete, specialised actions mediates pursuit and capture of prey. I will use a powerful experimental strategy that combines cellular-resolution calcium imaging, behavioural analyses, optogenetic circuit manipulations, neuroanatomical tracing and computational modelling to discover how brain-wide circuits operate at the cellular level to flexibly control the expression and coordination of behaviour. This paradigm will enable me to discover (1) how sensory and internal state information are integrated to control the sensorimotor decision to hunt, (2) how specific hunting actions are generated and (3) how command signals operate alongside dynamic sensory inputs to assemble a goal-directed sequential behaviour. Overall, the project will produce a mechanistic, cellular-resolution circuit model that explains how the brain controls and patterns multi-component behaviour. I expect this will reveal fundamental principles about the operational logic of the nervous system.

Amount: £2,078,748
Funder: The Wellcome Trust
Recipient: University College London

lvermectin Safety in Small Children 30 Sep 2020

lvermectin is a very safe and beneficial drug which is used for the treatment of more than a dozen different neglected tropical diseases (NTDs), many of which are associated with important public health problems. Current label indications for ivermectin prevent use in small children weighing less than 15kg, due to limited safety data in this group. Many of the NTD treatment options for small children rely on compounds that are less safe and/or efficacious compared to oral ivermectin. Our proposal will establish the safety and pharmacokinetics of escalating doses of ivermectin to treat scabies infected children weighing less than 15kg. The safety assessment will provide crucial evidence on the use of ivermectin for numerous diseases in children weighing less than 15kg. The information from measuring drug concentrations in the patients will inform the optimal dosing of this drug in small children. Assessment of the efficacy of ivermectin, compared to permethrin cream, for the treatment of scabies in small children can provide an important alternative treatment for this widespread disease.

Amount: £510,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms of spliceosome remodeling and splice site selection during the catalytic stage of mammalian pre-mRNA splicing 04 Mar 2020

The spliceosome produces mRNAs in two sequential transesterifications – branching and exon ligation. The post-branching C complex is remodeled by the ATPase Prp16 into the C* complex. Prp16 allows binding of the exon ligation factors Cactin and FAM32A, which stabilise docking of the 3’-splice site (3’SS) at the active site. While in yeast Prp18 is constitutively bound to C* spliceosomes, in humans Prp18 and other exon ligation factors of unknown function appear to engage the C* spliceosome in a transcript-specific manner. Here, I will reconstitute the C to C* transition in vitro in mammals and use biochemistry and cryo-electron microscopy to isolate and visualize novel intermediates and dissect the structural mechanisms by which Cactin, FAM32A, Prp18, and additional exon ligation factors cooperate to promote Prp16-mediated remodeling and to ensure correct 3’SS choice. In parallel, iCLIP studies will reveal where these exon ligation factors bind across all human pre-mRNAs and how RNA sequences around the splice sites determine the association of subsets of factors on specific pre-mRNAs. This work will elucidate how Prp16 drives remodeling of the human catalytic spliceosome and will investigate whether exon ligation factors regulate alternative splicing in a sequence-specific manner while proofreading 3'SS recognition during exon ligation.

Amount: £1,199,999
Funder: The Wellcome Trust
Recipient: University of Oxford

How cell migration and differentiation are coordinated during morphogenesis 31 Mar 2020

During development the embryo needs to generate functional organs composed of many different cell types, often originated in different embryonic location. Thus, it is clear that cell differentiation and migration need to be tightly coordinated, although they are often studied as independent processes. Here I will test the hypothesis that cell migration and differentiations are coordinated by tissue mechanics in vivo. Specifically, I will challenge the current view that cell migration is the result of differentiation, by testing instead whether the reverse occurs, i.e. migration controls differentiation. I will use neural crest cell, a multipotent embryonic cell population in which cell differentiation is always linked to cell migration. One of the problems to study biomechanics in vivo is the limited number of tools to measure and modify mechanical properties in vivo. Here I will develop new tools to analyse and change tissue stiffness in vivo. We will analyse how these mechanical changes influence cell migration and differentiation, and we will identify the molecular response elicited in the neural crest cells. We expect that this multidisciplinary project will provide answers to a central yet unresolved question in developmental biology: how cell fate and migration are integrated during embryo development.

Amount: £1,734,742
Funder: The Wellcome Trust
Recipient: University College London

Politics, elections, and inclusive decision-making: Do political institutions affect health? 30 Sep 2020

Do political institutions influence the health of populations? Political institutions once seemed fixed and stable, but now appear to be flexible and open to change. This project seeks to uncover whether changing political institutions could affect health. Political institutions are the rules that govern who participates and how they participate in decision-making processes within societies; for example, they dictate who gets to vote and how votes are counted. Political institutions potentially affect health because they make governments more (less) responsive to what citizens want. However, this straightforward view of how political institutions affect health overlooks how democracies can privilege some voices over others (e.g., party donors may matter more than voters) and so universal suffrage may not necessarily deliver better health. This project will shed light on these questions through a series of empirical case studies. For example, I propose to examine whether political incorporation improves the health of formerly excluded groups, and whether their influence on policy decisions is weaker in majoritarian political systems than proportional representation systems because votes are counted differently. This project speaks to the sustainable development agenda by illuminating whether inclusive and representative decision-making institutions may accelerate progress toward ensuring healthy lives for all.

Amount: £201,914
Funder: The Wellcome Trust
Recipient: University of Oxford

Highly sensitive brain blood flow measurements using ultra-high field magnetic resonance imaging 04 Mar 2020

Blood flow is critical for maintaining the steady supply of oxygen and nutrients to the brain, and blood flow changes are present in a range of diseases including stroke and dementia. Conventional methods for in vivo blood flow mapping have limitations and often cannot be used for longitudinal monitoring or research. In this proposal I aim to develop highly sensitive imaging methods for measuring brain blood flow based on a non-invasive magnetic resonance imaging technique, arterial spin labelling, applied at ultra-high field. The main goals of this research are: To establish a robust platform for ultra-high field arterial spin labelling by developing novel approaches to overcome a range of technical challenges associated with this technique; To develop advanced imaging approaches which allow richer cerebrovascular information to be obtained, including high resolution angiography and vessel-selective imaging; To demonstrate the high sensitivity achievable with these novel methods by measuring changes in white matter perfusion in patients with vascular cognitive impairment, and probing the brain’s response to tonic pain at unprecedented spatial resolution. These new methods will be actively shared with local, national and international collaborators, enabling previously unfeasible clinical and basic science research studies to be performed.

Amount: £1,017,466
Funder: The Wellcome Trust
Recipient: University of Oxford

Analyses of paired host-virus genomic data to understand disease heterogeneity of chronic viral infections. 04 Mar 2020

Host and pathogen genetic variations are major causes of clinical outcomes of infectious diseases. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. However, there is strong theoretical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology. The major limiting factor to date has been the lack of cohorts with paired host-virus data. Recent technological developments and reductions in the cost of high-throughput viral sequencing from clinical samples have provided new opportunities to analyse host-virus genomic data generated from the same patients. In this project I propose to analyse paired host-virus genomic data from patient cohorts infected with HBV, HCV and HIV (clinically the most important chronic viruses worldwide) to answer the following questions: 1) What are the host genetic pressures driving virus evolution across different host populations and virus lineages? 2) What host and virus genetic interactions drive disease phenotypes? 3) What are the host genetic variants and pathways linked to disease phenotype across the three chronic viral infections of HBV, HCV and HIV?

Amount: £1,153,494
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the impact of ‘near-coding’ variation in human disease 04 Mar 2020

Rare diseases (prevalence 250 million people globally. Current approaches for identifying the genetic cause of a disease focus on regions of the genome that code directly for protein, finding a disease-causing variant in only ~50% of cases. My aim is to identify novel genetic variants outside of these protein-coding regions that lead to disease, and the mechanisms through which they do so. I will do this by applying computational and statistical methods to pioneering large-scale genomic datasets, totalling ~700,000 individuals. My approach will focus on ‘near-coding’ regions, defined as those directly adjacent to protein-coding sequence that have important functions regulating protein expression. I will use complementary approaches that (a) look for near-coding variants in rare disease patients without a causative coding variant and (b) assess the strength of negative selection acting on categories of near-coding variants to predict which are deleterious and cause disease. The findings from my work will be translated into clinical care to enable more patients to receive a valuable genetic diagnosis. In addition, increasing our understanding of the near-coding variant types that are deleterious will inform on genetic mechanisms underlying disease and suggest novel therapeutic strategies.

Amount: £828,055
Funder: The Wellcome Trust
Recipient: University of Oxford

Open Access Award 2019/20 30 Sep 2020

Not available

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University College London

Open Access Award 2019/20 30 Sep 2020

Not available

Amount: £85,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Open Access Award 2019/20 30 Sep 2020

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Open Access (COAF) award 2019/20 30 Sep 2020

Not available

Amount: £813,243
Funder: The Wellcome Trust
Recipient: University College London

Open Access (COAF) award 2019/20 30 Sep 2020

Not available

Amount: £1,157,238
Funder: The Wellcome Trust
Recipient: University of Oxford

The Impact of Pneumococcal and Malaria Vaccines on Bacterial Resistance, Febrile Illness and Antibiotic Usage in Young Children In Malawi 30 Nov 2019

Across much of sub-Saharan Africa, pneumococcal disease (otitis media and pneumonia) and malaria are leading causes febrile illness, and therefore drivers of both appropriate and inappropriate antibiotic use. Prevention through vaccination has the potential to influence antimicrobial resistance (AMR) both directly and indirectly. We are in a unique position to leverage two large funded cluster-randomised vaccine evaluations in Malawi: 13-valent pneumococcal conjugate vaccine (PCV13) schedule change (3+0 to 2+1; extending immunity and potentially herd protection); and RTS,S malaria vaccine introduction. We will ask what are the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in young children in Malawi? We will determine whether in children S. pneumoniae carriage isolates; the upper respiratory tract resistome; and stool carriage of extended spectrum beta-lactamase (ESBL) E. coli or Klebsiella. We will assess whether the pneumococcal or malaria vaccines alter the frequency of febrile illness and antibiotic use in children

Amount: £764,996
Funder: The Wellcome Trust
Recipient: University College London

The Biosocial Lives of Birth Cohorts 28 Jan 2020

This four year project examines birth cohorts as sites of knowledge, practice and participation in the UK, Europe and Latin America. It aims to understand how they provide an infrastructure for and are a technology of biosocial science. It is the first study to take birth cohorts as an object of ethnographic inquiry in comparative national contexts. In an era of post-genomics, studies that follow research participants over their lifetimes have become vital to understanding how material and social environments ‘get under the skin’ and are dynamically shaped across the lifecourse. This is increasingly described as ‘biosocial science’, reflecting the importance to this field of the interaction between social and biological factors. Whilst a notion of the biosocial is not new, singular nor uncontested it is now being re-shaped in global research terrains with longitudinal cohort studies as important tools and technologies. By examining the ‘biosocial lives’ of birth cohorts in the global north and south, I will provide insight on the socio-cultural specificity of these developments. Comparison will inform theorisation of what the biosocial is, whilst an ethnographic perspective will facilitate methodological innovation in examining and intervening on birth cohort research and how biosocial science is coming into being.

Amount: £1,009,755
Funder: The Wellcome Trust
Recipient: University College London

Evaluating prevalence, incidence rates and mortality attributable to antibiotic-resistant bacterial infections and potential biases caused by underuse of blood culture in Wahidin Hospital, a tertiary-care hospital in South Sulawesi, Indonesia 19 Nov 2019

The burden of antibiotic-resistant bacterial infection (ARBI) in low and middle-income countries (LMICs) is largely unknown. Microbiology data is rarely analyzed and reported. Few publications available did not take account of bias caused by low number of blood culture utilization, categorize ARBI based on infection origin (community-onset or hospital-onset) and evaluate mortality attributable to ARBI. I propose to evaluate the situation of ARBI in a tertiary-care hospital in 2015-2018 in Sulawesi, Indonesia. I will analyze three routinely available data sets; including microbiology, hospital admission and antibiotic prescription data sets. I will use standard methods to estimate prevalence, incidence rates and mortality attributable to ARBI among bacteremia patients. I will categorize infection origin as recommended by WHO GLASS. I will evaluate and describe timing of blood culture collection and antibiotic prescription among patients who had parenteral antibiotic prescribed. I will evaluate whether reported parameters for ARBI were associated with timing of blood culture collection and antibiotic prescription. The results from this study will improve our standings on ARBI, diagnostic stewardship and antibiotic stewardship in Indonesia, and could be used to inform healthcare workers and policy makers in the country and other LMICs on resource allocation and intervention for actions against ARBI.

Amount: £120,000
Funder: The Wellcome Trust
Recipient: University of Oxford